miR-30c-5p serves a diagnostic biomarker in chronic heart failure patients and its regulatory role in vascular endothelial
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Dan Xiong
,
Yi Mei
,
Yao Zhu
and
Pan Deng
Abstract
Objectives
Chronic heart failure (CHF) is a syndrome of conflicting organ supply and demand caused by cardiac insufficiency. Previous studies have demonstrated that miR-30c-5p is strongly associated with cardiovascular diseases such as cardiac hypertrophy and acute coronary syndrome. The aim of this study was to explore the meaning of miR-30c-5p in the diagnosis of CHF patients and its effect on vascular endothelial cells.
Methods
Serum miR-30c-5p levels were detected in 113 CHF patients and 98 healthy individuals by RT-qPCR. ROC curve and logistic regression analysis were conducted to estimate the diagnostic ability and risk factors of miR-30c-5p for CHF. The relationship of miR-30c-5p with BNP and LVEF was analyzed by Pearson correlation. The influence of miR-30c-5p on HUVECs cell lines was explored by transfection with miR-30c-5p mimic/inhibitor. Cell apoptosis and proliferation were detected by flow cytometry and CCK8 assay. Transwell assay was used to detect the migration and invasion abilities of cells.
Results
miR-30c-5p was reduced in CHF patients’ serum and progressively decreased with increasing NYHA grade. The ROC curve demonstrated that miR-30c-5p had high sensitivity (83.19 %) and specificity (84.69 %) to diagnose CHF. Logistic regression revealed that miR-30c-5p was a pivotal risk factor for CHF development. Pearson correlation analysis suggested that miR-30c-5p was negatively related to BNP and positively correlated with LVEF. Transfection of miR-30c-5p mimic suppressed apoptosis and promoted cell proliferation, migration, and invasion in HUVECs.
Conclusions
Reduced serum miR-30c-5p levels in CHF patients may be a biomarker for CHF diagnosis. Aberrant miR-30c-5p expression may influence CHF development by affecting the HUVECs function.
Introduction
Chronic heart failure (CHF) is a clinical syndrome in which structural or functional changes occur in heart, resulting in impaired ventricular filling and ejection capacity [1]. The prevalence of CHF is rising yearly with the accelerated aging of our population, the prolonged human lifespan, and the growth of risk factors such as hypertension, obesity, and diabetes [2]. CHF is the end stage of many cardiac problems, in which the main clinical features are dyspnea, fatigue, sleep trouble and pain [3]. Brain natriuretic peptide (BNP) and NT-proBNP are considered specific biomarkers for CHF diagnosis [4]. However, elevated BNP and NT-proBNP may be caused by other factors, including weight, age, pneumonia, respiratory failure, atrial fibrillation, myocardial infarction, and chronic renal insufficiency [5]. Therefore, it is crucial to seek and develop novel biomarkers for CHF.
With the development of molecular biology, it has been discovered that miRNAs take part in post-transcriptional regulation of gene expression [6]. An increasing list of clinical trials illustrated that miRNAs may be efficiently and rapidly detected in peripheral blood. Consequently, a variety of miRNAs have been studied and discovered as biomarkers for clinical diagnosis and therapy [7]. Multiple studies suggest that miRNAs are associated with the regulation of various cardiovascular diseases. For example, miR-222 down expression promoted cardiac hypertrophy and heart failure [8]. miR-221-3p prevents angiogenesis by targeting Hif-1α in heart failure patients [9]. miR-106-5p exhibits downregulation in acute heart failure sufferers and may act as a diagnostic and prognostic biomarker [10]. Previous research has demonstrated that miR-30c-5p exerts a regulatory function in various diseases and tumors such as Parkinson’s disease, endometriosis, and thyroid cancer [11], [12], [13]. Moreover, miR-30c-5p is engaged in several cardiovascular diseases’ progression. For instance, miR-30c-5p attenuates myocardial ischemia-reperfusion injury and thus improves the evolution of coronary heart disease [14]. Zhang et al. discovered that miR-30c-5p was reduced in acute coronary syndromes and may have diagnostic and prognostic value [15]. Another research identified that miR-30c-5p reduction is a facilitator of early atherosclerosis [16]. A trend towards miR-30c-5p downregulation was observed during a meta-analysis of miRNAs targeting heart failure, with presumed diagnostic potential [17]. Nevertheless, the value of miR-30c-5p for CHF remains unexplored and unexamined.
The aim of the research was to investigate the meaning of miR-30c-5p in the diagnosis of CHF patients and its regulation of vascular endothelial function by analyzing its expression in CHF patients and its effect on human umbilical vein endothelial cells (HUVECs). It is expected to provide a new evaluation index for the diagnosis and development of CHF.
Materials and methods
Study subjects
The study was performed in line with the principles of the Declaration of Helsinki (as revised in 2013). The research was approved by the Medical Ethics Committee of Xi’an People’s Hospital (Xi’an Fourth Hospital, no. 202043). All study subjects signed a written informed consent.
The sample size was determined based on the G*Power 3.1 software. When the alpha error probability is 0.05, the power (1-β) is 0.95, and the medium effect size (d) is 0.5, the minimum sample size required for each group is 88 cases. In this study, we selected 113 patients with CHF who were hospitalized in Xi’an People’s Hospital (Xi’an Fourth Hospital) from September 2021 to February 2024 and met the inclusion and exclusion criteria. There were 98 healthy individuals chosen as controls who visited our hospital for physical check-ups during the same period. All study subjects were aged 35–85 years. Diagnosis of CHF followed the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [18]. Exclusion criteria included patients with new-onset acute heart failure and acute coronary syndromes; with cerebrovascular disease, bone and soft tissue disease, and autoimmune disease; with hepatic or renal insufficiency; with malignant tumors; and those who had undergone surgery within three months. Inclusion criteria for healthy individuals were the absence of clinical signs and symptoms in CHF patients, matching with the CHF in terms of age, gender, body mass index (BMI), history of hypertension and diabetes, as well as the same exclusion criteria as in the CHF patients.
Data collection
Age, gender, BMI, history of hypertension, diabetes and surgery data were collected from the study subjects. On the morning of the day following admission to the hospital, venous blood samples were obtained from the antecubital vein of all study subjects uniformly in the fasting state. Complete blood counts were measured without centrifugation after mixing EDTA anticoagulation tubes (MEIDIKE, Shenzhen, China). In addition, EDTA anticoagulation tubes were centrifuged at 3000 g for 10 min, and plasma was taken for BNP detection. Conventional serum collection tubes (MEIDIKE, Shenzhen, China) were centrifuged at 2000 g for 15 min, and the middle layer serum was taken to detect total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). All samples were sent to the laboratory department of our hospital for testing within 1 h of blood collection.
BNP was determined by the chemiluminescence method and the corresponding instrument (Abbott Architect i2000SR, USA). Complete blood counts were detected using an automated hematology analyzer (Bayer Advia-120, Germany) and the matching kits. Serum lipids (TC, TG, HDL-C and LDL-C) were assayed using a fully automated biochemical analysis system (Abbott Architect c16000, USA). Additionally, cardiac color Doppler ultrasound was carried out in all subjects within 48 h of admission to the hospital, and LVEF was determined.
Cell culture and transfection
HUVECs (Otwo Biotech, China) were incubated in complete medium (DMEM medium (Hyclone, USA) + 10 % FBS (Gibco, Thermo Fisher Scientific, USA) + 1 % P/S (Gibco, Thermo Fisher Scientific, USA)). The cells were cultivated at 37 °C in a 5 % CO2 thermostat incubator, the solution was replaced on alternate days, and the cells were observed daily.
Logarithmic growth phase HUVECs were taken and digested with 0.25 % trypsin (Gibco, Thermo Fisher Scientific, USA), and the transfection operation could be started when the cell fusion was 70–80 %. The miR-30c-5p mimic/inhibitor and negative control were synthesized by Sangon Biotech (Shanghai, China). Cell transfection was conducted following the instructions for Lipofectamine 3,000 (Thermo Fisher Scientific, USA). After 48 h, the total RNA of cells may be extracted, and other subsequent experiments may be undertaken.
miR-30c-5p detection
Serum or cells prepared in advance were taken and added to Trizol reagent (Thermo Fisher Scientific, USA) for RNA extraction. The reverse transcription reaction was performed using PrimeScript RT kit (Takara Bio Inc., Japan) with a 20 µL reaction system. Real-time quantitative PCR reaction (RT-qPCR) was achieved by ChamQ Universal SYBR qPCR Master Mix Kit (Vazyme Biotech, China) with 10 µL reaction system. The amplification conditions were 95 °C for 15 s, 60 °C for 30 s, 72 °C for 20 s, totaling 42 cycles. Data were counted using the 2−ΔΔct method. The primers were as follows: miR-30c-5p forward, 5′-GCCGAGUGUAAACAUCCUACA-3′ and reverse, 5′-CTCAACTGGTGTCGTGGA-3′; U6 forward, 5′-CTCGCTTCGGCAGCACA-3′ and reverse, 5′-AACGCTTCACGAATTTGCGT-3′.
Flow cytometry
Detection was carried out using PE Annexin V Apoptosis Detection Kit I (BD Biosciences, USA). The transfected HUVECs were picked up in centrifuge tubes, washed with PBS and digested with EDTA-free trypsin. After digestion was completed, centrifugation was performed at 1000 g for 10 min, then the supernatant was discarded. The collected cells were washed with PBS, centrifuged, and resuspended in 500 µL of 1 × binding buffer. Subsequently, 5 µL of Annexin V-FITC and 10 µL of PI were added and reacted in the dark for 15 min. Apoptosis was detected using flow cytometry.
CCK8 assay
The HUVECs were inoculated in 96-well plates until cells adhered and fused to 70 %. 100 µL of serum-free medium and 10 µL CCK8 solution (Invigentech, USA) were mixed and added to 96-well plates and incubated for 0, 24, 48, and 72 h. The 450 nm absorbance value was detected by an enzyme marker and plotted as cell proliferation curves.
Transwell assay
Transfected HUVECs were vaccinated in the upper chamber of a Transwell (Costar, Canada) to examine migration ability. Placed the FBS-containing medium in its lower chamber. Cells were incubated for 8 h and then fixed and stained with crystal violet. Microscopic observations were made and photographed for counting. Cells were vaccinated into Matrigel-lined Transwell chambers to detect cell invasion.
Statistical analysis
SPSS 27.0 (IBM Corp., USA) and GraphPad Prism 9.0 (GraphPad Software, USA) software were applied for data analysis. The Kolmogorov-Smirnov test was used to evaluate the normality of the data. Continuous type information that conforms to a normal distribution is described by mean±SD Differences in groups were calculated by t-test and one-way ANOVA. Post-hoc comparisons were conducted using the Tukey HSD test. The diagnostic ability of miR-30c-5p was determined using ROC analysis. Logistic regression was employed for the analysis of risk factors related to CHF patients. Pearson correlation was used for relevance analysis. A p-value of less than 0.05 was considered a statistically significant difference.
Results
Clinical baseline characteristics in healthy controls and CHF patients
This research enrolled 211 subjects, of which 103 males (48.8 %) and 108 females (51.2 %), ranging in age from 35 to 85 years. There were 98 subjects in the healthy control group and 113 subjects in the CHF group. Baseline characteristics of the two groups are compared in Table 1. There were no meaningful differences in age, gender, BMI, history of hypertension and diabetes, red blood cell count (RBC), total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) (p > 0.05). Compared to the healthy group, the CHF group showed a considerable increase in BNP (p < 0.001) and white blood cells (WBC) (p < 0.001), while left ventricular ejection fraction (LVEF) (p < 0.001) and HDL-C (p = 0.002) levels were reduced remarkably. Patients with CHF were differentiated into 63 subjects of grade II, 29 subjects of grade III and 21 subjects of grade IV according to New York Heart Association (NYHA) criteria.
Baseline characteristics between healthy controls and CHF patients.
| Variables | Healthy (n = 98) | CHF (n = 113) | p-Value |
|---|---|---|---|
| Age, years | 62.8 ± 14.6 | 60.5 ± 15.2 | 0.261 |
| Gender, male/female | 51/48 | 52/61 | 0.385 |
| BMI, kg/m2 | 23.3 ± 1.07 | 23.5 ± 1.13 | 0.073 |
| Hypertension, yes/no (n) | 60/38 | 78/35 | 0.237 |
| Diabetes, yes/no (n) | 52/46 | 64/49 | 0.605 |
| BNP, pg/mL | 53.7 ± 15.3 | 718 ± 86.1 | <0.001 |
| LVEF, % | 58.3 ± 4.7 | 40.4 ± 3.9 | <0.001 |
| WBC, 109/L | 4.91 ± 1.17 | 7.55 ± 1.94 | <0.001 |
| RBC, 1012/L | 4.19 ± 0.41 | 4.09 ± 0.38 | 0.062 |
| TC, mmol/L | 4.26 ± 1.33 | 4.63 ± 1.47 | 0.056 |
| TG, mmol/L | 1.22 ± 0.28 | 1.41 ± 0.32 | 0.092 |
| LDL-C, mmol/L | 2.46 ± 0.38 | 2.77 ± 0.39 | 0.095 |
| HDL-C, mmol/L | 1.26 ± 0.31 | 1.14 ± 0.27 | 0.002 |
| NYHA grades | |||
| II | – | 63 | – |
| III | – | 29 | – |
| IV | – | 21 | – |
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CHF, chronic heart failure; BMI, body mass index; BNP, brain natriuretic peptide; LVEF, left ventricle ejection fraction; WBC, white blood cell count; RBC, red blood cell count; TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; NYHA, New York heart association.
miR-30c-5p is reduced in CHF
We examined serum miR-30c-5p levels of all study subjects. Serum miR-30c-5p levels were dramatically lower in the CHF group (Figure 1A). The miR-30c-5p expression in CHF patients with various grades was counted according to the NYHA grades. The data revealed that miR-30c-5p levels gradually decreased following increasing NYHA grade (Figure 1B). Additionally, the ROC curve of miR-30c-5p expression of healthy subjects and CHF patients was assayed. The ROC result exhibited high AUC (0.914, 95 % CI =0.877–0.950, p < 0.001), sensitivity (83.19 %) and specificity (84.69 %) (Figure 1C). Risk factors relating to CHF were explored by logistic regression analysis. miR-30c-5p (p < 0.001) was highly correlated with CHF development, and the history of diabetes (p = 0.046) has also shown a correlation (Table 2).
miR-30c-5p expression is reduced in CHF patients. (A) miR-30c-5p levels were reduced in CHF patients compared to healthy subjects. (B) miR-30c-5p levels declined with increasing NYHA grades. (C) miR-30c-5p showed high diagnostic accuracy for CHF. *** p < 0.001.
Logistic regression analysis of risk factors related to CHF.
| Variables | B | OR | 95 % CI | p-Value |
|---|---|---|---|---|
| miR-30c-5p | −3.450 | 0.032 | 0.013–0.080 | <0.001 |
| Age, years | −0.515 | 0.597 | 0.253–1.412 | 0.240 |
| Gender | −0.371 | 0.690 | 0.297–1.602 | 0.388 |
| BMI, kg/m2 | 0.493 | 1.637 | 0.683–3.926 | 0.269 |
| Hypertension | 0.823 | 2.277 | 0.952–5.444 | 0.064 |
| Diabetes | 0.870 | 2.388 | 1.017–5.609 | 0.046 |
| WBC, 109/L | 0.723 | 2.060 | 0.792–5.358 | 0.138 |
| RBC, 1012/L | −0.673 | 0.510 | 0.204–1.275 | 0.150 |
| TC, mmol/L | 0.717 | 2.048 | 0.869–4.831 | 0.101 |
| TG, mmol/L | 0.657 | 1.930 | 0.821–4.535 | 0.132 |
| LDL-C, mmol/L | 0.625 | 1.868 | 0.782–4.465 | 0.160 |
| HDL-C, mmol/L | −0.526 | 0.891 | 0.260–1.344 | 0.210 |
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B, regression coefficient; OR, odds ratio; 95 % CI, 95 % confidence interval; CHF, chronic heart failure; BMI, body mass index; WBC, white blood cell count; RBC, red blood cell count; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
miR-30c-5p correlates with BNP and LVEF
BNP and LVEF exist clinically as objective evidence for detecting CHF. We examined miR-30c-5p in relation to BNP and LVEF by Pearson correlation. In CHF patients, miR-30c-5p exhibited a strong negative correlation with BNP (r = −0.665, p < 0.001, Figure 2A) and a positive correlation with LVEF levels (r = 0.707, p < 0.001, Figure 2B).
miR-30c-5p expression correlates with BNP and LVEF. (A) miR-30c-5p levels are negatively correlated with BNP in CHF patients. (B) miR-30c-5p levels are positively correlated with LVEF in CHF patients.
Differential expression of miR-30c-5p regulates HUVECs
To explore the effects of miR-30c-5p on vascular endothelial cells, we transfected miR-30c-5p mimic or miR-30c-5p inhibitor into HUVECs for the study. RT-qPCR outcomes revealed that transfection of miR-30c-5p mimic and miR-30c-5p inhibitor, respectively, enhanced and reduced miR-30c-5p levels in HUVECs (Figure 3A). Flow cytometry showed that overexpression of miR-30c-5p restricted apoptosis, while knockdown of miR-30c-5p greatly contributed to apoptosis (Figure 3B). The results of CCK8 suggested that transfection of miR-30c-5p mimic notably enhanced cell viability after 48 and 72 h of experimental treatment, while transfection of miR-30c-5p inhibitor caused a clear decrease in cell viability (Figure 3C). Transwell assay revealed that miR-30c-5p upregulation encouraged migration and invasion of HUVECs, whereas miR-30c-5p downregulation injured cell migration and invasion (Figure 3D and E).
Differential expression of miR-30c-5p regulates HUVECs (A) Transfection of miR-30c-5p mimic elevated miR-30c-5p levels in HUVECs, and transfection of miR-30c-5p inhibitor decreased miR-30c-5p. (B) Apoptosis is inhibited by high miR-30c-5p expression and promoted by low miR-30c-5p expression. High miR-30c-5p expression facilitated cell proliferation (C), migration (D), and invasion (E), whereas the opposite trend was observed for low miR-30c-5p expression. *** p < 0.001.
Discussion
In this study, we revealed the diagnostic potential of miR-30c-5p in CHF patients and its role in the functional regulation of HUVECs through clinical sample analysis and cellular experiments. The results showed that miR-30c-5p levels were significantly lower in CHF patients than in healthy individuals and correlated with their severity. Moreover, there was a significant correlation with the currently used clinical markers BNP and LVEF. Further experiments demonstrated that miR-30c-5p had a regulatory effect on HUVECs. These findings provide a new theoretical basis for early diagnosis and targeted therapy of CHF.
miRNAs are non-coding single-stranded ribonucleic acid molecules that perform vital regulatory actions in multiple cells [19]. As research continues, the mechanisms by which miRNAs regulate the human cardiovascular system are discovered [20]. miRNAs engage in regulating cardiac pathophysiological processes such as myocardial hypertrophy and myocardial infarction by modulating gene expression in various cardiovascular diseases [21], 22]. In addition, several studies have shown that miRNAs are closely connected to CHF etiology and progression. For example, miR-30a-5p plays a role in CHF by targeting SIRT1 and NF-κB/NLRP3 signaling pathways [23]. miR-129-5p targets ASPN and SOX9 to attenuate myocardial fibrosis and calcification due to heart failure [24]. The above research proved the crucial role of miRNAs in CHF.
Although a large number of studies demonstrated roles for miR-30c-5p in tumors, there has been progress on involvement of miR-30c-5p upon cardiovascular disease in recent years. For example, miR-30c-5p attenuates cardiac injury by regulating Bach1 and Nrf2 [25]. lncRNA OIP5-AS1 attenuates endothelial cell injury and slows atherosclerosis development by modulating miR-30c-5p expression [26]. Therefore, in our research, we assessed the clinical value of miR-30c-5p in CHF diagnosis by detecting its expression in CHF patients. miR-30c-5p was expressed at low levels in CHF patients and progressively decreased as the NYHA class increased. It was speculated that miR-30c-5p levels might be related to CHF severity. The ROC curve indicated that miR-30c-5p has good diagnostic value for CHF. This suggested that miR-30c-5p may be a biomarker for CHF clinical diagnosis.
BNP is a peptide hormone synthesized by the heart when the ventricular walls are dilated or strained and reflects the compensatory function of the cardiac [27]. It is a marker for evaluating cardiac function and is mainly used to diagnose heart failure and hypertension patients with left ventricular hypertrophy [28]. LVEF is defined as output per beat as a percentage of ventricular end-diastolic volume and is a key indication of the type of heart failure [29]. BNP and LVEF are widely accepted in CHF diagnosis, and CHF patients exhibit elevated BNP levels and reduced LVEF compared to normal individuals [30]. BNP and LVEF levels in CHF patients in this study respectively presented an increasing and decreasing trend, and correlation analysis demonstrated that miR-30c-5p was negatively linked to BNP and exhibited a positive correlation with LVEF. This indicated that miR-30c-5p, similar to BNP and LVEF, exhibited the ability to diagnose CHF.
Vascular endothelial cells are primarily involved in regulating vascular function in the body. If the endothelial cells of the body are dysfunctional, it may affect the contraction and diastole of vessels, leading to cardiovascular diseases [31]. When performing vascular endothelial experiments, HUVECs are often the cell model of choice. Di et al. showed that the miR33a-5p/Ets-1/DKK1 signaling pathway takes part in the induction of angiogenesis in HUVECs, providing a reliable basis for cardiovascular protection [32]. The lncRNA NOS2P3/miR-939-5p/iNOS/TNF-α pathway was discovered in CHF-related studies to regulate inflammatory cytokine-induced HUVECs apoptosis, providing a promising strategy for detection and therapy of heart failure [33]. It was demonstrated that high miR-30c-5p expression suppressed apoptosis in HUVECs and promoted cell proliferation, migration, and invasion. This indicated that miR-30c-5p may influence CHF development by affecting the function of HUVECs.
Although this study revealed the diagnostic value of miR-30c-5p, there are still several shortcomings. Firstly, the clinical sample size was relatively small, and it is necessary to expand the sample size in the future to validate the results and prognostic predictive value. Secondly, the effect of miR-30c-5p knockdown or overexpression on CHF in animal models has not been clarified, which needs to be constructed for further validation. Finally, the regulatory network in which miR-30c-5p functions in CHF needs to be further resolved.
Taken together, dysregulation of miR-30c-5p is linked to the occurrence and seriousness of CHF, suggesting that miR-30c-5p may be a biomarker for CHF clinical diagnosis. Additionally, miR-30c-5p affects the function of HUVECs, which in turn affects CHF progression. This may serve as a potential target for CHF therapy.
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Research ethics: The study was performed in line with the principles of the Declaration of Helsinki (as revised in 2013). The research was approved by the Medical Ethics Committee of Xi’an People’s Hospital (Xi’an Fourth Hospital, no. 202043).
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Informed consent: All study subjects signed a written informed consent.
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Author contributions: Conceptualization, D. X., Y. M., Y. Z., and P. D.; Data curation, D. X., and Y. M.; Formal analysis, D. X., and Y. M.; Funding acquisition, Y. Z. and P. D.; Investigation, D. X., and Y. M.; Methodology, D. X., Y. M., Y. Z. and P. D.; Project administration, Y. Z. and P. D.; Resources, D. X., and Y. M.; Software, D. X., and Y. M.; Supervision, Y. Z. and P. D.; Validation, D. X., and Y. M.; Visualization, D. X., and Y. M.; Roles/Writing – original draft, D. X., and Y. M.; Writing – review & editing, Y. Z. and P. D.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: This work was funded by Bijie Science and Technology Joint Fund. Project number is SY[2019] No.12.
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Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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