CircRNA, lncRNA and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia

CircRNA, lncRNA and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article CircRNA, lncRNA and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia Yu Wang, Xuan Wang, Qiushi Xu, Jiao Yin, Huaiyan Wang, Lin Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1404043/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background: Bronchopulmonary dysplasia (BPD) represents a multifactorial chronic pulmonary pathology and a major factor causing premature illness and death. The therapeutic role of exosomes in BPD has been feverishly investigated. Meanwhile, the potential roles of exosomal circRNAs, lncRNAs, and mRNAs in umbilical cord blood (UCB) serum have not been studied. This study aimed to detect the expression profiles of circRNAs, lncRNAs, and mRNAs in UCB-derived exosomes of infants with BPD. Methods: Microarray analysis was performed to compare the RNA profiles of UCB-derived exosomes of a preterm newborn with (BPD group) and without (non-BPD, NBPD group) BPD. Then, circRNA/lncRNA–miRNA–mRNA co-expression networks were built to determine their association with BPD. In addition, cell counting kit-8 (CCK-8) assay was used to evaluate the proliferation of lipopolysaccharide (LPS)-induced human bronchial epithelial cells (BEAS-2B cells) and human umbilical vein endothelial cells (HUVECs). The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in LPS-induced BEAS-2B cells and HUVECs were assessed through Western blot analysis. Then, quantitative reverse transcription–polymerase chain reaction assay was used to evaluate the expression levels of four differentially expressed circRNAs (hsa_circ_0086913, hsa_circ_0049170, hsa_circ_0087059, and hsa_circ_0065188) and two lncRNAs [small nucleolar RNA host gene 20 (SNHG20) and LINC00582] detected in LPS-induced BEAS-2B cells or HUVECs. Results: A total of 317 circRNAs, 104 lncRNAs, and 135 mRNAs showed significant differential expression in UCB-derived exosomes of preterm infants with BPD compared with those with NBPD. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to examine differentially expressed exosomal circRNAs, lncRNAs, and mRNAs. The results showed that the GO terms and KEGG pathways mostly involving differentially expressed exosomal RNAs were closely associated with endothelial or epithelial cell development. In vitro , CCK-8 and Western blot assays revealed that LPS remarkably inhibited the viability and promoted inflammatory responses [TNF-α and IL-1β] of BEAS-2B cells or HUVECs. The expression levels of circRNAs hsa_circ_0049170 and hsa_circ_0087059 were upregulated in LPS-induced BEAS-2B cells; the expression level of hsa_circ_0086913 was upregulated and that of hsa_circ_0065188 was downregulated in LPS-induced HUVECs. Moreover, the expression level of lncRNA SNHG20 was upregulated and that of LINC00582 was downregulated in LPS-induced BEAS-2B cells. Further, 455 circRNA/lncRNA–miRNA–mRNA interaction networks were predicted, including hsa_circ_0086913/hsa-miR-103a-3p/transmembrane 4 L six family member 1 (TM4SF1) and lncRNA-SNHG20/hsa-miR-6720-5p/spermine synthase (SMS) networks, which may take part in BPD. Conclusions : This study provided a systematic perspective on UCB-derived exosomal circRNAs and lncRNAs and laid an important foundation for further investigating the potential biological functions of exosomal circRNAs and lncRNAs in BPD. bronchopulmonary dysplasia exosome circRNA lncRNA umbilical cord blood Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Bronchopulmonary dysplasia (BPD) represents a multifactorial chronic pulmonary pathology and a major factor causing premature illness and death, especially in premature infants with gestational age (GA) <28 weeks [1]. The survival rate in extremely preterm infants has markedly increased with the progress in perinatal medicine; however, the morbidity of BPD has also increased. In the United States, the survival rate of infants with a GA of 22–28 weeks has increased from 70% to 79% in the past two decades. Meanwhile, the incidence of BPD has increased from 32% to 45% [2]. In Japan, the mortality rate of extremely preterm infants has decreased from 19.0% in 2003 to 8.0% in 2016, but the rate of BPD has increased from 41.40% to 52.0% among survivors [3]. Meanwhile, Chao Chen et al. found an increase in survival from 2010 (56.4%) to 2019 (67.1%) for infants born at a GA ＜28 weeks, with BPD prevalence increasing from 55.7% to 79.9% among survivors in China [4]. From a pathophysiological point of view, aberrant reparative responses in the prenatal setting and recurrent postnatal injuries to the developing lungs jointly cause BPD [5]. In addition, the umbilical cord vein transports oxygenated blood with nutrition and other factors from the placenta to the developing fetus. Changes in certain nutrients and factors included in the umbilical cord blood (UCB) may have an important role in fetal programming, including lung development [6]. Assessing the substances contained in UCB may therefore help understand their influence on lung development and BPD. Exosomes represent single-membrane organelles with 30–200 nm diameters secreted from cells [7] and can be obtained from UCB simultaneously [8-10]. Many researchers reported that exosomes played a crucial role in BPD [11-13], and may function through selected proteins, lipids, nucleic acids, and glycoconjugates [14, 15]. In addition, a recent study demonstrated that UCB-derived exosomes of infants with BPD impair angiogenesis, potentially through differentially expressed exosomal miRNAs [16]. However, the roles of UCB-derived exosomal circular RNAs (circRNAs) of infants with BPD remain poorly understood. As another class of noncoding RNAs, circRNAs regulate gene expression in eukaryotes and are involved in multiple pathologies, including cancer, cardiovascular diseases, and diabetes mellitus [17]. In addition, differentially expressed circRNAs have been detected in UCB-derived exosomes of patients with gestational diabetes mellitus (GDM) and preeclampsia, clearly suggesting pathological and developmental roles of exosomal circRNAs [18, 19]. Therefore, the present study applied microarrays to comparatively assess circRNA, lncRNA, and mRNA profiles of UCB-derived exosomes between preterm newborns with (BPD group) and without (NBPD group) BPD, aiming to provide a basis for more researches examining the role of exosomal circRNAs in BPD. Materials And Methods 2.1 Patients and samples This descriptive study followed the recommendations of the ethics committee of the Changzhou Maternal and Child Health Care Hospital (approval number: 2021142) and was registered in the Chinese Clinical Trial Registry (approval number: ChiCTR2100049129). All participants and clinical data were collected from the Changzhou Maternal and Child Health Care Hospital from April to July 2021. BPD was defined as treatment with oxygen >21% for at least 28 days as proposed by the National Institute of Child Health and Human Development [20]. The time point of assessment was 36-week postmenstrual age or discharge to home in infants with a GA 28 days but 32 weeks, whichever came first [20]. The inclusion criteria were as follows: preterm infants without genetic or structural anomalies, delivered at less than 32 weeks of gestation, and showing BPD (BPD group) or not (NBPD group). The exclusion criteria were as follows: pregnant women with infectious diseases; neonates with severe heart and lung malformations; and patients with severe hypoxic–ischemic encephalopathy, abnormal development of the intracranial hemorrhagic brain, or chromosomal abnormalities. Finally, eight UCB specimens were obtained from the umbilical vein right after fetal delivery (four BPD and four NBPD preterm infants). After clipping the umbilical cord, 5 mL of umbilical venous blood was immediately extracted from the placental end using a syringe and placed in a vacuum blood collection tube containing coagulant and inert separation glue. Then, the blood was laid aside at room temperature for 1 h. After the blood was curdled and the light yellow transparent liquid was precipitated, the collected samples were centrifuged at 1000 g at room temperature for 10 min. Finally, the supernatant, which was umbilical venous blood serum, was extracted into new Eppendorf tubes and stored at –80°C until further use. 2.2 Isolation of exosomes from UCB serum Exosomes were isolated following the protocol of ExoQuick exosome precipitation solution [Cat#EXOTC50A-1 (5 mL), System Biosciences (SBI), CA, USA]. First, 1 mL of UCB serum was centrifuged for 15 min at 3000 g and 4℃ for the removal of cells and debris. The resulting serum was absorbed and added to 1.5-mL centrifuge tubes with 5 μL of thrombin (T4648-1KU, Sigma, MO, USA). After mixing, the samples were incubated for 15 min at 37℃. After centrifugation at 10,000 g for 15 min at 4℃, the resulting supernatants were removed and the precipitated exosomes in the pellet were added with 250 μL of ExoQuick exosome precipitation solution. Then, specimens were mixed well and incubated for 30 min at 4℃. Exosomes were pelleted by 5-min centrifugation at 1500 g at 4℃. The isolated exosomes were eluted in phosphate-buffered saline (PBS) and used immediately or stored at -80℃ for later use. 2.2 Nanoparticle tracking analysis Exosome particle number was measured by nanoparticle tracking analysis (NTA) based on a previously published technique [21]. In brief, exosomes diluted in PBS were analyzed by nanoparticle tracking using the ZetaView (Particle Metrix, Germany) equipment. A 405-nm excitation laser was used in instruments precalibrated with a 100-nm PSL standard (Applied Microspheres, Netherlands). NTA was performed with the same camera settings and tracking parameters, appropriate for detecting extracellular vesicle (EV) (sensitivity, 85; shutter, 70 min; brightness, 20 min; size, 10; maximum size, 200). Video acquisition was carried out at 30 frames/s, and videos were assessed for size and concentration using ZetaView. 2.3 Transmission electron microscopy For transmission electron microscopy (TEM), exosomes pelleted by ultracentrifugation were resuspended in PBS. A drop thereof was placed on a copper mesh for 5 min. This was followed by 1-min staining with 1% phosphotungstic acid 44-hydrate and 20-min drying at room temperature. The preparations were examined under a transmission electron microscope (FEI, Tecnai G2 Spirit BioTwin; acceleration voltage, 80 kV). 2.5 RNA purification from exosomes and microarrays Total RNA extraction uses an miRNeasy Serum Kit (Cat#217184, QIAGEN, GmBH, Germany) as directed by the manufacturer. RNA integrity was examined on an Agilent Bioanalyzer 2100 (Agilent Technologies, CA, USA). Then, total RNA amplification and labeling used a Low Input Quick Amp Labeling Kit, One-Color (Cat# 5190-2305, Agilent Technologies) according to the manufacturer’s protocol. Labeled circRNAs were obtained using an RNeasy Mini Kit (Cat.# 74106, QIAGEN, GmBH). The slides were hybridized using 1.65 μg of Cy3-labeled circRNA and a Gene Expression Hybridization Kit (Cat. #5188-5242, Agilent Technologies) as directed by the manufacturer for 17 h. Staining dishes (Cat. # 121, Thermo Shandon, MA, USA) were used for washing with a Gene Expression Wash Buffer Kit (Cat.# 5188-5327, Agilent Technologies), according to the manufacturer’s protocol. An Agilent Microarray Scanner (Cat. #G2565CA, Agilent Technologies) was used for scanning, with default settings. Data were extracted using Feature Extraction v10.7 (Agilent Technologies). Raw data were normalized using the Quantile algorithm and limma in R. Microarray analysis was carried out by Shanghai Biotechnology (China). 2.6 Functional enrichment analyses Ratios were calculated between four preterm infants with BPD and four with NBPD. Genes showing fold changes ≥2 and P <0.05 ( t test) were considered significantly differentially expressed. The chosen genes for exosomal circRNAs, lncRNAs, and mRNAs were analyzed using Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) with enrichment analysis software by Shanghai Biotechnology. 2.7 CircRNA/lncRNA – miRNA – mRNA network building The miRanda database was used for predicting circRNA/microRNA (miRNA) interactions based on miRNA response elements (MREs) on circRNAs, with miRanda v3.3a. MREs on circRNA/lncRNAs were retrieved, and miRNAs were selected according to the seed matching sequences. For lncRNAs and mRNAs paired with the identical miRNA, the Pearson correlation coefficient (PCC) was determined for identifying the inferred circRNA/lncRNA–miRNA–mRNA pairs. Then, circRNA/lncRNA–miRNA–mRNA pairs showing PCC ≥0.90 were included to construct a circRNA/lncRNA–miRNA–mRNA network. 2.8 Cell culture and treatment Human bronchial epithelial (BEAS-2B) cells and human umbilical vein endothelial cells (HUVECs) were provided by American Type Culture Collection (USA). These cells were routinely incubated in Dulbecco’s modified Eagle’s medium (Invitrogen, CA, USA) containing 10% fetal bovine serum (Invitrogen, Grand Island, NY, USA) and 1% penicillin–streptomycin (Sigma–Aldrich, MO, USA) at 37ºC with 5% CO 2 The BEAS-2B cells were treated with lipopolysaccharide (LPS, 1 µg/mL) for 12 h, and HUVECs were treated with LPS (1 µg/mL) for 18 h. 2.9 Cell counting kit-8 assay For cell viability, the BEAS-2B cells and HUVECs were seeded in 96-well plates at a density of 1 × 10 4 cells/well stimulated with LPS (1 µg/mL) for 12 h and 18 h, respectively. Then, a cell counting kit-8 (CCK-8) (Beyotime Biotechnology, China) was used to examine the cell viability, according to the manufacturer’s specification. The optical density was detected at 490 nm using a microplate reader (Tecan Infinite M200 Micro Plate Reader; LabX, Switzerland). 2.10 Western blot analysis Proteins extracted from BEAS-2B cells and HUVECs were measured using a bicinchoninic acid kit (Beyotime Biotechnology, China). Then, the proteins were resolved on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (10%) and transferred to polyvinylidene fluoride (PVDF) membranes (Millipore, MA, USA). The PVDF membranes were incubated using 5% skimmed milk, and then with primary antibodies at 4 o C overnight. Blots were probed using the following antibodies: anti-IL-1β (1: 1, 000, ab234437; Abcam, Cambridge, UK), anti-TNF-α (1: 1, 000, ab183218; Abcam), and anti-glyceraldehyde-3-phosphate dehydrogenase (anti-GAPDH; 1: 2, 000, bs0755R; Bioss, China), with GAPDH being the endogenous control. Then, membranes were further incubated for 1 h using a secondary antibody (1: 2, 000, b-0311P-HRP; Bioss). 2.11 Quantitative real-time polymerase chain reaction After extracting total RNA from LPS-induced BEAS-2B cells and HUVECs, cDNA was prepared with RNA using an RNeasy plus micro kit, as the starting material of quantitative polymerase chain reaction (qPCR), carried out using a Step One System (Life Technologies Corp). Subsequently, four differentially expressed circRNAs (hsa_circ_0086913, hsa_circ_0049170, hsa_circ_0087059, and hsa_circ_0065188) and two lncRNAs [small nucleolar RNA host gene 20 (SNHG20) and LINC00582] selected based on the P value and fold change were evaluated by quantitative reverse transcription (qRT)-PCR analysis. Primer Premier software 4.0 (Premier, Canada) was used to design sequences of all primers (see Table 3 ). GAPDH was normalized using the 2 -ΔΔCT approach. 2.12 Statistical analyses SPSS 25.0 was used for data analysis. Quantitative data were expressed as mean ± standard deviation. Group pairs were compared using the Student t test. A P value <0.05 indicated statistical significance. Results 3.1 Description of preterm infants with BPD and NBPD The demographic and clinical characteristics of preterm infants with BPD and NBPD are described in Table 1 . All the puerpera and newborns in this study belonged to the Han Chinese nationality and the yellow race. Specifically, birth weight, GA, gender, Apgar score, intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, necrotizing enterocolitis, early-onset neonatal sepsis, late-onset neonatal sepsis, retinopathy of prematurity, surfactant treatment, mechanical ventilation, mother with preeclampsia, antenatal steroids, premature rupture of membranes (PROM), and chorioamnionitis were similar in both groups. In addition, the continuous positive airway pressure, oxygen inhalation, and hospitalization days of preterm infants were longer in the BPD group than in the NBPD group. 3.2 Detection of exosomes NTA and TEM analyses were performed for identifying the purified exosomes. The cup-shaped morphology and clear, intact membrane were identified by TEM ( Fig. S1A ), and particles between 30 and 120 nm were detected by NTA ( Fig. S1B ). These findings indicated that the serum-derived particles isolated from the study subjects were exosomes. No differences were observed in the size distribution and morphology between exosomes isolated from the BPD and NBPD groups. 3.3 Exosomal circRNA, lncRNA, and mRNA profiles by microarray analysis of UCB in the BPD and NBPD groups A total of 105,509 circRNAs, 32,953 lncRNAs, and 34,549 mRNAs were identified as indicated in Figure 1A . Of these, 317 circRNAs, 104 lncRNAs, and 135 mRNAs showed significant differential expression based on the aforementioned criteria in UCB-derived exosomes of preterm infants in the BPD group compared with those in the NBPD group. Among them, 68 and 249 circRNAs, 94 and 10 lncRNAs, and 81 and 54 mRNAs were upregulated and downregulated, respectively, as presented in Figure 1 . The heatmap analysis disclosed low internal variation, suggesting that these gene alterations may be meaningful for BPD pathogenesis ( Fig. 1B ). Further, differentially expressed exosomal circRNAs, lncRNAs, and mRNAs were used to generate scatter ( Fig. 1C ) and volcano ( Fig. 1D ) plots. Next, differentially expressed circRNAs, lncRNAs, and mRNAs in UCB-derived exosomes were assessed for general features by preliminarily analyzing microarray data. Figure 2 shows that the parent genes of these circRNAs, lncRNAs, and mRNAs were broadly distributed in virtually all human chromosomes, also depicting their length distributions. 3.4 GO and KEGG analyses of exosomal circRNAs, lncRNAs, and mRNAs GO and KEGG analyses were executed for investigating the potential functions of differentially expressed genes ( Figs. 3–5 ). The GO analysis revealed enrichment of 1165 circRNAs, 2475 lncRNAs, and 395 mRNAs in different physiological functions, such as molecular functions, cellular components, and biological processes ( Fig. 3 ). Meanwhile, exosomal circRNAs, lncRNAs, and mRNAs were involved in 221, 365, and 135 KEGG pathways, respectively. Figure 4 shows the top 30 enriched KEGG terms of differentially expressed exosomal circRNAs, lncRNAs, and mRNAs between the BPD and NBPD groups. GO function and KEGG classifications of differentially expressed RNAs are shown in Figure 5 . The classification of KEGG included Organismal System, Metabolism, Human Disease, Genetic Information Processing, Environmental Information Processing, and Cellular Process, as shown in Figure 5B. 3.5 Prediction of exosomal circRNA/lncRNA – miRNA – mRNA interactions circRNAs and lncRNAs have been shown to possess multiple binding sites for miRNAs, which they sponge, thus relieving the inhibitory effects of miRNAs on their target mRNAs. This effect is known as the competitive endogenous RNA (ceRNA) mechanism [22-24]. Therefore, miRanda was used to predict the potential ceRNAs of the first 10 upregulated and downregulated circRNAs and lncRNAs based on MREs, respectively. A total of 13 circRNAs, 97 miRNAs, and 45 mRNAs were retrieved ( Fig. 6A ). A total of 187 circRNA/lncRNA–miRNA–mRNA regulations with PPC >0.90 were predicted as shown in Table S1 . Moreover, 268 regulations existed among 164 transcripts that included 16 lncRNAs, 119 miRNAs, and 59 mRNAs, as shown in Figure 6B and Table S2 . 3.6 Expression levels of differentially expressed circRNAs and lncRNAs in LPS-induced BEAS-2B cells and HUVECs LPS-induced injury in BEAS-2B cells and HUVECs is related to increased inflammation. As observed, TNF-α and IL-1β were higher in BEAS-2B cells and HUVECs after the stimulation of LPS, as analyzed by Western blot ( Fig. 7A ). Moreover, LPS also significantly inhibited the cell viability of BEAS-2B cells and HUVECs ( Fig. 7B ). According to the high fold change, expression level, and host gene/GeneSymbol, four differentially expressed circRNAs (hsa_circ_0049170, hsa_circ_0087059, hsa_circ_0086913, and hsa_circ_0065188) and two lncRNAs (SNHG20 and LINC00582) were selected for future study. The expression levels of circRNAs hsa_circ_0049170 and hsa_circ_0087059 were found to be upregulated in LPS-induced BEAS-2B cells ( Fig. 7C ); the expression level of hsa_circ_0086913 was upregulated and that of hsa_circ_0065188 was downregulated in LPS-induced HUVECs ( Fig. 7D ). Meanwhile, the expression level of lncRNA SNHG20 was upregulated and that of LINC00582 was downregulated in LPS-induced BEAS-2B cells ( Fig. 7E ). These results were consistent with the results of exosomal circRNA and lncRNA profiles by microarray analysis of UCB in the BPD and NBPD groups. Discussion Exosomal circRNAs and lncRNAs attract increasing attention owing to their high regulatory potential [25-27]. Previous studies have examined UCB-derived exosomes from patients with preeclampsia and GDM [18, 19] because of their distant regulatory potency. Further, exosomal circRNAs and lncRNAs may carry important information and play roles while in cells, belonging to exosomes released from synaptoneurosomes [28-32]. These studies indicated exosomal circRNAs and lncRNAs could be used as molecular markers for clinically diagnosing and treating various pathologies [33, 34]. In the present study, exosomal circRNAs, lncRNAs, and mRNAs in UCB were significantly altered in infants with BPD. In all, 317 circRNAs, 104 lncRNAs, and 135 mRNAs were differentially expressed in UCB-derived exosomes of infants with BPD compared with those with NBPD. GO and KEGG analyses were carried out to further examine the roles of the differentially expressed exosomal circRNAs, lncRNAs, and mRNAs. As shown earlier, the most enriched GO terms and KEGG pathways of exosomal RNAs were associated with endothelial or epithelial cell development, including “angiogenesis” [35], “mammalian target of rapamycin (mTOR) signaling pathway” [36], “Wnt signaling pathway” [37, 38], “Epidermal growth factor receptor tyrosine kinase inhibitor resistance” [39], and “transforming growth factor-beta receptor signaling” [40]. Meanwhile, several GO terms and pathways connected with exosome transport were also significantly enriched, including “regulation of vesicle-mediated transport,” “vacuolar acidification,” and “extracellular matrix (ECM)–receptor interaction.” The aforementioned results showed that KEGG terms for differentially expressed exosomal circRNAs, lncRNAs, and mRNAs with most enriched genes were “transport and catabolism,” “signal transduction,” “translation,” “infectious diseases: viral,” “immune system,” and “carbohydrate metabolism.” These results suggested that BPD development involved complex and diverse pathophysiological events. Among them, the “mTOR signaling pathway” and the identified coding genes have gained interest because of their high enrichment factor and large gene number. mTOR is known to have two protein complexes with distinct functions, which are complex 1 (mTORC1) and 2 (mTORC2) [41]. mTORC1 comprises mTOR, MTOR Associated Protein, LST8 Homolog (mLST8), raptor, and two repressors (PRAS40 and DEPTOR). Recent data revealed that hyperoxia exposure of murine and baboon lungs in BPD is associated with insufficient activation of 5'- Adenosine monophosphate (AMP)-activated protein kinase and mTORC1 hyperactivity [42]. In vitro , mTOR inhibition significantly promotes the proliferation of basal cells derived from neonatal tracheal aspirate, which may constitute a critical model system for studying late fetal lung development and perinatal lung diseases, including BPD [36]. Another study found that inhibition of regulatory-associated protein of mTOR, a major subunit of mTORC1, prevented hyperoxia-stimulated lung damage by heightening autophagy and weakening apoptotic death in newborn mice [43]. These results and the aforementioned findings suggested that differentially expressed exosomal RNAs might play a crucial role in BPD through the mTOR signaling pathway. At present, many pathways related to BPD exist. Interestingly, in this study, “ECM–receptor interaction” was found, which is rarely studied in BPD and has been found in both lncRNA and circRNA KEGG analysis results. The ECM is a noncellular three-dimensional network polymer consisting of fibronectin, elastin, collagens, proteoglycans, and several other glycoproteins [44]. Damaged ECM is known to provoke apoptosis of overlying pulmonary epithelial cells and alveolar unit loss associated with BPD [45, 46]. Further, exosomes are part of the ECM and are involved in the remodeling of the extracellular environment [7]. Exosomes from mesenchymal stem cells (MSCs) could reverse alveolar injury and septal thickness associated with hyperoxia-dependent lung damage in mice with experimental BPD [15]. Meanwhile, in BPD lung secretions, pathogenic exosomes are also detected, and hyperoxia and microbial products could induce the abnormal expression of exosomal miRNAs [12, 47]. In addition, numerous reports have demonstrated that exosomes regulate vascular growth, proliferation, metastasis, and apoptosis through exosomal circRNAs and lncRNAs [48-51]. These results suggested that ECM–receptor interactions and enriched circRNAs and lncRNAs might be pivotal in the role of exosomes in BPD progression. In this study, lung epithelial cells BEAS-2B and HUVECs were used as research objects for future analyses to verify the differentially expressed RNAs. Excessive inflammation persists in infants with BPD, which could be caused by a variety of factors, including mechanical ventilation and infection. Therefore, the inflammatory response of BPD by LPS was reflected in this study. Further, studies have reported that BEAS-2B cells and HUVECs could be stimulated by LPS to induce inflammatory response [52-54], consistent with the results of this study. Then, the expression levels of differentially expressed circRNAs and lncRNAs in LPS-induced BEAS-2B cells and HUVECs were explored. The results of qRT-PCR analyses showed similar change trends as in UCB-derived exosomes of preterm infants with BPD. These results suggested that these differentially expressed RNAs may play a potential role in BPD, which are worthy of deeper functional studies. The molecular functions of differentially expressed exosomal circRNAs were studied by exploring them from the perspective of ceRNA. In this study, 13 of the top 10 upregulated and downregulated expression of circRNAs showed binding sites for miRNAs, of which some were connected with pulmonary diseases. For instance, miR-1207-5p, miR-608, and miR-4640-5p were reported to be related to non-small-cell lung cancer [55-58]. According to the PCC, fold change, and expression level, the possible role of exosomal hsa_circ_0086913 was explored, which was 3.60-fold upregulated in UCB-derived exosomes from the BPD group and LPS-induced HUVECs. The ceRNA analysis revealed that hsa-miR-330-5p, hsa-miR-4656, hsa-miR-6829-3p, hsa-miR-103a-3p, hsa-miR-107, hsa-miR-4688, hsa-miR-7161-3p, hsa-miR-3192-5p, hsa-miR-3620-5p, hsa-miR-4656, hsa-miR-1182, hsa-miR-4656, hsa-miR-4688, and hsa-miR-6783-3p potentially interacted with hsa_circ_0086913. Among them, hsa_circ_0086913/hsa-miR-103a-3p/transmembrane 4 L six family member 1 (TM4SF1) was predicted with a PCC of 0.93. In a recent study, the researchers found that the expression level of hsa-miR-103a-3p related to the phosphatidylinositol 3‑kinase/protein kinase B (PI3K/Akt) signaling pathway was decreased in UCB-derived exosomes from the BPD group compared with the NBPD group [16]. Further, the overexpression of hsa-miR-103a-3p in normal HUVECs significantly promoted cell proliferation, cell migration, and tube formation [16]. In addition, the expression level of TM4SF1, a potential target gene of hsa-miR-103a-3p, was upregulated in UCB-derived exosomes of infants with BPD. It has been found to promote angiogenesis via the Akt signaling pathway [59]. These results demonstrated that UCB-derived exosomal hsa_circ_0086913 of infants with BPD might contribute to the development of BPD, possibly via the interaction network hsa_circ_0086913/hsa-miR-103a-3p/TM4SF1. Meanwhile, in this study, most of the exosomal lncRNAs were found to have predicted target miRNAs that may be related to BPD. For instance, a total of 27 miRNAs were found to potentially match with upregulated lncRNA SNHG20 (also referred to as ENST00000566583); of them, the interaction network lncRNA-SNHG20/hsa-miR-6720-5p/spermine synthase was predicted with the highest PCC of 0.99. Previous studies reported that the knockdown of SNHG20 inhibited cell proliferation and invasion in human lung epithelial cells A549 cells [60-62]. In addition, the expression level of lncRNA SNHG20 has been shown to be significantly upregulated in hepatocellular carcinoma and could promote the epithelial-to-mesenchymal transition (EMT) [63]. The expression level of lncRNA SNHG20 was upregulated in UCB-derived exosomes of infants with BPD as well as in LPS-induced BEAS-2B cells. EMT is a process of conversion of epithelial cells into mesenchymal cells and occurs in long-term survivors with BPD [64, 65]. Therefore, in this study, it was predicted that lncRNA SNHG20 might promote EMT in BPD, which is worthy of future studies. In summary, exosomal circRNA, lncRNA, and mRNA profiles in the UCB of newborns with BPD were determined, and 317 circRNAs, 104 lncRNAs, and 135 mRNAs were found to be significantly altered. The aforementioned findings indicated that exosomal circRNAs/lncRNAs might have vital roles in BPD pathogenesis. Through bioinformatics, several potential exosomal circRNA/lncRNA–miRNA–mRNA networks were also successfully constructed, which might be involved in BPD. Two differentially expressed circRNAs (hsa_circ_0049170, hsa_circ_0087059) and two lncRNAs (SNHG20 and LINC00582) were identified in LPS-induced BEAS-2B cells, and two other circRNAs (hsa_circ_0086913 and hsa_circ_0065188) were also identified in LPS-induced HUVECs. These results provided a sound basis for further investigations assessing the potential biological functions of exosomal circRNAs and lncRNAs in BPD. Abbreviations BPD: Bronchopulmonary dysplasia CCK-8: cell counting kit-8 circRNAs: circular RNAs EOS: Early-onset neonatal sepsis ECM: extracellular matrix EV: extracellular vesicle GO: Gene Ontology GA: gestational age GDM: gestational diabetes mellitus HUVECs: human umbilical vein endothelial cells IL: interleukin IVH: Intraventricular hemorrhage KEGG: Kyoto Encyclopedia of Genes and Genomes LOS: Late-onset neonatal sepsis LPS: lipopolysaccharide mTOR: mammalian target of rapamycin MSCs: mesenchymal stem cells miRNA microRNA MREs: miRNA response elements NTA: nanoparticle tracking analysis NEC: Necrotizing enterocolitis PDA: Patent ductus arteriosus PCC: Pearson correlation coefficient PBS: phosphate-buffered saline PVDF: polyvinylidene fluoride PROM: premature rupture of membranes qPCR: quantitative polymerase chain reaction RDS: Respiratory distress syndrome ROP: retinopathy of prematurity SNHG20: small nucleolar RNA host gene 20 TM4SF1: transmembrane 4 L six family member 1 TEM: transmission electron microscopy TNF: tumor necrosis factor UCB: umbilical cord blood Declarations Funding This work was supported by Young Talents Science and Technology Project of Changzhou Municipal Health Commission (Grant number QN202049, Yu Wang) and Changzhou Applied Basic Research Program (Grant number CJ20210148, Huaiyan Wang). Conflict of Interest The authors have no relevant financial or non-financial interests to disclose. Availability of data and material Relevant data has been uploaded to GEO repository, and is scheduled to be released on Dec 31, 2023. The access number is GSE190215. Code availability Not applicable Author s’ Contributions YW and XW performed the experiments, interpreted the results of the experiments and drafted the manuscript. QSX and JY prepared the figures and analyzed the data. HYW and LZ conceived and designed the experiments, provided funding to regents. All authors read and approved the final manuscript. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Changzhou Maternal and Child Health Care Hospital ( No . 2021142) and registered in the Chinese Clinical Trial Registry ( No. ChiCTR2100049129). 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Mol Med Rep 22:2564–2572. https://doi.org/10.3892/mmr.2020.11306 Tables Table 1 Clinical characteristics of the BPD and non-BPD infants in the microarray analysis Group BPD(n=4) NBPD(n=4) P 1# 2# 3# 4# (Mean ± SEM)/n% 1# 2# 3# 4# (Mean ± SEM)/n% Infants' characteristics Sex gender Female Male Male Female 2(50%) Male Female Male Female 2(50%) 1.00 Birthweight (g) 1580 1350 1340 1250 1380.00± 140.71 1450 1580 1580 1830 1610.00± 158.95 0.07 Gestational age (d) 31+6 (31.86) 29+6 (29.86) 28+2 (28.29) 27+6 (27.86) 29.47±1.81 29+1 (29.14) 30+4 (30.57) 30+6 (30.86) 30+6 (30.86) 30.36±0.41 0.41 Apgar 1 min 8 7 6 8 7.25±0.96 6 5 8 8 7.00±1.41 0.78 Apgar 5 min 8 8 8 8 8.00±0.00 7 8 8 8 7.75±0.50 0.39 Intraventricular hemorrhage (IVH) Yes Yes Yes Yes 4(100%) Yes Yes Yes Yes 4(100%) 0.13 Respiratory distress syndrome (RDS) Yes No Yes No 2(50%) No No Yes Yes 2(50%) 1.00 Patent ductus arteriosus (PDA) Yes Yes Yes No 3(75%) Yes Yes Yes Yes 4(100%) 0.29 Age at determination of PDA (d) 2d 1d 1d - 1d 1d 2d 1d Necrotizing enterocolitis (NEC) No No No No 0(0%) No No No No 0(0%) 0.13 retinopathy of prematurity (ROP) No Zone Ⅲ, stage 1, Plus (-) Zone Ⅲ, stage 2, Plus (-) No 2(50%) No Zone Ⅲ, stage 2, Plus (-) No No 1(25%) 0.47 Early-onset neonatal sepsis (EOS) No No Yes No 1(25%) No No No No 0(0%) 0.29 Late-onset neonatal sepsis (LOS) Yes No No No 1(25%) Yes No No No 1(25%) 1.00 Surfactant treatment Yes Yes Yes Yes 4(100%) Yes No Yes Yes 3(75%) 0.29 Mechanical ventilation(d) 15 11 7 0 8.25±6.40 4 0 0 7 2.75±3.40 0.18 CPAP(d) 16 10 14 10 12.50±3.00 6 3 3 4 4.00±1.41 0.01 Days with oxygen(d) 57 61 76 32 56.50±18.27 21 11 7 11 12.50±5.97 0.00 Hospitalization days(d) 59 69 77 50 63.75±11.76 56 37 33 40 41.50±10.08 0.03 Maternal characteristics Preeclampsia No No No No 0(0%) No No No Yes 1(25%) 0.29 Antenatal steroids Yes Yes Yes Yes 4(100%) No Yes Yes Yes 3(75%) 0.29 Premature rupture of membranes (PROM) Yes Yes No No 2(50%) No No No No 0(0%) 2.67 Chorioamnionitis Yes No Yes No 2(50%) No No Yes No 1(25%) 0.47 Table 2 Differentially expressed circRNA, lncRNA and mRNA in UCB-derived exosomes from the BPD and NBPD groups Gene Type TargetID p-values Fold change Regulation hostgene/ GeneSymbol circRNA hsa_circ_0049170 0.007549 4.491964 up OLFM2 circRNA hsa_circ_0087059 0.015400 3.942138 up GRHPR circRNA hsa_circ_0118639 0.009878 3.811908 up TRAK2 circRNA hsa_circ_0132613 0.026462 3.729238 up RNGTT circRNA hsa_circ_0086913 0.007987 3.598227 up TLN1 circRNA hsa_circ_0009420 0.033789 3.533802 up LOC388588 circRNA hsa_circ_0061761 0.032548 3.338253 up WRB circRNA hsa_circ_0002540 0.019826 3.277644 up TCONS_l2_00004567 circRNA hsa_circ_0013996 0.036328 3.202700 up PLEKHO1 circRNA hsa_circ_0073391 0.015983 3.101576 up MCTP1 circRNA hsa_circ_0092030 0.027085 3.039648 up FLNA circRNA hsa_circ_0036403 0.031816 2.977274 up ETFA circRNA hsa_circ_0138092 0.032494 2.957627 up ZER1 circRNA hsa_circ_0018712 0.011858 2.893296 up PSAP circRNA hsa_circ_0036407 0.040910 2.857984 up ETFA circRNA hsa_circ_0075931 0.001353 2.810139 up - circRNA hsa_circ_0018723 0.039450 2.625034 up PSAP circRNA hsa_circ_0063129 0.001627 2.607178 up MYH9 circRNA hsa_circ_0037578 0.010280 2.547076 up TCEB2 circRNA hsa_circ_0036509 0.040011 2.539615 up ZFAND6 circRNA hsa_circ_0007372 0.006241 4.642343 down IFT46 circRNA hsa_circ_0028145 0.025837 4.246691 down TRPV4 circRNA hsa_circ_0078460 0.010902 3.802345 down TULP4 circRNA hsa_circ_0065188 0.000092 3.494472 down PTPN23 circRNA hsa_circ_0037782 0.011926 3.353644 down METTL22 circRNA hsa_circ_0034846 0.018938 3.155511 down CDAN1 circRNA hsa_circ_0045828 0.007738 3.142472 down MXRA7 circRNA hsa_circ_0084333 0.004997 3.140422 down PRKDC circRNA hsa_circ_0086018 0.008154 3.138347 down BOP1 circRNA hsa_circ_0081368 0.025939 3.122619 down ZNF498 circRNA hsa_circ_0028505 0.011100 3.087724 down SLC24A6 circRNA hsa_circ_0038205 0.026746 3.065186 down - circRNA hsa_circ_0034360 0.018680 3.001853 down AQR circRNA hsa_circ_0028200 0.000758 2.993999 down ANAPC7 circRNA hsa_circ_0011901 0.010229 2.977045 down RIMS3 circRNA hsa_circ_0026805 0.000338 2.947501 down RPS26 circRNA hsa_circ_0014196 0.000098 2.906941 down RORC circRNA hsa_circ_0111747 0.005713 2.870392 down PIK3C2B circRNA hsa_circ_0023216 0.002814 2.842620 down LRP5 circRNA hsa_circ_0077639 0.006088 2.832914 down SLC16A10 lncRNA ENST00000613892 3.605620 3.605620 up MAGI2-AS3 lncRNA ENST00000566583 3.177118 3.177118 up SNHG20 lncRNA ENST00000456953 2.657584 2.657584 up SNHG17 lncRNA ENST00000434411 2.584309 2.584309 up SNHG20 lncRNA ENST00000430373 2.432956 2.432956 up INKA2-AS1 lncRNA ENST00000458314 2.284379 2.284379 up ITGA6-AS1 lncRNA ENST00000505718 2.275216 2.275216 up ARHGAP22-IT1 lncRNA ENST00000616527 2.097051 2.097051 up MALAT1 lncRNA ENST00000663422 2.029238 2.029238 up MAGI2-AS3 lncRNA ENST00000662112 2.013230 2.013230 up AC068733.3 lncRNA ENST00000502301 0.269295 3.713394 down LINC00461 lncRNA ENST00000553812 0.284493 3.515019 down AC008056.2 lncRNA ENST00000671622 0.295918 3.379320 down LINC01094 lncRNA ENST00000661332 0.310585 3.219735 down BASP1-AS1 lncRNA ENST00000442305 0.325902 3.068406 down AL139246.4 lncRNA LINC01467:4 0.344071 2.906373 down LINC01467 lncRNA ENST00000444346 0.345258 2.896384 down LINC01983 lncRNA ENST00000555433 0.353812 2.826360 down AL356022.1 lncRNA ENST00000431759 0.358385 2.790299 down SLC2A1-AS1 lncRNA ENST00000448058 0.362807 2.756284 down LINC00582 lncRNA TEX41:26 0.368298 2.715191 down TEX41 lncRNA ENST00000668542 0.379396 2.635771 down LINC01322 lncRNA ENST00000447119 0.386033 2.590454 down UNC5B-AS1 lncRNA ENST00000659430 0.386040 2.590404 down LINC01322 lncRNA ENST00000553321 0.387800 2.578649 down AC068831.2 lncRNA ENST00000663040 0.395291 2.529780 down AP001981.2 lncRNA ENST00000577850 0.395566 2.528020 down AC002094.2 lncRNA ENST00000657104 0.396799 2.520169 down LINC00308 lncRNA LINC01149:1 0.401669 2.489613 down LINC01149 lncRNA ENST00000655586 0.402178 2.486460 down LINC01322 mRNA NM_005252 0.002311 5.254707 up FOS mRNA NM_003662 0.004022 3.217883 up PIR mRNA NM_004345 0.039567 3.111624 up CAMP mRNA NM_004417 0.004903 3.030365 up DUSP1 mRNA NM_001267608 0.023351 2.939260 up FAM189B mRNA NM_000117 0.016202 2.882916 up EMD mRNA NM_005332 0.006985 2.838787 up HBZ mRNA NM_001145033 0.038541 2.699928 up C11orf96 mRNA NM_022167 0.001038 2.583704 up XYLT2 mRNA NM_003720 0.015725 2.569150 up PSMG1 mRNA NM_014220 0.025066 2.527983 up TM4SF1 mRNA NM_021213 0.011023 2.520859 up PCTP mRNA NM_003546 0.014696 2.504952 up HIST1H4L mRNA NM_030572 0.012157 2.459270 up SPX mRNA NM_001172415 0.045366 2.429838 up BAG1 mRNA NM_001004318 0.009948 2.372999 up ACP7 mRNA NM_032470 0.003170 2.330444 up TNXB mRNA NM_005332 0.016376 2.329259 up HBZ mRNA NM_000476 0.003512 2.320396 up AK1 mRNA NM_001178056 0.049708 2.310605 up PARP8 mRNA NM_198696 0.008439 4.096204 down KRTAP10-3 mRNA NM_020994 0.000142 3.775682 down CTAG2 mRNA NM_001164405 0.016215 3.428569 down BHLHA9 mRNA ENST00000417284 0.001892 3.242241 down RGPD4-AS1 mRNA ENST00000519609 0.014836 2.988594 down RP11-32D16.1 mRNA ENST00000527997 0.006348 2.774404 down RP13-631K18.5 mRNA NM_032862 0.000462 2.750719 down TIGD5 mRNA NM_022822 0.003375 2.718796 down KLC2 mRNA NM_001195520 0.046637 2.699180 down LRCOL1 mRNA NM_024902 0.000019 2.666748 down DNAJC22 mRNA NM_001277372 0.007239 2.640840 down KIAA2012 mRNA NM_024522 0.016315 2.617907 down NKAIN1 mRNA NM_001008409 0.005572 2.609773 down TTLL9 mRNA ENST00000441860 0.004645 2.607226 down RPL23AP76 mRNA ENST00000566382 0.003392 2.569043 down LARP4P mRNA NM_022752 0.002576 2.568464 down ZNF574 mRNA ENST00000564204 0.005544 2.567630 down KIFC3 mRNA NM_001018078 0.034002 2.554457 down FPGS mRNA NM_032512 0.002354 2.534126 down PDZD4 mRNA ENST00000422723 0.005925 2.531463 down LINC01122 Table 3 Primer sequences Gene name Primer sequences CircRNA hsa_circ_0086913 F: 5'-CTGCTGAAAATGAAGAGGCTCA-3' R: 5'-TGCTGCCTTCACTTCCTGTA-3' CircRNA hsa_circ_0049170 F: 5'-ATTCAGGAGGAGATGGGTGC-3' R: 5'-TCCCGACCCCAGCTTCTG-3' CircRNA hsa_circ_0087059 F: 5'-AGTGAAGAATGGTGGCTGGA-3' R: 5'-TCCACCTCACAGCTATGCG-3' CircRNA hsa_circ_0065188 F: 5'-TTCATTACCTGCAGAGTCGG-3' R: 5'-ACTTGCGGAGGACACTACAG-3' lncRNA SNHG20 F: 5'-AATATCCCCCGACGATTGGC-3' GGGAGCAGGAAGGCATCTTT-3' lincRNA LINC00582 F: 5'-AGGCGGAAAGAACTACGTGA-3' R: 5'-TCACACCCAGACTCTGCATT-3' GAPDH F: 5'-GAAGGTGAAGGTCGGAGTC-3' R: 5'-GAAGATGGTGATGGGATTTC-3' Supplementary Files SupplementaryMaterials.docx SupplementaryFigureS1.tif SupplementaryTableS1.docx SupplementaryTableS2.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 14 Mar, 2022 Reviewers invited by journal 09 Mar, 2022 Editor assigned by journal 06 Mar, 2022 First submitted to journal 28 Feb, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1404043","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":89365952,"identity":"eba0b96e-5507-4a58-8511-d5611d197de4","order_by":0,"name":"Yu Wang","email":"","orcid":"","institution":"Changzhou maternal and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wang","suffix":""},{"id":89365953,"identity":"3a70d977-76e0-4dd7-bd5c-ca07fd9e5ecc","order_by":1,"name":"Xuan Wang","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xuan","middleName":"","lastName":"Wang","suffix":""},{"id":89365954,"identity":"0256e53d-fce3-4277-8d3e-b3df9207ab07","order_by":2,"name":"Qiushi Xu","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qiushi","middleName":"","lastName":"Xu","suffix":""},{"id":89365955,"identity":"5fb064cc-2298-4823-999d-cc38f39bd08e","order_by":3,"name":"Jiao Yin","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiao","middleName":"","lastName":"Yin","suffix":""},{"id":89365956,"identity":"8358e687-96f2-4f77-b1e5-084ef3cc0073","order_by":4,"name":"Huaiyan Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIiWNgGAWjYBACAyA+AGUzPmDggQsSp4XZgGgtMMAmgUUQE5hLJD88zFNzJ7F/dvu16gKZbYkN7M3bJBhq7uDUYjkjzeAwz7FniTPunCm7PYPndmIDz7EyCYZjz3A77EYCUAvb4dyGGzlpt3lAWiRyzCQYGw7j0ZL+4TDPv8O584FaisFa5N8Q0pJjcJi37XDuhhvpx5ghtvAQ0HLmTcHBuX2H6zfeyGGWBmoxbuNJK7ZIOIZHy/H0zR/efDtsLHcj/eFn3p7bsv3shzfe+FCDWwsIMEEikMeAgbEHGDsgdgJeDcCE8gNMsT9gYPhBQOkoGAWjYBSMSAAALJ5eqPSnqvYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2929-3559","institution":"Changzhou Maternal and Child Health Care Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Huaiyan","middleName":"","lastName":"Wang","suffix":""},{"id":89365957,"identity":"7e7f2abc-0f0f-41cb-a499-952a18f6b2e8","order_by":5,"name":"Lin Zhang","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2022-02-28 12:39:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1404043/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1404043/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":19134940,"identity":"80cfd3e3-5f0b-4ef3-8f0e-fc89dabade74","added_by":"auto","created_at":"2022-03-11 16:24:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":929518,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ecircRNAs, lncRNAs and mRNAs with differential expression in umbilical cord blood exosomes between BPD and NBPD newborns.\u003c/strong\u003e (A) Correlations among the eight specimens according to the expression of significantly regulated circRNAs, lncRNAs and mRNAs. (B) Clustering heatmap of differentially expressed circRNAs, lncRNAs and mRNAs. (C\u0026amp;D) Scatter and volcano plots depicting RNAs with differential expression between the BPD and NBPD groups. Red and blue represent upregulated and downregulated RNAs, respectively.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/2f012b0c89693e0246f3c4ae.png"},{"id":19134059,"identity":"4b000eac-0eac-4b3a-8b56-08c8cc4a4197","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":428001,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGeneral characteristics of differentially expressed circRNAs, lncRNAs and mRNAs in umbilical cord blood exosomes between the BPD and NBPD groups.\u003c/strong\u003e Length distributions (left) and chromosomal distributions (right) of differentially expressed circRNAs (A), lncRNAs (B) and mRNAs (C). The X- and Y-axes represent gene length or chromosome and gene number, respectively.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/c50aed38f4a2e6282b2cff15.png"},{"id":19134062,"identity":"1509723a-a44f-40e8-8799-c2acd2cb0a20","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1059537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGO analyses circRNAs, lncRNAs and miRNAs with differential expression.\u003c/strong\u003e Scatter plots of top 30 enriched GO terms involving circRNAs (A), lncRNAs-trans (B), lncRNAs-cis (C) and miRNAs (D) with differential expression. Ordinates represent GO terms, and abscissas are richness factors (richness factor=number of differentially expressed RNAs annotated to various terms/number of RNAs annotated to various terms). Dots reflect and are proportional to the amounts of RNAs with significant differential expression. \u003cem\u003eQ\u003c/em\u003e\u0026nbsp;values (0-1) are corrected \u003cem\u003ep\u003c/em\u003e\u0026nbsp;values. Points of different colors reflect distinct Q values.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/8124a5c2644557429356a89a.png"},{"id":19134060,"identity":"6df1cc1a-0c6a-4e8d-91f9-97012c5771cb","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":756887,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKEGG analyses circRNAs, lncRNAs and miRNAs with differential expression.\u003c/strong\u003e Scatter plots of top 30 enriched KEGG pathways involving circRNAs (A), lncRNAs-trans (B), lncRNAs-cis (C) and miRNAs (D) with differential expression. Ordinates represent pathway types, and abscissas are richness factors (richness factor=number of differentially expressed RNAs annotated to various terms/number of RNAs annotated to various terms). Dots reflect and are proportional to the amounts of RNAs with significant differential expression. \u003cem\u003eQ\u003c/em\u003e\u0026nbsp;values (0-1) are corrected \u003cem\u003ep\u003c/em\u003e\u0026nbsp;values. Points of different colors reflect distinct Q values.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F4.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/bf8ad4ff049f63ad3c9b15da.png"},{"id":19134942,"identity":"5f01ba05-3ffa-4728-b190-6b86cad25b77","added_by":"auto","created_at":"2022-03-11 16:24:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":925607,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClassification of enriched GO functions and KEGG pathways.\u003c/strong\u003e (A) Classification of enriched GO functions. The amounts of differentially expressed genes enriched in biological processes, cellular components and molecular function are shown. Abscissas and ordinates indicate GO terms and the amounts (and proportions) of genes enriched in various GO terms, respectively. (B) Classification of differentially KEGG pathways. The numbers of differentially expressed genes enriched in cellular processes, environmental information processing, genetic information processing, human diseases, metabolism and organismal systems are shown. Abscissas and ordinates indicate KEGG pathways and numbers (and proportions) of genes enriched in various KEGG pathways, respectively.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F5.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/c6ee3b699b8869fecd386be1.png"},{"id":19134065,"identity":"5b7adee3-90ec-452f-a162-9976e16801a9","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1193000,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ecircRNA/lncRNA–miRNA–mRNA regulatory network in BPD.\u003c/strong\u003e (A) Interaction network of circRNA–miRNA–mRNA predicted with PPC \u0026gt; 0.90. (B) Interaction network of lncRNA–miRNA–mRNA predicted with PPC \u0026gt; 0.90. Rhombuses, squares, circles, and triangles denote circRNAs, lncRNAs, mRNAs and miRNAs, respectively. Red and green nodes reflect up- and downregulation, respectively; yellow nodes are undefined cases. The size of each node is proportional to the degree of involvement.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F6.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/c6e5bcf65ffbe8ae31c2c2a2.png"},{"id":19134066,"identity":"f1b80d0a-aa6d-41fb-a0d9-e9d298860cb7","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":744685,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExpression levels of differentially expressed circRNAs and lncRNAs in LPS-induced BEAS-2B cells and HUVECs. \u003c/strong\u003e(A) Expression levels of TNF-α and IL-1β evaluated by Western blot in LPS-induced BEAS-2B cells and HUVECs. (B) Cell proliferation of LPS-induced BEAS-2B cells and HUVECs evaluated by CCK-8 assay. (C) CircRNAs hsa_circ_0049170 and hsa_circ_0087059 assessed by qRT-PCR in LPS-induced BEAS-2B cells. (D) CircRNAs hsa_circ_0086913 and hsa_circ_0065188 assessed by qRT-PCR in LPS-induced HUVECs. (E) LncRNAs SNHG20 and LINC00582 assessed by qRT-PCR in LPS-induced BEAS-2B cells. (\u003cem\u003en\u003c/em\u003e = 3 biological independent samples per group in qRT-PCR and Western blot, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01).\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"F7.png","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/98f77ed3287aca55672dc721.png"},{"id":19134948,"identity":"16008055-628d-4000-8edc-40ea4a2351a4","added_by":"auto","created_at":"2022-03-11 16:24:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":696272,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/0b9a8e0c-bace-42e4-baef-ba044c500196.pdf"},{"id":19134063,"identity":"3220e2a7-f44a-4ea6-93dc-2dd7c188f9f4","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"docx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":13874,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/a0f902440c598c68a2851312.docx"},{"id":19134069,"identity":"1d29e78b-e4fb-417d-88c0-33552d11fc3f","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"tif","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":9184176,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS1.tif","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/9930d8e3c7069985fdbafc5f.tif"},{"id":19134941,"identity":"4f7106a6-3640-44d1-838d-453f9b8e7ccc","added_by":"auto","created_at":"2022-03-11 16:24:07","extension":"docx","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":35062,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/623260b3c7ff3c925aad1d91.docx"},{"id":19134068,"identity":"3eec3c11-1b8b-43dc-b4bb-400b76de3432","added_by":"auto","created_at":"2022-03-11 16:21:07","extension":"docx","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":39837,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS2.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404043/v1/d0a0347697052abeae5a96fe.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eCircRNA, lncRNA and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBronchopulmonary dysplasia (BPD) represents a multifactorial chronic pulmonary pathology and a major factor causing premature illness and death, especially in premature infants with gestational age (GA) \u0026lt;28 weeks [1]. The survival rate in extremely preterm infants has markedly increased with the progress in perinatal medicine; however, the morbidity of BPD has also increased. In the United States, the survival rate of infants with a GA of 22\u0026ndash;28 weeks has increased from 70% to 79% in the past two decades. Meanwhile, the incidence of BPD has increased from 32% to 45% [2]. In Japan, the mortality rate of extremely preterm infants has decreased from 19.0% in 2003 to 8.0% in 2016, but the rate of BPD has increased from 41.40% to 52.0% among survivors [3]. Meanwhile, Chao Chen et al. found an increase in survival from 2010 (56.4%) to 2019 (67.1%) for infants born at a GA ＜28 weeks, with BPD prevalence increasing from 55.7% to 79.9% among survivors in China [4]. From a pathophysiological point of view, aberrant reparative responses in the prenatal setting and recurrent postnatal injuries to the developing lungs jointly cause BPD [5]. In addition, the umbilical cord vein transports oxygenated blood with nutrition and other factors from the placenta to the developing fetus. Changes in certain nutrients and factors included in the umbilical cord blood (UCB) may have an important role in fetal programming, including lung development [6]. Assessing the substances contained in UCB may therefore help understand their influence on lung development and BPD.\u003c/p\u003e\n\u003cp\u003eExosomes represent single-membrane organelles with 30\u0026ndash;200 nm diameters secreted from cells [7] and can be obtained from UCB simultaneously [8-10]. Many researchers reported that exosomes played a crucial role in BPD [11-13], and may function through selected proteins, lipids, nucleic acids, and glycoconjugates [14, 15]. In addition, a recent study demonstrated that UCB-derived exosomes of infants with BPD impair angiogenesis, potentially through differentially expressed exosomal miRNAs [16]. However, the roles of UCB-derived exosomal circular RNAs (circRNAs) of infants with BPD remain poorly understood. As another class of noncoding RNAs, circRNAs regulate gene expression in eukaryotes and are involved in multiple pathologies, including cancer, cardiovascular diseases, and diabetes mellitus [17]. In addition, differentially expressed circRNAs have been detected in UCB-derived exosomes of patients with gestational diabetes mellitus (GDM) and preeclampsia, clearly suggesting pathological and developmental roles of exosomal circRNAs [18, 19]. Therefore, the present study applied microarrays to comparatively assess circRNA, lncRNA, and mRNA profiles of UCB-derived exosomes between preterm newborns with (BPD group) and without (NBPD group) BPD, aiming to provide a basis for more researches examining the role of exosomal circRNAs in BPD.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Patients and samples\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis descriptive study followed the recommendations of the ethics committee of the Changzhou Maternal and Child Health Care Hospital (approval number: 2021142) and was registered in the Chinese Clinical Trial Registry (approval number: ChiCTR2100049129). All participants and clinical data were collected from the Changzhou Maternal and Child Health Care Hospital from April to July 2021. BPD was defined as treatment with oxygen \u0026gt;21% for at least 28 days as proposed by the National Institute of Child Health and Human Development [20]. The time point of assessment was 36-week postmenstrual age or discharge to home in infants with a GA \u0026lt;32 weeks, or \u0026gt;28 days but \u0026lt;56 days postnatal age, or discharge to home in infants with a GA \u0026gt;32 weeks, whichever came first [20]. The inclusion criteria were as follows: preterm infants without genetic or structural anomalies, delivered at less than 32 weeks of gestation, and showing BPD (BPD group) or not (NBPD group). The exclusion criteria were as follows: pregnant women with infectious diseases; neonates with severe heart and lung malformations; and patients with severe hypoxic\u0026ndash;ischemic encephalopathy, abnormal development of the intracranial hemorrhagic brain, or chromosomal abnormalities. Finally, eight UCB specimens were obtained from the umbilical vein right after fetal delivery (four BPD and four NBPD preterm infants). After clipping the umbilical cord, 5 mL of umbilical venous blood was immediately extracted from the placental end using a syringe and placed in a vacuum blood collection tube containing coagulant and inert separation glue. Then, the blood was laid aside at room temperature for 1 h. After the blood was curdled and the light yellow transparent liquid was precipitated, the collected samples were centrifuged at 1000\u003cem\u003eg\u003c/em\u003e at room temperature for 10 min. Finally, the supernatant, which was umbilical venous blood serum, was extracted into new Eppendorf tubes and stored at \u0026ndash;80\u0026deg;C until further use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Isolation of exosomes from UCB serum\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExosomes were isolated following the protocol of ExoQuick exosome precipitation solution [Cat#EXOTC50A-1 (5 mL), System Biosciences (SBI), CA, USA]. First, 1 mL of UCB serum was centrifuged for 15 min at 3000\u003cem\u003eg\u003c/em\u003e and 4℃ for the removal of cells and debris. The resulting serum was absorbed and added to 1.5-mL centrifuge tubes with 5 \u0026mu;L of thrombin (T4648-1KU, Sigma, MO, USA). After mixing, the samples were incubated for 15 min at 37℃. After centrifugation at 10,000\u003cem\u003eg\u003c/em\u003e for 15 min at 4℃, the resulting supernatants were removed and the precipitated exosomes in the pellet were added with 250 \u0026mu;L of ExoQuick exosome precipitation solution. Then, specimens were mixed well and incubated for 30 min at 4℃. Exosomes were pelleted by 5-min centrifugation at 1500\u003cem\u003eg\u003c/em\u003e at 4℃. The isolated exosomes were eluted in phosphate-buffered saline (PBS) and used immediately or stored at -80℃ for later use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Nanoparticle tracking analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExosome particle number was measured by nanoparticle tracking analysis (NTA) based on a previously published technique [21]. In brief, exosomes diluted in PBS were analyzed by nanoparticle tracking using the ZetaView (Particle Metrix, Germany) equipment. A 405-nm excitation laser was used in instruments precalibrated with a 100-nm PSL standard (Applied Microspheres, Netherlands). NTA was performed with the same camera settings and tracking parameters, appropriate for detecting extracellular vesicle (EV) (sensitivity, 85; shutter, 70 min; brightness, 20 min; size, 10; maximum size, 200). Video acquisition was carried out at 30 frames/s, and videos were assessed for size and concentration using ZetaView.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Transmission electron microscopy\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor transmission electron microscopy (TEM), exosomes pelleted by ultracentrifugation were resuspended in PBS. A drop thereof was placed on a copper mesh for 5 min. This was followed by 1-min staining with 1% phosphotungstic acid 44-hydrate and 20-min drying at room temperature. The preparations were examined under a transmission electron microscope (FEI, Tecnai G2 Spirit BioTwin; acceleration voltage, 80 kV).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 RNA purification from exosomes and microarrays\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal RNA extraction uses an miRNeasy Serum Kit (Cat#217184, QIAGEN, GmBH, Germany) as directed by the manufacturer. RNA integrity was examined on an Agilent Bioanalyzer 2100 (Agilent Technologies, CA, USA). Then, total RNA amplification and labeling used a Low Input Quick Amp Labeling Kit, One-Color (Cat# 5190-2305, Agilent Technologies) according to the manufacturer\u0026rsquo;s protocol. Labeled circRNAs were obtained using an RNeasy Mini Kit (Cat.# 74106, QIAGEN, GmBH).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe slides were hybridized using 1.65 \u0026mu;g of Cy3-labeled circRNA and a Gene Expression Hybridization Kit (Cat. #5188-5242, Agilent Technologies) as directed by the manufacturer for 17 h. Staining dishes (Cat. # 121, Thermo Shandon, MA, USA) were used for washing with a Gene Expression Wash Buffer Kit (Cat.# 5188-5327, Agilent Technologies), according to the manufacturer\u0026rsquo;s protocol.\u003c/p\u003e\n\u003cp\u003eAn Agilent Microarray Scanner (Cat. #G2565CA, Agilent Technologies) was used for scanning, with default settings. Data were extracted using Feature Extraction v10.7 (Agilent Technologies). Raw data were normalized using the Quantile algorithm and limma in R.\u0026nbsp;Microarray analysis was carried out by Shanghai Biotechnology (China).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6 Functional enrichment analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRatios were calculated between four preterm infants with BPD and four with NBPD. Genes showing fold changes \u0026ge;2 and \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt;0.05 (\u003cem\u003et\u003c/em\u003e test) were considered significantly differentially expressed. The chosen genes for exosomal circRNAs, lncRNAs, and mRNAs were analyzed using Gene Ontology\u0026nbsp;(GO)\u0026nbsp;enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) with enrichment analysis software by Shanghai Biotechnology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.7 CircRNA/lncRNA\u003c/strong\u003e\u0026ndash;\u003cstrong\u003emiRNA\u003c/strong\u003e\u0026ndash;\u003cstrong\u003emRNA network building\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe miRanda database\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ewas used for predicting circRNA/microRNA (miRNA) interactions based on miRNA response elements (MREs) on circRNAs, with miRanda v3.3a. MREs on circRNA/lncRNAs were retrieved, and miRNAs were selected according to the seed matching sequences. For lncRNAs and mRNAs paired with the identical miRNA, the\u0026nbsp;Pearson correlation coefficient\u0026nbsp;(PCC) was determined for identifying the inferred circRNA/lncRNA\u0026ndash;miRNA\u0026ndash;mRNA pairs. Then, circRNA/lncRNA\u0026ndash;miRNA\u0026ndash;mRNA pairs showing PCC \u0026ge;0.90 were included to construct a circRNA/lncRNA\u0026ndash;miRNA\u0026ndash;mRNA network.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.8 Cell culture and treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman bronchial epithelial (BEAS-2B) cells and human umbilical vein endothelial cells (HUVECs) were provided by American Type Culture Collection (USA). These cells were routinely incubated in Dulbecco\u0026rsquo;s modified Eagle\u0026rsquo;s medium (Invitrogen, CA, USA) containing 10% fetal bovine serum (Invitrogen, Grand Island, NY, USA) and 1% penicillin\u0026ndash;streptomycin (Sigma\u0026ndash;Aldrich, MO, USA) at 37\u0026ordm;C with 5% CO\u003csub\u003e2\u003c/sub\u003e The BEAS-2B cells were treated with lipopolysaccharide (LPS, 1 \u0026micro;g/mL) for 12 h, and HUVECs were treated with LPS (1 \u0026micro;g/mL) for 18 h.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.9 Cell counting kit-8 assay\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor cell viability, the BEAS-2B cells and HUVECs were seeded in 96-well plates at a density of 1 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e cells/well stimulated with LPS (1 \u0026micro;g/mL) for 12 h and 18 h, respectively. Then, a cell counting kit-8 (CCK-8) (Beyotime Biotechnology, China) was used to examine the cell viability, according to the manufacturer\u0026rsquo;s specification. The optical density was detected at 490 nm using a microplate reader (Tecan Infinite M200 Micro Plate Reader; LabX, Switzerland).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.10 Western blot analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProteins extracted from BEAS-2B cells and HUVECs were measured using a bicinchoninic acid kit (Beyotime Biotechnology, China). Then, the proteins were resolved on sodium dodecyl sulfate\u0026ndash;polyacrylamide gel electrophoresis (10%) and transferred to polyvinylidene fluoride (PVDF) membranes (Millipore, MA, USA). The PVDF membranes were incubated using 5% skimmed milk, and then with primary antibodies at 4\u003csup\u003eo\u003c/sup\u003eC overnight. Blots were probed using the following antibodies:\u0026nbsp;anti-IL-1\u0026beta; (1: 1, 000, ab234437; Abcam, Cambridge, UK), anti-TNF-\u0026alpha; (1: 1, 000, ab183218; Abcam), and anti-glyceraldehyde-3-phosphate dehydrogenase (anti-GAPDH; 1: 2, 000, bs0755R; Bioss, China), with GAPDH being the endogenous control. Then, membranes were further incubated for 1 h using a secondary antibody (1: 2, 000, b-0311P-HRP; Bioss).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.11 Quantitative real-time polymerase chain reaction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter extracting total RNA from LPS-induced\u0026nbsp;BEAS-2B cells\u0026nbsp;and\u0026nbsp;HUVECs, cDNA was prepared with RNA using an RNeasy plus micro kit, as the starting material of quantitative polymerase chain reaction (qPCR), carried out using a Step One System (Life Technologies Corp). Subsequently, four differentially expressed circRNAs (hsa_circ_0086913, hsa_circ_0049170, hsa_circ_0087059, and hsa_circ_0065188) and two lncRNAs [small nucleolar RNA host gene 20 (SNHG20) and LINC00582] selected based on the \u003cem\u003eP\u003c/em\u003e value and fold change\u0026nbsp;were\u0026nbsp;evaluated by quantitative reverse transcription (qRT)-PCR\u0026nbsp;analysis.\u0026nbsp;Primer Premier software 4.0 (Premier, Canada) was used to design sequences of all primers (see \u003cstrong\u003eTable 3\u003c/strong\u003e). GAPDH was normalized using the 2\u003csup\u003e-\u0026Delta;\u0026Delta;CT\u003c/sup\u003eapproach.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.12 Statistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSPSS 25.0 was used for data analysis. Quantitative data were expressed as mean \u0026plusmn; standard deviation. Group pairs were compared using the Student \u003cem\u003et\u003c/em\u003e test. A \u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue \u0026lt;0.05 indicated statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Description of preterm infants with BPD and NBPD \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe demographic and clinical characteristics of preterm infants with BPD and NBPD are described in \u003cstrong\u003eTable 1\u003c/strong\u003e. All the puerpera and newborns in this study belonged to the Han Chinese nationality and the yellow race. Specifically, birth weight, GA, gender, Apgar score, intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, necrotizing enterocolitis, early-onset neonatal sepsis, late-onset neonatal sepsis, retinopathy of prematurity, surfactant treatment, mechanical ventilation, mother with preeclampsia, antenatal steroids, premature rupture of membranes (PROM), and chorioamnionitis were similar in both groups. In addition, the continuous positive airway pressure, oxygen inhalation, and hospitalization days of preterm infants were longer in the BPD group than in the NBPD group. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Detection of exosomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNTA and TEM analyses were performed for identifying the purified exosomes. The cup-shaped morphology and clear, intact membrane were identified by TEM (\u003cstrong\u003eFig. S1A\u003c/strong\u003e), and particles between 30 and 120 nm were detected by NTA (\u003cstrong\u003eFig. S1B\u003c/strong\u003e). These findings indicated that the serum-derived particles isolated from the study subjects were exosomes. No differences were observed in the size distribution and morphology between exosomes isolated from the BPD and NBPD groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Exosomal circRNA, lncRNA, and mRNA profiles by microarray \u003c/strong\u003e\u003cstrong\u003eanalysis of UCB in the BPD and NBPD groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 105,509 circRNAs, 32,953 lncRNAs, and 34,549 mRNAs were identified as indicated in \u003cstrong\u003eFigure 1A\u003c/strong\u003e. Of these, 317 circRNAs, 104 lncRNAs, and 135 mRNAs showed significant differential expression based on the aforementioned criteria in UCB-derived exosomes of preterm infants in the BPD group compared with those in the NBPD group. Among them, 68 and 249 circRNAs, 94 and 10 lncRNAs, and 81 and 54 mRNAs were upregulated and downregulated, respectively, as presented in \u003cstrong\u003eFigure 1\u003c/strong\u003e. The heatmap analysis disclosed low internal variation, suggesting that these gene alterations may be meaningful for BPD pathogenesis (\u003cstrong\u003eFig. 1B\u003c/strong\u003e). Further, differentially expressed exosomal circRNAs, lncRNAs, and mRNAs were used to generate scatter (\u003cstrong\u003eFig. 1C\u003c/strong\u003e) and volcano (\u003cstrong\u003eFig. 1D\u003c/strong\u003e) plots. \u003c/p\u003e\n\u003cp\u003eNext, differentially expressed circRNAs, lncRNAs, and mRNAs in UCB-derived exosomes were assessed for general features by preliminarily analyzing microarray data. \u003cstrong\u003eFigure 2\u003c/strong\u003e shows that the parent genes of these circRNAs, lncRNAs, and mRNAs were broadly distributed in virtually all human chromosomes, also depicting their length distributions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 GO and KEGG analyses of exosomal circRNAs, lncRNAs, and mRNAs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGO and KEGG analyses were executed for investigating the potential functions of differentially expressed genes (\u003cstrong\u003eFigs. 3\u0026ndash;5\u003c/strong\u003e). The GO analysis revealed enrichment of 1165 circRNAs, 2475 lncRNAs, and 395 mRNAs in different physiological functions, such as molecular functions, cellular components, and biological processes (\u003cstrong\u003eFig. 3\u003c/strong\u003e). Meanwhile, exosomal circRNAs, lncRNAs, and mRNAs were involved in 221, 365, and 135 KEGG pathways, respectively. \u003cstrong\u003eFigure 4\u003c/strong\u003e shows the top 30 enriched KEGG terms of differentially expressed exosomal circRNAs, lncRNAs, and mRNAs between the BPD and NBPD groups. GO function and KEGG classifications of differentially expressed RNAs are shown in \u003cstrong\u003eFigure \u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e. The classification of KEGG included Organismal System, Metabolism, Human Disease, Genetic Information Processing, Environmental Information Processing, and Cellular Process, as shown in \u003cstrong\u003eFigure \u003c/strong\u003e\u003cstrong\u003e5B.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Prediction of exosomal \u003c/strong\u003e\u003cstrong\u003ecircRNA/lncRNA\u003c/strong\u003e\u0026ndash;\u003cstrong\u003emiRNA\u003c/strong\u003e\u0026ndash;\u003cstrong\u003emRNA interactions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ecircRNAs and lncRNAs have been shown to possess multiple binding sites for miRNAs, which they sponge, thus relieving the inhibitory effects of miRNAs on their target mRNAs. This effect is known as the competitive endogenous RNA (ceRNA) mechanism [22-24]. Therefore, miRanda was used to predict the potential ceRNAs of the first 10 upregulated and downregulated circRNAs and lncRNAs based on MREs, respectively. A total of 13 circRNAs, 97 miRNAs, and 45 mRNAs were retrieved (\u003cstrong\u003eFig. 6A\u003c/strong\u003e). A total of 187 circRNA/lncRNA\u0026ndash;miRNA\u0026ndash;mRNA regulations with PPC \u0026gt;0.90 were predicted as shown in \u003cstrong\u003eTable S1\u003c/strong\u003e. Moreover, 268 regulations existed among 164 transcripts that included 16 lncRNAs, 119 miRNAs, and 59 mRNAs, as shown in \u003cstrong\u003eFigure 6B \u003c/strong\u003eand \u003cstrong\u003eTable S2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6\u003c/strong\u003e \u003cstrong\u003eExpression levels of differentially expressed circRNAs and lncRNAs in LPS-induced BEAS-2B cells and HUVECs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLPS-induced injury in \u003cstrong\u003eBEAS-2B cells\u003c/strong\u003e and HUVECs is related to increased inflammation. As observed, TNF-\u0026alpha; and IL-1\u0026beta; were higher in BEAS-2B cells and HUVECs after the stimulation of LPS, as analyzed by Western blot (\u003cstrong\u003eFig. 7A\u003c/strong\u003e). Moreover, LPS also significantly inhibited the cell viability of BEAS-2B cells and HUVECs (\u003cstrong\u003eFig. 7B\u003c/strong\u003e). \u003c/p\u003e\n\u003cp\u003eAccording to the high fold change, expression level, and host gene/GeneSymbol, four differentially expressed circRNAs (hsa_circ_0049170, hsa_circ_0087059, hsa_circ_0086913, and hsa_circ_0065188) and two lncRNAs (SNHG20 and LINC00582) were selected for future study. The expression levels of circRNAs hsa_circ_0049170 and hsa_circ_0087059 were found to be upregulated in LPS-induced BEAS-2B cells (\u003cstrong\u003eFig. 7C\u003c/strong\u003e); the expression level of hsa_circ_0086913 was upregulated and that of hsa_circ_0065188 was downregulated in LPS-induced HUVECs (\u003cstrong\u003eFig. 7D\u003c/strong\u003e). Meanwhile, the expression level of lncRNA SNHG20 was upregulated and that of LINC00582 was downregulated in LPS-induced BEAS-2B cells (\u003cstrong\u003eFig. 7E\u003c/strong\u003e). These results were consistent with the results of exosomal circRNA and lncRNA profiles by microarray analysis of UCB in the BPD and NBPD groups.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eExosomal circRNAs and lncRNAs attract increasing attention owing to their high regulatory potential [25-27]. Previous studies have examined UCB-derived exosomes from patients with preeclampsia and GDM [18, 19] because of their distant regulatory potency. Further, exosomal circRNAs and lncRNAs may carry important information and play roles while in cells, belonging to exosomes released from synaptoneurosomes [28-32]. These studies indicated exosomal circRNAs and lncRNAs could be used as molecular markers for clinically diagnosing and treating various pathologies [33, 34]. In the present study, exosomal circRNAs, lncRNAs, and mRNAs in UCB were significantly altered in infants with BPD. In all, 317 circRNAs, 104 lncRNAs, and 135 mRNAs were differentially expressed in UCB-derived exosomes of infants with BPD compared with those with NBPD.\u003c/p\u003e\n\u003cp\u003eGO and KEGG analyses were carried out to further examine the roles of the differentially expressed exosomal circRNAs, lncRNAs, and mRNAs. As shown earlier, the most enriched GO terms and KEGG pathways of exosomal RNAs were associated with endothelial or epithelial cell development, including \u0026ldquo;angiogenesis\u0026rdquo; [35], \u0026ldquo;mammalian target of rapamycin (mTOR) signaling pathway\u0026rdquo; [36], \u0026ldquo;Wnt signaling pathway\u0026rdquo; [37, 38], \u0026ldquo;Epidermal growth factor receptor tyrosine kinase inhibitor resistance\u0026rdquo; [39], and \u0026ldquo;transforming growth factor-beta receptor signaling\u0026rdquo; [40]. Meanwhile, several GO terms and pathways connected with exosome transport were also significantly enriched, including \u0026ldquo;regulation of vesicle-mediated transport,\u0026rdquo; \u0026ldquo;vacuolar acidification,\u0026rdquo; and \u0026ldquo;extracellular matrix (ECM)\u0026ndash;receptor interaction.\u0026rdquo; The aforementioned results showed that KEGG terms for differentially expressed exosomal circRNAs, lncRNAs, and mRNAs with most enriched genes were \u0026ldquo;transport and catabolism,\u0026rdquo; \u0026ldquo;signal transduction,\u0026rdquo; \u0026ldquo;translation,\u0026rdquo; \u0026ldquo;infectious diseases: viral,\u0026rdquo; \u0026ldquo;immune system,\u0026rdquo; and \u0026ldquo;carbohydrate metabolism.\u0026rdquo; These results suggested that BPD development involved complex and diverse pathophysiological events. \u003c/p\u003e\n\u003cp\u003eAmong them, the \u0026ldquo;mTOR signaling pathway\u0026rdquo; and the identified coding genes have gained interest because of their high enrichment factor and large gene number. mTOR is known to have two protein complexes with distinct functions, which are complex 1 (mTORC1) and 2 (mTORC2) [41]. mTORC1 comprises mTOR, MTOR Associated Protein, LST8 Homolog (mLST8), raptor, and two repressors (PRAS40 and DEPTOR). Recent data revealed that hyperoxia exposure of murine and baboon lungs in BPD is associated with insufficient activation of 5\u0026apos;- Adenosine monophosphate (AMP)-activated protein kinase and mTORC1 hyperactivity [42]. \u003cem\u003eIn vitro\u003c/em\u003e, mTOR inhibition significantly promotes the proliferation of basal cells derived from neonatal tracheal aspirate, which may constitute a critical model system for studying late fetal lung development and perinatal lung diseases, including BPD [36]. Another study found that inhibition of regulatory-associated protein of mTOR, a major subunit of mTORC1, prevented hyperoxia-stimulated lung damage by heightening autophagy and weakening apoptotic death in newborn mice [43]. These results and the aforementioned findings suggested that differentially expressed exosomal RNAs might play a crucial role in BPD through the mTOR signaling pathway.\u003c/p\u003e\n\u003cp\u003eAt present, many pathways related to BPD exist. Interestingly, in this study, \u0026ldquo;ECM\u0026ndash;receptor interaction\u0026rdquo; was found, which is rarely studied in BPD and has been found in both lncRNA and circRNA KEGG analysis results. The ECM is a noncellular three-dimensional network polymer consisting of fibronectin, elastin, collagens, proteoglycans, and several other glycoproteins [44]. Damaged ECM is known to provoke apoptosis of overlying pulmonary epithelial cells and alveolar unit loss associated with BPD [45, 46]. Further, exosomes are part of the ECM and are involved in the remodeling of the extracellular environment [7]. Exosomes from mesenchymal stem cells (MSCs) could reverse alveolar injury and septal thickness associated with hyperoxia-dependent lung damage in mice with experimental BPD [15]. Meanwhile, in BPD lung secretions, pathogenic exosomes are also detected, and hyperoxia and microbial products could induce the abnormal expression of exosomal miRNAs [12, 47]. In addition, numerous reports have demonstrated that exosomes regulate vascular growth, proliferation, metastasis, and apoptosis through exosomal circRNAs and lncRNAs [48-51]. These results suggested that ECM\u0026ndash;receptor interactions and enriched circRNAs and lncRNAs might be pivotal in the role of exosomes in BPD progression.\u003c/p\u003e\n\u003cp\u003eIn this study, lung epithelial cells BEAS-2B and HUVECs were used as research objects for future analyses to verify the differentially expressed RNAs. Excessive inflammation persists in infants with BPD, which could be caused by a variety of factors, including mechanical ventilation and infection. Therefore, the inflammatory response of BPD by LPS was reflected in this study. Further, studies have reported that BEAS-2B cells and HUVECs could be stimulated by LPS to induce inflammatory response [52-54], consistent with the results of this study. Then, the expression levels of differentially expressed circRNAs and lncRNAs in LPS-induced BEAS-2B cells and HUVECs were explored. The results of qRT-PCR analyses showed similar change trends as in UCB-derived exosomes of preterm infants with BPD. These results suggested that these differentially expressed RNAs may play a potential role in BPD, which are worthy of deeper functional studies.\u003c/p\u003e\n\u003cp\u003eThe molecular functions of differentially expressed exosomal circRNAs were studied by exploring them from the perspective of ceRNA. In this study, 13 of the top 10 upregulated and downregulated expression of circRNAs showed binding sites for miRNAs, of which some were connected with pulmonary diseases. For instance, miR-1207-5p, miR-608, and miR-4640-5p were reported to be related to non-small-cell lung cancer [55-58]. According to the PCC, fold change, and expression level, the possible role of exosomal hsa_circ_0086913 was explored, which was 3.60-fold upregulated in UCB-derived exosomes from the BPD group and LPS-induced HUVECs. The ceRNA analysis revealed that hsa-miR-330-5p, hsa-miR-4656, hsa-miR-6829-3p, hsa-miR-103a-3p, hsa-miR-107, hsa-miR-4688, hsa-miR-7161-3p, hsa-miR-3192-5p, hsa-miR-3620-5p, hsa-miR-4656, hsa-miR-1182, hsa-miR-4656, hsa-miR-4688, and hsa-miR-6783-3p potentially interacted with hsa_circ_0086913. Among them, hsa_circ_0086913/hsa-miR-103a-3p/transmembrane 4 L six family member 1 (TM4SF1) was predicted with a PCC of 0.93. In a recent study, the researchers found that the expression level of hsa-miR-103a-3p related to the phosphatidylinositol 3‑kinase/protein kinase B (PI3K/Akt) signaling pathway was decreased in UCB-derived exosomes from the BPD group compared with the NBPD group [16]. Further, the overexpression of hsa-miR-103a-3p in normal HUVECs significantly promoted cell proliferation, cell migration, and tube formation [16]. In addition, the expression level of TM4SF1, a potential target gene of hsa-miR-103a-3p, was upregulated in UCB-derived exosomes of infants with BPD. It has been found to promote angiogenesis via the Akt signaling pathway [59]. These results demonstrated that UCB-derived exosomal hsa_circ_0086913 of infants with BPD might contribute to the development of BPD, possibly via the interaction network hsa_circ_0086913/hsa-miR-103a-3p/TM4SF1.\u003c/p\u003e\n\u003cp\u003eMeanwhile, in this study, most of the exosomal lncRNAs were found to have predicted target miRNAs that may be related to BPD. For instance, a total of 27 miRNAs were found to potentially match with upregulated lncRNA SNHG20 (also referred to as ENST00000566583); of them, the interaction network lncRNA-SNHG20/hsa-miR-6720-5p/spermine synthase was predicted with the highest PCC of 0.99. Previous studies reported that the knockdown of SNHG20 inhibited cell proliferation and invasion in human lung epithelial cells A549 cells [60-62]. In addition, the expression level of lncRNA SNHG20 has been shown to be significantly upregulated in hepatocellular carcinoma and could promote the epithelial-to-mesenchymal transition (EMT) [63]. The expression level of lncRNA SNHG20 was upregulated in UCB-derived exosomes of infants with BPD as well as in LPS-induced BEAS-2B cells. EMT is a process of conversion of epithelial cells into mesenchymal cells and occurs in long-term survivors with BPD [64, 65]. Therefore, in this study, it was predicted that lncRNA SNHG20 might promote EMT in BPD, which is worthy of future studies.\u003c/p\u003e\n\u003cp\u003eIn summary, exosomal circRNA, lncRNA, and mRNA profiles in the UCB of newborns with BPD were determined, and 317 circRNAs, 104 lncRNAs, and 135 mRNAs were found to be significantly altered. The aforementioned findings indicated that exosomal circRNAs/lncRNAs might have vital roles in BPD pathogenesis. Through bioinformatics, several potential exosomal circRNA/lncRNA\u0026ndash;miRNA\u0026ndash;mRNA networks were also successfully constructed, which might be involved in BPD. Two differentially expressed circRNAs (hsa_circ_0049170, hsa_circ_0087059) and two lncRNAs (SNHG20 and LINC00582) were identified in LPS-induced BEAS-2B cells, and two other circRNAs (hsa_circ_0086913 and hsa_circ_0065188) were also identified in LPS-induced HUVECs. These results provided a sound basis for further investigations assessing the potential biological functions of exosomal circRNAs and lncRNAs in BPD.\u003cem\u003e \u003c/em\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBPD: Bronchopulmonary dysplasia \u003c/p\u003e\n\u003cp\u003eCCK-8: cell counting kit-8 \u003c/p\u003e\n\u003cp\u003ecircRNAs: circular RNAs \u003c/p\u003e\n\u003cp\u003eEOS: Early-onset neonatal sepsis \u003c/p\u003e\n\u003cp\u003eECM: extracellular matrix \u003c/p\u003e\n\u003cp\u003eEV: extracellular vesicle \u003c/p\u003e\n\u003cp\u003eGO: Gene Ontology \u003c/p\u003e\n\u003cp\u003eGA: gestational age \u003c/p\u003e\n\u003cp\u003eGDM: gestational diabetes mellitus \u003c/p\u003e\n\u003cp\u003eHUVECs: human umbilical vein endothelial cells \u003c/p\u003e\n\u003cp\u003eIL: interleukin \u003c/p\u003e\n\u003cp\u003eIVH: Intraventricular hemorrhage \u003c/p\u003e\n\u003cp\u003eKEGG: Kyoto Encyclopedia of Genes and Genomes \u003c/p\u003e\n\u003cp\u003eLOS: Late-onset neonatal sepsis \u003c/p\u003e\n\u003cp\u003eLPS: lipopolysaccharide \u003c/p\u003e\n\u003cp\u003emTOR: mammalian target of rapamycin \u003c/p\u003e\n\u003cp\u003eMSCs: mesenchymal stem cells \u003c/p\u003e\n\u003cp\u003emiRNA microRNA \u003c/p\u003e\n\u003cp\u003eMREs: miRNA response elements \u003c/p\u003e\n\u003cp\u003eNTA: nanoparticle tracking analysis \u003c/p\u003e\n\u003cp\u003eNEC: Necrotizing enterocolitis \u003c/p\u003e\n\u003cp\u003ePDA: Patent ductus arteriosus \u003c/p\u003e\n\u003cp\u003ePCC: Pearson correlation coefficient \u003c/p\u003e\n\u003cp\u003ePBS: phosphate-buffered saline \u003c/p\u003e\n\u003cp\u003ePVDF: polyvinylidene fluoride \u003c/p\u003e\n\u003cp\u003ePROM: premature rupture of membranes \u003c/p\u003e\n\u003cp\u003eqPCR: quantitative polymerase chain reaction \u003c/p\u003e\n\u003cp\u003eRDS: Respiratory distress syndrome \u003c/p\u003e\n\u003cp\u003eROP: retinopathy of prematurity \u003c/p\u003e\n\u003cp\u003eSNHG20: small nucleolar RNA host gene 20 \u003c/p\u003e\n\u003cp\u003eTM4SF1: transmembrane 4 L six family member 1 \u003c/p\u003e\n\u003cp\u003eTEM: transmission electron microscopy \u003c/p\u003e\n\u003cp\u003eTNF: tumor necrosis factor \u003c/p\u003e\n\u003cp\u003eUCB: umbilical cord blood\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Young Talents Science and Technology Project of Changzhou Municipal Health Commission (Grant \u003cem\u003enumber\u003c/em\u003e QN202049, Yu Wang) and Changzhou Applied Basic Research Program (Grant \u003cem\u003enumber\u003c/em\u003e CJ20210148, Huaiyan Wang).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRelevant data has been uploaded to GEO repository, and is scheduled to be released on Dec 31, 2023. The access number is GSE190215.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003es\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003e Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYW and XW performed the experiments, interpreted the results of the experiments and drafted the manuscript. QSX and JY prepared the figures and analyzed the data. HYW and LZ conceived and designed the experiments, provided funding to regents. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the \u003c/em\u003eEthics Committee of Changzhou Maternal and Child Health Care Hospital (\u003cem\u003eNo\u003c/em\u003e. 2021142) and registered in the Chinese Clinical Trial Registry (\u003cem\u003eNo.\u003c/em\u003e ChiCTR2100049129).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWritten informed consent for \u003c/em\u003eparticipation\u003cem\u003e was obtained from the parents.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from \u003cem\u003ethe parents.\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShukla VV, Ambalavanan N (2021) Recent Advances in Bronchopulmonary Dysplasia. 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Mol Med Rep 22:2564\u0026ndash;2572. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3892/mmr.2020.11306\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Clinical characteristics of the BPD and non-BPD infants in the microarray analysis\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"13.903743315508022%\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" width=\"40.64171122994652%\"\u003e\n \u003cp\u003eBPD(n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" width=\"40.37433155080214%\"\u003e\n \u003cp\u003eNBPD(n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.390444810543658%\"\u003e\n \u003cp\u003e1#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.71993410214168%\"\u003e\n \u003cp\u003e2#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.378912685337726%\"\u003e\n \u003cp\u003e3#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401976935749587%\"\u003e\n \u003cp\u003e4#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.355848434925864%\"\u003e\n \u003cp\u003e(Mean \u0026plusmn; SEM)/n%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.390444810543658%\"\u003e\n \u003cp\u003e1#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.884678747940692%\"\u003e\n \u003cp\u003e2#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.731466227347612%\"\u003e\n \u003cp\u003e3#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.390444810543658%\"\u003e\n \u003cp\u003e4#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.355848434925864%\"\u003e\n \u003cp\u003e(Mean \u0026plusmn; SEM)/n%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eInfants\u0026apos; characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eSex gender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eBirthweight (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e1580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e1350\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e1340\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e1250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1380.00\u0026plusmn;\u003c/p\u003e\n \u003cp\u003e140.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e1450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e1580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e1580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e1830\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1610.00\u0026plusmn;\u003c/p\u003e\n \u003cp\u003e158.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eGestational age (d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e31+6\u003c/p\u003e\n \u003cp\u003e(31.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e29+6\u003c/p\u003e\n \u003cp\u003e(29.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e28+2\u003c/p\u003e\n \u003cp\u003e(28.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e27+6\u003c/p\u003e\n \u003cp\u003e(27.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e29.47\u0026plusmn;1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e29+1\u003c/p\u003e\n \u003cp\u003e(29.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e30+4\u003c/p\u003e\n \u003cp\u003e(30.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e30+6\u003c/p\u003e\n \u003cp\u003e(30.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e30+6\u003c/p\u003e\n \u003cp\u003e(30.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e30.36\u0026plusmn;0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eApgar 1 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e7.25\u0026plusmn;0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e7.00\u0026plusmn;1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eApgar 5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e8.00\u0026plusmn;0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e7.75\u0026plusmn;0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eIntraventricular hemorrhage (IVH)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e4(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e4(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eRespiratory distress syndrome (RDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003ePatent ductus arteriosus (PDA)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e3(75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e4(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eAge at determination of PDA (d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e2d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e1d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e1d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e1d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e1d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e2d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e1d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eNecrotizing enterocolitis (NEC)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eretinopathy of prematurity (ROP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eZone Ⅲ, stage 1,\u003c/p\u003e\n \u003cp\u003ePlus (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eZone Ⅲ, stage 2,\u003c/p\u003e\n \u003cp\u003ePlus (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eZone Ⅲ, stage 2,\u003c/p\u003e\n \u003cp\u003ePlus (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eEarly-onset neonatal sepsis (EOS)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eLate-onset neonatal sepsis (LOS)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eSurfactant treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e4(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e3(75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eMechanical ventilation(d)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e8.25\u0026plusmn;6.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2.75\u0026plusmn;3.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eCPAP(d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e12.50\u0026plusmn;3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e4.00\u0026plusmn;1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eDays with oxygen(d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e56.50\u0026plusmn;18.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e12.50\u0026plusmn;5.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eHospitalization days(d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e63.75\u0026plusmn;11.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e41.50\u0026plusmn;10.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eMaternal characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003ePreeclampsia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eAntenatal steroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e4(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e3(75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003ePremature rupture of membranes (PROM)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e2.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.885180240320427%\"\u003e\n \u003cp\u003eChorioamnionitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.87716955941255%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.411214953271028%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.809078771695594%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e2(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01068090787717%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.076101468624833%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.610146862483311%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.013351134846461%\"\u003e\n \u003cp\u003e1(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.073431241655541%\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eDifferentially expressed\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;circRNA, lncRNA and mRNA in UCB-derived\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;exosomes\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;from the BPD and NBPD groups\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eGene Type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eTargetID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003ep-values\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003eFold change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eRegulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ehostgene/\u003c/p\u003e\n \u003cp\u003eGeneSymbol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0049170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.007549\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e4.491964\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eOLFM2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0087059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.015400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.942138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eGRHPR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0118639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.009878\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.811908\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTRAK2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0132613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.026462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.729238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eRNGTT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0086913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.007987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.598227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTLN1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0009420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.033789\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.533802\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLOC388588\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0061761\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.032548\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.338253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eWRB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0002540\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.019826\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.277644\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTCONS_l2_00004567\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0013996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.036328\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.202700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ePLEKHO1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0073391\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.015983\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.101576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMCTP1\u003c/p\u003e\n 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width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.857984\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eETFA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0075931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.001353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.810139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0018723\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.039450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.625034\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ePSAP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0063129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.001627\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.607178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMYH9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0037578\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.010280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.547076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTCEB2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0036509\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.040011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.539615\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eZFAND6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0007372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.006241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e4.642343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eIFT46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0028145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.025837\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e4.246691\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTRPV4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0078460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.010902\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.802345\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTULP4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0065188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.000092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.494472\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ePTPN23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0037782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.011926\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.353644\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMETTL22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0034846\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.018938\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.155511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eCDAN1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0045828\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.007738\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.142472\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMXRA7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0084333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.004997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.140422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ePRKDC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0086018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.008154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.138347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eBOP1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0081368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.025939\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.122619\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eZNF498\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0028505\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.011100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.087724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSLC24A6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0038205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.026746\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.065186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0034360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.018680\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n 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\u003cp\u003e2.842620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLRP5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003ecircRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003ehsa_circ_0077639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.006088\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.832914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSLC16A10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000613892\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.605620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.605620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMAGI2-AS3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000566583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.177118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.177118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSNHG20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000456953\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.657584\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.657584\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSNHG17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000434411\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.584309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.584309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSNHG20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000430373\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.432956\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.432956\u003c/p\u003e\n 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width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMALAT1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000663422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.029238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.029238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eMAGI2-AS3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000662112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.013230\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.013230\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAC068733.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000502301\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.269295\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.713394\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC00461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000553812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.284493\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.515019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAC008056.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000671622\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.295918\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.379320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000661332\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.310585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.219735\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eBASP1-AS1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000442305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.325902\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.068406\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAL139246.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eLINC01467:4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.344071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.906373\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01467\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000444346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.345258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.896384\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01983\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000555433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.353812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.826360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAL356022.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000431759\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.358385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.790299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSLC2A1-AS1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000448058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.362807\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.756284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC00582\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eTEX41:26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.368298\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.715191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTEX41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000668542\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.379396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.635771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000447119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.386033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.590454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eUNC5B-AS1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000659430\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.386040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.590404\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000553321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.387800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.578649\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAC068831.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000663040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.395291\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.529780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAP001981.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000577850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.395566\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.528020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eAC002094.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000657104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.396799\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.520169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC00308\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eLINC01149:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.401669\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.489613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01149\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003elncRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000655586\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.402178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.486460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_005252\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.002311\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e5.254707\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eFOS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_003662\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.004022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.217883\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n 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\u003cp\u003eC11orf96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_022167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.001038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.583704\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eXYLT2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_003720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.015725\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.569150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ePSMG1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_014220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.025066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.527983\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTM4SF1\u003c/p\u003e\n \u003c/td\u003e\n 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width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.504952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eHIST1H4L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_030572\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.012157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.459270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eSPX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_001172415\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.045366\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.429838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003eup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eBAG1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_001004318\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.009948\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n 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width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_198696\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.008439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e4.096204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eKRTAP10-3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_020994\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.000142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e3.775682\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n 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\u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eKLC2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_001195520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.046637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.699180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLRCOL1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_024902\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.000019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.666748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eDNAJC22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_001277372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.007239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.640840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eKIAA2012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_024522\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.016315\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.617907\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eNKAIN1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_001008409\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.005572\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.609773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eTTLL9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000441860\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.004645\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.607226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eRPL23AP76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000566382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.003392\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.569043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLARP4P\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_022752\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.002576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.568464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eZNF574\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000564204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.005544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.567630\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eKIFC3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_001018078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.034002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.554457\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eFPGS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eNM_032512\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.002354\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.534126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003ePDZD4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.36283185840708%\"\u003e\n \u003cp\u003eENST00000422723\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e0.005925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.451327433628318%\"\u003e\n \u003cp\u003e2.531463\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.920353982300885%\"\u003e\n \u003cp\u003edown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.893805309734514%\"\u003e\n \u003cp\u003eLINC01122\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Primer sequences\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.21052631578947%\"\u003e\n \u003cp\u003eGene name\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003ePrimer sequences\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\n \u003cp\u003eCircRNA hsa_circ_0086913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-CTGCTGAAAATGAAGAGGCTCA-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eR: 5\u0026apos;-TGCTGCCTTCACTTCCTGTA-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\n \u003cp\u003eCircRNA hsa_circ_0049170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-ATTCAGGAGGAGATGGGTGC-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eR: 5\u0026apos;-TCCCGACCCCAGCTTCTG-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\n \u003cp\u003eCircRNA hsa_circ_0087059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-AGTGAAGAATGGTGGCTGGA-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eR: 5\u0026apos;-TCCACCTCACAGCTATGCG-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\n \u003cp\u003eCircRNA hsa_circ_0065188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-TTCATTACCTGCAGAGTCGG-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"59.78947368421053%\"\u003e\n \u003cp\u003eR: 5\u0026apos;-ACTTGCGGAGGACACTACAG-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.21052631578947%\"\u003e\n \u003cp\u003elncRNA SNHG20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-AATATCCCCCGACGATTGGC-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eGGGAGCAGGAAGGCATCTTT-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.21052631578947%\"\u003e\n \u003cp\u003elincRNA LINC00582\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-AGGCGGAAAGAACTACGTGA-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eR: 5\u0026apos;-TCACACCCAGACTCTGCATT-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.21052631578947%\"\u003e\n \u003cp\u003eGAPDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eF: 5\u0026apos;-GAAGGTGAAGGTCGGAGTC-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"40.21052631578947%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"59.78947368421053%\"\u003e\n \u003cp\u003eR: 5\u0026apos;-GAAGATGGTGATGGGATTTC-3\u0026apos;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"bronchopulmonary dysplasia, exosome, circRNA, lncRNA, umbilical cord blood","lastPublishedDoi":"10.21203/rs.3.rs-1404043/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1404043/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eBronchopulmonary dysplasia (BPD) represents a multifactorial chronic pulmonary pathology and a major factor causing premature illness and death. The therapeutic role of exosomes in BPD has been feverishly investigated. Meanwhile, the potential roles of exosomal circRNAs, lncRNAs, and mRNAs in umbilical cord blood (UCB) serum have not been studied. This study aimed to detect the expression profiles of circRNAs, lncRNAs, and mRNAs in UCB-derived exosomes of infants with BPD. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eMicroarray analysis was performed to compare the RNA profiles of UCB-derived exosomes of a preterm newborn with (BPD group) and without (non-BPD, NBPD group) BPD. Then, circRNA/lncRNA–miRNA–mRNA co-expression networks were built to determine their association with BPD. In addition, cell counting kit-8 (CCK-8) assay was used to evaluate the proliferation of lipopolysaccharide (LPS)-induced human bronchial epithelial cells (BEAS-2B cells) and human umbilical vein endothelial cells (HUVECs). The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in LPS-induced BEAS-2B cells and HUVECs were assessed through Western blot analysis. Then, quantitative reverse transcription–polymerase chain reaction assay was used to evaluate the expression levels of four differentially expressed circRNAs (hsa_circ_0086913, hsa_circ_0049170, hsa_circ_0087059, and hsa_circ_0065188) and two lncRNAs [small nucleolar RNA host gene 20 (SNHG20) and LINC00582] detected in LPS-induced BEAS-2B cells or HUVECs. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA total of 317 circRNAs, 104 lncRNAs, and 135 mRNAs showed significant differential expression in UCB-derived exosomes of preterm infants with BPD compared with those with NBPD. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to examine differentially expressed exosomal circRNAs, lncRNAs, and mRNAs. The results showed that the GO terms and KEGG pathways mostly involving differentially expressed exosomal RNAs were closely associated with endothelial or epithelial cell development. \u003cem\u003eIn vitro\u003c/em\u003e, CCK-8 and Western blot assays revealed that LPS remarkably inhibited the viability and promoted inflammatory responses [TNF-α and IL-1β] of BEAS-2B cells or HUVECs. The expression levels of circRNAs hsa_circ_0049170 and hsa_circ_0087059 were upregulated in LPS-induced BEAS-2B cells; the expression level of hsa_circ_0086913 was upregulated and that of hsa_circ_0065188 was downregulated in LPS-induced HUVECs. Moreover, the expression level of lncRNA SNHG20 was upregulated and that of LINC00582 was downregulated in LPS-induced BEAS-2B cells. Further, 455 circRNA/lncRNA–miRNA–mRNA interaction networks were predicted, including hsa_circ_0086913/hsa-miR-103a-3p/transmembrane 4 L six family member 1 (TM4SF1) and lncRNA-SNHG20/hsa-miR-6720-5p/spermine synthase (SMS) networks, which may take part in BPD.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: \u003c/p\u003e\u003cp\u003eThis study provided a systematic perspective on UCB-derived exosomal circRNAs and lncRNAs and laid an important foundation for further investigating the potential biological functions of exosomal circRNAs and lncRNAs in BPD.\u003c/p\u003e","manuscriptTitle":"CircRNA, lncRNA and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-03-11 16:21:05","doi":"10.21203/rs.3.rs-1404043/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2022-03-14T10:15:36+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-03-09T07:27:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-03-07T01:30:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2022-02-28T07:38:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d606c9d8-eb51-4758-8d68-6325184d21c1","owner":[],"postedDate":"March 11th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-06-23T08:50:31+00:00","versionOfRecord":[],"versionCreatedAt":"2022-03-11 16:21:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1404043","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1404043","identity":"rs-1404043","version":["v1"]},"buildId":"re_ckhLnmML6MCF96OHNJ","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}