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22 publications mentioning hsa-mir-1224

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-1224. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 262
In order to determine the target genes responsible for miR-1224 -induced upregulation of the tube formation, we predicted the target genes of miR-1224 in silico using two sequence -based target prediction software programs, miRanda and TargetScan. [score:12]
Taken together, our studies demonstrated that: 1) miR-1224 induces angiogenesis by upregulating VEGF signaling and downregulating NOTCH signaling; 2) miR-1224 promotes angiogenesis by targeting EPN2, a negative regulator of angiogenesis; 3) therefore a novel modulation of angiogenesis by a species-specific mechanism, miR-1224/EPN2 pathway, was identified. [score:10]
Two microRNA target site prediction methods, TargetScan Human (Release 5.1) and miRanda [59], were used to predict hsa-miR-1224-5p target candidates and putative binding sites in the 3′-untranslated region (3′-UTR) of each gene. [score:9]
Knockdown of EPN2 enhances in vitro angiogenesisTo determine whether the reduced expression of EPN2, likely caused by elevated expression of miR-1224, could contribute to the stimulation of tube formation in our experiments, EPN2 and EPN1 expression was knocked down by small interfering RNA (siRNA) independently or together in HUVECs (Fig.   5A). [score:9]
This analysis revealed that the expression from the reporter containing miR-1224 target sites was repressed in M-HUVEC compared to the expression in P-HUVEC, indicating that functional miR-1224 was actually upregulated in M-HUVEC (Fig.   1C). [score:9]
Importantly, the EPN2 -expressing Ad vector suppressed tube formation in miR-1224 -transfected cells to a similar extent to control, indicating that the function of miR-1224 was mediated by suppression of EPN2 expression at least in part (Fig.   5E). [score:9]
To determine whether the reduced expression of EPN2, likely caused by elevated expression of miR-1224, could contribute to the stimulation of tube formation in our experiments, EPN2 and EPN1 expression was knocked down by small interfering RNA (siRNA) independently or together in HUVECs (Fig.   5A). [score:8]
Our observations in Fig.   3 are highly reminiscent of these previous reports, suggesting that miR-1224 might target the EPN2 mRNA and downregulate its expression. [score:8]
Consistently, expression of NOTCH target genes, HES1 and HEY1 44, 45, was downregulated in miR-1224 -transfected HUVECs (Fig.   3B). [score:8]
Next, we asked whether endogenous EPN2 expression was suppressed in M-HUVEC where miR-1224 was upregulated. [score:8]
Taken together, these observations suggested that miR-1224 negatively regulates EPN2 expression by directly targeting its 3′-UTR. [score:7]
These observations were consistent with the notion that elevated expression of miR-1224, as shown in Fig.   1, caused the suppression of EPN2 expression in M-HUVEC. [score:7]
In order to examine that suppression of EPN2 has effects on NOTCH and VEGFR signals as in miR-1224-transfectd cells, expression of NOTCH target genes and the phosphorylation of VEGFR2 were examined. [score:7]
miR-1224 expression is upregulated during in vitro tube formationAngiogenesis is an evolutionarily conserved event driven by highly conserved angiogenic factors. [score:6]
miR-1224 expression is upregulated during in vitro tube formation. [score:6]
Furthermore, this finding suggested that miR-1224 could be a specific regulator of angiogenesis depending on the expression of both miR-1224 and targetable EPN2. [score:6]
To determine whether miR-1224 directly regulates EPN2 expression, fragments from the 3′-UTR of human EPN2 and mouse Epn2 were cloned downstream from a renilla-luciferase gene in reporter plasmids. [score:5]
Conversely, tube formation was inhibited following the transfection of miR-1224-Tough Decoy (TuD) [43], which is a double-stranded RNA oligonucleotide designed to bind to and inhibit endogenous miR-1224 molecules (Fig.   2B). [score:5]
The sensor plasmid was constructed by insertion of double-stranded oligonucleotides perfectly matched to the miR-1224 sequence into psiCHECK-2. For the mutations (hEPN2mut and mEpn2mut), the seed sequences of the predicted miR-1224 target sites were mutated from GTCCTCA to GGCGTGA by site-directed mutagenesis [55] with the oligonucleotides listed in Table  S3. [score:5]
Figure 4EPN2 expression was suppressed by miR-1224 through its 3′-UTR. [score:5]
This is consistent to the notion that the miR-1224’s effects on these signals were mediated by suppressing its target gene EPN2. [score:5]
This finding clearly indicated that temporally regulated expression of miR-1224 modulates basic angiogenesis. [score:4]
In total, miR-1224 suppressed the NOTCH signal pathway and activated VEGF signaling to regulate tube formation. [score:4]
These results indicated that both human and mouse EPN2 mRNAs are direct targets of miR-1224 through binding to the seed-matched sequences in the 3′-UTRs. [score:4]
EPN2 mRNA is a direct target of miR-1224. [score:4]
To explore whether miR-1224 regulates the endogenous EPN2, HUVECs were transfected with a control mimic or miR-1224 mimic, and endogenous EPN2 expression was assessed. [score:4]
Increased expression of miR-1224 in M-HUVEC suggested that miR-1224 positively regulated in vitro tube formation. [score:4]
As expected, the introduction of miR-1224 mimic to HUVECs resulted in significant (~50%) downregulation of EPN2 mRNA as well as EPN2 protein (Fig.   4A and B). [score:4]
In this study, we found a proangiogenic function of miR-1224 in in vitro angiogenesis using human umbilical vein endothelial cells (HUVECs) and epsin2 as a direct target of mir-1224, providing a novel player for angiogenic modulation specific to particular mammals. [score:4]
miR-1224 stimulates in vitro angiogenesisIncreased expression of miR-1224 in M-HUVEC suggested that miR-1224 positively regulated in vitro tube formation. [score:4]
Sequence alignment of miR-1224 and the target region of 3′-UTRs. [score:3]
Therefore, it was also possible that activated VEGFR2 was elevated by miR-1224 expression in HUVECs. [score:3]
First, we validated the increased expression of miR-1224 after tube formation. [score:3]
miR-1224 overexpression repressed the luciferase activity both of the reporter plasmid containing the 3′-UTR fragment of human EPN2 or mouse Epn2 gene but not the control empty reporter. [score:3]
The fragment containing the putative target sites for miR-1224 in the 3′-UTR of human EPN2 and mouse Epn2 was amplified using PCR with genomic DNA prepared from HepG2 cells (a human hepatocellular carcinoma cell line) and C57/B6Ncr mouse tail, respectively, as templates. [score:3]
Our study revealed the proangiogenic function of miR-1224 in an in vitro system where miR-1224 expression was induced during angiogenesis. [score:3]
The stimulation by miR-1224 was suppressed in the presence of Ki8751. [score:3]
Each program yielded a large number of genes as possible miR-1224 targets. [score:3]
HUVECs were transfected with miR-1224 mimics and subsequently transduced with EPN2- or control LacZ -expressing adenovirus (Ad) vectors. [score:3]
In the miR-1224 -transfected cells, tube formation was stimulated in the absence of DAPT and no further stimulation was observed in the presence of DAPT suggesting that the stimulatory function of miR-1224 was replaced by NOTCH inhibition to a similar extent (Fig.   3C). [score:3]
The target sequence of miR-1224 was identified in many mammalian EPN2 genes (Fig.   4E). [score:3]
Next, to explore the mechanism by which miR-1224 stimulates tube formation, we examined the influence of increased miR-1224 expression on major angiogenic signaling through VEGF and NOTCH. [score:3]
Therefore, we started with miR-1224 in this study among the rest of two to elucidate the regulation of vessel formation by mammalian-specific mirtrons. [score:2]
Furthermore, point mutations of the seed-matched sequence prevented repression by miR-1224. [score:2]
In this study, the P-HUVEC showed lower expression of miR-1224 compared with M-HUVEC, and the increase in miR-1224 in either endogenous or exogenous mode was associated with a higher capacity for tube formation in these cells. [score:2]
The upregulation of miR-1224 was further confirmed by measuring post-transcriptional silencing activity using reporter constructs. [score:2]
These results indicated that NOTCH signaling was negatively regulated by miR-1224. [score:2]
To examine the functional relevance of the VEGFR2 activation by miR-1224, the tube formation assay was performed in the presence of VEGFR2 specific inhibitor Ki8751. [score:2]
The quantitative analysis of mature miR-1224 by quantitative reverse transcription polymerase chain reaction (qRT-PCR) further confirmed that miR-1224 expression was several-fold higher at 24 hours after culture onset on Matrigel compared to that at one hour after onset (Fig.   1B). [score:2]
miR-1224 stimulates in vitro angiogenesis. [score:1]
Our finding that the miR-1224/EPN2 pathway was active during angiogenesis of umbilical veins is interesting from this point of view. [score:1]
The renilla-luciferase “sensor” reporter containing two complementary sites for miR-1224 was transfected into HUVECs. [score:1]
Figure 3Reduced NOTCH signaling and elevated VEGF signaling in miR-1224–transfected HUVECs. [score:1]
miR-1224 modulates NOTCH/VEGF signaling. [score:1]
Blots were hybridized with a [32]P -labelled locked nucleic acid (LNA)-oligonucleotide probe to detect miR-1224 as previously described [58]. [score:1]
Negative control 2′ –O-methylated RNA and anti-miR-1224 2′ –O-methylated RNA sense and antisense oligonucleotides were synthesized by Fasmac (Kanagawa, Japan). [score:1]
These results indicate that miR-1224 stimulated the tube formation through VEGFR2 activation (Fig.   3E). [score:1]
The signal intensity of mature miR-1224 was normalized with that of U6. [score:1]
Taken together, these results indicate that miR-1224 stimulates tube formation in vitro. [score:1]
HUVECs were transfected with miRIDIAN microRNA Mimics-miR-1224, miRIDIAN microRNA Mimic Negative Control #1 (Thermo Fisher Scientific, Lafayette, CO), siGENOME SMART pool (Thermo Fisher Scientific) (10 nM), and Tough Decoy (50 nM) with Lipofectamine RNAiMAX reagent (Invitrogen Life Technologies, Carlsbad, CA). [score:1]
miR-1224 was detected at the expected size (~22nt) by northern blot analysis, and its signal intensity was 3.7-fold stronger in M-HUVEC than in P-HUVEC (Fig.   1A). [score:1]
Interestingly, three mirtrons (miR-877, miR-1224, miR-1225) were included. [score:1]
The decrease in the luciferase activity in the control mimic or TuD -transfected cells indicates endogenous miR-1224 activity. [score:1]
Mirtrons are derived from short hairpin introns and bypass Drosha cleavage by using the spliceosome to generate their precursors (pri-miRNAs) 30, 31 and mirtrons have often evolved in species-specific ways 31– 34. miR-1224 is a mammalian mirtron encompassed in the last intron of von Willebrand factor A domain containing 5B2 (VWA5B2) gene, and its function has been shown only in macrophages [35]. [score:1]
Species that have miRBase-registered miR-1224-5p are indicated by + in the right column (top panel). [score:1]
To verify this, HUVECs were transfected with a miR-1224 mimic and then cultured on Matrigel. [score:1]
To explore whether miR-1224 affects EC behavior by modulating NOTCH, the level of NICD was assessed by intracellular flow cytometry using an antibody specifically recognizing NICD. [score:1]
miR-1224 in the isolated RNA was determined by quantitative reverse transcription PCR (qRT-PCR). [score:1]
How and why the miR-1224/EPN2 pathway was acquired in these species remains elusive. [score:1]
To evaluate the effects of the decrease in NOTCH activity on the stimulatory activity of miR-1224 to tube formation, HUVECs were cultured on Matrigel in the presence of DAPT, a ɣ-secretase inhibitor. [score:1]
VEGFR2 phosphorylation was significantly enhanced at 5 and 10 minutes after stimulation in miR-1224-transfectants. [score:1]
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2
[+] score: 244
Consistent with the finding that down-regulated miR-1224-5p has a restored mitophagy levels in TEM analysis, fibroblasts transfected with miR-1224-5p inhibitor appeared to be increased PINK1 and PARK2 protein expression and decreased p62 levels after expose of TGF-β1 (Figure 3D and Supplementary Table S5). [score:8]
These data suggested that translational inhibition of BECN1 by miR-1224-5p blocks PARK2 translocation and thereby, inhibits cells from the maintaining of mitophagy activity under the silica stimulation. [score:7]
Furthermore, the reduced expression of miR-1224-5p resulted in a decrease of the protein expression of α-SMA, Vimentin and Collagen I and a recovery of the protein expression of E-cadherin (Figure 2D and Supplementary Table S3). [score:7]
To further test the hypothesis that miR-1224-5p suppresses PARK2 translocation then mitophagy by targeting BECN1 in silica -induced pulmonary fibrosis network, fibroblasts were also transfected with miR-1224-5p inhibitor alone or with BECN1 siRNA, and Western blot analyses were performed from mitochondrial fractions. [score:7]
Repression of miR-1224-5p expression attenuated silica -induced pulmonary fibrosis both in vivo and in vitro by regulating its one of the target genes, BECN1, which is critical mediator in the PARK2 translocation to mitochondria and the degradation of damaged mitochondria. [score:6]
To assess the impact of down-regulated miR-1224-5p on mitochondrial damage and mitophagy in vivo, we detected the protein expression of PINK1, PARK2, and p62 in lung tissues. [score:6]
These data suggested that miR-1224-5p directly targets BECN1 and thereby inhibits the subsequent mitophagy signaling events. [score:6]
In contrast, enhanced BECN1 protein expression was observed in the miR-1224-5p down-regulated mouse mo del (Figure 4D and Supplementary Table S7). [score:6]
Thus, both microscopic and WB evidence suggested that miR-1224-5p knockdown promoted PARK2 translocation to mitochondria following TGF-β1 treatment whereas silencing target gene BECN1 inhibit PARK2 translocation in either case. [score:6]
miR-1224-5p down-regulated mice exhibited the restored PINK1 and PARK2 expression and an attenuation of p62 levels upon silica treatment (Figure 2E, Supplementary Table S4). [score:6]
Moreover, miR-1224-5p appears to target Parkinson’s disease -associated LRRK2 and α-synuclein genes [14]. [score:5]
To understand whether miR-1224-5p have potential function in the development of silicosis in vivo, we conditionally downregulated miR-1224-5p in lung tissues in silica -induced pulmonary fibrosis mouse mo dels using antagomir (anta-1224-5p). [score:5]
Approximately 1 × 10 [5] fibroblasts were seeded in 6-well plates for 24 h. Subsequently, 100 nM of miR-1224-5p inhibitor or inhibitor-NC (RiboBio Co. [score:5]
2.3. miR-1224-5p Suppresses Mitophagy by Targeting BECN1. [score:5]
miR-1224-5p promoted silica -induced pulmonary fibrosis primarily by targeting BECN1 expression, thereby blocking PARK2 translocation to mitochondria and inducing the accumulation of damaged mitochondria. [score:5]
In contrast, significantly increased PARK2 levels in mitochondria were observed in the miR-1224-5p inhibitor transfected cells, whereas the facilitative effect of miR-1224-5p inhibitor on PARK2 translocation was blocked by BECN1 siRNA transfection (Figure 5B,C and Supplementary Table S9). [score:5]
Therefore, repression of miR-1224-5p expression might provide a novel therapeutic target of the silicosis. [score:5]
Furthermore, lung fibroblasts in silica -treated mice had accumulated enlarged mitochondria with irregular shape and disorganized cristae (Figure 2F(ii,vi)), whereas lung fibroblasts in miR-1224-5p down-regulated mice had nearly normal mitochondria (Figure 2F(iv,viii)). [score:4]
Our results represented a significant advance in our understanding of the regulation of mitochondrial damage and mitophagy activity by miRNAs in silica -induced pulmonary fibrosis and indicated that miR-1224-5p may represent a potential therapeutic target for silicosis. [score:4]
As expected, at day 28 after the silica injection, miR-1224-5p levels were significantly downregulated in mouse fibrotic lung tissues (Figure 2A). [score:4]
The observation that damaged mitochondria and decreased mitophagy levels by miR-1224-5p promoted us to hypothesize that miR-1224-5p functions to suppress one or more key regulators of mitophagy, thereby maintaining the accumulation of abnormal mitochondria. [score:4]
These may be related with the evidence that BECN1 is an important target of miR-1224-5p involved in the regulation of PARK2 translocation to the mitochondria. [score:4]
Down-Regulated miR-1224-5p Attenuates Silica-Induced Pulmonary Fibrosis and Restores Mitophagy In Vivo. [score:4]
Our previous miRNA microarray analysis of mouse lung tissues identified the significant up-regulation of miR-1224-5p in response to silica exposure (Supplementary Figure S1). [score:4]
Our data showed that mitochondria are impaired in mouse lung tissues in a mo del of silica -induced pulmonary fibrosis and are restored in the miR-1224-5p down-regulated mouse mo del. [score:4]
Together, these observations suggested that the down-regulated miR-1224-5p could attenuate silica -induced pulmonary fibrosis in vivo. [score:4]
Histological examination showed attenuated pulmonary fibrosis after silica treatment in miR-1224-5p down-regulated group, as evidenced by reduced destruction of alveolar architecture, less severe fibrotic foci and decreased collagen deposition (Figure 2B,C). [score:4]
For the miR-1224-5p downregulation mouse mo del of silica -induced pulmonary fibrosis, C57BL/6 male mice were divided into 4 groups randomly (n = 6 in each group): saline, silica, silica plus anta-NC and silica plus anta-1224-5p. [score:4]
Conversely, fibroblasts from miR-1224-5p down-regulated mouse lung tissues had more visualized vacuoles (Figure 2F(iv,viii)). [score:4]
Our further studies indicated that the down-regulated miR-1224-5p could attenuate silica -induced pulmonary fibrosis in vivo. [score:4]
Concomitantly, we observed obvious amelioration both in the severity and distribution of lung lesions in the down-regulation of miR-1224-5p (p < 0.01) (Table 1). [score:4]
However, knockdown of BECN1 was able to reverse the effect of miR-1224-5p inhibitor -induced PARK2 dots accumulation. [score:4]
Together, these results indicated that down-regulated miR-1224-5p restores mitophagy, thus removing damaged mitochondria in vivo. [score:4]
Here, we showed that the expression levels of miR-1224-5p are increased in fibrotic lung tissues in mouse mo dels of silicosis. [score:3]
miR-1224-5p has been demonstrated to be a negative regulator of TNF-α and is involved in the regulation of the LPS -mediated inflammatory responses [13]. [score:3]
After miR-1224-5p inhibitor and siBECN1 co-transfection then TGF-β1 treatment, the cells were fixed with carbinol for 30 min and blocked with 5% BSA for 60 min. [score:3]
Inhibition of miR-1224-5p significantly increased the BECN1 protein levels under the silica stimulation. [score:3]
To this end, we predicted the targets of miR-1224-5p according to their conserved binding sites. [score:3]
Together, these experiments demonstrated that miR-1224-5p regulates mitophagy in a BECN1 -dependent manner and that BECN1 regulates PARK2 translocation to mitochondria by interacting with PARK2. [score:3]
The fibroblasts transfected with miR-1224-5p inhibitor resulted in restored mitophagy levels, in which the number of abnormal mitochondria were decreased and displayed some vacuolization in the cytoplasm (Figure 3C(iv,viii)). [score:3]
To determine if miR-1224-5p is specifically expressed in silicosis, we administered silica particles suspended in saline intratracheally to establish a mouse silicosis mo del. [score:3]
miRNA antagomir injection via the tail vein was an efficient method to repress miRNA expression, but it is not yet clarified whether entire miR-1224-5p are repressed in any organs/tissues, which will be explored in our future study. [score:3]
So the closer discussion of miR-1224-5p expression and function is needed to gain further insight into the roles of miR-1224-5p in the pathogenesis of silicosis. [score:3]
Fibroblasts were transfected with miR-1224-5p inhibitor then treated with TGF-β1 for 48 h. After treatment, fibroblasts were fixed with 2.5% glutaraldehyde in phosphate buffer (pH 7.4) and postfixed for 2 h in 1% osmium tetroxide in phosphate buffer (pH 7.4). [score:3]
miR-1224-5p inhibitor transfected fibroblasts exhibited a significant increase in accumulation of PARK2 dots in TOMM20-stained mitochondria in response to TGF-β1 exposure. [score:3]
In contrast, further analysis after miR-1224-5p inhibitor (in-1224-5p) transfection revealed significant reduction in the levels of α-SMA and Vimentin in fibroblasts (Supplementary Figure S2C,D). [score:3]
Moreover, the transfection of miR-1224-5p inhibitor in fibroblasts induced restored BECN1 levels (Figure 4E and Supplementary Table S8). [score:3]
The expression levels of miR-1224-5p in mouse fibrotic lung tissues were verified by qRT-PCR method. [score:3]
In conclusion, we identified miR-1224-5p as a novel therapeutic target in silica -induced pulmonary fibrosis. [score:3]
Our previous microarray analysis has suggested that miR-1224-5p is highly expressed in mouse lung tissues of silica -induced lung fibrosis [12]. [score:3]
As shown in Figure 4A, miR-1224-5p was shown to bind to the 3′ untranslated region (UTR) of BECN1 mRNA, which is an important mitophagy molecule and play a central role in autophagosome formation and maturation. [score:3]
This study firstly reported that miR-1224-5p participates in silica -induced pulmonary fibrosis by directly repressing BECN1, thereby impairing mitochondria. [score:2]
In this study, miR-1224-5p antagomir was instilled directly through the trachea at the first time point, but then via the tail vein for three subsequent time points in order to decrease injury and promote blood absorption. [score:2]
To clarify if BECN1 has similar effects in the pathogenesis of silica -induced pulmonary fibrosis, and if miR-1224-5p interferes with these effects by targeting BECN1, fibroblasts were transfected with miR-1224-5p inhibitor alone or with BECN1 siRNA, then treated with 2 ng/mL TGF-β1 for 48 h. As shown in Figure 5A, confocal microscopy evaluation revealed a smaller proportion of PARK2 dots accumulation in TOMM20-stained mitochondria in TGF-β1-exposing cells compared with those in control cells. [score:2]
Here, we confirmed that miR-1224-5p exerts a specific regulation of BECN1. [score:2]
In this study, we confirmed that miR-1224-5p expression was increased in mouse lung tissues of silica -induced pulmonary fibrosis compared with the mouse saline lung tissues. [score:2]
It is possible that miR-1224-5p related regulation to silica -induced pulmonary fibrosis was associated with mitochondrial damage, which may be an important feature in the pathogenesis of silica -induced pulmonary fibrosis. [score:2]
To determine the effect of miR-1224-5p on mitochondrial damage and mitophagy visually, we used transmission electron microscopy (TEM) to examine the mitochondrial structure and autophagic vacuoles of fibroblasts in mouse fibrotic lung tissues. [score:1]
miR-1224-5p antagomir or its negative control (anta-NC) was co -injected via intratracheal instillation for the first time and via the tail vein at 7, 14 and 21 days after silica treatment. [score:1]
, Nanjing, China) was used for miR-1224-5p amplification. [score:1]
Cells were co -transfected with BECN1 3′UTR wt or mut plasmid and miR-1224-5p mimic (miR-1224-5p) or mimic control (mimic-NC) using transfection reagent (RiboBio Co. [score:1]
These data suggested that miR-1224-5p and mitochondrial damage may participate in silica -induced pulmonary fibrosis. [score:1]
Consistent with the microarray analysis, the miR-1224-5p levels on days 14 and 28 after silica exposure were significantly increased comparing with those in the saline group (Figure 1D). [score:1]
To test this, wild-type and mutant sequences of the 3′UTR of BECN1 were cloned downstream of a luciferase reporter, and these reporter constructs were co -transfected with miR-1224-5p mimic or mimic-NC into fibroblasts. [score:1]
In the presence of miR-1224-5p, the relative luciferase activity of wild-type BECN1 3′UTR was effectively reduced, whereas the BECN1-mut was unaffected (Figure 4B). [score:1]
The relative expression levels of miR-1224-5p were normalized to the levels of U6 and calculated by the 2−ΔΔ Ct method. [score:1]
2.1. miR-1224-5p Is Increased and Mitophagy is Impaired in Mouse Lung Tissues in a Mo del of Silica-Induced Pulmonary Fibrosis. [score:1]
This suggested that miR-1224-5p-related dysfunction in the lung tissues may have an unrecognized role in the pathogenesis of silicosis. [score:1]
Either 5 nmol of miR-1224-5p antagomir (anta-1224-5p) or its negative control anta-NC (RiboBio Co. [score:1]
Subsequently, 3 nmol of miR-1224-5p antagomir or anta-NC was injected via the tail vein weekly. [score:1]
However, the possible roles of miR-1224-5p in silicosis remain unclear. [score:1]
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3
[+] score: 85
b miRNA RT-qPCR analysis showing the complete regulation of Hsa-miR-93, Hsa-miR-20a, Hsa-miR-125b and Hsa-miR-27b and, significant increase in the expression of Hsa-miR-1260 and Hsa-miR-1224-3p in metastatic tumors as compared to the non-metastatic xenograftTo validate the altered expression levels observed with whole genome miRNA array, we examined the expression levels of select miRNAs including hsa-miR-1260, hsa-miR-1224-3p (showing significant upregulation; see Fig.   2), hsa-miR-93, hsa-miR-20a, hsa-miR-125b, hsa-miR-27b (showing significant downregulation; see Fig.   3a), using individual miRNA QPCR analysis. [score:13]
b miRNA RT-qPCR analysis showing the complete regulation of Hsa-miR-93, Hsa-miR-20a, Hsa-miR-125b and Hsa-miR-27b and, significant increase in the expression of Hsa-miR-1260 and Hsa-miR-1224-3p in metastatic tumors as compared to the non-metastatic xenograft To validate the altered expression levels observed with whole genome miRNA array, we examined the expression levels of select miRNAs including hsa-miR-1260, hsa-miR-1224-3p (showing significant upregulation; see Fig.   2), hsa-miR-93, hsa-miR-20a, hsa-miR-125b, hsa-miR-27b (showing significant downregulation; see Fig.   3a), using individual miRNA QPCR analysis. [score:13]
In order to validate the miRNA expression obtained from whole genome profiling, expression of selected metastamiRs, including hsa-miR-1224-3p, hsa-miR-1260 (both significantly upregulated), hsa-miR-125b, hsa-miR-27b, hsa-miR-93,and hsa-miR-20a (all significantly downregulated) were confirmed using QPCR. [score:11]
To define the effect of characterized metastamiRs on the putative target proteins, we adopted two approaches: (i) inhibited hsa-miR-1224-3p or hsa-miR-1260 (both significantly upregulated) and (ii) functionally mimicked hsa-miR-125b, hsa-miR-27b, hsa-miR-93 or hsa-miR-20a (all significantly downregulated) and examined for the miRNA -dependent modulations in protein targets. [score:11]
Thus, we validated our microarray results with RT-qPCR for upregulation (Hsa-miR-1260; Hsa-miR-1224-3p) and downregulation (Hsa-miR-20a, Hsa-miR-27b, Hsa-miR-125b, Hsa-miR-93) profiles (see Fig.   3b). [score:7]
miRNA mimic (hsa-miR-125b, hsa-miR-27b, hsa-miR-93, hsa-miR-20a) and inhibitor (hsa-miR-1224-3p, hsa-miR-1260) approach for select miRNAs revealed the direct influence of the altered metastamiRs in the regulation of identified protein targets. [score:7]
c Histograms of mean cell–Alexa Fluor intensity showing alterations in the expression of (i) ADAMTS-1 and CREB with hsa-miR-1224-3p inhibition and, (ii) ADAMTS-1, ASK1, FOSB and AKT-1 with hsa-miR-1260 inhibition. [score:7]
Transient transfection of MSDACs with hsa-miR-125b-, hsa-miR-27b-, hsa-miR-93- or hsa-miR-20a- mimics (MISSION® microRNA Mimics, Sigma-Aldrich) as well as hsa-miR-1224-3p- and hsa-miR-1260 -inhibitors (MISSION® Synthetic miRNA Inhibitors, Sigma-Aldrich) were carried out by using either TurboFectin 8.0 reagent (Origene) or Neon electroporation transfection system (Life Technologies). [score:5]
Next, MSDACs transiently transfected with inhibitors for hsa-miR-1224-3p or hsa-miR-1260 (both showed profound induction in metastatic tumors) and examined for the alterations in protein targets. [score:5]
Conversely, we observed a significant (P < 0.001) upregulation of hsa-miR-1260 and hsa-miR-1224-3p in metastatic tumor compared with the non-metastatic control (Fig.   3b). [score:3]
Inhibiting hsa-miR-1224-3p resulted in the significant (P < 0.001) induction of ADAMTS-1 and CREB (Fig.   6c i). [score:3]
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4
[+] score: 21
The miRWalk database also contains experimentally validated target genes for the additional three miRNAs (miR-1224-3p, miR-197 and miR-532-3p) that were differentially overexpressed in response to both proanthocyanidin extracts (Table 5), although the number of target genes for these miRNAs was much lower than for miR-30b*. [score:7]
On the other hand, the two procyanidin extracts upregulated the expression of miR-1224-3p, miR-197 and miR-532-3p. [score:6]
miR-1224-3p, miR-197 and miR-532-3p were differentially expressed after treatment with the two procyanidin extracts; however, only miR-30b* was differentially expressed in response to all the three treatments. [score:5]
The targeted miRNA assay sequences were 5′-CCCCACCUCCUCUCUCCUCAG-3′ for miR-1224-3p and 5′-CUGGGAGGUGGAUGUUUACUUC-3′ for miR-30b*. [score:2]
To validate the microarray results, two miRNAs (miR-1224-3p and miR-30b*) were selected for QRT-PCR quantification. [score:1]
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5
[+] score: 15
Other miRNAs from this paper: hsa-mir-425, hsa-mir-484, hsa-mir-1293
miR-1224 regulates the expression of lipid-related genes that are directly regulated by transcription factors such as SP1 [60]. [score:6]
Thus, one of the dysregulated exosomal miRNAs found in this study, miR-1224, is involved in the regulation of lipid metabolism. [score:3]
These included miR-1224, -1293, -425, -4467, -4732, -484, -5094, -6848-6849, -4488 and -96 all of which were predicted to target metabolism and energy production-related pathways. [score:3]
38 of these miRNAs (~78%) were present in both infected and uninfected exosomes but 11 miRNAs (miR-1224, -1293, -425, -4467, -4732, -484, -5094, -6848 and -6849, -96 and -4488) were predominantly expressed in exosomes derived from M. tb infected cells. [score:3]
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[+] score: 13
Figure 4 A. Histograms of individual miRNA QPCR analysis showing circulating levels of randomly selected miRNAs (miR-20a, miR-27b, miR-1224-3p, miR-1260, and miR-93) in the serum of animals with non-metastatic primary disease or with high-risk metastatic disease. [score:5]
Compared with the non-metastatic favorable disease animals, we observed marginal variations in the expression of miR-20a, miR-27b, miR-93, miR-1260, and miR-1224 (Figure 4A). [score:4]
For the present study, we used QPCR to confirm expression of selected miRNAs, including hsa-miR-1224-3p, hsa-miR-1260, hsa-miR-27b, hsa-miR-93, and hsa-miR-20a. [score:3]
B. Correlation analysis of the serum-circulating profiles of miR-20a, miR-27b, miR-1224-3p, miR-1260, and miR-93 observed using the miRnome approach. [score:1]
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[+] score: 11
The results showed that fucoidan increased the expression of tumor suppressive miRs such as miR-29 family and miR-1224 (Table 1). [score:5]
miR-ID Increased Fold-Changes miR-ID Decreased Fold-Changes miR-29b 8.5 miR-17 15.7 miR-29a 7.7 miR-92a 13.6 miR-29c 7.3 miR-18a 12.0 miR-1224 6.6 miR-192 7.2 miR-133b 2.0 miR-127 2.4 miR-200c 1.7 miR-154 1.9 miR-200a 1.4 miR-21 1.7 miR-205 1.3 miR-680 1.3 miR-208a 1.2 miR-377 1.2 miR-669b 1.2 miR-153 1.1 Figure 3Fucoidan increases the expression of miR-29b. [score:3]
miR-ID Increased Fold-Changes miR-ID Decreased Fold-Changes miR-29b 8.5 miR-17 15.7 miR-29a 7.7 miR-92a 13.6 miR-29c 7.3 miR-18a 12.0 miR-1224 6.6 miR-192 7.2 miR-133b 2.0 miR-127 2.4 miR-200c 1.7 miR-154 1.9 miR-200a 1.4 miR-21 1.7 miR-205 1.3 miR-680 1.3 miR-208a 1.2 miR-377 1.2 miR-669b 1.2 miR-153 1.1 Figure 3Fucoidan increases the expression of miR-29b. [score:3]
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control Expression in case group 1 hsa-mir-1290 0.26 down 2 hsa-mir-342-5p 0.22 down 3 hsa-mir-1224-5p 0.23 down 4 hsa-mir-345 0.38 down 5 hsa-mir-1228 0.38 down 6 hsa-mir-1249 0.32 down 7 hsa-mir-1826 0.26 down 8 hsa-miR-1306 0.38 down 9 hsa-miR-188-5p 0.43 down 10 hsa-miR-320a 0.48 down 11 hsa-miR-320c 0.26 down 12 hsa-miR-365 0.31 down 13 hsa-miR-423-5p 0.35 down 14 hsa-miR-483-5p 0.25 down 15 hsa-miR-634 0.31 down 16 hsa-miR-671-5p 0.23 down 17 hsa-miR-939 0.24 down 18 hsa-miR-1246 2.22 up 19 hsa-miR-150 10.41 up 20 hsa-miR-574-5p 8.04 up Table 3 MiRNAs Target Gene Symbol hsa-miR-345PUM2, PPP2R3A, BCAT1, ZFHX4, CHSY3, ARNT, SHE, SLC7A5, SOS1,. [score:5]
control Expression in case group 1 hsa-mir-1290 0.26 down 2 hsa-mir-342-5p 0.22 down 3 hsa-mir-1224-5p 0.23 down 4 hsa-mir-345 0.38 down 5 hsa-mir-1228 0.38 down 6 hsa-mir-1249 0.32 down 7 hsa-mir-1826 0.26 down 8 hsa-miR-1306 0.38 down 9 hsa-miR-188-5p 0.43 down 10 hsa-miR-320a 0.48 down 11 hsa-miR-320c 0.26 down 12 hsa-miR-365 0.31 down 13 hsa-miR-423-5p 0.35 down 14 hsa-miR-483-5p 0.25 down 15 hsa-miR-634 0.31 down 16 hsa-miR-671-5p 0.23 down 17 hsa-miR-939 0.24 down 18 hsa-miR-1246 2.22 up 19 hsa-miR-150 10.41 up 20 hsa-miR-574-5p 8.04 up Table 3 MiRNAs Target Gene Symbol hsa-miR-345PUM2, PPP2R3A, BCAT1, ZFHX4, CHSY3, ARNT, SHE, SLC7A5, SOS1,. [score:5]
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[+] score: 9
The miRmap algorithm reported that 6 of the 19 miRNAs dysregulated in bovine serum in response to FMDV could potentially target different regions of the FMDV A24 Cruzeiro RNA genome: bta-miR-17-5p, bta-miR-497, bta-miR-146a, bta-miR-1224, bta-miR-31, and bta-miR-150. [score:4]
Of the differentially regulated miRNAs, 16 (bta-miR-23b-5p, let-7 g, bta-miR-22-5p, bta-miR-1224, bta-miR-144, bta-miR-497, bta-miR-455-3p, bta-miR-154a, bta-miR-369-3p, bta-miR-26b, bta-miR-34a, bta-miR-205, bta-miR-181b, bta-miR-146a, bta-miR-17-5p, and bta-miR-31) have previously been described to play a role in cellular proliferation or apoptosis (Fig.   6b, orange circle). [score:2]
As shown in the top portion of Table  3: bta-miR-22-5p, bta-miR-147, bta-miR-1224, bta-miR-144, bta-miR-497, bta-miR-154a, bta-miR-17-5p, bta-miR-205, and bta-miR-31, with fold changes of 2.17, 5.28, 5.69, 23.78, 24.62, 24.05, 40.84, 41.22, and 43.37, respectively. [score:1]
The non-clustered miRNAs included: let-7 g, bta-miR-26b, bta-miR-150, bta-miR-34a, bta-miR-146a, bta-miR-147, bta-miR-205, bta-miR-455-3p, bta-miR-1224, bta-miR-1281, and bta-miR-31. [score:1]
The remaining 8 miRNAs are encoded within intronic regions: bta-miR-26b, bta-miR-455-3p, bta-miR-23b-5p, bta-let-7 g, bta-miR-22-5p, bta-miR-147, bta-miR-369-3p, and bta-miR-1224. [score:1]
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[+] score: 6
For example, hsa-miR-1226-3p processed from an artificial conventional mirtron effectively silences aberrant myotonic dystrophy protein kinase [35], mmu-miR-1224 leucine-rich repeat serine/threonine-protein kinase 2, and α-synuclein Parkinson disease -associated genes [36], while an artificial 3′-tailed mirtron knocks down the expression of the vascular endothelial growth factor A [34]. [score:6]
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11
[+] score: 5
Out of 12 miRNA families that were predicted to target the PRKAG1 sense promoter in both human and mouse, nine (miR-718, miR-1224, miR-188, miR-346, miR-296, miR-671, miR-221, miR-1306, miR-506) can form highly stable duplex structures with their target sites (MFE ≤ −30 kcal/mol) in both organisms. [score:5]
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[+] score: 5
Other miRNAs from this paper: hsa-mir-200b, hsa-mir-433
It has been shown that miR-1224-5p and miR-200b act as tumor suppressors by targeting CREB in malignant gliomas [33, 34]. [score:5]
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[+] score: 3
24 *** hsa-mir-770-5p 19 *** 75.47 *** hsa-mir-93* 9.5 *** 92.1 - Inhibited differentiation & low cell count *** hsa-let-7b* 4.75 *** 28.64 *** hsa-mir-1224-3p 2.38 *** 51.46 *** hsa-mir-1228 2.38 ** 9.43 *** hsa-mir-1249 1.66 *** 53.17 *** hsa-mir-125a-5p 19 *** 69.8 *** hsa-mir-1260 7.12 *** 61.75 *** hsa-mir-1280 11.88 *** 68.95 *** hsa-mir-129-3p 9.5 *** 65.64 - hsa-mir-1296 9.5 *** 36.36 *** hsa-mir-133a/hsa-mir-133b 42.75 * 0.85 *** hsa-mir-150 4.75 *** 60.37 *** hsa-mir-197 4.75 *** 27.79 *** hsa-mir-204 2.85 *** 27.44 *** hsa-mir-328 0.1 ** 30.87 *** hsa-mir-342-3p 33.25 *** 58. [score:3]
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[+] score: 3
Other miRNAs from this paper: hsa-mir-145, hsa-mir-603, hsa-mir-645
The seed sequences of three human miRNAs (hsa-miR-645, hsa-miR-603 and hsa-miR-1224-5p) were identified within the endo-siRNA derived from RMRP (Supplementary Figure S1A). [score:1]
Although hsa-miR-1224-5p was detected in all cell types, hsa-miR-645 and hsa-miR-603 were not. [score:1]
The seed sequence of hsa-miR-1224-5p is located at the 3′ end of the endo-siRNA derived from RMRP. [score:1]
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[+] score: 3
included Pri-miR-193a, −9-3, and −375, which were known to be transcriptionally regulated by DNA methylation in HCT116 cells [8], as positive controls and Pri-miR-1224, which was demethylated but remained silenced in D KO cells in this study, as a negative control. [score:2]
miR-1224 was included as a negative control. [score:1]
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[+] score: 3
Interestingly, members of cancer -inhibitory miRNA family miR-200a, miR-200b, miR-429 and miR-551a are located in the region of loss at 1p36 while the 3q26-27 region harbors miR-15b, miR-16-2 and other microRNAs including miR-1263, miR-720, miR-551b, miR-569, miR-1224. [score:3]
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[+] score: 3
They are distinguished by additional suffixes (e. g. hsa-miR-1224-5p (5'arm) and hsa-miR-1224-3p (3'arm)). [score:1]
If complete names are used, e. g. hsa-miR-1224-5p, the author likely means the 5'arm predominant mature form of human miRNA-1224. [score:1]
On the other hand, an incomplete form e. g. miR-1224 could mean precursor or mature microRNAs, the 3' or the 5' variant or an unspecified variant of microRNA 1224 in some species depending on the context. [score:1]
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[+] score: 1
Also present were miR-1777b (6.71%), miR-1777a (4.88%), miR-1246 (4.42%), miR-126-3p (2.44%), miR-2305 (2.07%), miR-1584-5p (1.90%), miR-2413 (1.74%), miR-4286 (1.58%), miR-1224 (1.56%), and miR-451 (1.41%). [score:1]
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[+] score: 1
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-16-1, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-32, hsa-mir-33a, hsa-mir-96, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-16-2, hsa-mir-192, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-182, hsa-mir-183, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-204, hsa-mir-211, hsa-mir-212, hsa-mir-181a-1, hsa-mir-214, hsa-mir-217, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-27b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-137, hsa-mir-138-2, hsa-mir-145, hsa-mir-152, hsa-mir-153-1, hsa-mir-153-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-136, hsa-mir-138-1, hsa-mir-146a, hsa-mir-150, hsa-mir-185, hsa-mir-193a, hsa-mir-194-1, hsa-mir-320a, hsa-mir-155, hsa-mir-181b-2, hsa-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-34c, hsa-mir-26a-2, hsa-mir-302b, hsa-mir-369, hsa-mir-375, hsa-mir-378a, hsa-mir-328, hsa-mir-335, hsa-mir-133b, hsa-mir-409, hsa-mir-484, hsa-mir-485, hsa-mir-486-1, hsa-mir-490, hsa-mir-495, hsa-mir-193b, hsa-mir-497, hsa-mir-512-1, hsa-mir-512-2, hsa-mir-506, hsa-mir-509-1, hsa-mir-532, hsa-mir-92b, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-33b, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-802, hsa-mir-509-2, hsa-mir-509-3, hsa-mir-548e, hsa-mir-548j, hsa-mir-548k, hsa-mir-548l, hsa-mir-548f-1, hsa-mir-548f-2, hsa-mir-548f-3, hsa-mir-548f-4, hsa-mir-548f-5, hsa-mir-548g, hsa-mir-548n, hsa-mir-548m, hsa-mir-548o, hsa-mir-548h-1, hsa-mir-548h-2, hsa-mir-548h-3, hsa-mir-548h-4, hsa-mir-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-548q, hsa-mir-548s, hsa-mir-378b, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-320e, hsa-mir-548x, hsa-mir-378c, hsa-mir-4262, hsa-mir-548y, hsa-mir-548z, hsa-mir-548aa-1, hsa-mir-548aa-2, hsa-mir-548o-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-548h-5, hsa-mir-548ab, hsa-mir-378f, hsa-mir-378g, hsa-mir-548ac, hsa-mir-548ad, hsa-mir-548ae-1, hsa-mir-548ae-2, hsa-mir-548ag-1, hsa-mir-548ag-2, hsa-mir-548ah, hsa-mir-378h, hsa-mir-548ai, hsa-mir-548aj-1, hsa-mir-548aj-2, hsa-mir-548x-2, hsa-mir-548ak, hsa-mir-548al, hsa-mir-378i, hsa-mir-548am, hsa-mir-548an, hsa-mir-203b, hsa-mir-548ao, hsa-mir-548ap, hsa-mir-548aq, hsa-mir-548ar, hsa-mir-548as, hsa-mir-548at, hsa-mir-548au, hsa-mir-548av, hsa-mir-548aw, hsa-mir-548ax, hsa-mir-378j, hsa-mir-548ay, hsa-mir-548az, hsa-mir-486-2, hsa-mir-548ba, hsa-mir-548bb, hsa-mir-548bc
The increased microRNAs include miR-320, miR-486, miR-705, and miR-1224. [score:1]
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2 −2.40(52) hsa-miR-127-5p 14q32.2 −2.35(12, 29) hsa-miR-127-3p 14q32.2 −2.35(52, 59) hsa-miR-411* 14q32.2 −2.30 hsa-miR-125b-1* 11q24.1/21q21.1 −2.27 hsa-miR-411 14q32.2 −2.23(29) hsa-miR-379 14q32.2 −2.22(29, 52) hsa-miR-431* 14q32.2 −2.22 hsa-miR-767-5p Xq28 −2.20 hsa-miR-139-3p 11q13.4 −2.17 hsa-miR-154 14q32.2 −2.16(12) hsa-miR-1224-5p 3q27.2 −2.15 hsa-miR-187 18q12.1 −2.14(12) hsa-miR-95 4p16.1 −2.10(14) hsa-miR-369-5p 14q32.2 −2.05 hsa-miR-665 14q32.2 −2.05 hsa-miR-494 14q32. [score:1]
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The 800 kb analytical window included a total of 22 genes (KLHL6, KLHL24, YEATS2, MAP6D1, PARL, ABCC5, HTR3D, HTR3E, EIF2B5, DVL3, AP2M1, ABCF3, VWA5B2, MIR1224, ALG3, ECE2, CAMK2N2, PSMD2, EIF4G1, SNORD66, FAM131A and CLCN2) located within this region, with the entire region assessed as part of one single Malécot test of association. [score:1]
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Note that there is not evidence for small RNA generation across most of the aligned species, and only in a small number of the species exhibit a classic "saddle-shaped" evolutionary profile in which the hairpin loop clearly evolves more quickly than does the hairpin arms (e. g. as is seen for mir-1224, mir-3064, and mir-877). [score:1]
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