• Title/Summary/Keyword: dual targets

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Sp1-Induced SETDB1 Overexpression Transcriptionally Inhibits HPGD in a β-Catenin-Dependent Manner and Promotes the Proliferation and Metastasis of Gastric Cancer

  • Fan, Yaguan;Yang, Libo;Ren, Yi;Wu, Yunhua;Li, Linhai;Li, Lihua
    • Journal of Gastric Cancer
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    • v.22 no.4
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    • pp.319-338
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    • 2022
  • Purpose: Gastric cancer (GC) has high morbidity and mortality, the cure rate of surgical treatment and drug chemotherapy is not ideal. Therefore, development of new treatment strategies is necessary. We aimed to identify the mechanism underlying Sp1 regulation of GC progression. Methods and Methods: The levels of Sp1, β-catenin, SET domain bifurcated 1 (SETDB1), and 15-hydroxyprostaglandin dehydrogenase (HPGD) were detected by quantitative reverse transcription polymerase chain reaction and western blot analysis. The targets of SETDB1 were predicted by AnimalTFDB, and dual-luciferase reporter assay was used for confirming the combination of Sp1, β-catenin, and SETDB1. HGC27 or AGS cells (1×106 cells/mouse) were injected into mice via the caudal vein for GC model establishment. The level of Ki67 was detected using immunohistochemistry, and hematoxylin and eosin staining was performed for evaluating tumor metastasis in mice with GC. Results: HPGD was inhibited, while the protein levels of Sp1, β-catenin, and SETDB1 were up-regulated in GC tissues and cell lines. HPGD overexpression or SETDB1 silencing inhibited the proliferation, invasion, and migration of GC cells, and Sp1 regulated the proliferation, invasion, and migration of GC cells in a β-catenin-dependent manner. Furthermore, HPGD served as a target of SETDB1, and it was negatively regulated by SETDB1; additionally, Sp1 and β-catenin bound to the SETDB1 promoter and negatively regulated HPGD expression. We proved that Sp1 regulated GC progression via the SETDB1/HPGD axis. Conclusions: Our findings revealed that Sp1 transcriptionally inhibited HPGD via SETDB1 in a β-catenin-dependent manner and promoted the proliferation and metastasis of GC cells.

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.

Target-Aspect-Sentiment Joint Detection with CNN Auxiliary Loss for Aspect-Based Sentiment Analysis (CNN 보조 손실을 이용한 차원 기반 감성 분석)

  • Jeon, Min Jin;Hwang, Ji Won;Kim, Jong Woo
    • Journal of Intelligence and Information Systems
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    • v.27 no.4
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    • pp.1-22
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    • 2021
  • Aspect Based Sentiment Analysis (ABSA), which analyzes sentiment based on aspects that appear in the text, is drawing attention because it can be used in various business industries. ABSA is a study that analyzes sentiment by aspects for multiple aspects that a text has. It is being studied in various forms depending on the purpose, such as analyzing all targets or just aspects and sentiments. Here, the aspect refers to the property of a target, and the target refers to the text that causes the sentiment. For example, for restaurant reviews, you could set the aspect into food taste, food price, quality of service, mood of the restaurant, etc. Also, if there is a review that says, "The pasta was delicious, but the salad was not," the words "steak" and "salad," which are directly mentioned in the sentence, become the "target." So far, in ABSA, most studies have analyzed sentiment only based on aspects or targets. However, even with the same aspects or targets, sentiment analysis may be inaccurate. Instances would be when aspects or sentiment are divided or when sentiment exists without a target. For example, sentences like, "Pizza and the salad were good, but the steak was disappointing." Although the aspect of this sentence is limited to "food," conflicting sentiments coexist. In addition, in the case of sentences such as "Shrimp was delicious, but the price was extravagant," although the target here is "shrimp," there are opposite sentiments coexisting that are dependent on the aspect. Finally, in sentences like "The food arrived too late and is cold now." there is no target (NULL), but it transmits a negative sentiment toward the aspect "service." Like this, failure to consider both aspects and targets - when sentiment or aspect is divided or when sentiment exists without a target - creates a dual dependency problem. To address this problem, this research analyzes sentiment by considering both aspects and targets (Target-Aspect-Sentiment Detection, hereby TASD). This study detected the limitations of existing research in the field of TASD: local contexts are not fully captured, and the number of epochs and batch size dramatically lowers the F1-score. The current model excels in spotting overall context and relations between each word. However, it struggles with phrases in the local context and is relatively slow when learning. Therefore, this study tries to improve the model's performance. To achieve the objective of this research, we additionally used auxiliary loss in aspect-sentiment classification by constructing CNN(Convolutional Neural Network) layers parallel to existing models. If existing models have analyzed aspect-sentiment through BERT encoding, Pooler, and Linear layers, this research added CNN layer-adaptive average pooling to existing models, and learning was progressed by adding additional loss values for aspect-sentiment to existing loss. In other words, when learning, the auxiliary loss, computed through CNN layers, allowed the local context to be captured more fitted. After learning, the model is designed to do aspect-sentiment analysis through the existing method. To evaluate the performance of this model, two datasets, SemEval-2015 task 12 and SemEval-2016 task 5, were used and the f1-score increased compared to the existing models. When the batch was 8 and epoch was 5, the difference was largest between the F1-score of existing models and this study with 29 and 45, respectively. Even when batch and epoch were adjusted, the F1-scores were higher than the existing models. It can be said that even when the batch and epoch numbers were small, they can be learned effectively compared to the existing models. Therefore, it can be useful in situations where resources are limited. Through this study, aspect-based sentiments can be more accurately analyzed. Through various uses in business, such as development or establishing marketing strategies, both consumers and sellers will be able to make efficient decisions. In addition, it is believed that the model can be fully learned and utilized by small businesses, those that do not have much data, given that they use a pre-training model and recorded a relatively high F1-score even with limited resources.

The Effect Of Job Insecurity To The Union Commitment, Dual Commitment and The Union-Related Orientation (고용불안이 노조몰입, 이중몰입, 노사관계행동지향성에 미치는 영향에 관한 연구)

  • Son, Heon-I;Jung, Hyun-Woo
    • Management & Information Systems Review
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    • v.34 no.2
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    • pp.131-149
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    • 2015
  • Recently many organizations have engaged in widespread restructuring as well as more flexible usage of labor in an attempt to cut costs and to increase profit. As a result of lays offs resulting from frequent restructuring, many people no longer consider their jobs as permanent positions. many employees have an increased feeling of job insecurity. There structuring and following downsizing have created an uncertain environment within creased fear offer ther job losses. therefore the study of job insecurity is significant. especially To understand the relationship between job security and union-relation behaviors on the industrial relations. The purpose of this study suggested the strategies to company and union. The purpose of this study is to examine how the union-relation behaviors are influenced by the job security. This study built a exploratory model that there is causal relationship of job security to union commitment, dual commitment, and labor related behaviors. For the verification of this study model, the regression analysis was applied to the surveys of 236 members of union that are located in Busan, Gyeongnam, Ulsan, and Pohang. The result of this research shows that the job insecurity is strongly related to the union commitment and union related behaviors. According to the research, the effect that the job security affects union commitment and union related behaviors are positive. With the research outputs, we have discussed about the academic and pragmatic viewpoint. We proposed comprehensive model to verify how the job insecurity affects the union-related behaviors, and objectively analyzed the model. The research result was opposite to what the existing theories have said that high job insecurity derives high union-related behaviors. This result is meaningful because it is concerned with the social issues-present situation of Korean company, low-employment, unstable employment and so on. Moreover, this research may contribute to expand the aspect of academic research on job insecurity as there are few research conducted in korea. This research also suggests the realistic alternative of union-related behaviors because it is proved that job security can contribute to innovation activities. Also, this research implies that the matter of job insecurity is the basic need of organizational individual and presents that job security is not a notion but the alternative by using of the positional stability and situational control power. The limitation of this research is that it is only utilized the cross-sectional study. To remedy the cross-sectional study, vertical, and serial method of research is needed. And there is no enough sample to secure more comprehensive data as the targets of the research is limited to Busan and Gyeongnam regions. Finally, the measurement tool for job security is needed to be suitably modified to by the South Korea's economic, linguistic, and cultural situation.

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Crystal Structure of an Activity-enhancing Mutant of DUSP19 (효소활성 증가 돌연변이를 함유한 DUSP19의 결정구조)

  • Ju, Da Gyung;Jeon, Tae Jin;Ryu, Seong Eon
    • Journal of Life Science
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    • v.28 no.10
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    • pp.1140-1146
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    • 2018
  • Dual-specificity phosphatases (DUSPs) play a role in cell growth and differentiation by modulating mitogen-activated protein kinases. DUSPs are considered targets for drugs against cancers, diabetes, immune diseases, and neuronal diseases. Part of the DUSP family, DUSP19 modulates c-Jun N-terminal kinase activity and is involved in osteoarthritis pathogenesis. Here, we report screening of cavity-creating mutants and the crystal structure of a cavity-creating L75A mutant of DUSP19 which has significantly enhanced enzyme activity in comparison to the wild-type protein. The crystal structure reveals a well-formed cavity due to the absent Leu75 side chain and a rotation of the active site-bound sulfate ion. Despite the cavity creation, residues surrounding the cavity did not rearrange significantly. Instead, a tightened hydrophobic interaction by a remote tryptophan residue was observed, indicating that the protein folding of the L75A mutant is stabilized by global folding energy minimization, not by local rearrangements in the cavity region. Conformation of the rotated active site sulfate ion resembles that of the phosphor-tyrosine substrate, indicating that cavity creation induces an optimal active site conformation. The activity enhancement by an internal cavity and its structural information provide insight on allosteric modulation of DUSP19 activity and development of therapeutics.

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

  • Dai, Wenwen;Wu, Yu;Bi, Jinpeng;Wang, Jingyu;Wang, Shuai;Kong, Wei;Barbier, Julien;Cintrat, Jean-Christophe;Gao, Feng;Jiang, Zhengran;Gillet, Daniel;Su, Weiheng;Jiang, Chunlai
    • Journal of Microbiology and Biotechnology
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    • v.28 no.6
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    • pp.849-859
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    • 2018
  • Herpes simplex virus type 2 (HSV-2) infection has been a public health concern worldwide. It is the leading cause of genital herpes and a contributing factor to cervical cancer and human immunodeficiency virus (HIV) infection. No vaccine is available yet for the treatment of HSV-2 infection, and routinely used synthetic nucleoside analogs have led to the emergence of drug resistance. The small molecule $Retro-2^{cycl}$ has been reported to be active against several pathogens by acting on intracellular vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that Retro-2.1, which is an optimized, more potent derivative of $Retro-2^{cycl}$, could inhibit HSV-2 infection, with 50% inhibitory concentrations of $5.58{\mu}M$ and $6.35{\mu}M$ in cytopathic effect inhibition and plaque reduction assays, respectively. The cytotoxicity of Retro-2.1 was relatively low, with a 50% cytotoxicity concentration of $116.5{\mu}M$. We also preliminarily identified that Retro-2.1 exerted the antiviral effect against HSV-2 by a dual mechanism of action on virus entry and late stages of infection. Therefore, our study for the first time demonstrated Retro-2.1 as an effective antiviral agent against HSV-2 in vitro with targets distinct from those of nucleoside analogs.

LncRNA H19/miR-29b-3p/PGRN Axis Promoted Epithelial-Mesenchymal Transition of Colorectal Cancer Cells by Acting on Wnt Signaling

  • Ding, Dayong;Li, Changfeng;Zhao, Tiancheng;Li, Dandan;Yang, Lei;Zhang, Bin
    • Molecules and Cells
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    • v.41 no.5
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    • pp.423-435
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    • 2018
  • This investigation was aimed at working out the combined role of lncRNA H19, miR-29b and Wnt signaling in the development of colorectal cancer (CRC). In the aggregate, 185 CRC tissues and corresponding para-carcinoma tissues were gathered. The human CRC cell lines (i.e. HT29, HCT116, SW480 and SW620) and normal colorectal mucosa cell line (NCM460) were also purchased. Si-H19, si-NC, miR-29b-3p mimics, miR-29b-3p inhibitor, si-PGRN and negative control (NC) were, respectively, transfected into the CRC cells. Luciferase reporter plasmids were prepared to evaluate the transduction activity of $Wnt/{\beta}-catenin$ signaling pathway, and dual-luciferase reporter gene assay was arranged to confirm the targeted relationship between H19 and miR-29b-3p, as well as between miR-29b-3p and PGRN. Finally, the proliferative and invasive capacities of CRC cells were appraised through transwell, MTT and scratch assays. As a result, overexpressed H19 and down-expressed miR-29b-3p displayed close associations with the CRC patients' poor prognosis (P < 0.05). Besides, transfection with si-H19, miR-29b-3p mimic or si-PGRN were correlated with elevated E-cadherin expression, decreased snail and vimentin expressions, as well as less-motivated cell proliferation and cell metastasis (P < 0.05). Moreover, H19 was verified to directly target miR-29b-3p based on the luciferase reporter gene assay (P < 0.05), and miR-29b-3p also bound to PGRN in a direct manner (P < 0.05). Finally, addition of LiCl ($Wnt/{\beta}-catenin$ pathway activator) or XAV93920 ($Wnt/{\beta}-catenin$ pathway inhibitor) would cause remarkably altered E-cadherin, c-Myc, vimentin and snail expressions, as well as significantly changed transcriptional activity of ${\beta}-catenin/Tcf$ reporter plasmid (P < 0.05). In conclusion, the lncRNA H19/miR-29b-3p/PGRN/Wnt axis counted a great deal for seeking appropriate diagnostic biomarkers and treatment targets for CRC.

Alfalfa xenomiR-162 targets G protein subunit gamma 11 to regulate milk protein synthesis in bovine mammary epithelial cells

  • Guizhi Meng;Hongjuan Duan;Jingying Jia;Baobao Liu;Yun Ma;Xiaoyan Cai
    • Animal Bioscience
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    • v.37 no.3
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    • pp.509-521
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    • 2024
  • Objective: It was shown that microRNAs (miRNAs) play an important role in milk protein synthesis. However, the post-transcriptional regulation of casein expression by exogenous miRNA (xeno-miRNAs) in ruminants remains unclear. This study explores the regulatory roles of alfalfa xeno-miR162 on casein synthesis in bovine mammary epithelial cells (bMECs). Methods: The effects of alfalfa xenomiR-162 and G protein subunit gamma 11 (GNG11) on proliferation and milk protein metabolism of bMECs were detected by 5-Ethynyl-2'-Deoxyuridine (EdU) staining, flow cytometry, cell counting kit-8 (CCK-8), enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. Dual-luciferase reporter assay was used to verify the targeting relationship between GNG11 and xenomiR-162. Results: Results showed that over-expression of xenomiR-162 inhibited cell proliferation but promoted apoptosis, which also up-regulated the expression of several casein coding genes, including CSN1S1, CSN1S2, and CSN3, while decreasing the expression of CSN2. Furthermore, the targeting relationship between GNG11 and xenomiR-162 was determined, and it was confirmed that GNG11 silencing also inhibited cell proliferation but promoted apoptosis and reduced the expression of casein coding genes and genes related to the mammalian target of rapamycin (mTOR) pathway. Conclusion: Alfalfa xenomiR-162 appears to regulate bMECs proliferation and milk protein synthesis via GNG11 in the mTOR pathway, suggesting that this xeno-miRNA could be harnessed to modulate CSN3 expression in dairy cows, and increase κ-casein contents in milk.

Analyzing the Economic Value and Planning Factors of Hubs within Urban Green Infrastructure - Focusing on the Case of Sejong Lake Park - (도시 그린인프라 핵심지역의 경제적 가치와 계획 요소 분석 - 세종호수공원 사례를 중심으로 -)

  • Lee, Dong-Kyu;An, Byung-Chul
    • Journal of the Korean Institute of Landscape Architecture
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    • v.49 no.4
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    • pp.41-54
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    • 2021
  • This study targets the urban park corresponding to the core areas (Hubs) of Green Infrastructure and estimates their value utilizing the Contingent Valuation Method (CVM) and determines the planning factors which affect them. The research aims to provide basic data for supporting the value improvement in the planning stage for urban parks representing green infrastructure. The primary purpose of this research is to derive variables that affect economic value and planning factors to improve the use-value of urban parks, one of the Hubs of the green infrastructure. In this study, Sejong Lake Park, located in Sejong City, is the target site. This study collected the responses of 105 people by conducting a survey on the intention to pay for the use-value and the planning factors that affect it, targeting visitors to Sejong Lake Park. The study conducts Contingent Valuation Method (CVM) on this survey responses. The results are as follows: first, as a result of analyzing the variables which affect willingness to pay for use-value, residence and age influence the willingness to pay significantly among socioeconomic characteristics. Next, the survey responses of Double-bounded dichotomous choices (DB-DC) CVM are converted into variables through statistic techniques. Furthermore, the variables are used for a Logit model to draw coefficients. The average willingness to pay per person for the use-value of Sejong Lake Park using the derived coefficients was approximately found to be 8,597 won. Therefore, as of 2019, Sejong Lake Park, with a total of 430,000 visitors, is estimated to have an annual economic value of 3.7 billion won. Third, the average Likert scale of the planning factor affecting the decision to pay for the economic value of Sejong Lake Park was the highest along the waterfront landscape, and the convenience facilities and waterfront landscape showed the highest willingness to pay, 10,000 won. In the range between 2,500 won and 5,000 won, the waterfront area ranks highest. Therefore, it can be said that visitors to Sejong Lake Park take account of the economic value of using the waterfront landscape the most. This study is meaningful as a thesis on use-value and the planning factors that affected value evaluation results of urban parks, and the analysis of the correlation between the planning factors of urban parks as hubs located in urban areas.

The Effects of Self-Determination on Entrepreneurial Intention in Office Workers: Focusing on the Dual Mediation of Innovativeness and Prception of the Startup Support System (직장인의 자기결정성이 창업의지에 미치는 영향: 혁신성과 창업지원정책인식의 이중매개를 중심으로)

  • Lim, Jae Sung
    • Asia-Pacific Journal of Business Venturing and Entrepreneurship
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    • v.19 no.1
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    • pp.75-91
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    • 2024
  • Recently, global business environment is changing dramatically along with the acceleration of technological innovation amid the war, climatic change, and geopolitical instability. Accordingly, it is difficult to predict or plan for the future as the volatility, complexity, ambiguity, and uncertainty of the industrial ecosystem continue to increase. Therefore, organizations are undergoing inevitable restructuring in accordance with their survival strategy, for instance, removing marginal businesses or firing. Accordingly, office workers are seeking a startup as an alternative for their continuous economic activity amid rising anxiety factors that make them think they would lose their jobs unintentionally. Here, this study is aimed to verify through what paths office workers' self-determination influences the process of converting to a startup. For this study, an online survey was carried out, and 310 respondents' valid data were analyzed through SPSS and AMOS. To sum up the results, first, office workers' self-determination did not have significant effects on entrepreneurial intention. However, it was confirmed that self-determination had positive (+) effects on innovativeness and perception of the startup support system. This result shows that their psychology works to prepare step by step by accumulating innovative experiences and increasing perception of the startup support system from a long-term life path perspective rather than challenging startups right way. Second, innovativeness is found to have positive (+) effects on entrepreneurial intention. Also, perception of the startup support system had positive (+) effects on entrepreneurial intention. This implies that when considering startups, they are highly aware of the government's various startup support systems. Third, innovativeness is found to have positive (+) effects on perception of the startup support system. It is judged that perception of the startup support system is valid for prospective founders to exhibit their innovativeness and realize new ideas. Fourth, it was confirmed that innovativeness and perception of the startup support system mediated correlation between self-determination and entrepreneurial intention, and perception of the startup support system mediated correlation between innovativeness and entrepreneurial intention, which shows that it is a crucial factor in entrepreneurial intention. Although previous studies related to startups deal with students mostly, this study targets office workers who form a great part in economic activities, which makes it academically valuable in terms of being differentiated from others and extending the scope of research. Also, when we consider the fact that the motivation for self-determination alone fails to stimulate entrepreneurial intention and the complete mediation of innovativeness and the startup support system, it has great implications in practical aspects such as the government's human and material support systems. In the selection and analysis of samples, this study exhibits a limitation that the problem of common method bias is not completely resolved. Also, additional definitive research is needed on whether entrepreneurial intention is formed and converted into startup behavior. Academically and practically, this study deals with the relationship between humans' psychological motives and startups which has not been handled sufficiently in previous studies. The conversion of office workers to startups is expected to have effects on individuals' economic stability and the state's job creation; therefore, it needs to be investigated continuously for its great value.

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