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Circ-USP9X accelerates deep vein thrombosis after fracture by acting as a miR-148b-3p sponge and upregulates SRC kinase signaling inhibitor 1
YongChao Wanga,1, Qin Sua,1, HaiRong Tangb, Xin Lina, YanHua Yia, Qiang Tiana, ZhangFeng Luoa, MeiChun Fua, JiaQi Penga, KeYun Zhanga,
Corresponding author
wyc_wangyc@hotmail.com

Corresponding author.
a Department of Joint Sport Medicine, The First Affiliated Hospital of Hunan Medical College, Huaihua City, Hunan Province, PR China
b School of Nursing, Hunan Medical College, Huaihua City, Hunan Province, PR China
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          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">Overexpressing circUSP9X increases CoCl<span class="elsevierStyleInf">2</span> toxicity to HUVECs&#44; but this effect is inhibited by knocking down SRCIN1&#46; pcDNA 3&#46;1-circUSP9X and si-SRCIN1 were co-transfected into CoCl2-treated HUVECs&#46; &#40;A&#41; Western blot tests of SRCIN1&#46; &#40;B&#41; Commercial kit to detect LDH release&#46; &#40;C&#41; MTT assay tests of cell viability&#46; &#40;D&#41; Flow cytometry analysis of apoptosis rate&#46; &#40;E&#41; ELISA measurements of IL-1&#946;&#44; IL-6 and TNF-&#945;&#46; &#40;F&#41; Western blot detection of cleaved caspase-3&#44; Bax&#44; p-p65 and Bcl-2&#59; Data expressed as mean &#177; SD &#40;n &#61; 3&#41;&#46; &#42; p &#60; 0&#46;05&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Introduction</span><p id="para0010" class="elsevierStylePara elsevierViewall">Deep Vein Thrombosis &#40;DVT&#41;&#44; as a critical subset of Venous Thromboembolism &#40;VTE&#41;&#44; represents a significant global health challenge due to its high mortality rate&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> This condition predominantly affects deep veins in the lower leg and thigh&#44; often emerging as a secondary complication post-fracture surgeries&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Despite extensive research&#44; the precise etiological factors and pathogenic mechanisms underlying DVT remain elusive&#46; Studies have consistently highlighted the role of vascular endothelial cell damage and subsequent tissue inflammation under hypoxic conditions as a central feature in DVT development&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0011" class="elsevierStylePara elsevierViewall">In the realm of vascular biology&#44; the emerging role of Circular RNAs &#40;circRNAs&#41;&#44; noted for their stability and abundant expression in human tissues&#44; has garnered considerable attention&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> These non-coding RNAs&#44; characterized by their unique circular structure&#44; function predominantly within the cytoplasm where they modulate gene expression&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> This modulation occurs through the sequestration of microRNAs &#40;miRNAs&#41;&#44; thereby influencing the expression of downstream messenger RNAs &#40;mRNAs&#41; and playing a pivotal role in the pathophysiology of various diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a></p><p id="para0012" class="elsevierStylePara elsevierViewall">Among the diverse array of circRNAs&#44; circUSP9X has emerged as a molecule of interest&#46; Preliminary findings indicate an abnormal upregulation of circUSP9X in patients with DVT compared to healthy individuals&#44; suggesting a potential role in modulating endothelial cell functions and contributing to the pathogenesis of DVT&#46; The intricate interactions of circRNAs&#44; particularly circUSP9X&#44; within the endothelial milieu underscore the complexity of DVT and highlight the need for further investigation&#46; The concept of competing endogenous RNA &#40;ceRNA&#41; networks&#44; wherein circRNAs act as molecular sponges for miRNAs&#44; has been established as a crucial mechanism in disease progression&#44; including DVT&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> These networks modulate gene expression by freeing miRNA target mRNAs&#44; thereby increasing their expression levels&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> Understanding the role of circUSP9X within these networks could provide valuable insights into the molecular underpinnings of DVT&#44; offering potential avenues for novel therapeutic interventions&#46;</p><p id="para0013" class="elsevierStylePara elsevierViewall">In this study&#44; the authors hypothesize that circUSP9X is intricately involved in the pathogenesis of DVT&#46; The authors aim to elucidate its role and downstream molecular pathways in regulating endothelial cell damage&#44; particularly under hypoxic conditions induced by Cobalt &#40;II&#41; Chloride &#40;CoCl<span class="elsevierStyleInf">2</span>&#41;&#46; Furthermore&#44; the authors investigate the impact of circUSP9X modulation on DVT formation in an animal model&#44; paving the way for a deeper understanding of this complex vascular condition&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Patients and specimens</span><p id="para0014" class="elsevierStylePara elsevierViewall">This study received approval from the Ethics Committee of The First Affiliated Hospital of Hunan Medical College &#40;n&#176; 201802HN14&#41;&#46; Informed consent was obtained from all participants&#46; Clinical trials were conducted in accordance with the ARRIVE guidelines&#46; Between September 2021 and March 2023&#44; peripheral venous blood samples were collected from 28 patients diagnosed with DVT following knee replacement surgery at The First Affiliated Hospital of Hunan Medical College&#46; Blood samples from all DVT patients were collected within 24 hours post-surgery&#46; According to the Clinical Practice Guidelines of the American College of Chest Physicians&#44;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> these fracture patients were diagnosed with lower extremity venous thrombosis using color Doppler ultrasonography and lower limb venography&#46; All DVT patients received a therapeutic dose of low molecular weight heparin &#40;4100 U&#44; twice daily&#41; for chemical prophylaxis post-admission&#46; Post-discharge&#44; prophylactic Rivaroxaban &#40;Bayer&#44; Leverkusen&#44; Germany&#41; at 10 mg daily was administered until 5 weeks post-surgery&#46; Patients were included in the study based on the following criteria&#58; &#40;1&#41; Diagnosed with DVT in lower extremity fractures&#59; &#40;2&#41; No history of DVT in lower extremity fractures&#59; &#40;3&#41; Absence of pathological fractures or cardiac&#44; pulmonary&#44; hepatic&#44; or renal dysfunction&#46; Patients with malignancies&#44; myeloproliferative disorders&#44; common infections&#44; severe autoimmune diseases&#44; or severe psychiatric illnesses were excluded&#46; Additionally&#44; peripheral venous blood samples from 35 healthy subjects were included as controls&#46; Inclusion criteria for healthy subjects were&#58; 1&#41; No history of DVT&#59; 2&#41; Absence of chronic cardiac&#44; pulmonary&#44; hepatic&#44; or renal diseases or other chronic health issues&#59; 3&#41; Age and gender-matched as closely as possible to the DVT patient group&#59; 4&#41; Absence of acute infection or inflammatory symptoms&#59; 5&#41; Generally healthy with no significant medical issues&#46; Exclusion criteria were&#58; 1&#41; Undergoing medication treatments that could affect blood coagulation&#59; 2&#41; Malignancies or diseases affecting the blood&#59; 3&#41; Recent major surgical procedures or trauma&#46; Basic clinical information of the subjects is presented in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46; The sample size for the study was calculated using the formula&#58; n&#61;2&#215;&#40;Z1&#8722;&#945;2&#43;Z1&#8722;&#946;&#948;&#41;2&#215;&#963;2&#44; where &#945; &#61; 0&#46;05&#44; 1-&#946; &#61; 0&#46;8&#44; &#948; &#61; 0&#46;6&#44; &#963; &#61; 1&#46; This calculation yielded n &#61; 21&#46;8&#46; Therefore&#44; the sample sizes for both the healthy and DVT groups in this study were deemed sufficient&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Quantitative reverse transcription PCR &#40;RT-qPCR&#41;</span><p id="para0015" class="elsevierStylePara elsevierViewall">To mitigate RNA degradation&#44; repeated freeze-thaw cycles were strictly avoided in sample handling&#46; RNAse contamination was prevented using SUPERase&#8226;In&#8482; RNase Inhibitor &#40;Thermo Fisher Scientific&#41;&#46; Total RNA was extracted from human blood samples&#44; murine inferior vena cava tissues&#44; and Human Umbilical Vein Endothelial Cells &#40;HUVECs&#41; using the RNA extraction kit &#40;Invitrogen&#44; CA&#44; USA&#41;&#46; Complementary DNA was synthesized from extracted total RNA using the PrimeScript Reverse Transcription Kit&#46; Quantitative PCR for miRNA was performed using the miRNA qPCR Quantitation Kit &#40;GenePharma&#44; Shanghai&#44; China&#41; and SYBR Premix Ex Taq II &#40;Takara&#44; Tokyo&#44; Japan&#41;&#46; Glyceraldehyde 3-phosphate dehydrogenase &#40;GAPDH&#41; and U6 were employed as endogenous reference genes&#46; Relative gene expression was calculated using the 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method&#46; Primer sequences are listed in <a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Cell culture</span><p id="para0016" class="elsevierStylePara elsevierViewall">HUVECs&#44; acquired from the American Type Culture Collection &#40;ATCC&#59; Manassas&#44; VA&#44; USA&#41;&#44; were cultured in endothelial cell medium containing 5&#37; Fetal Bovine Serum&#44; 1&#37; penicillin&#47;streptomycin solution &#40;Life Technologies&#44; Paisley&#44; UK&#41;&#44; and 10&#37; endothelial cell growth supplement &#40;Sigma-Aldrich&#44; MO&#44; USA&#41;&#46; To simulate hypoxia&#47;ischemia&#44; HUVECs were treated with 250 &#956;M CoCl<span class="elsevierStyleInf">2</span> for 12 hours&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Actinomycin D and RNase R experiments</span><p id="para0017" class="elsevierStylePara elsevierViewall">For the actinomycin D assay&#44; HUVECs were seeded in six-well plates &#40;4 &#215; 10<span class="elsevierStyleSup">5</span> cells per well&#41;&#46; Twenty-four hours later&#44; cells were exposed to 2 &#956;g&#47;mL actinomycin D &#40;Sigma&#41; and collected at designated time points for RNA stability analysis using RT-qPCR&#46; RNase R &#40;3 U&#47;g&#44; Epicenter&#41; was used to treat RNA &#40;10 &#956;g&#41; from HUVECs&#44; followed by incubation at 37&#176;C for 30 minutes&#46; RT-qPCR was employed to detect circular RNA and linear RNA&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Cell transfection</span><p id="para0018" class="elsevierStylePara elsevierViewall">siRNAs targeting circUSP9X and SRC1N1&#44; pcDNA 3&#46;1 overexpression vectors&#44; miR-148b-3p mimic&#44; miR-148b-3p inhibitor&#44; and their negative controls were purchased from GenePharma&#46; According to the manufacturer&#39;s instructions&#44; these reagents were transiently transfected into HUVECs using Lipofectamine 3000 &#40;Invitrogen&#41;&#46; Transfection efficiency was assessed using RT-qPCR and Western blot 48 hours post-transfection&#46; Details of the pcDNA 3&#46;1 overexpression vectors are provided in Supplementary Material 1&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Lactate Dehydrogenase &#40;LDH&#41; assay</span><p id="para0019" class="elsevierStylePara elsevierViewall">LDH release in the culture supernatant&#44; indicative of cytotoxicity&#44; was assessed using the Pierce LDH Cytotoxicity Assay Kit &#40;Thermo Scientific&#41; as per the kit protocol&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-2&#44;5-diphenyltetrazolium bromide &#40;MTT&#41; assay</span><p id="para0020" class="elsevierStylePara elsevierViewall">HUVECs were seeded in a 96-well plate &#40;1 &#215; 10<span class="elsevierStyleSup">4</span> cells&#47;well&#41; and incubated at 37&#176;C for 24 hours&#46; Cells were then exposed to MTT &#40;10 &#181;L of 5 mg&#47;mL per well&#41; at 37&#176;C for 4 hours&#46; Post-treatment&#44; the solution was removed&#44; and 100 &#181;L of Dimethyl sulfoxide was added to each well to dissolve the formazan product&#46; Finally&#44; the optical density at 570 nm was assessed using a multi-function plate reader &#40;BioTek China&#41; following 15 minutes of shaking as per the manufacturer&#39;s protocol&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Flow cytometry</span><p id="para0021" class="elsevierStylePara elsevierViewall">Apoptosis in HUVECs was detected using the Annexin V&#47;fluorescein isothiocyanate Apoptosis Detection Kit &#40;Southern Biotech&#44; Birmingham&#44; AL&#44; USA&#41;&#46; Briefly&#44; cells were harvested&#44; washed with PBS &#40;Invitrogen&#41;&#44; and resuspended in a binding buffer&#46; To each sample&#44; 100 &#956;L of cell suspension &#40;1 &#215; 10<span class="elsevierStyleSup">6</span> cells&#47;mL&#41; was added to 5 &#956;L of Annexin V-FITC &#40;Partec GmbH&#44; CyFlow Space&#41; and 10 &#956;L of Propidium Iodide&#44; incubated at room temperature for 15 minutes&#44; and washed twice with PBS&#46; Cell apoptosis was analyzed using a FACSan flow cytometer &#40;BD Bioscience&#44; Heidelberg&#44; Germany&#41;&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Enzyme-linked immunosorbent assay &#40;ELISA&#41;</span><p id="para0022" class="elsevierStylePara elsevierViewall">Levels of inflammatory cytokines Tumor Necrosis Factor &#40;TNF&#41;-&#945;&#44; Interleukin &#40;IL&#41;-1&#946;&#44; and IL-6 in culture supernatants and tissues were quantified using ELISA Kits as per the manufacturer&#39;s instructions &#40;R&#38;D Systems&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Western blot</span><p id="para0023" class="elsevierStylePara elsevierViewall">Total protein from tissues and cells was extracted using radioimmunoprecipitation assay lysis buffer &#40;Servicebio&#44; Wuhan&#44; China&#41; and quantified with the bicinchoninic acid Protein Assay Kit &#40;Solarbio&#44; Beijing&#44; China&#41;&#46; Samples were boiled for 10 minutes with loading buffer&#44; separated on sodium dodecyl sulphate-polyacrylamide gel electrophoresis&#44; and transferred to Polyvinylidene Difluoride membranes&#46; Membranes were blocked &#40;5&#37; non-fat milk in TBST&#41; at room temperature for 2 hours and incubated overnight at 4&#176;C with primary antibodies&#46; This was followed by incubation with immunoglobulin G-Horseradish Peroxidase secondary antibodies for 2 hours&#44; and membranes were washed thrice&#44; 10 minutes each time&#46; Immunoreactivity was detected using the Enhanced Chemiluminescence detection system &#40;Thermo Fisher Scientific&#44; Frederick&#44; MD&#44; USA&#41;&#46; Protein bands were analyzed using Image Lab software&#46; Primary antibodies used were as follows&#58; GAPDH &#40;60004-1-Ig&#44; Proteintech&#41;&#44; cleaved caspase-3 &#40;ab2302&#44; Abcam&#41;&#44; Bax &#40;ab32503&#44; Abcam&#41;&#44; Bcl-2 &#40;sc-7382&#44; Santa Cruz Biotechnology&#41;&#44; p-p65 &#40;ab86299&#44; Abcam&#41;&#44; p65 &#40;ab86299&#44; Abcam&#41;&#44; SRCIN1 &#40;ABIN350838&#44; antibodies-online&#41;&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Dual-luciferase reporter assay</span><p id="para0024" class="elsevierStylePara elsevierViewall">Wild-type &#40;WT&#41; 3&#8242;-UTR fragments of circUSP9X and SRCIN1 containing predicted miR-148b-3p binding sites were amplified and cloned into the pmirGLO Dual-Luciferase Expression Vector &#40;Promega&#44; Madison&#44; WI&#44; USA&#41; to construct reporter vectors SRCIN1-WT and circUSP9X-WT&#46; The putative binding sites for miR-148b-3p in the 3&#8242;-UTR of circUSP9X and SRCIN1 were mutated using the GeneArt&#8482; Site-Directed Mutagenesis PLUS System &#40;cat&#46; no&#46; A14604&#59; Thermo Fisher Scientific&#44; Inc&#46;&#41;&#46; Mutant &#40;Mut&#41; 3&#8242;-UTRs of circUSP9X and SRCIN1 were cloned into the pmirGLO vector to construct reporter vectors circUSP9X-MUT and SRCIN1-MUT&#46; Reporter vectors and miR-148b-3p mimic or mimic NC were co-transfected into HUVECs using Lipofectamine 3000 reagent&#46; Luciferase activity was measured 48 hours post-transfection using the Dual-Luciferase Reporter Assay System &#40;Promega&#44; Madison&#44; WI&#44; USA&#41;&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">RNA Immunoprecipitation &#40;RIP&#41; experiment</span><p id="para0025" class="elsevierStylePara elsevierViewall">RIP was conducted using the RIP Kit &#40;Millipore&#44; Bedford&#44; MA&#44; USA&#41;&#46; Briefly&#44; cells were collected and lysed using RIP lysis buffer&#46; Cell extracts were then incubated with RIP buffer containing magnetic beads conjugated with anti-human Ago2 antibody&#46; Proteinase K was applied to digest proteins&#44; and immunoprecipitated RNA was isolated&#46; RNA expression was detected by RT-qPCR&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">DVT animal model</span><p id="para0026" class="elsevierStylePara elsevierViewall">Animal experiments were approved by the Ethics Committee of The First Affiliated Hospital of Hunan Medical College &#40;n&#176; 201808HN61&#41;&#46; Clinical trials were conducted in accordance with the ARRIVE guidelines&#46; Efforts were made to minimize animal suffering&#46; Forty C57BL&#47;6J mice &#40;6&#8210;8 weeks old&#41; were obtained from Beijing Vital River Laboratory Animal Technology Co&#46;&#44; Ltd&#46; &#40;Beijing&#44; China&#41;&#46; Animals were housed in standard laboratory conditions &#40;temperature&#58; 24&#176;&#177;1&#176;C&#59; humidity&#58; 40&#37;&#8210;60&#37;&#59; 12h light-dark cycle&#41; with free access to food and water&#46; After a week of acclimatization&#44; thirty mice were used to establish a DVT model&#46; Briefly&#44; mice were anesthetized with pentobarbital sodium &#40;30 mg&#47;kg&#44; intraperitoneal&#41;&#46; The medial thigh hair was removed&#44; and mice were positioned supine&#46; A longitudinal incision was made on the medial thigh to expose the femoral vein 2 cm from the incision&#46; The vein was clamped at three different positions for 30 seconds each with mosquito forceps&#44; followed by suturing the incision&#46; The sham operation group underwent exposure of the inferior vena cava without clamping&#46; Mice were regularly fed post-recovery&#46; Limb swelling and skin color changes were visible on day 1 post-modeling&#46; Venous thrombosis formation in mice was monitored using a high-frequency ultrasound imaging system &#40;Vevo 770&#44; FUJIFILM VisualSonics&#41;&#46; To knock down circUSP9X&#44; one week prior to surgery&#44; AVV-shRNA-circUSP9X and control adenovirus AVV-GFP-NC were injected into mice via tail vein &#40;1&#46;6 &#215; 10<span class="elsevierStyleSup">11</span> vector genomes&#47;mouse&#41;&#46; 24 hours post-modeling&#44; mice were euthanized&#44; and inferior vena cava tissues were harvested&#46; Some tissues were fixed in 4&#37; paraformaldehyde&#44; while the rest were frozen at -80&#176;C for further studies&#46;</p></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">Hematoxylin and Eosin &#40;H&#38;E&#41; staining</span><p id="para0027" class="elsevierStylePara elsevierViewall">Collected inferior vena cava tissues fixed in 4&#37; paraformaldehyde were dehydrated using graded alcohols&#44; embedded in paraffin&#44; and sectioned into 4 &#956;m slices&#46; Tissue sections were deparaffinized in xylene and subjected to routine H&#38;E staining&#46; Morphological changes were assessed under a light microscope &#40;LX51&#44; Olympus Optical Co&#46;&#44; Ltd&#44; Tokyo&#44; Japan&#41; in five random fields per section&#46;</p></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">Data analysis</span><p id="para0028" class="elsevierStylePara elsevierViewall">Data were analyzed using GraphPad Prism 9&#46;0 software &#40;GraphPad&#44; La Jolla&#44; CA&#44; USA&#41; and presented as mean &#177; Standard Deviation &#40;SD&#41;&#46; Unpaired Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used to evaluate differences between the two groups&#46; One-way Analysis of Variance &#40;ANOVA&#41; and Tukey&#39;s post-hoc test were employed to assess differences among multiple groups&#46; A p-value &#60; 0&#46;05 was considered statistically significant&#46; All experiments in this study were performed with at least three biological replicates&#46;</p></span></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">Results</span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">Enhanced circUSP9X expression in DVT context</span><p id="para0029" class="elsevierStylePara elsevierViewall">In examining the role of circUSP9X within the context of DVT&#44; the initial analyses focused on its expression patterns&#46; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>A reveals that circUSP9X levels are markedly elevated in the blood of DVT patients compared to those in healthy individuals&#46; Additionally&#44; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>B illustrates that the expression of circUSP9X is significantly augmented in HUVECs following CoCl<span class="elsevierStyleInf">2</span> treatment&#46; Furthering this exploration&#44; the authors established a DVT mouse model and noted a pronounced increase in circUSP9X expression in the inferior vena cava tissue&#44; as indicated in <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>C&#46; To assess the circular nature of circUSP9X&#44; the authors conducted experiments using Actinomycin D and RNase R&#46; The present findings&#44; depicted in <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>D&#44; show that while Actinomycin D treatment reduces the half-life of GAPDH&#44; it does not affect the stability of circUSP9X&#46; Additionally&#44; RNase R treatment&#44; which digests linear GAPDH mRNA&#44; leaves circUSP9X intact&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>E&#46; The authors further referenced the circUSP9X gene information from the biological information website circBank &#40;<a href="http://www.circbank.cn">http&#58;&#47;&#47;www&#46;circbank&#46;cn</a>&#41;&#44; identifying circUSP9X &#40;circBase ID&#58; hsa&#95;circ&#95;0090221&#41; as located on chrX&#58; 40982723-40988398 strand&#58; &#43;&#44; spanning 400 bp and comprising exons 2 and 3 of the USP9X gene &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>F&#41;&#46; These collective data underscore the abnormal elevation of circUSP9X&#44; a circular RNA&#44; in the milieu of DVT&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Impact of circUSP9X Knockdown on HUVECs&#58; enhanced viability and reduced apoptosis and inflammation</span><p id="para0030" class="elsevierStylePara elsevierViewall">Investigating the functional role of circUSP9X in DVT&#44; the authors employed siRNA targeting circUSP9X &#40;si-circUSP9X&#41; to modulate its expression in HUVECs&#46; As evidenced in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#44; si-circUSP9X transfection effectively reduced circUSP9X expression&#46; CoCl<span class="elsevierStyleInf">2</span>-induced cytotoxicity&#44; marked by an increase in LDH release&#44; was notably decreased following circUSP9X knockdown&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>B&#46; Further&#44; the viability of HUVECs under CoCl<span class="elsevierStyleInf">2</span> stress&#44; assessed through MTT assays &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>C&#41;&#44; was significantly improved with circUSP9X knockdown&#46; This was accompanied by a reduction in apoptosis rates&#44; depicted in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>D&#44; indicating a protective effect against CoCl<span class="elsevierStyleInf">2</span>-induced cellular injury&#46; Moreover&#44; ELISA analyses&#44; presented in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>E&#44; demonstrated a CoCl<span class="elsevierStyleInf">2</span>-driven increase in pro-inflammatory cytokines&#44; which was effectively countered by circUSP9X knockdown&#46; Western blot results&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>F&#44; revealed an altered expression of apoptosis-related proteins under CoCl<span class="elsevierStyleInf">2</span> treatment&#44; which was modulated by circUSP9X knockdown&#46; These findings collectively underscore the potential of circUSP9X as a regulatory factor in endothelial cell dysfunction&#44; suggesting its knockdown as a viable approach to ameliorate cellular injury in the context of DVT&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Selective Interaction of circUSP9X with miR-148b-3p in DVT</span><p id="para0031" class="elsevierStylePara elsevierViewall">In exploring the molecular dynamics within DVT&#44; the focus turned to the miRNAs interacting with circUSP9X&#46; Employing the bioinformatics tool starbase for an in-depth analysis&#44; the authors identified miR-148b-3p&#44; known for its protective role against endothelial cell damage&#44; as a key miRNA interacting with circUSP9X&#46; This discovery led us to conjecture a similar function for miR-148b-3p within the DVT framework&#46; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>A demonstrates potential binding sites between circUSP9X and miR-148b-3p&#44; suggesting a direct molecular interaction&#46; The subsequent studies involved assessing miR-148b-3p&#39;s expression patterns in DVT&#46; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>B and C illustrate a notable decrease in miR-148b-3p expression in HUVECs following CoCl<span class="elsevierStyleInf">2</span> treatment&#44; a trend also observed in DVT mouse models&#46; To elucidate the binding specificity between circUSP9X and miR-148b-3p&#44; the authors conducted dual-luciferase reporter assays&#46; The results&#44; shown in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>D&#44; revealed a significant reduction in luciferase activity upon co-transfection with WT-circUSP9X and miR-148b-3p mimic&#44; whereas the MUT-circUSP9X and miR-148b-3p co-transfection did not exhibit such effects&#46; Additionally&#44; RIP experiments highlighted a pronounced enrichment of circUSP9X and miR-148b-3p in Ago2 magnetic beads&#44; as depicted in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>E&#46; Furthermore&#44; RT-qPCR experiments&#44; presented in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a>F&#44; indicated that the knockdown of circUSP9X led to an upregulation of miR-148b-3p in HUVECs&#46; These findings collectively suggest a targeted regulatory mechanism by circUSP9X on the downstream gene miR-148b-3p&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">circUSP9X modulates cellular toxicity&#44; viability&#44; and apoptosis in HUVECs through miR-148b-3p interaction</span><p id="para0032" class="elsevierStylePara elsevierViewall">In advancing understanding of miR-148b-3p&#39;s role&#44; the authors transfected miR-148b-3p mimic into HUVECs treated with CoCl<span class="elsevierStyleInf">2</span> and concurrently conducted co-transfection experiments with si-circUSP9X and miR-148b-3p inhibitor in similar conditions&#46; Illustrated in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>A&#44; transfection with miR-148b-3p mimic and si-circUSP9X substantially increased miR-148b-3p levels&#46; LDH release assays revealed that miR-148b-3p mimics reduced LDH secretion&#44; and notably&#44; the inhibitory effect of si-circUSP9X on LDH release was counteracted by the miR-148b-3p inhibitor&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>B&#46; Moreover&#44; <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>C indicates that miR-148b-3p mimics enhanced cellular viability&#44; while the positive impact of si-circUSP9X on cell vitality was attenuated by the miR-148b-3p inhibitor&#46; Flow cytometry analysis&#44; presented in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>D&#44; demonstrated that miR-148b-3p mimic reduced the rate of cell apoptosis&#44; and this reduction was reversed upon introduction of the miR-148b-3p inhibitor in the presence of si-circUSP9X&#46; ELISA results&#44; as seen in <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>E&#44; indicated that miR-148b-3p mimic decreased the release of inflammatory cytokines&#44; whereas the suppressive effect of si-circUSP9X on these cytokines was negated by the miR-148b-3p inhibitor&#46; Finally&#44; Western blot analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>F&#41; showed that both miR-148b-3p mimic and si-circUSP9X reduced the expression of cleaved caspase-3&#44; Bax&#44; and p-p65&#44; while increasing Bcl-2 expression&#46; However&#44; these effects of si-circUSP9X were reversed by the miR-148b-3p inhibitor&#46; These findings collectively highlight that circUSP9X regulates key cellular processes in CoCl<span class="elsevierStyleInf">2</span>-treated HUVECs through the modulation of miR-148b-3p&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">SRCIN1&#58; a downstream target of miR-148b-3p in DVT pathogenesis</span><p id="para0033" class="elsevierStylePara elsevierViewall">In furthering this investigation into the molecular mechanisms of DVT&#44; attention was focused on the downstream targets of miR-148b-3p&#46; Notably&#44; SRCIN1 has been implicated in DVT&#44; exhibiting aberrant expression patterns&#44; a finding corroborated by the present study as illustrated in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>A and B&#46; Utilizing the starbase bioinformatics portal&#44; the authors identified putative interaction sites between miR-148b-3p and SRCIN1&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>C&#46; Subsequent experimental validation using dual-luciferase reporter assays and RIP experiments affirmed this interaction&#46; Co-transfection with WT-SRCIN1 and miR-148b-3p mimic led to a notable reduction in luciferase activity&#46; Additionally&#44; SRCIN1 and miR-148b-3p were found to be enriched in Ago2 magnetic beads&#44; as presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>D and E&#46; Moreover&#44; the modulation of miR-148b-3p levels&#44; either through overexpression or knockdown&#44; inversely affected SRCIN1 protein expression&#44; as evidenced in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>F&#46; These findings elucidate SRCIN1 as a key downstream target of miR-148b-3p&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0024" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0032">Exacerbation of CoCl<span class="elsevierStyleInf">2</span> toxicity in HUVECs by overexpressed circUSP9X and its reversal by SRCIN1 knockdown</span><p id="para0034" class="elsevierStylePara elsevierViewall">In these subsequent experiments&#44; the authors co-transfected pcDNA 3&#46;1-circUSP9X and si-SRCIN1 into HUVECs treated with CoCl<span class="elsevierStyleInf">2</span>&#46; <a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>A shows that overexpression of circUSP9X via pcDNA 3&#46;1-circUSP9X enhanced SRCIN1 protein expression&#44; an effect that was reversed upon SRCIN1 knockdown&#46; Rescue experiments further revealed that overexpression of circUSP9X increased LDH release&#44; reduced cellular viability&#44; promoted apoptosis&#44; and elevated the release of inflammatory cytokines TNF-&#945;&#44; IL-1&#946;&#44; and IL-6&#46; Additionally&#44; it upregulated cleaved caspase-3&#44; Bax&#44; and p-p65 protein expression while suppressing Bcl-2 expression&#46; Notably&#44; all these effects were reversed by the knockdown of SRCIN1&#44; as depicted in <a class="elsevierStyleCrossRef" href="#fig0006">Fig&#46; 6</a>B&#8210;F&#46; These findings underscore SRCIN1 as a functional protein in the circUSP9X-mediated regulatory pathway in DVT&#44; highlighting its potential role as a key modulator of endothelial cell toxicity&#46;</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0033">Knockdown of circUSP9X mitigates venous thrombosis in a murine model</span><p id="para0035" class="elsevierStylePara elsevierViewall">In the <span class="elsevierStyleItalic">in vivo</span> investigation of circUSP9X&#39;s role in DVT&#44; a DVT mouse model was employed&#46; Results from RT-qPCR and Western blot analyses illuminated that circUSP9X knockdown effectively diminished SRCIN1 expression while concurrently augmenting miR-148b-3p expression &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7</a>A and B&#41;&#46; HE-staining further illustrated the impact of circUSP9X knockdown&#44; revealing a marked reduction in thrombus formation in DVT mice &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7</a>C&#41;&#46; ELISA assays &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7</a>D&#41; showed a pronounced decrease in the levels of inflammatory cytokines in the inferior vena cava tissues of mice with circUSP9X knockdown&#46; Additionally&#44; Western blot analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0007">Fig&#46; 7</a>E&#41; confirmed that this genetic intervention led to a notable suppression of cleaved caspase-3&#44; Bax&#44; and p-p65 proteins&#44; alongside an increase in Bcl-2 expression&#46; These collective findings underscore the therapeutic potential of circUSP9X knockdown in mitigating venous thrombosis&#46;</p><elsevierMultimedia ident="fig0007"></elsevierMultimedia></span></span><span id="sec0026" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0034">Discussion</span><p id="para0036" class="elsevierStylePara elsevierViewall">DVT involves the interaction of vascular endothelial cells&#44; platelets&#44; and clotting-related proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> DVT is asymptomatic and is easily overlooked in its early stages&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Apoptosis and inflammation of vascular endothelial cells can be observed during DVT formation&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> Therefore&#44; VEC injury is an important reason for DVT&#46; Here&#44; HUVECs were exposed to CoCl<span class="elsevierStyleInf">2</span> to simulate hypoxia during DVT&#44; and circUSP9X&#39;s role in hypoxia injury in HUVECs was probed&#46; Finally&#44; it was delineated that circUSP9X increased CoCl<span class="elsevierStyleInf">2</span>-mediated cytotoxicity&#44; increased apoptosis and inflammation&#44; and decreased cell viability by competitively adsorbing miR-148b-3p and mediating SRCIN1 expression&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">It is a major problem to detect DVT early&#46; circRNA can be used as an early diagnostic biomarker for a variety of diseases&#44; such as gestational diabetes&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> and osteoarthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> This study noted that circUSP9X was forced in the peripheral blood of fracture patients with DVT&#46; The same trend was observed in the blood of mice with DVT modeling&#46; This suggests that abnormally expressed circUSP9X may serve as a potential biomarker for DVT&#44; which will be beneficial for the early detection and treatment of DVT&#46; However&#44; ROC curve analysis is needed to prove the possibility of circUSP9X as a biomarker of DVR in subsequent studies&#46;</p><p id="para0038" class="elsevierStylePara elsevierViewall">Apoptosis and inflammation of VECs are significant causes of DVT&#46; It is discussed that circUSP9X exacerbates oxidized Low-Density Lipoprotein &#40;ox-LDL&#41;-induced HUVECs damage&#44; which includes apoptosis&#44; inflammation&#44; and oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> This study further indicated that circUSP9X controlled endothelial cell function&#46; In detail&#44; knocking down circUSP9X effectively reduced CoCl<span class="elsevierStyleInf">2</span>-induced apoptosis and inflammation of HUVECs and increased cell viability&#46; As suggested&#44; Nuclear Factor &#40;NF&#41;-&#954;B pathway hyper-activation accelerates DVT formation&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> Therefore&#44; inhibiting NF-&#954;B phosphorylation by knockdown of circUSP9X may be an important reason for reducing tissue inflammatory factors and accelerating thrombolysis&#46; miR-148b-3p&#47;SRCIN1 axis was confirmed as the downstream target of circUSP9X&#46; MiR-148b-3p mediates VEC activity and VEC damage&#46; It can protect against ox-LDL&#44; and oxygen-glucose deprivation&#47;reoxygenation-induced VEC injury&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> The present results also confirm the beneficial role of miR-148b-3p in protecting against VEC damage&#46; Overexpressing miR-148b-3p effectively improved CoCl<span class="elsevierStyleInf">2</span>-induced HUVEC inflammation and apoptosis&#46; Mechanistically&#44; miR-148b-3p acted by regulating the downstream gene SRCIN1&#46; SRCIN1 triggered the activation of SRC tyrosine Kinase &#40;Csk&#41;&#44; which is a member of a family of non-receptor tyrosine kinase proteins and plays a crucial role in angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> It has been documented that the activity of SRC is markedly diminished in HUVECs exposed to ox-LDL&#44; and the pro-angiogenic effects of miR-150 mimic in HUVECs exposed to ox-LDL are entirely nullified in the presence of an SRC inhibitor&#46; Upregulation of miR-150 promoted angiogenesis and proliferation of endothelial progenitor cells by targeting SRCIN1 <span class="elsevierStyleItalic">in vitro</span> and thrombus resolution <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a></p><p id="para0040" class="elsevierStylePara elsevierViewall">In conclusion&#44; this study suggests that circUSP9X is a key regulator of CoCl<span class="elsevierStyleInf">2</span>-induced HUVEC dysfunction&#46; It affects cytotoxicity&#44; apoptosis&#44; and inflammation of HUVECs by adsorbing miR-148b-3p and mediating SRCIN1&#46; Moreover&#44; knocking down circUSP9X can promote the decomposition of DVT&#46; The results of this study provide a new molecular target for DVT-targeting drugs&#46;</p></span><span id="sec0027" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0035">Ethics approval</span><p id="para0041" class="elsevierStylePara elsevierViewall">The present study was approved by the Ethics Committee of The First Affiliated Hospital of Hunan Medical College &#40;n&#176; 201802HN14&#41; and written informed consent was provided by all patients prior to the study start&#46; All procedures were performed in accordance with the ethical standards of the Institutional Review Board and The Declaration of Helsinki&#44; and its later amendments or comparable ethical standards&#46;</p><p id="para0042" class="elsevierStylePara elsevierViewall">And the animal experiment research protocol was approved by The First Affiliated Hospital of Hunan Medical College &#40;n&#176; 201808HN61&#41; and performed in accordance with the &#8220;Guidelines for the care and use of experimental animals&#8221;&#46;</p></span><span id="sec0028" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0036">Authors&#8217; contributions</span><p id="para0043" class="elsevierStylePara elsevierViewall">Conceptualization&#44; KeYun Zhang and Qin Su&#59; methodology&#44; HaiRong Tang&#44; Qiang Tian and Xin Lin&#59; formal analysis&#44; ZhangFeng Luo and MeiChun Fu&#59; investigation&#44; JiaQi Peng and HongTao Zhao&#59; data curation&#44; YongChao Wang&#59; writing-original draft preparation&#44; KeYun Zhang and Qin Su&#59; writing-review and editing&#44; YongChao Wang&#59; project administration&#44; YongChao Wang&#46; All authors have read and agreed to the published version of the manuscript&#46;</p></span><span id="sec0029" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0037">Funding</span><p id="para9003" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="celist0002"><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">1&#41;</span><p id="para0044" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs0001">Hunan Provincial Natural Science Foundation</span> of the general project&#44; Differences and molecular mechanisms of postoperative lower limb VTE formation in elderly patients with hip fractures of different blood types &#40;n&#176; <span class="elsevierStyleGrantNumber" refid="gs0001">2020JJ4061</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0005"><span class="elsevierStyleLabel">2&#41;</span><p id="para0045" class="elsevierStylePara elsevierViewall">2022 annual project of <span class="elsevierStyleGrantSponsor" id="gs0002">Hunan Disabled Persons&#39; Rehabilitation Association</span>&#44; Research on the Effect of Virtual Reality Technology &#40;VR&#41; Combined with Ontological Function Training on the Rehabilitation of Limb Function in Children with Cerebral Palsy &#40;n&#176; <span class="elsevierStyleGrantNumber" refid="gs0002">2022XK0223</span>&#41;</p></li><li class="elsevierStyleListItem" id="celistitem0006"><span class="elsevierStyleLabel">3&#41;</span><p id="para0046" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs0003">Hunan Provincial Innovation Platform and Talent Plan&#44; Hunan Province Multiple Severe Trauma Treatment Clinical Medical Technology Demonstration Base</span> &#40;n&#176; <span class="elsevierStyleGrantNumber" refid="gs0003">2019SK4019</span>&#41;</p></li></ul></p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Patients and specimens"
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            1 => array:2 [
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              "titulo" => "Quantitative reverse transcription PCR &#40;RT-qPCR&#41;"
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              "titulo" => "Cell culture"
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              "titulo" => "Actinomycin D and RNase R experiments"
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              "identificador" => "sec0007"
              "titulo" => "Cell transfection"
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            5 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "Lactate Dehydrogenase &#40;LDH&#41; assay"
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            6 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "3-&#40;4&#44;5-dimethylthiazol-2-yl&#41;-2&#44;5-diphenyltetrazolium bromide &#40;MTT&#41; assay"
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              "identificador" => "sec0010"
              "titulo" => "Flow cytometry"
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              "titulo" => "Enzyme-linked immunosorbent assay &#40;ELISA&#41;"
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              "titulo" => "Western blot"
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              "titulo" => "Dual-luciferase reporter assay"
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              "titulo" => "RNA Immunoprecipitation &#40;RIP&#41; experiment"
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              "identificador" => "sec0015"
              "titulo" => "DVT animal model"
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              "identificador" => "sec0016"
              "titulo" => "Hematoxylin and Eosin &#40;H&#38;E&#41; staining"
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              "identificador" => "sec0019"
              "titulo" => "Enhanced circUSP9X expression in DVT context"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Impact of circUSP9X Knockdown on HUVECs&#58; enhanced viability and reduced apoptosis and inflammation"
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              "identificador" => "sec0021"
              "titulo" => "Selective Interaction of circUSP9X with miR-148b-3p in DVT"
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              "titulo" => "circUSP9X modulates cellular toxicity&#44; viability&#44; and apoptosis in HUVECs through miR-148b-3p interaction"
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              "identificador" => "sec0023"
              "titulo" => "SRCIN1&#58; a downstream target of miR-148b-3p in DVT pathogenesis"
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              "identificador" => "sec0024"
              "titulo" => "Exacerbation of CoCl toxicity in HUVECs by overexpressed circUSP9X and its reversal by SRCIN1 knockdown"
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            6 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Knockdown of circUSP9X mitigates venous thrombosis in a murine model"
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          "titulo" => "Discussion"
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    "fechaRecibido" => "2023-12-01"
    "fechaAceptado" => "2024-05-12"
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            1 => "miR-148b-3p"
            2 => "Deep vein thrombosis"
            3 => "SRCIN1"
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    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara010" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">circUSP9X reduction increases cell viability and decreases apoptosis and inflammation in HUVECs</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">SRCIN1&#58; A Downstream Target of miR-148b-3p in DVT Pathogenesis&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0004" class="elsevierStylePara elsevierViewall">SRC Kinase Signaling Inhibitor 1 &#40;SRCIN1&#41; is controlled by miR-148b-3p&#46;</p></li></ul></p></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objectives</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">This study aims to elucidate the role of circUSP9X &#40;Circular RNA Ubiquitin Specific Peptidase 9 X-Linked&#41; in the development of venous thrombosis in the lower extremities&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">An animal model of Deep Vein Thrombosis &#40;DVT&#41; and a hypoxic model of Human Umbilical Vein Endothelial Cells &#40;HUVECs&#41; treated with Cobalt &#40;II&#41; Chloride &#40;CoCl<span class="elsevierStyleInf">2</span>&#41; were developed&#46; The expression levels of circUSP9X&#44; microRNA-148b-3p &#40;miR-148b-3p&#41;&#44; and SRC Kinase Signaling Inhibitor 1 &#40;SRCIN1&#41; were quantified using quantitative reverse transcription Polymerase Chain Reaction and Western blot analysis&#46; Cell cytotoxicity&#44; viability&#44; apoptosis&#44; and inflammation in HUVECs were assessed via Lactate Dehydrogenase &#40;LDH&#41; assay&#44; MTT assay&#44; flow cytometry&#44; Enzyme-Linked Immunosorbent Assay&#44; and Western blot&#44; respectively&#46; Hematoxylin and Eosin staining were employed for histopathological examination of the venous tissues in the animal model&#46; The interaction between circUSP9X&#44; miR-148b-3p&#44; and SRCIN1 was further explored through dual-luciferase reporter assays and RNA Immunoprecipitation experiments&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">The present findings reveal a significant upregulation of circUSP9X and SRCIN1 and a concurrent downregulation of miR-148b-3p in DVT cases&#46; Knockdown of circUSP9X or overexpression of miR-148b-3p ameliorated CoCl<span class="elsevierStyleInf">2</span>-induced apoptosis in HUVECs&#44; reduced LDH release&#44; enhanced cellular viability&#44; and mitigated inflammation&#46; Conversely&#44; overexpression of circUSP9X intensified CoCl<span class="elsevierStyleInf">2</span>&#39;s cytotoxic effects&#46; The effects of manipulating circUSP9X expression were counteracted by the corresponding modulation of miR-148b-3p and SRCIN1 levels&#46; Additionally&#44; circUSP9X knockdown effectively inhibited the formation of DVT in the mouse model&#46; A competitive binding mechanism of circUSP9X for miR-148b-3p&#44; modulating SRCIN1 expression&#44; was identified&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara014" class="elsevierStyleSimplePara elsevierViewall">circUSP9X promotes the formation of DVT through the regulation of the miR-148b-3p&#47;SRCIN1 axis&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Abnormally high expression of circUSP9X in DVT&#46; &#40;A&#41; RT-qPCR tests of circUSP9X in healthy subjects and DVT patients&#46; &#40;B&#41; RT-qPCR tests of circUSP9X in ClCl<span class="elsevierStyleInf">2</span>-treated HUVECs&#46; &#40;C&#41; RT-qPCR tests of circUSP9X in inferior vena cava tissues of DVT mice&#46; &#40;D&#41; Actinomycin D test of the ring structure of circUSP9X&#46; &#40;E&#41; RNAse R experiment to detect the circUSP9X ring structure&#59; &#40;F&#41; Bioinformatics website circbank for gene information for hsa&#95;circ&#95;0090221&#59; Data are expressed as mean &#177; SD &#40;C&#44; n &#61; 10&#59; For the rest&#44; n &#61; 3&#41;&#46; &#42;p &#60; 0&#46;05&#46;</p>"
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            "Alto" => 2258
            "Ancho" => 3458
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          0 => array:3 [
            "identificador" => "alt0002"
            "detalle" => "Fig "
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        "descripcion" => array:1 [
          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">circUSP9X knockdown increases cell viability and decreases apoptosis and inflammation in HUVECs&#46; si-circUSP9X was transfected into CoCl<span class="elsevierStyleInf">2</span>-treated HUVECs&#46; &#40;A&#41; RT-qPCR tests of circUSP9X&#46; &#40;B&#41; Commercial kit to detect LDH release&#46; &#40;C&#41; MTT assay tests of cell viability&#46; &#40;D&#41; Flow cytometry analysis of apoptosis rate&#46; &#40;E&#41; ELISA measurements of IL-1&#946;&#44; IL-6 and TNF-&#945;&#46; &#40;F&#41; Western blot detection of cleaved caspase-3&#44; Bax&#44; p-p65&#44; and Bcl-2&#59; Data expressed as mean &#177; SD &#40;n &#61; 3&#41;&#46; &#42; p &#60; 0&#46;05&#46;</p>"
        ]
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        "identificador" => "fig0003"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1798
            "Ancho" => 3458
            "Tamanyo" => 289411
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0003"
            "detalle" => "Fig "
            "rol" => "short"
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        "descripcion" => array:1 [
          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Competitive adsorption of miR-148b-3p by circUSP9X&#46; &#40;A&#41; Starbase predicted the potential binding sites of circUSP9X and miR-148b-3p&#46; &#40;B&#41; RT-qPCR tests of miR-148b-3p in ClCl<span class="elsevierStyleInf">2</span>-treated HUVECs&#46; &#40;C&#41; RT-qPCR tests of miR-148b-3p in inferior vena cava tissues of DVT mice&#46; &#40;D&#41; Dual luciferase reporting assay detection of the targeting binding relationship between circUSP9X and miR-148b-3p&#46; &#40;E&#41; RIP experiment detection of the targeting binding relationship between circUSP9X and miR-148b-3p&#46; &#40;F&#41; RT-qPCR tests of miR-148b-3p&#59; Data are expressed as mean &#177; SD &#40;C&#44; n &#61; 10&#59; For the rest&#44; n &#61; 3&#41;&#46; &#42;p &#60; 0&#46;05&#46;</p>"
        ]
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        "identificador" => "fig0004"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 2671
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            "Tamanyo" => 593546
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            "identificador" => "alt0004"
            "detalle" => "Fig "
            "rol" => "short"
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">CircUSP9X regulates the cytotoxicity&#44; activity and apoptosis of HUVECs by adsorption of miR-148b-3p&#46; miR-148b-3p mimic was transfected into CoCl<span class="elsevierStyleInf">2</span>-treated HUVECs alone or si-USP9X and miR-148b-3p inhibitor were co-transfected&#46; &#40;A&#41; RT-qPCR tests of miR-148b-3p&#46; &#40;B&#41; Commercial kit to detect LDH release&#46; &#40;C&#41; MTT assay tests of cell viability&#46; &#40;D&#41; Flow cytometry analysis of apoptosis rate&#46; &#40;E&#41; ELISA measurements of IL-1&#946;&#44; IL-6 and TNF-&#945;&#46; &#40;F&#41; Western blot detection of cleaved caspase-3&#44; Bax&#44; p-p65 and Bcl-2&#59; Data expressed as mean &#177; SD &#40;n &#61; 3&#41;&#46; &#42;p &#60; 0&#46;05&#46;</p>"
        ]
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        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 2537
            "Ancho" => 3458
            "Tamanyo" => 378507
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0005"
            "detalle" => "Fig "
            "rol" => "short"
          ]
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          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">SRCIN1 is the downstream target gene of miR-148b-3p&#46; &#40;A&#41; Western blot tests of SRCIN1 in ClCl<span class="elsevierStyleInf">2</span>-treated HUVECs&#46; &#40;B&#41; Western blot tests of SRCIN1 in inferior vena cava tissues of DVT mice&#46; &#40;C&#41; Starbase predicted the targeted binding sites of miR-148b-3p and SRCIN1&#46; &#40;D&#41; Dual luciferase reporting assay detection of the targeting binding relationship between SRCIN1 and miR-148b-3p&#46; &#40;E&#41; RIP experiment detection of the targeting binding relationship between SRCIN1 and miR-148b-3p&#46; &#40;F&#41; Western blot tests of SRCIN1&#46; Data are expressed as mean &#177; SD &#40;n &#61; 3&#41;&#46; &#42;p &#60; 0&#46;05&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "fig0006"
        "etiqueta" => "Fig&#46; 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 2396
            "Ancho" => 3458
            "Tamanyo" => 472564
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          0 => array:3 [
            "identificador" => "alt0006"
            "detalle" => "Fig "
            "rol" => "short"
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        "descripcion" => array:1 [
          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">Overexpressing circUSP9X increases CoCl<span class="elsevierStyleInf">2</span> toxicity to HUVECs&#44; but this effect is inhibited by knocking down SRCIN1&#46; pcDNA 3&#46;1-circUSP9X and si-SRCIN1 were co-transfected into CoCl2-treated HUVECs&#46; &#40;A&#41; Western blot tests of SRCIN1&#46; &#40;B&#41; Commercial kit to detect LDH release&#46; &#40;C&#41; MTT assay tests of cell viability&#46; &#40;D&#41; Flow cytometry analysis of apoptosis rate&#46; &#40;E&#41; ELISA measurements of IL-1&#946;&#44; IL-6 and TNF-&#945;&#46; &#40;F&#41; Western blot detection of cleaved caspase-3&#44; Bax&#44; p-p65 and Bcl-2&#59; Data expressed as mean &#177; SD &#40;n &#61; 3&#41;&#46; &#42; p &#60; 0&#46;05&#46;</p>"
        ]
      ]
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        "etiqueta" => "Fig&#46; 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
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        "detalles" => array:1 [
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            "identificador" => "alt0007"
            "detalle" => "Fig "
            "rol" => "short"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall">Knocking down circUSP9X improves DVT <span class="elsevierStyleItalic">in vivo</span>&#46; &#40;A&#41; RT-qPCR tests of circUSP9X and miR-148b-3p in blood of mice&#46; &#40;B&#41; Western blot tests of SRCIN1 in inferior vena cava tissues of mice&#46; &#40;C&#41; HE-staining representative images of inferior vena cava tissue of mice&#44; thrombus length and thrombus weight&#59; &#40;D&#41; ELISA measurements of IL-1&#946;&#44; IL-6 and TNF-&#945;&#46; &#40;F&#41; Western blot tests of cleaved caspase-3&#44; Bax&#44; p-p65 and Bcl-2&#59; Data are expressed as mean &#177; SD &#40;n &#61; 10&#41;&#46; &#42;p &#60; 0&#46;05&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0001"
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        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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        "tabla" => array:1 [
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy subjects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">DVT patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0004"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Sample size &#40;n&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0005"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Age &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8805; 60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#60; 60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0019"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0028"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#8804; 18 kg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0031"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#62; 18&#8764;25kg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0034"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&#62; 25 kg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3711698.png"
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            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara008" class="elsevierStyleSimplePara elsevierViewall">Clinical data&#46;</p>"
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl0002"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0009"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0037"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0038"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Primer sequences &#40;5&#8242;&#8211;3&#8242;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0039"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top">Human circUSP9X</td><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Forward &#40;F&#41;&#58; 5&#8242;-GTTGCTCCCAGACTTCATCGC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reverse &#40;R&#41;&#58; 5&#8242;-GACCTTGCTCATCTGGGGGA-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0043"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top">Mice circUSP9X</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Forward&#58; 5&#8242;- TGATCAACAGGTTATGCAATGGT-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0046"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reverse&#58; 5&#8242;- ACGAGTCGTGGCTGTCATAC-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0047"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top">miR-148b-3p</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Forward&#58; 5&#8242;- GCGTCAGTGCATCACAGAA-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reverse&#58; 5&#8242;- TGGTGTCGTGGAGTCG-3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0051"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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