Research article

The potential effects and mechanism of echinacoside powder in the treatment of Hirschsprung's Disease

  • Received: 30 March 2023 Revised: 22 May 2023 Accepted: 08 June 2023 Published: 27 June 2023
  • Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. Genes related to the disease were obtained through analysis of the GSE96854 dataset and four databases: OMIM, DisGeNET, Genecard and NCBI. The targets of echinacoside were obtained from three databases: PharmMapper, Drugbank and TargetNet. The intersection of disease genes and drug targets was validated by molecular docking. The valid docked targets were further explored for their expression by using immunohistochemistry. In this study, enrichment analysis was used to explore the mechanistic pathways involved in the genes. Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. RIMS2 possesses a high mutation phenomenon in pan-cancer, while a validated ceRNA network of eight genes was constructed. The core genes are involved in several signaling pathways, including the one-carbon metabolic process, carbonate dehydratase activity and others. This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.

    Citation: Enyang He, Yuhang Jiang, Diwei Wei, Yifan Wang, Wenjing Sun, Miao Jia, Bowen Shi, Hualei Cui. The potential effects and mechanism of echinacoside powder in the treatment of Hirschsprung's Disease[J]. Mathematical Biosciences and Engineering, 2023, 20(8): 14222-14240. doi: 10.3934/mbe.2023636

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  • Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. Genes related to the disease were obtained through analysis of the GSE96854 dataset and four databases: OMIM, DisGeNET, Genecard and NCBI. The targets of echinacoside were obtained from three databases: PharmMapper, Drugbank and TargetNet. The intersection of disease genes and drug targets was validated by molecular docking. The valid docked targets were further explored for their expression by using immunohistochemistry. In this study, enrichment analysis was used to explore the mechanistic pathways involved in the genes. Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. RIMS2 possesses a high mutation phenomenon in pan-cancer, while a validated ceRNA network of eight genes was constructed. The core genes are involved in several signaling pathways, including the one-carbon metabolic process, carbonate dehydratase activity and others. This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.



    Firm value, also known as corporate valuation or enterprise value, represents the total economic worth of a business entity, encompassing both equity and debt components. It serves as a critical measure to assess a company's financial health, growth potential, and overall performance (Dwicahyani et al., 2022; Suzan et al., 2023). Firm value also functions as a benchmark to evaluate investment opportunities, inform strategic decisions, conduct mergers and acquisitions, and appraise overall business outcomes.

    The determination of firm value depends on various factors, including a company's future cash flows, growth prospects, risk profile, and prevailing market conditions. These factors often interact in complex ways, making their interplay crucial for understanding and predicting firm value. A comprehensive analysis that accounts for these interactions empowers investors and management to optimize firm value and make informed, strategic decisions essential for effective management.

    Regression models have been widely employed in studies examining firm value (Cheng et al., 2010; Sunarsih et al., 2019; Hirdinis, 2019; Ispriyahadi and Abdullah, 2021; Siregar et al., 2023). However, these models typically rely on predefined functional forms and require the prior specification of both response and explanatory variables. Additionally, regression models often face challenges in identifying complex association terms among explanatory variables. Moreover, uncovering causal relationships using regression models is inherently challenging without relying on strong assumptions, such as the presence of randomized trials or the use of instrumental variables.

    Bayesian Networks (BNs) have recently gained significant attention as a powerful analytical method for handling highly complex interdependencies across various disciplines, including economics, medicine, biology, and environmental science. A BN is a directed probabilistic graph that connects related variables with edges, where these connections represent conditional dependencies between the variables (Pearl, 1988). By employing graphical structures, BNs provide a visual representation of dependencies, enabling intuitive interpretation and facilitating a deeper understanding of underlying dynamics. Foundational work on BNs is attributed to Pearl (1988), and recent works that provide comprehensive summaries of BNs and their applications include Friedman et al. (1997), Koski and Noble (2011), and Scutari and Denis (2021).

    BNs provide significant advantages over traditional regression methods, particularly in complex and uncertain contexts such as firm value analysis. First, BNs do not require predefined functional forms, allowing them to uncover interdependencies and key interactions among variables directly from the data. Second, BNs can provide a formal framework for causal reasoning, enabling deeper insights into how changes in one variable can propagate through the network to influence firm value. This capability is crucial for realistic scenario analyses, allowing analysts to test various potential conditions and observe their effects on firm value comprehensively. Third, BNs can incorporate expert knowledge, such as industry-specific risks or forward-looking insights. This is especially valuable when historical data is limited or when market conditions are expected to deviate from past trends (Madden, 2009; Liu and Motoda, 2012; Oh et al., 2022; Jo et al., 2023). By integrating data-driven insights with expert knowledge, BNs provide a flexible and insightful framework for firm value analysis, supporting more accurate and resilient valuations in complex financial contexts. Finally, BNs handle missing data naturally through probabilistic reasoning, enabling robust analysis even in incomplete datasets. In contrast, regression models typically address missing data through imputation techniques or by excluding incomplete cases, which can introduce bias or reduce the sample size. This inherent advantage of BNs ensures a more reliable analysis in data-constrained scenarios.

    Given these advantages, BNs have gained considerable attention in recent years for their application in firm value analysis (Ali and Anis, 2012; Sun, 2015; Sun and Park, 2017; Teles et al., 2020; Cao et al., 2022; Chan et al., 2023). However, despite their growing prominence, most existing research overlooks the temporal dependencies and causal structures in this domain.

    Firm value is influenced by factors that are typically observed over consecutive time periods and often exhibit temporal dependencies. In other words, the value at a given time point is frequently affected by values from preceding periods (Campbell et al., 1997; Tsay, 2010; Enders, 2014). Considering these temporal dependencies is essential for understanding how these factors evolve and interact dynamically over time.

    Causal discovery offers significant advantages in understanding complex systems by identifying underlying cause-and-effect relationships rather than relying solely on correlations. This enables better prediction, explanation, and intervention strategies. By revealing the mechanisms driving observed data, causal discovery enhances decision-making, supports the development of effective policies, and enables targeted interventions. Researchers are particularly interested in identifying causal structures from observational data rather than experimental data, because observational data often comes from naturally occurring events or retrospective studies, while experimental data is often difficult to obtain in real-world settings.

    This study investigated the causal relationships among factors influencing firm value, while accounting for temporal dependencies. To achieve this, a Causal Dynamic Bayesian Network (CDBN) model was developed using panel data from listed manufacturing companies in Korea, spanning the period from 2009 to 2022.

    Dynamic Bayesian Networks (DBNs) build on traditional BNs by incorporating temporal dependencies, enabling the identification of both contemporaneous and temporal relationships among variables. This allows DBNs to capture interactions at a single time point as well as the evolution of these relationships over time (Dagum et al., 1992). CDBNs further extend the DBN framework by explicitly modeling causal relationships. In CDBNs, edges represent cause-and-effect relationships, facilitating the identification of both within-time and between-time causal pathways.

    The remainder of this paper is organized as follows: Section 2 describes the data used in this study. Section 3 outlines the theoretical foundation and structure of the CDBN. Section 4 details the methodology for constructing the CDBN model. Section 5 presents the results, including the final CDBN model and the identified causal relationships. Section 6 concludes the study, and Section 7 discusses its limitations and suggests directions for future research.

    The data used in this study is a panel dataset comprising 11 variables from 227 listed manufacturing companies in Korea, observed over 14 years (2009–2022). Annual financial statement data and market capitalization were sourced from DeepSearch, a corporate data platform (https://www.deepsearch.com/). Foreign ownership percentages were extracted from the Korea Exchange (KRX) Information Data System (http://data.krx.co.kr/contents/MDC/MAIN/main/index.cmd), capturing values from the last day of trading each year.

    Among the various approaches to measuring firm value, Tobin's Q (Tobin, 1969) is the most widely used metric. Tobin's Q is defined as the ratio of a company's market value to its replacement cost or book value. A Tobin's Q greater than 1 indicates that the company is overvalued, while a value less than 1 suggests that it is undervalued. In this study, firm value was measured by considering the market value of a company as the sum of its market capitalization and total debt. Tobin's Q was then calculated as the ratio of this sum to the company's total assets.

    Financial variables related to firm value were selected based on the previous research (Francis and Schipper, 1999; Pástor and Veronesi, 2003; Rountree et al., 2008; Sun and Park, 2017). The selected variables are Sales growth rate (Growth), Return on assets ratio (ROA), Tangible assets ratio (TA), Company leverage (LEV), Liquidity (LIQ), Fixed assets to long-term capital ratio (FA), Firm size (Size), Foreign ownership ratio (FOR), Intangible assets ratio (ITA), and Depreciation charge (DC). These variables reflect a company's sales growth, profitability, stability and liquidity, capital structure, and other characteristics.

    Additionally, numerous studies have highlighted the significant impact of the Coronavirus Disease 2019 (COVID-19) on the financial sector (Afrina et al., 2020; Hertati et al., 2020; Mishra and Mishra, 2020). To incorporate the effects of COVID-19 in the analysis, a dummy variable, COVID-19, was introduced to differentiate between the pre-COVID period (2009–2019) and the post-COVID period (2020–2022).

    The final dataset comprises observations for 11 variables across 227 companies over 14 years, along with the COVID-19 dummy variable. Table 1 provides detailed descriptions, means, and standard deviations of these variables.

    Table 1.  Descriptions and summary statistics of the variables.
    Name Description Formula Mean SD
    COVID-19 Before/After COVID-19 0=(Year<=19),1=(Year > = 20) - -
    Size Logarithm of Total Assets ln(Total Assets) 26.7294 1.4735
    TobinsQ Tobin's Q (Market Capitalization+Total Debt)/Total Assets 1.1002 0.8804
    DC Depreciation Charge Depreciation/Total Assets 0.0032 0.0050
    LEV Leverage Total Debt/Total Capital 0.9366 1.4763
    LIQ Liquidity Cash & Cash Equivalents/Total Assets 0.0535 0.0577
    TA Tangible Assets Ratio Total Tangible Assets/Total Assets 0.3226 0.1692
    ITA Intangible Assets Ratio Total Intangible Assets/Total Assets 0.015 0.036
    Growth Growth Rate of Sales (Current Sales - Previous Sales)/Previous Sales 0.0007 0.0039
    ROA Return on Assets Ratio Operating Profit/Total Assets 0.0346 0.0689
    FOR Foreign Ownership Number of Foreign Shares/Total Number of Shares 0.0971 0.1282
    FA Fixed Assets Ratio Fixed Assets/Long-term Capital 0.8495 0.3396

     | Show Table
    DownLoad: CSV

    A BN is a machine learning technique that models relationships between variables as a probabilistic graph, consisting of nodes and directed acyclic edges. These edges represent dependencies between variables, based on the concept of conditional independence (Pearl, 1988). In a Directed Acyclic Graph (DAG), each node corresponds to a variable, while the edges illustrate the dependencies, with their presence and direction determined by conditional probabilities.

    The starting point of a directed edge is referred to as the parent node, and the receiving end is called the child node. If the i-th node in a BN represents variable Xi for i=1,...,n, the parent set Pa(Xi) of Xi is the set of variables from which edges originate and point towards Xi. Then the joint probability distribution of X=(X1,...,Xn) can be represented by Equation (3.1) according to the product rule of probability.

    P(X1,...,Xn)=ni=1P(Xi|Pa(Xi)) (3.1)

    BNs use Equation (3.1) to visually display the relationships between variables through DAGs, making it easy to interpret the relationships.

    A DBN is an extension of a traditional (static) BN to encounter temporal dependencies in dynamic variables observed over time. Developed by Dagum et al. (1992), DBNs have been applied to various time series data, including those by Çambaşı et al. (2019), Chang et al. (2023), and Lee and Kwon (2023).

    To effectively model temporal dependencies, DBNs rely on several key assumptions: 1) Discrete Time Slices: Data is observed at distinct, discrete time points, enabling the analysis of temporal patterns and trends; 2) Markov Property: Variables at each time point are conditionally independent of all earlier time points, given the variables at the immediately preceding time point. This assumption simplifies the network structure and computational requirements; 3) Stationarity: The relationships among variables within a time slice and the transition probabilities between consecutive time slices are assumed to remain constant over time, further streamlining the model's complexity.

    Under the aforementioned assumptions, a DBN comprises two components: a static BN (B0) and a transition network (B) (Li et al., 2013). The static network B0 represents intra-slice dependencies, capturing contemporaneous relationships among variables within the same time slice t. The transition network B models inter-slice dependencies, describing how variables at time t1 influence those at time t and capturing temporal (lagged) effects. Together, these components allow a DBN to effectively model both contemporaneous and temporal dependencies.

    A CDBN builds on the DBN framework by explicitly modeling causal relationships. In a CDBN, edges represent causal mechanisms rather than mere statistical dependencies, integrating causal discovery into the DBN structure. This enhancement allows for a deeper understanding of how changes in one variable causally affect others, offering clear explanations for observed outcomes and improving the model's interpretability.

    This section describes the process of constructing the CDBN model using panel data from listed manufacturing companies in Korea.

    To infer the structure of the CDBN from the data, the study employed the PC algorithm, originally developed by Spirtes and Glymour (1991) and Spirtes et al. (2000). The PC algorithm is a constraint-based method widely used to uncover the causal structure of a BN.

    The key assumptions of the PC algorithm are as follows: i) All relevant variables are included in the dataset, ensuring that there are no hidden or unmeasured confounding variables that influence relationships among the observed variables (causal sufficiency); ii) Given the structure of the causal graph, each variable is conditionally independent of its non-descendants, given its parents (causal Markov condition); iii) the observed independencies in the data must align with the independencies implied by the underlying causal structure (faithfulness).

    A brief outline of the PC algorithm is as follows (Spirtes and Glymour, 1991; Spirtes et al., 2000):

    ● Start with a fully connected graph: Start with an undirected graph where each node represents a variable, and every pair of nodes is connected.

    ● Skeleton formation: Iteratively test each pair of nodes for conditional independence, given various subsets of adjacent nodes (conditioning sets). Remove an edge between two nodes if they are conditionally independent. After testing all possible pairs, the remaining undirected graph (skeleton) represents the dependencies between nodes.

    ● Collider orientation (V-Structure): For any three nodes X, Z, and Y, where X and Yare not directly connected but share a common neighbor Z (i.e., the structure XZY), if X and Y are conditionally independent given any subset that does not include Z, then Z is a collider. The edges are directed as XZY, forming a V-structure.

    ● Propagate edge directions: Orient the remaining edges based on constraints to maintain a DAG structure and prevent the formation of new colliders. Iterate until no further orientations are possible without creating cycles or violating the conditional independencies inferred from the data.

    The data used in this study includes a dummy variable, COVID-19, which indicates the outbreak of the COVID-19 pandemic along with a panel data consisting of observations for 11 variables from 227 companies in Korea over 14 years (2009–2022). To construct a CDBN for this panel data, the data was reshaped to ensure that observations for each dynamic variable were available at two consecutive time points, t0 and t1, for each company (Scutari et al., 2024).

    Let Xij be the jth variable for the ith company, with 14 observations corresponding to the years 2009-2022. For each Xij, new variables Xijt0 and Xijt1 were created: Xijt0 is a collection of observations of Xij from the years 2009-2021 and Xijt1 from the years 2010–2022. This restructuring aligns each observation of Xij at t0 with the corresponding observation at t1, The new data has variables at time t0 and t1, enabling the construction of edges from the previous time point to the current time point. The PC algorithm can then be applied to both the static (intra-slice) and transition (inter-slice) components of the DBN, facilitating the identification of causal relationships within and across time slices.

    To ensure the validity of the causal structure, the following constraints were applied during the construction of the causal network: i) Edges from any financial variables to COVID-19 were prohibited, as financial variables cannot causally influence the occurrence of COVID-19; ii) To maintain temporal causality, edges from t1 to t0 were disallowed, ensuring that future events do not exert any influence on past events; iii) Variables at time t0 were not permitted to influence each other, reflecting an assumption of no contemporaneous causation within this timeframe; iv) Variables at time t1 were allowed to influence each other, accounting for potential contemporaneous causation in this timeframe.

    The PC-Stable algorithm (Colombo and Maathuis, 2014), a robust variation of the original PC algorithm, was used to improve the consistency and reliability of structure learning (Kalisch et al., 2024). The algorithm was implemented using the pc.stable function from the R package bnlearn (Scutari, 2023).

    A single dataset does not provide sufficient information on the reliability of the relationships between nodes in the network. To address this limitation, bootstrap aggregation (bagging) was applied. For each bootstrap sample, 181 companies (approximately 80% of the dataset) were randomly selected, with replacement, and the variable order was shuffled to increase sample variability (Scutari et al., 2024). The bootstrap sampling was repeated 1500 times and the CDBN structure was learned from each of the samples. From the resulting 1,500 CDBN networks, edge strength and direction were computed for each edge. The edge strength is the relative frequency of the edge's presence across the networks, regardless of direction. The edge direction is the relative frequency of the edge's specific direction across the networks. Both metrics range from 0 to 1, with values close to 1 indicating strong support for the presence or direction of the edge (Friedman et al., 1999).

    Using model averaging, a consensus network was constructed by including only edges with edge strengths exceeding a specified threshold to eliminate weak or spurious connections and retain only robust relationships. Higher thresholds correspond to sparser networks. Following the approach by Scutari and Nagarajan (2013), the threshold was determined as the edge strength significance level that minimized the L1-norm between the cumulative density function (CDF) of the observed edge strengths and its asymptotic counterpart. For this study, a threshold of approximately 0.5 was applied.

    The final consensus network, created using the averaged.network function in the R package bnlearn, includes robust causal relationships supported by the data. The edge strengths and directions for the final CDBN are presented in Table 2.

    Table 2.  Edge strengths and directions in the final CDBN.
    inter-year intra-year
    From(t1) To(t) Strength Direction From To Strength Direction
    Size Size 1.000 1.000 COVID-19 TobinsQ 0.925 1.000
    TobinsQ TobinsQ 1.000 1.000 COVID-19 DC 0.987 1.000
    TobinsQ ITA 0.829 1.000 COVID-19 LEV 0.610 1.000
    DC DC 1.000 1.000 COVID-19 LIQ 0.582 1.000
    LEV LEV 1.000 1.000 COVID-19 ITA 0.839 1.000
    LIQ LIQ 1.000 1.000 COVID-19 Growth 0.962 1.000
    TA TA 1.000 1.000 COVID-19 ROA 0.697 1.000
    ITA TobinsQ 0.713 1.000 COVID-19 FA 0.535 1.000
    ITA ITA 1.000 1.000 TobinsQ LIQ 0.670 0.555
    Growth Growth 0.825 1.000 LIQ FA 1.000 0.685
    ROA ITA 0.553 1.000 TA FA 0.975 0.884
    ROA ROA 1.000 1.000 Growth ROA 0.920 0.731
    FOR FOR 1.000 1.000 ROA DC 0.783 0.512
    FA FA 1.000 1.000 FOR ROA 0.636 0.847
    LEV FA 1.000 0.819

     | Show Table
    DownLoad: CSV

    The flow chart of the CDBN model development process is shown in Figure 1.

    Figure 1.  Flow chart of the CDBN model development process.

    The constructed CDBN model, displayed in Figure 2, consists of (a) inter-year (temporal) causal relationships and (b) intra-year (contemporaneous) causal relationships. In (a), autocorrelation effects are represented by dashed lines to distinguish lagged effects between different variables. In (b), two edges, one between LIQ and TobinsQ and another between ROA and DC, have edge directions close to 0.5. This indicates that, while these pairs of variables are related, the cause-and-effect relationships between them are ambiguous. To represent this uncertainty in directionality, these edges are depicted as blue bi-directional lines.

    Figure 2.  The Causal Dynamic Bayesian Network structure of financial variables relevant to firm value for listed manufacturing companies in Korea consists of (a) inter-year (temporal) causal relationships and (b) intra-year (contemporaneous) causal relationships. In (a), autocorrelation effects are represented by dashed lines, while in (b), edges with directionality close to 0.5 are displayed as blue bi-directional lines.

    Figure 2 highlights that all dynamic variables exhibit autocorrelation effects. It is well known that in most financial variables, past values tend to influence future values due to market inertia, information dissemination processes, and investor reactions.

    Notably, a lagged feedback loop exists between ITA and TobinsQ: ITA positively influences TobinsQ in subsequent year, which, in turn, elevates ITA at the following year, thereby creating a virtuous cycle. ITA is a non-physical asset that provides value to a company, such as research and development (investments in innovation and new product development), intellectual property (patents, trademarks, copyrights), goodwill, brand recognition, and proprietary technologies.

    The lagged feedback loop between intangible assets and TobinsQ may arise because of the delayed impact of intangible investments on both financial statements and market value. When firms invest in intangible assets, accounting conservatism requires these costs to be expensed immediately rather than capitalized. This keeps book value low and initially suppresses TobinsQ (Chen and Srinivasan, 2024; McNichols et al., 2014). Over time, as these intangible investments begin to generate measurable returns - such as increased revenues, competitive advantage, or market share - the firm's market value rises, which eventually lifts TobinsQ. This adjustment occurs gradually, introducing a temporal lag between the time of investment and the point at which TobinsQ reflects the full value of these intangibles.

    An increase in TobinsQ, due to the market recognizing the value of intangible assets, may prompt companies to focus on intangible growth, leading to further improvements in intangible assets. This cycle can create a feedback effect where higher TobinsQ stimulates investment in intangibles, which, in turn, could elevate TobinsQ further.

    In"New Economy" firms - companies focused on technology, digital services, biotech, and other sectors driven by intangible assets - the lagged feedback effect between intangible assets and TobinsQ can be pronounced. This is because these firms often rely heavily on intangible assets, which are underreported in financial statements (Core et al., 2003).

    The lagged feedback loop between ITA and TobinsQ suggests that the market often takes time to recognize the value of intangibles, impacting investment strategies for various stakeholders. For investors, this effect presents an opportunity to identify and invest in undervalued firms with significant intangible assets, anticipating future gains as market recognition catches up. Corporate managers can use this insight to justify strategic investments in intangibles such as R&D and brand-building, even if these do not immediately boost market value, while enhancing transparency around these assets to reduce the recognition lag. Policymakers, recognizing the limitations of current accounting standards, may consider reforms to improve intangible asset reporting and introduce incentives that encourage firms to invest in intangibles, fostering innovation and supporting knowledge-driven sectors. This understanding promotes a balanced approach, focusing on sustainable long-term growth rather than short-term gains.

    Valuation of the intangible assets has been a widespread topic of interest and many studies revealed the positive effect of intangible assets to firm value. See Nagaraja and Vinay (2016), Ocak and Findik (2019), Tsai and et al. (2012), Glova and Mrázková (2018), Mohammed and Al-Ani (2020), among others. The lagged feedback loop between ITA and TobinsQ found in this study goes in line with the results of previous research.

    Additionally, the study reveals a lagged effect of ROA on ITA. A higher ROA in the current year leads to an increase in ITA in the following year. This indicates that as companies experience better asset utilization and profitability, they are more likely to reinvest those returns into intangible assets after a period of financial evaluation and strategic decision-making.

    The intra-year structure, depicted in Figure 2(b), underscores the broad impact of COVID-19 on the financial sector. COVID-19 directly or indirectly influences all variables except Size, FOR, and TA. Notably, the distributions of Size, FOR, and TA remained nearly identical between the pre-COVID and post-COVID periods. Furthermore, these variables exhibit high autocorrelation coefficients—0.995 for Size, 0.964 for FOR, and 0.942 for TA—indicating that their values from the previous year almost entirely determine their current-year values. As a result, given their previous-year values, these variables need no other parent nodes in the model, with their only parent being their respective value from the previous year.

    To examine the impact of COVID-19 in greater detail, particularly its influence on the causal network structure among financial variables, the dataset was divided into pre-COVID (2009–2019) and post-COVID (2020–2022) subsets, and separate CDBN models were constructed (Figures 3 and 4). Figure 3 illustrates the inter-year structures of the pre-COVID and post-COVID CDBN models, while Figure 4 depicts their intra-year structures. Figure 3 illustrates that, while autocorrelation effects are maintained, the lagged feedback loop between ITA and TobinsQ, as well as the lagged impact of ROA on ITA, are absent in the post-COVID model. Similarly, Figure 4 shows that only the edges from LEV to FA and LIQ to FA persist in the post-COVID model. These findings suggest that most of the previously observed relationships have disappeared during the pandemic, highlighting the significant disruption to existing financial structures caused by COVID-19.

    Figure 3.  The inter-year (temporal) structures of the pre-COVID and post-COVID CDBN models. The autocorrelation effects are represented by dashed lines.
    Figure 4.  The intra-year (contemporaneous) structures of the pre-COVID and post-COVID CDBN models. Isolated nodes are omitted.

    One notable new relationship in Figure 4 is the influence of ROA on DC during the pandemic. This likely reflects firms' strategic adjustments to their depreciation practices in response to declining profitability. For instance, firms experiencing lower profitability may have accelerated depreciation to reduce taxable income or align asset book values with diminished expectations for their utility in an uncertain economic environment.

    The contemporaneous relationships illustrated in Figure 2(b) identify two distinct groups of variables—(LIQ, LEV, FA, TA, TobinsQ) and (ROA, Growth, FOR, DC)—that are linked exclusively through COVID-19. This indicates that the two groups are conditionally independent, given the influence of COVID-19 in the same year. The first group comprises key financial variables—LEV, LIQ, TA, FA, and TobinsQ—that provide critical insights into a firm's financial stability and operational efficiency. The edge directions in Table 2 offer strong evidence that LEV and TA influence FA, and moderate evidence that LIQ influences FA. Additionally, while TobinsQ and LIQ are related, the causal direction between the two remains unclear, as the edge direction is approximately 0.5. In the second group, Growth and ROA capture performance and profitability, while DC and FOR influence financial statements and investor perceptions. The edge directions in Table 2 provide moderate evidence that Growth and FOR influence ROA. However, the causal relationship between ROA and DC remains ambiguous, as the edge direction is also close to 0.5.

    Finally, Size (the logarithm of total assets) is not connected to any other variables. In this study, all asset-related variables are expressed as ratios relative to total assets, inherently capturing the influence of total assets in their values. The correlation coefficients between Size and other variables are close to zero, except for FOR, which has a correlation coefficient of approximately 0.5 with Size. However, both Size and FOR show strong autocorrelation effects, with autocorrelation coefficients close to 1. The dominant influence of their previous-year values mitigates the connection between Size and FOR in the current year.

    We have developed a CDBN model to uncover and visualize the temporal and contemporaneous causal relationships among financial variables associated with firm value, using data from listed manufacturing companies in Korea. The CDBN structure revealed strong evidence of autocorrelation across all dynamic variables, as well as a lagged feedback loop between intangible assets (ITA) and TobinsQ (TobinsQ), and a lagged effect of return on assets (ROA) on ITA.

    The model also highlighted the extensive impact of the COVID-19 pandemic on the financial sector; key factors influencing important financial metrics such as FA, TobinsQ, and ROA; and two distinct groups of variables—(LIQ, LEV, FA, ITA, TA, TobinsQ) and (ROA, Growth, FOR, DC)—connected only through COVID-19 and the previous year's ROA. These findings offer a clear understanding of the dynamic and instantaneous interactions between financial variables, shedding light on the complex relationships.

    The primary focus of this study was to explore the interrelationships between variables associated with firm value, rather than building a predictive model for firm value. Accordingly, we did not distinguish between dependent (target) and independent (explanatory) variables. Instead, we examined the joint causal dynamics among all variables. This approach offers great flexibility, as any variable can be treated as a target or explanatory variable depending on the context of the analysis. For example, if TobinsQ is the variable of interest, the effects of its ancestor nodes, which directly or indirectly influence TobinsQ (such as COVID-19; previous year's ITA and TobinsQ), can be inferred using the CDBN model. Likewise, if ROA is the focus, the same CDBN model also allows inference on the effects of its ancestor nodes (COVID-19; previous year's ROA; Growth; FOR).

    The process of constructing the CDBN model proposed in this study can be tailored for specific inference tasks by selectively blocking or enforcing certain edges within the network. If the goal is to assess the influence of all other variables on a specific variable, that variable can be designated as the target, while the remaining variables serve as explanatory variables. In this setup, the target variable is treated as an end node with no child nodes, and the explanatory variables are considered as potential parent nodes. As an illustration, we constructed a CDBN with TobinsQ as the target variable and all other variables as explanatory variables, while blocking any edges from TobinsQ to other variables in addition to the edge direction constraints described in Section 4. Using the same dataset, the resulting CDBN model is identical to the one shown in Figure 2, except that the direction of the edge between LIQ and TobinsQ is reversed, pointing from TobinsQ to LIQ.

    To the best of our knowledge, the CDBN model is the first to assess both temporal and contemporaneous causal relationships between financial variables related to firm value. However, it is essential to acknowledge several limitations and caveats associated with this research. First, we advise readers against over-generalizing our findings, as the dataset used pertains to the manufacturing sector in Korea. Although the CDBN model proposed here can be applied to datasets from other countries, contexts, or sectors, the resulting causal relationships may vary depending on the financial environments from which these datasets were derived. Second, the inferred causal relationships in this study are valid only under the assumption that all relevant causes are represented within the graph and that no unmeasured confounders exist to explain the relationships between any two observed variables.

    Future research could focus on expanding the dataset to include multiple countries and sectors, facilitating a more comprehensive analysis of causal network structures related to firm value and its determinants. Another promising direction is to incorporate a broader range of firm characteristics, as suggested by Green et al. (2017), along with key macroeconomic variables such as interest rates, exchange rates, and unemployment rates.

    To assess the predictive performance of the CDBN model relative to a standard regression model for panel data, we used data from 2015 to 2021 to build both models and predicted TobinsQ for 2022. The CDBN model achieved a mean squared prediction error of 0.184, which was significantly lower than the 0.379 of the regression model. Although this is a relatively simple comparison, it highlights the CDBN model's superior predictive accuracy, likely due to its ability to capture essential interactions within the data. A more thorough evaluation of the CDBN model's performance, particularly in comparison with Structural Equation Models and other machine learning methods, is recommended as a valuable direction for future research.

    M.O.: Conceptualization, Methodology, Writing - Original Draft, Writing - Review & Editing.

    J.C., C.L.: Data Curation, Software, Formal analysis, Writing - Original Draft.

    The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.

    We are grateful for insightful comments from the Editor and two anonymous reviewers, which helped us improve the paper. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2022R1A2C1091256).

    All authors declare no conflicts of interest in this paper.



    [1] E. Panza, C. H. Knowles, C. Graziano, N. Thapar, A. J. Burns, M. Seri, et al., Genetics of human enteric neuropathies, Prog. Neurobiol., 96 (2012), 176–189. https://doi.org/10.1016/j.pneurobio.2012.01.001 doi: 10.1016/j.pneurobio.2012.01.001
    [2] A. M. Goldstein, N. Thapar, T. B. Karunaratne, R. De Giorgio, Clinical aspects of neurointestinal disease: Pathophysiology, diagnosis, and treatment, Dev. Biol., 417 (2016), 217–228. https://doi.org/10.1016/j.ydbio.2016.03.032 doi: 10.1016/j.ydbio.2016.03.032
    [3] S. B. Gabriel, R. Salomon, A. Pelet, M. Angrist, J. Amiel, M. Fornage, et al., Segregation at three loci explains familial and population risk in Hirschsprung disease, Nat. Genet., 31 (2002), 89–93. https://doi.org/10.1038/ng868 doi: 10.1038/ng868
    [4] E. G. Puffenberger, K. Hosoda, S. S. Washington, K. Nakao, D. deWit, M. Yanagisawa, et al., A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease, Cell. 79 (1994), 1257–1266. https://doi.org/10.1016/0092-8674(94)90016-7 doi: 10.1016/0092-8674(94)90016-7
    [5] R. M. Hofstra, J. Osinga, G. Tan-Sindhunata, Y. Wu, E. J. Kamsteeg, R. P. Stulp, et al., A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome), Nat. Genet., 12 (1996), 445–447. https://doi.org/10.1038/ng0496-445 doi: 10.1038/ng0496-445
    [6] R. M. Hofstra, O. Valdenaire, E. Arch, J. Osinga, H. Kroes, B. M. Löffler, et al., A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction, Am. J. Hum. Genet., 64 (1999), 304–308. https://doi.org/10.1086/302184 doi: 10.1086/302184
    [7] V. Pingault, N. Bondurand, K. Kuhlbrodt, D. E. Goerich, M. O. Préhu, A. Puliti, et al., SOX10 mutations in patients with Waardenburg-Hirschsprung disease, Nat. Genet., 18 (1998), 171–173. https://doi.org/10.1038/ng0298-171 doi: 10.1038/ng0298-171
    [8] J. Amiel, B. Laudier, T. Attié-Bitach, H. Trang, L. de Pontual, B. Gener, et al., Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome, Nat. Genet., 33 (2003), 459–461. https://doi.org/10.1038/ng1130 doi: 10.1038/ng1130
    [9] R. O. Heuckeroth, Hirschsprung disease - integrating basic science and clinical medicine to improve outcomes, Nat. Rev. Gastroenterol. Hepatol., 15 (2018), 152–167. https://doi.org/10.1038/nrgastro.2017.149 doi: 10.1038/nrgastro.2017.149
    [10] S. S. Short, M. M. Durham, M. D. Rollins, Hirschsprung disease outcomes, Semin. Pediatr. Surg., 31 (2022), 151160. https://doi.org/10.1016/j.sempedsurg.2022.151160 doi: 10.1016/j.sempedsurg.2022.151160
    [11] T. Wang, X. Zhang, W. Xie, Cistanche deserticola Y. C. Ma, "Desert ginseng": a review, Am. J. Chin. Med., 40 (2012), 1123–1141. https://doi.org/10.1142/s0192415x12500838 doi: 10.1142/S0192415X12500838
    [12] J. Li, H. Yu, C. Yang, T. Ma, Y. Dai, Therapeutic Potential and Molecular Mechanisms of Echinacoside in Neurodegenerative Diseases, Front. Pharmacol., 13 (2022), 841110. https://doi.org/10.3389/fphar.2022.841110 doi: 10.3389/fphar.2022.841110
    [13] Y. Ni, J. Deng, X. Liu, Q. Li, J. Zhang, H. Bai, et al., Echinacoside reverses myocardial remodeling and improves heart function via regulating SIRT1/FOXO3a/MnSOD axis in HF rats induced by isoproterenol, J. Cell. Mol. Med., 25 (2021), 203–216. https://doi.org/10.1111/jcmm.15904 doi: 10.1111/jcmm.15904
    [14] X. Yang, Q. Yv, F. Ye, S. Chen, Z. He, W. Li, et al., Echinacoside Protects Dopaminergic Neurons Through Regulating IL-6/JAK2/STAT3 Pathway in Parkinson's Disease Model, Front. Pharmacol., 13 (2022), 848813. https://doi.org/10.3389/fphar.2022.848813 doi: 10.3389/fphar.2022.848813
    [15] Q. Song, J. Li, H. Huo, Y. Cao, Y. Wang, Y. Song, et al., Retention Time and Optimal Collision Energy Advance Structural Annotation Relied on LC-MS/MS: An Application in Metabolite Identification of an Antidementia Agent Namely Echinacoside, Anal. Chem., 91 (2019), 15040–15048. https://doi.org/10.1021/acs.analchem.9b03720 doi: 10.1021/acs.analchem.9b03720
    [16] L. Li, G. Wan, B. Han, Z. Zhang, Echinacoside alleviated LPS-induced cell apoptosis and inflammation in rat intestine epithelial cells by inhibiting the mTOR/STAT3 pathway, Biomed. Pharmacother., 104 (2018), 622–628. https://doi.org/10.1016/j.biopha.2018.05.072 doi: 10.1016/j.biopha.2018.05.072
    [17] S. Gao, T. Xu, H. Guo, Q. Deng, C. Xun, W. Liang, et al., Ameliorative effects of echinacoside against spinal cord injury via inhibiting NLRP3 inflammasome signaling pathway, Life Sci., 237 (2019), 116978. https://doi.org/10.1016/j.lfs.2019.116978 doi: 10.1016/j.lfs.2019.116978
    [18] D. M. Laughlin, F. Friedmacher, P. Puri, Total colonic aganglionosis: a systematic review and meta-analysis of long-term clinical outcome, Pediatr. Surg. Int., 28 (2012), 773–779. https://doi.org/10.1007/s00383-012-3117-3 doi: 10.1007/s00383-012-3117-3
    [19] L. S. Cheng, H. K. Graham, W. H. Pan, N. Nagy, A. Carreon-Rodriguez, A. M. Goldstein, et al., Optimizing neurogenic potential of enteric neurospheres for treatment of neurointestinal diseases, J. Surg. Res., 206 (2016), 451–459. https://doi.org/10.1016/j.jss.2016.08.035 doi: 10.1016/j.jss.2016.08.035
    [20] J. L. Mueller, A. M. Goldstein, The science of Hirschsprung disease: What we know and where we are headed, Semin. Pediatr. Surg., 31 (2022), 151157. https://doi.org/10.1016/j.sempedsurg.2022.151157 doi: 10.1016/j.sempedsurg.2022.151157
    [21] Y. Rehman, K. Bjørnland, K. J. Stensrud, I. N. Farstad, R. Emblem, Low incidence of enterocolitis and colonic mucosal inflammation in Norwegian patients with Hirschsprung's disease, Pediatr. Surg. Int., 25 (2009), 133–138. https://doi.org/10.1007/s00383-008-2300-z doi: 10.1007/s00383-008-2300-z
    [22] M. Heinrich, B. Häberle, D. von Schweinitz, M. Stehr, Re-operations for Hirschsprung's disease: long-term complications, Eur. J. Pediatr. Surg., 21 (2011), 325–330. https://doi.org/10.1055/s-0031-1284423 doi: 10.1055/s-0031-1284423
    [23] A. Gosain, A. S. Brinkman, Hirschsprung's associated enterocolitis, Curr. Opin. Pediatr., 27 (2015), 364–369. https://doi.org/10.1097/mop.0000000000000210 doi: 10.1097/MOP.0000000000000210
    [24] M. E. Ritchie, B. Phipson, D. Wu, Y. Hu, C. W. Law, W. Shi, et al., limma powers differential expression analyses for RNA-sequencing and microarray studies, Nucleic Acids Res., 43 (2015), e47. https://doi.org/10.1093/nar/gkv007 doi: 10.1093/nar/gkv007
    [25] J. S. Amberger, C. A. Bocchini, F. Schiettecatte, A. F. Scott, A. Hamosh, OMIM.org: Online Mendelian Inheritance in Man (OMIMⓇ), an online catalog of human genes and genetic disorders, Nucleic Acids Res., 43 (2015), D789–798. https://doi.org/10.1093/nar/gku1205 doi: 10.1093/nar/gku1205
    [26] J. Piñero, À. Bravo, N. Queralt-Rosinach, A. Gutiérrez-Sacristán, J. Deu-Pons, E. Centeno, et al., DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants, Nucleic Acids Res., 45 (2017), D833–d839. https://doi.org/10.1093/nar/gkw943 doi: 10.1093/nar/gkw943
    [27] J. Piñero, J. M. Ramírez-Anguita, J. Saüch-Pitarch, F. Ronzano, E. Centeno, F. Sanz, et al., The DisGeNET knowledge platform for disease genomics: 2019 update, Nucleic Acids Res., 48 (2020), D845-d855. https://doi.org/10.1093/nar/gkz1021 doi: 10.1093/nar/gkz1021
    [28] G. Stelzer, N. Rosen, I. Plaschkes, S. Zimmerman, M. Twik, S. Fishilevich, et al., The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses, Curr Protoc Bioinformatics. 54 (2016), 1.30.31–31.30.33. https://doi.org/10.1002/cpbi.5 doi: 10.1002/cpbi.5
    [29] X. Liu, S. Ouyang, B. Yu, Y. Liu, K. Huang, J. Gong, et al., PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach, Nucleic Acids Res., 38 (2010), W609–614. https://doi.org/10.1093/nar/gkq300 doi: 10.1093/nar/gkq300
    [30] D. S. Wishart, Y. D. Feunang, A. C. Guo, E. J. Lo, A. Marcu, J. R. Grant, et al., DrugBank 5.0: A major update to the DrugBank database for 2018, Nucleic Acids Res., 46 (2018), D1074–d1082. https://doi.org/10.1093/nar/gkx1037 doi: 10.1093/nar/gkx1037
    [31] Z. J. Yao, J. Dong, Y. J. Che, M. F. Zhu, M. Wen, N. N. Wang, et al., TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models, J. Comput. Aided Mol. Des., 30 (2016), 413–424. https://doi.org/10.1007/s10822-016-9915-2 doi: 10.1007/s10822-016-9915-2
    [32] G. Yu, L. G. Wang, Y. Han, Q. Y. He, clusterProfiler: an R package for comparing biological themes among gene clusters, OMICS. 16 (2012), 284–287. https://doi.org/10.1089/omi.2011.0118 doi: 10.1089/omi.2011.0118
    [33] M. Ashburner, C. A. Ball, J. A. Blake, D. Botstein, H. Butler, J. M. Cherry, et al., Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium, Nat. Genet., 25 (2000), 25–29. https://doi.org/10.1038/75556 doi: 10.1038/75556
    [34] M. Kanehisa, S. Goto, KEGG: kyoto encyclopedia of genes and genomes, Nucleic Acids Res., 28 (2000), 27-30. https://doi.org/10.1093/nar/28.1.27 doi: 10.1093/nar/28.1.27
    [35] Y. Ru, K. J. Kechris, B. Tabakoff, P. Hoffman, R. A. Radcliffe, R. Bowler, et al., The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations, Nucleic Acids Res., 42 (2014), e133. https://doi.org/10.1093/nar/gku631 doi: 10.1093/nar/gku631
    [36] S. K. Burley, H. M. Berman, G. J. Kleywegt, J. L. Markley, H. Nakamura, S. Velankar, Protein Data Bank (PDB): The Single Global Macromolecular Structure Archive, Methods Mol. Biol., 1607 (2017), 627–641. https://doi.org/10.1007/978-1-4939-7000-1_26 doi: 10.1007/978-1-4939-7000-1_26
    [37] Schrödinger, LLC The PyMOL Molecular Graphics System (Version 2.0).
    [38] D. Santos-Martins, L. Solis-Vasquez, A. F. Tillack, M. F. Sanner, A. Koch, S. Forli, Accelerating AutoDock4 with GPUs and Gradient-Based Local Search, J. Chem. Theory Comput., 17 (2021), 1060–1073. https://doi.org/10.1021/acs.jctc.0c01006 doi: 10.1021/acs.jctc.0c01006
    [39] M. F. Sanner, Python: a programming language for software integration and development, J. Mol. Graph. Model., 17 (1999), 57–61.
    [40] J. Gao, B. A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S. O. Sumer, et al., Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci Signal., 6 (2013), pl1. https://doi.org/10.1126/scisignal.2004088 doi: 10.1126/scisignal.2004088
    [41] F. Pontén, K. Jirström, M. Uhlen, The Human Protein Atlas--a tool for pathology, J. Pathol., 216 (2008), 387–393. https://doi.org/10.1002/path.2440 doi: 10.1002/path.2440
    [42] N. E. Butler Tjaden, P. A. Trainor, The developmental etiology and pathogenesis of Hirschsprung disease, Transl. Res., 162 (2013), 1–15. https://doi.org/10.1016/j.trsl.2013.03.001 doi: 10.1016/j.trsl.2013.03.001
    [43] A. Torroglosa, L. Villalba-Benito, B. Luzón-Toro, R. M. Fernández, G. Antiñolo, S. Borrego, Epigenetic Mechanisms in Hirschsprung Disease, Int. J. Mol. Sci., 20 (2019). https://doi.org/10.3390/ijms20133123 doi: 10.3390/ijms20133123
    [44] L. Pinzi, G. Rastelli, Molecular Docking: Shifting Paradigms in Drug Discovery, Int. J. Mol. Sci., 20 (2019). https://doi.org/10.3390/ijms20184331 doi: 10.3390/ijms20184331
    [45] N. Lolak, S. Akocak, S. Bua, R. K. K. Sanku, C. T. Supuran, Discovery of new ureido benzenesulfonamides incorporating 1, 3, 5-triazine moieties as carbonic anhydrase Ⅰ, Ⅱ, Ⅸ and Ⅻ inhibitors, Bioorg. Med. Chem., 27 (2019), 1588–1594. https://doi.org/10.1016/j.bmc.2019.03.001 doi: 10.1016/j.bmc.2019.03.001
    [46] C. T. Supuran, Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators, Nat. Rev. Drug Discov., 7 (2008), 168–181. https://doi.org/10.1038/nrd2467 doi: 10.1038/nrd2467
    [47] K. N. Mohan, DNMT1: Catalytic and non-catalytic roles in different biological processes, Epigenomics. 14 (2022), 629–643. https://doi.org/10.2217/epi-2022-0035 doi: 10.2217/epi-2022-0035
    [48] K. K. Wong, DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications, Cell. Oncol. (Dordr.). 43 (2020), 779–792. https://doi.org/10.1007/s13402-020-00526-4 doi: 10.1007/s13402-020-00526-4
    [49] K. K. Wong, DNMT1: A key drug target in triple-negative breast cancer, Semin. Cancer Biol., 72 (2021), 198–213. https://doi.org/10.1016/j.semcancer.2020.05.010 doi: 10.1016/j.semcancer.2020.05.010
    [50] S. C. Yang, W. Y. Wang, J. J. Zhou, L. Wu, M. J. Zhang, Q. C. Yang, et al., Inhibition of DNMT1 potentiates antitumor immunity in oral squamous cell carcinoma, Int. Immunopharmacol., 111 (2022), 109113. https://doi.org/10.1016/j.intimp.2022.109113 doi: 10.1016/j.intimp.2022.109113
    [51] E. N. Elliott, K. L. Sheaffer, J. Schug, T. S. Stappenbeck, K. H. Kaestner, Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium, Development. 142 (2015), 2163–2172. https://doi.org/10.1242/dev.117341 doi: 10.1242/dev.117341
    [52] L. Li, X. Li, X. Wang, W. Liu, R. Wu, Aberrant expression of LINC00346 regulates cell migration and proliferation via competitively binding to miRNA-148a-3p/Dnmt1 in Hirschsprung's disease, Pediatr. Surg. Int., 38 (2022), 1273–1281. https://doi.org/10.1007/s00383-022-05144-9 doi: 10.1007/s00383-022-05144-9
    [53] A. Alkelai, L. Greenbaum, E. L. Heinzen, E. H. Baugh, A. Teitelbaum, X. Zhu, et al., New insights into tardive dyskinesia genetics: Implementation of whole-exome sequencing approach, Prog. Neuropsychopharmacol. Biol. Psychiatry. 94 (2019), 109659. https://doi.org/10.1016/j.pnpbp.2019.109659 doi: 10.1016/j.pnpbp.2019.109659
    [54] G. Liu, J. Peng, Z. Liao, J. J. Locascio, J. C. Corvol, F. Zhu, et al., Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease, Nat. Genet., 53 (2021), 787–793. https://doi.org/10.1038/s41588-021-00847-6 doi: 10.1038/s41588-021-00847-6
    [55] Y. J. Choi, C. Laclef, N. Yang, A. Andreu-Cervera, J. Lewis, X. Mao, et al., RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis, PLoS Genet., 15 (2019), e1007914. https://doi.org/10.1371/journal.pgen.1007914 doi: 10.1371/journal.pgen.1007914
    [56] L. Wang, A. J. De Solis, Y. Goffer, K. E. Birkenbach, S. E. Engle, R. Tanis, et al., Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development, JCI Insight., 4 (2019), https://doi.org/10.1172/jci.insight.123337 doi: 10.1172/jci.insight.123337
    [57] C. L. Scott, W. T'Jonck, L. Martens, H. Todorov, D. Sichien, B. Soen, et al., The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages, Immunity, 49 (2018), 312–325.e315. https://doi.org/10.1016/j.immuni.2018.07.004 doi: 10.1016/j.immuni.2018.07.004
    [58] B. De Craene, G. Berx, Regulatory networks defining EMT during cancer initiation and progression, Nat. Rev. Cancer. 13 (2013), 97–110. https://doi.org/10.1038/nrc3447 doi: 10.1038/nrc3447
    [59] L. Garavelli, P. C. Mainardi, Mowat-Wilson syndrome, Orphanet J. Rare Dis., 2 (2007), 42. https://doi.org/10.1186/1750-1172-2-42 doi: 10.1186/1750-1172-2-42
    [60] F. Gan, X. Zhou, Y. Zhou, L. Hou, X. Chen, C. Pan, et al., Nephrotoxicity instead of immunotoxicity of OTA is induced through DNMT1-dependent activation of JAK2/STAT3 signaling pathway by targeting SOCS3, Arch. Toxicol., 93 (2019), 1067–1082. https://doi.org/10.1007/s00204-019-02434-5 doi: 10.1007/s00204-019-02434-5
    [61] X. Kong, Z. Gong, L. Zhang, X. Sun, Z. Ou, B. Xu, et al., JAK2/STAT3 signaling mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation, Brain. Behav. Immun., 79 (2019), 159–173. https://doi.org/10.1016/j.bbi.2019.01.027 doi: 10.1016/j.bbi.2019.01.027
    [62] É. Boros, M. Csatári, C. Varga, B. Bálint, I. Nagy, Specific Gene- and MicroRNA-Expression Pattern Contributes to the Epithelial to Mesenchymal Transition in a Rat Model of Experimental Colitis, Mediat. Inflamm., 2017 (2017), 5257378. https://doi.org/10.1155/2017/5257378 doi: 10.1155/2017/5257378
    [63] A. Struchtrup, A. Wiegering, B. Stork, U. Rüther, C. Gerhardt, The ciliary protein RPGRIP1L governs autophagy independently of its proteasome-regulating function at the ciliary base in mouse embryonic fibroblasts, Autophagy, 14 (2018), 567–583. https://doi.org/10.1080/15548627.2018.1429874 doi: 10.1080/15548627.2018.1429874
    [64] J. Liu, X. Hu, L. Feng, Y. Lin, S. Liang, Z. Zhu, et al., Carbonic anhydrase Ⅸ-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation, J Nanobiotechnol., 20 (2022), 187. https://doi.org/10.1186/s12951-022-01394-w doi: 10.1186/s12951-022-01394-w
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