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136 publications mentioning hsa-mir-499a (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-499a. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

[+] score: 226
From a survey of microRNA target prediction programs including MiRanda, TargetScan, and Mirtarget, Sox6 emerged as an attractive candidate, given three potential miR-499 binding sites and potential roles for Sox6 in muscle and heart [36]– [38], [45], [46]. [score:7]
To determine the consequence of persistent miR-499 expression in pressure-overload stress, we first generated transgenic mice with increased levels of miR-499 in the heart by expressing miR-499 under control of the cardiac, alpha-myosin heavy chain (Myh6) promoter, as it confers increasing postnatal ventricular cardiomyocyte expression [42]– [44]. [score:7]
We hypothesized that miR-499 expression may be playing an important role in cardiac gene regulation given its expression pattern, its evolutionary conservation, and its decrement in pressure-overload conditions such as human aortic stenosis [40]. [score:6]
Elevated miR-499 levels are associated with cardiac hypertrophy in vivo We hypothesized that miR-499 expression may be playing an important role in cardiac gene regulation given its expression pattern, its evolutionary conservation, and its decrement in pressure-overload conditions such as human aortic stenosis [40]. [score:6]
We suspect the failure of normal miR-499 down-regulation in our transgenic mice disrupted the normal response to cardiac pressure stress; similar theories have recently been put forward for cardiac transgenic mice expressing miR-133a [53]. [score:6]
Similar to TG-17 mice expressing miR-499, mice deficient in Egr1 are normal at baseline, but have an impaired response to cardiac stress [49], as do transgenic mice expressing the Egr1-repressor, Nab1 [50]. [score:5]
Although the Sox6 3′UTR could be targeted by miR-499, as we and others have demonstrated [36]– [38], [46], Sox6 levels were not altered in the transgenic mice, suggesting that Sox6 was not targeted by increased miR-499 levels in vivo, or that additional compensatory mechanisms may be involved in vivo. [score:5]
To determine the dose-responsiveness of miR-499 sensitive genes, we analyzed gene expression in the higher miR-499 expressing TG-9 line at 17 days of age. [score:5]
Given the baseline hypertrophy in miR-499-transgenic mice, we hypothesized that miR-499 expression may alter genes important in this cellular program, either directly or indirectly. [score:5]
Initially, we examined genes predicted to be targets of miR-499 using a targeted approach. [score:5]
We assessed miR-499 expression in human tissue to confirm its potential relevance to human cardiac gene regulation. [score:4]
To test whether miR-499 directly or indirectly regulates the immediate early genes, we cloned the 3′ UTRs of the immediate early response genes and placed each downstream of luciferase and tested these in H9c2 and 293T cells. [score:4]
We amplified fragments containing miR-499 from genomic DNA using high-fi delity PCR (PlatinumTaq, Invitrogen) and directional cloning into pcDNA3.1-TOPO (Invitrogen) for expression studies in cell culture. [score:4]
Second, inhibition of miR-499 in culture led to increases in induced Egr1 and Fos levels, which demonstrates that this regulation is present even outside of the context of the cardiac transgene. [score:4]
Interestingly, in a study that analyzed microRNAs in human aortic valve stenosis, miR-499 levels were decreased [40], and it is possible that this decrement may regulate cardiac gene expression changes that are important in the physiologic response to cardiac pressure load. [score:4]
The limited magnitude of transcript changes by miR-499 suggests that the hypertrophic phenotype observed was not due to gross gene expression disruption. [score:3]
We verified that the predicted human miR-499 genomic region encoded the microRNA by cloning the pre-miR-499 region, expressing it in cell culture, and performing Northern blot analysis (Fig. 1C ). [score:3]
Elevated miR-499 levels affect cardiac gene expression and predispose to cardiac stress -induced dysfunction. [score:3]
First, Egr1 and Fos were the most diminished transcripts in TG-17 miR-499-altered hearts, suggesting a robust alteration in the immediate early gene expression program, while in TG-9 Egr1 was also altered (although Fos was not significantly changed). [score:3]
A second line of miR-499 transgenic mice, expressing relatively lower levels of miR-499 (line #17, TG-17), had hearts that appeared unremarkable under basal conditions (Fig. 3A ). [score:3]
miR-499 targeting of Sox6. [score:3]
We used an antisense morpholino to inhibit miR-499 generation in the ventricular cardiomyocyte line, H9c2. [score:3]
miR-499 is expressed in human heart and skeletal muscle. [score:3]
Consistent with a role for miR-499 in blunting the response to cardiac stress, asymptomatic miR-499 -expressing mice had an impaired response to pressure overload and accentuated cardiac dysfunction. [score:3]
The dot indicated in red (arrow) represents miR-499 expression. [score:3]
Furthermore, microRNA levels vary in many cardiac disease states [30], [39]– [41], and in cardiac samples from individuals with aortic stenosis leading to pressure-overload and heart failure, miR-499 levels are altered [40]. [score:3]
miR-499 Expressing Mice Are Predisposed to Stress-Induced Cardiac Dysfunction. [score:3]
We transfected 293T cells (ATCC) with miR-499 -expression construct or vector alone for RNA for positive and negative controls. [score:3]
High levels of miR-499 led to spontaneous cardiac contractile dysfunction, while more modest levels of transgenic expression conferred susceptibility to pressure -induced dysfunction. [score:3]
Modest levels of miR-499 expression results in mild hypertrophy. [score:3]
expressing higher levels of miR-499 (line #9 or TG-9) developed enlarged hearts (n = 16) as demonstrated by gross pathology at 5 weeks of life (Fig. 2B ). [score:3]
This suggests gene expression changes due to miR-499 that favor hypertrophy. [score:3]
Mice expressing lower levels of miR-499 (line #17 or TG-17) appeared normal under basal conditions (n = 20). [score:3]
Global microRNA expression profiling studies have identified miR-499 in the heart [32]– [35], however its function is just beginning to be elucidated. [score:3]
We transfected increasing amounts of miR-499 into 293T cells in culture and found dose -dependent inhibition of the Sox6 UTR-luciferase construct, however another cardiac microRNA, miR-133, had no effect regardless of the dose (Fig. 4A ). [score:3]
Sox6, which was a target for miR-499 in luciferase assays, was not altered in transgenic mice (1.0 fold, not significant). [score:2]
miR-499 may titrate the cardiac response to stress in part by regulating the immediate early gene response. [score:2]
Importantly, pathway analysis revealed enrichment for the GO terms sarcomere (P = 0.0074), contractile fiber part (P = 0.0085), myofibril (P = 0.0095), and contractile fiber (P = 0.010), further highlighting the potential role of miR-499 in regulating sarcomeric function in the heart. [score:2]
To express miR-499 in vivo, we amplified DNA surrounding the mouse pre-miR-499 region and cloned the 574-bp fragment into the alpha-myosin heavy chain promoter vector using the following primers and SalI linkers: 5′-CGT GTC GAC CAA GTC TGG GGT GAA AGA GAA G-3′ (forward), 5′-TGT GTC GAC GGT CAT GAG CTT GTT GAG GTT C-3′ (reverse) and injected into one-cell FVB/NCrl embryos before implantation in pseudopregnant females. [score:2]
0019481.g002 Figure 2 (A) Cardiac miR-499 expression levels (mean ± standard deviation) in transgenic mouse lines compared to littermate controls. [score:2]
These data are consistent with a role for miR-499 in regulating the immediate early gene response. [score:2]
RNA was prepared from the ventricles of postnatal day 17 miR-499 transgenic mice or littermate controls, and gene expression was compared by microarray analysis (Fig. 5A ). [score:2]
Knockdown of miR-499 levels led to an increase in Egr1 and Fos levels 30 min following immediate early gene response activation by serum (Fig. 6A ), however the effect was temporally limited, as it resolved by 60 min. [score:2]
A distinctive pattern of cardiac gene regulation mediated by miR-499. [score:2]
To modulate microRNA levels, miR-499 mimic or control mimic (Dharmacon) or a morpholino directed against the miR-499 precursor or a scrambled control morpholino (GeneTools) was electroporated (Amaxa) into H9c2 and allowed to recover overnight. [score:2]
miR-499 plays a role in myosin gene regulation [36]– [38], however the functional effects of altered microRNA dosage may depend on the tissue's physiologic state. [score:2]
The higher expressing miR-499 transgenic mice (TG-9) had larger hearts (Fig. 2C ) and increased heart-to-body weight ratios compared to littermate controls (Fig. 2D ), while the brain-to-body weight ratios were similar. [score:2]
The conserved intronic location of miR-499 is indicated between exons 20 and 21 in humans and exons 19 and 20 in mouse; arrows indicate the direction of transcription. [score:2]
These data suggested that miR-499 levels negatively regulate the stress -induced activation of Egr1 and this may be important in the cardiac response to stress and in hypertrophy. [score:2]
Sequence of morpholino directed against the miR-499 precursor 5′-ATG CAG AGG AGC TAA ACA TCA CTG C-3′ or a scrambled control morpholino 5′-GAT TGC GAA GAG TCT CAC AAG ACC A-3′. [score:2]
We established two transgenic lines, which varied in degree of miR-499 expression compared to littermate controls (Fig. 2A ). [score:2]
We verified that Sox6 was an in vitro target of miR-499 by cloning the Sox6 3′-UTR and then tested for microRNA repression by luciferase assays. [score:2]
miR-499 is distinct from miR-1 and miR-133 in that it is encoded in only one genomic locus. [score:1]
The observation that miR-499 transgenic mice develop or are predisposed to cardiac dysfunction may reflect the fact that the immediate early response genes hold a key position in the hierarchy of the cardiac transcriptional response to stress. [score:1]
The Immediate Early Gene Response is Altered by miR-499 Levels. [score:1]
miR-499 did not repress luciferase constructs with the Egr1, Egr2, or Fos UTRs (Fig. 6E ), whereas miR-499 repressed constructs containing the Sox6 3′UTR. [score:1]
miR-499 elevation predisposes to stress -induced cardiac dysfunction in vivo. [score:1]
To avoid changes secondary to heart failure, we used the miR-499 transgenic line (TG-17) that did not display overt cardiac dysfunction. [score:1]
Activation of Fos was not different in the miR-499 transgenic mice, similar to what we observed in cultured cells. [score:1]
Altered cardiac transcripts from global analysis of miR-499 TG hearts. [score:1]
Sox6 3′UTR -mediated repression by miR-499 was evident, however Egr1, Egr2, and Fos 3′UTRs were not repressed by miR-499 (n = 3 per condition, *P<0.05). [score:1]
To determine the tissue-specificity of miR-499, we surveyed various human tissue types by Northern blot; miR-499 was detected only in the heart and in skeletal muscle (Fig. 1D ) in agreement with what has been reported in mice [36], [37]. [score:1]
Conversely, introduction of miR-499 mimic lowered Egr1 levels in cell culture after serum stimulation (Fig. 6B ). [score:1]
0019481.g004 Figure 4. (A) The 3′UTR of Sox6 was placed downstream of a luciferase reporter construct and tested for repression by miR-499 in 293T cells. [score:1]
We present several lines of evidence that demonstrate that miR-499 levels fundamentally alter the immediate early gene response, which is known to be important in the cardiac stress response. [score:1]
In this study we show that elevated levels of miR-499 in hearts of transgenic mice result in cardiomyocyte hypertrophy and stress -dependent cardiac dysfunction. [score:1]
We assessed whether serum response factor (SRF), which is upstream of the immediate early genes, was altered in the miR-499 transgenics. [score:1]
miR-499 is an evolutionarily conserved muscle-specific microRNA that is encoded within the intron of myosin heavy chain 7B (Myh7B) and is highly enriched in the cardiac ventricles. [score:1]
Our studies support an association between elevated cardiac miR-499 levels and cardiac dysfunction, particularly in the setting of pressure overload. [score:1]
Since the 3′ UTRs of Egr1, Egr2, and Fos were insufficient to mediate miR-499 repression, we suspect they are affected by miR-499 in a yet unknown manner that is not dependent on altered SRF levels. [score:1]
miR-499 was among the top cardiac-enriched microRNAs (Fig. 1A, Table S1), along with the well-studied microRNAs, miR-1 and miR-133. [score:1]
We reasoned that the immediate early response genes may be playing a role in the hypertrophic phenotype for several reasons: 1) the immediate early response genes are rapidly altered in response to cardiac stress [8], [47], [48]; 2) perturbation of the immediate early response alters cardiac hypertrophy [49], [50]; and 3) immediate early genes are typically SRF -dependent, and the cardiac abnormalities in the miR-499 transgenic partially resembled that of mice where SRF was temporally deleted [51]. [score:1]
In silico analysis revealed that miR-499 was located in an intron of the human myosin heavy chain gene, MYH7B (Fig. 1E ), analogous to the arrangement in Myh7B in mice. [score:1]
Overall, these results suggest elevated miR-499 levels predispose the heart to cardiac dysfunction. [score:1]
We therefore hypothesize that miR-499 alters the cardiac response to stress in part by modulating the immediate early gene response. [score:1]
We identified a discrete set of altered transcripts in unmanipulated, normally functioning, miR-499 transgenic hearts, including natriuretic peptide precursor type B (Nppb), ß-MyHC (Myh7) and alpha 1 skeletal muscle actin (Acta1). [score:1]
Given the effect of miR-499 levels on the immediate early gene response, which is known to be involved in cardiac stress and hypertrophy [12]– [14], we hypothesized that increased miR-499 levels may predispose to stress -induced cardiac dysfunction. [score:1]
We verified the effect of miR-499 on the immediate early response genes by miR-499 gain- and loss-of-function in vitro. [score:1]
Membranes were probed with [32]P -labelled locked nucleic acid probe (Exiqon) or DNA oligonucleotide probe complementary to mature miR-499 or to U6. [score:1]
Human miR-499 is a conserved muscle-specific microRNA. [score:1]
In screening for microRNAs enriched in the human heart, we identified an abundant microRNA, miR-499, which has been the subject of several recent studies. [score:1]
miR-499 blunts the induction of the immediate early response genes. [score:1]
Interestingly, mice lacking the cardiac-specific microRNA miR-208a have decreased amounts of miR-499 [25], [36]. [score:1]
Each dot represents a single transcript from three miR-499 transgenic mice and three littermate controls. [score:1]
We therefore tested whether the TG-17 miR-499-transgenic mice, which had normal function at baseline, were predisposed to increased cardiac dysfunction upon cardiac pressure overload. [score:1]
Total RNA was isolated from ventricular tissue from three miR-499-transgenic mice (line #17, TG-17) and three littermate controls at postnatal day 17. [score:1]
The connection between miR-499 and the immediate early gene response is important since activation of this pathway is thought to precede further transcriptional responses to stress. [score:1]
Evaluation of genes reported to be dysregulated in miR-208a mutant mice revealed elevated levels of Egr1, Egr2, and Fos in the heart, suggesting a potential relationship between miR-499 and miR-208 in regulation of the immediate early gene response to cardiac stress. [score:1]
Table S2 Common genes altered in miR-499 transgenic lines, TG-17 and TG-9. For each gene, the gene symbol, genomic location, log ratios and fold change of TG versus WT are shown. [score:1]
miR-499 levels and mRNAs were quantified using RNA from transgenic mouse hearts and littermate controls. [score:1]
Using a transgenic mouse mo del, we found that elevated miR-499 levels caused cellular hypertrophy and cardiac dysfunction in a dose -dependent manner. [score:1]
Sox6 3′UTR -mediated repression increased as amounts of miR-499 was increased; this was not observed with miR-133 or when the UTR orientation was reversed, n = 3–4 transfections per condition, *P<0.05. [score:1]
miR-499 levels were increased 12.6-fold, in agreement with our microRNA qPCR results. [score:1]
miR-499-transgenic mice (TG-17) displayed a blunted activation of Egr1 in response to systemic administration of EGF (Fig. 6C ). [score:1]
Interestingly, a recent study [39] reported that miR-499 levels increase in human cardiac failure, and the findings in our transgenic mouse mo del may support a detrimental role for elevated miR-499 levels. [score:1]
Furthermore, we found miR-499 alters the immediate early gene response to cardiac stress, which may partially contribute to the effects of elevated miR-499. [score:1]
In this study, we found that elevated levels of miR-499 in the heart can lead to cardiomyocyte hypertrophy and cardiomyopathy in a dose -dependent manner. [score:1]
0019481.g003 Figure 3 (A) Gross appearance of hearts from miR-499 transgenic mice (line #17, TG-17) and littermate controls (WT) was similar. [score:1]
Here we investigate miR-499, a microRNA embedded within a ventricular-specific myosin heavy chain gene, which is expressed in heart and skeletal muscle. [score:1]
RNA from miR-499 transfected 293T cells or control vector -transfected cells was used as positive or negative controls (ctrl). [score:1]
First, to examine the miR-499:immediate early gene relationship independent of the potential complexity of the in vivo transgenic system, we tested whether the immediate early gene response was altered using cultured cells where miR-499 levels were manipulated. [score:1]
We also tested whether repression was lost when we transfected the reversed 3′UTR sequence construct with our miR-499 vector (250 ng). [score:1]
By genomic sequence alignment, miR-499 is completely conserved throughout evolution with the exception of a single nucleotide change in chicken (Fig. 1B ). [score:1]
Echo Assessment of miR-499 Transgenic Mice. [score:1]
When we compared SRF protein levels in WT and TG mice, there was no difference (Fig. 6D ), suggesting that the immediate early genes are regulated by miR-499 independent of SRF levels. [score:1]
0019481.g006 Figure 6(A) Egr1 and Fos mRNA levels by qPCR relative to Gapdh in the ventricular cell line H9c2, upon introduction of a morpholino (MO) that blocks miR-499 generation or a control MO. [score:1]
Elevated miR-499 levels are associated with cardiac hypertrophy in vivo. [score:1]
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Over -expression of miRNA499 induces the expression of myosin heavy-chain (MHC) and cardiac-specific transcription factors in mouse and human ESC [33], while the inhibition of miRNA499 impairs the cardiac differentiation process [18]. [score:7]
Of extreme relevance, WB analysis showed that the combination of miRNA499 plus miRNA133 upregulated the protein expression of both Cx43 and cTnT (Fig. 6B). [score:6]
Expression of cardiac cytoskeletal protein (α-sarcomeric actinin) and of other important proteins involved in cardiac excitation/contraction (EC)-coupling (Cav1.2, SERCA2a, and RyR2) was analyzed by ICC on EB coexpressing miRNA499 and miRNA133, selected from the same batch of EB showing caffeine-responsiveness. [score:5]
ICC further confirmed that miRNA499 and miRNA133 coexpression was able to induce the expression of cardiac-specific proteins like cTnT, Cx43, Serca2a, and Cav1.2 (Fig. 6C) even in the absence of DMSO. [score:5]
The coexpression of miRNA499 and miRNA133 further increased the expression of the atrial marker Mlc. [score:5]
At the 14 days time point, WB showed that miRNA1 alone had no effect on both Cx43 and cTnT, miRNA133 increased only the expression of cTnT, while miRNA499 was able to markedly increase the expression of both Cx43 and cTnT (Fig. 3A). [score:5]
Gene and protein expression analysis showed that miRNA499 and miRNA133 are able to induce the differentiation of AMSC into cells expressing typical cardiac markers such as Nkx2.5, GATA4, cTnT, Cx43, Ryr2, and Cav1.2. [score:5]
The over -expression of miRNA499 resulted in the upregulation of both genes compared with DMSO (Supporting Information Fig. S3A, S3B). [score:5]
Recently, it has been suggested that certain miRNA are powerful regulators of cardiac differentiation processes [32], and it has been shown that miRNA1, miRNA133, and miRNA499 are highly expressed in muscle cells [32]. [score:4]
Most importantly, by simultaneously over -expressing miRNA499 and miRNA133 the number of P19 cells expressing cTnI was 30-fold greater compared with the standard differentiation protocol. [score:4]
2A (Supporting Information Fig. S3C) and the ventricular marker IRX4 (Supporting Information Fig. S3D) were upregulated in P19 cells treated with pre-miRNA499 plus 133. [score:4]
Real-time PCR analysis showed that also in P19 cells not exposed to DMSO, treatment with miRNA499 and miRNA133 upregulated GATA4 (+4.9-fold, p < . [score:4]
On the contrary, the coexpression of miRNA1 with miRNA499 did not increase the expression of the two cardiac-specific proteins compared with miRNA499 alone (Fig. 3A). [score:4]
The over -expression of miRNA1 alone or in association with miRNA499 failed to increase the expression level of the cardiac-specific differentiation markers considered. [score:4]
When miRNA499 and miRNA133 were coexpressed, we documented a significant increase in both GATA4 and Nkx2.5 expression compared with all other conditions tested (Fig. 2A, 2B). [score:4]
However, the coexpression of miRNA499 and miRNA133 resulted in a significantly higher expression of both cardiac markers compared with the other conditions tested (Fig. 7A). [score:4]
However, when we coexpressed miRNA499 together with miRNA133 the results were significantly and strikingly superior compared with the over -expression of miRNA499 alone. [score:4]
Also miRNA499 alone increased the expression of both Cx43 (+3.1-fold vs. [score:3]
In particular, coexpression of Cx43 and cTnT was always present in those cells forming beating clusters, confirming that both contractile and channels proteins are present in the EB treated with the combination of miRNA499 and 133. [score:3]
CMC derived from P19 cells over -expressing miRNA499 and miRNA133 develop EC-coupling properties typical of mature CMC. [score:3]
The Combination of miRNA499 and miRNA133 Increases the Expression of Cardiac-Specific Genes. [score:3]
Indeed, also miRNA499 alone induced a significant over -expression of GATA4 (+5.8-fold, p < . [score:3]
As already observed in P19 cells, the combination of miRNA499 with miRNA133 triggered the over -expression of both the nuclear transcription factor GATA4 (+13-fold, p < . [score:3]
The combination of miRNA499 and 133 greatly enhanced the expression of both Cx43 and cTnT (Fig. 3A). [score:3]
Coexpression of miRNA499 and miRNA133 induced a 3.5-fold increase in the number of responsive cells with respect to cells exposed to DMSO (p < . [score:3]
WB (Fig. 7B) and ICC (Fig. 7C,D) analysis confirmed that AMSC treated with miRNA499 and miRNA133 differentiated in cells expressing Cx43 and cTnT (Fig. 7B, 7C) but also Cav1.2 and Ryr2 (Fig. 7D). [score:3]
Coexpression of miRNA499 and miRNA133 sharply increased the proportion of caffeine-responsive cells. [score:3]
Treatment of P19 cells with miRNA499 or miRNA499 + 133 increased also the expression of the ventricular marker IRX4 (Supporting Information Fig. S3B). [score:3]
The expression of both GATA4 and Nkx2.5 was significantly increased by miRNA499 alone (Fig. 2A, 2B). [score:3]
WB and ICC analysis confirmed that cardiac proteins are indeed expressed at higher levels when P19 cells are cotransfected with miRNA499 plus miRNA133. [score:3]
In addition, the expression of genes encoding for cardiac-specific transcription factors, such as GATA4 and Nkx2.5, and cardiac-specific proteins, such as Cx43 and cTnT, was enhanced in cells treated with miRNA499 plus miRNA133. [score:3]
In particular, untreated EB showed responses compatible with Ca [2+] -dependent electrical activity, typical of immature CMC, while Na [+] -dependent excitability was recorded in EB over -expressing miRNA499 and miRNA133. [score:3]
Importantly for translational purposes, we have also shown that the same combination miRNA499 and miRNA133 is a powerful inducer of cardiac differentiation for human MSC. [score:3]
Cardiac-Specific Proteins Are Highly Expressed in P19 Cells Treated with miRNA499 and miRNA133. [score:3]
It is currently unknown whether the concomitant over -expression of miRNA1, miRNA133, and miRNA499 or if the combination of two of these miRNA would result in a synergistic action, further increasing the efficiency of cardiac differentiation. [score:3]
By simultaneously over -expressing miRNA499 and miRNA1, the number of beating EB significantly increased compared with: DMSO (+2.8-fold; p < . [score:2]
After 14 days, Cx43 was significantly over-expressed in cells treated with miRNA133 or miRNA499 and cTnT was significantly higher in the miRNA499 group compared with naïve cells (Fig. 7A). [score:2]
The Synergic Effect of miRNA499 and miRNA133 on AMSC. [score:1]
The synergistic effect exerted by the combination of miRNA133 and miRNA499 was confirmed by activation of the cTnI cardiac-specific promoter (Fig. 1B). [score:1]
Furthermore, the spontaneous mechanical activity response of miRNA499 and miRNA133 transfected cells to modulators of Ca [2+] handling effectors (CaV, RyRs, and IP3R) is consistent with that expected for cardiac but not skeletal muscle. [score:1]
miRNA499). [score:1]
DMSO, scramble miRNA, miRNA1, and miRNA499 + 1; #, p < . [score:1]
Finally, functional analysis showed that the percentage of responsive EB grown without DMSO but transfected with pre-miRNA499 and pre-miRNA133 did not significantly differ from the percentage of EB grown in the presence of 0.5% DMSO (Fig. 6D). [score:1]
It was impossible to document the same results using different combination of miRNAs, confirming that only the couple miRNA499/miRNA133 triggers the differentiation of MSC toward a cardiac-like phenotype. [score:1]
To verify whether miRNA499 and miRNA133 exert their effects also on other cell types, we tested our protocol on AMSC. [score:1]
Therefore, the effect of miRNA499 and miRNA133 synergism on cardiogenic differentiation was further tested based on the notion that mature excitation-contraction coupling relies on the presence of Ryrs-operated intracellular Ca [2+] stores. [score:1]
DMSO, scramble miRNA, miRNA1, and miRNA499 + 1). [score:1]
In particular, it has been clearly shown that miRNA133 and miRNA1 promote myoblast proliferation and differentiation, respectively, and that miRNA499 enhances the differentiation of cardiac progenitor cells into CMC [17– 20]. [score:1]
DMSO, scramble miRNA, miRNA1, miRNA133, and miRNA499 + 1, and p < . [score:1]
In summary, we demonstrated that miRNA499 and miRNA133 act in a synergic manner inducing P19 differentiation into CMC even in the absence of DMSO. [score:1]
DMSO, scramble miRNA, miRNA499 + 1; §, p < . [score:1]
miRNA499; ≠, p < . [score:1]
The treatment of EB with both pre-miRNA499 and pre-miRNA133 resulted in the strongest activation of the cTnI promoter (Fig. 1B). [score:1]
Figure 5MEA and twitch recordings of embryoid bodies treated with pre-miRNA499 together with pre-miRNA133. [score:1]
After 14 days, quantification of late cardiac-specific genes confirmed the synergistic effect exerted by miRNA499 and miRNA133 (Fig. 2C, 2D). [score:1]
Figure 7Amniotic mesenchymal stromal cells (AMSC) differentiation using miRNA499 and miRNA133 precursors. [score:1]
Further studies demonstrated that miRNA499 is highly enriched in cardiac committed adult progenitor cells [18] and human ESC [33]. [score:1]
Our results clearly showed that miRNA499 is a powerful activator of cardiac differentiation, particularly in comparison with miRNA1 and miRNA133. [score:1]
To strengthen our observation, we aimed to test whether treatment with miRNA499 plus miRNA133 in the absence of DMSO exposure was sufficient to trigger cardiac differentiation. [score:1]
miRNA precursors were diluted in Opti-MEM I medium at the following concentration: miRNA1 and miRNA499 precursors 10 nM, miRNA133 precursor and scrambled miRNA 5 nM. [score:1]
These data strongly suggest a synergistic effect of miRNA499 and miRNA133. [score:1]
001), and 2-fold versus miRNA499 alone (p < . [score:1]
Caffeine responsiveness was not significantly increased by any other treatment, thus supporting the specificity of miRNA499 + 133 effect (Fig. 4B). [score:1]
naïve, scramble miRNA, miRNA1, miRNA133, and miRNA499 + 1; †, p < . [score:1]
After 4 days, the EB were transferred to plastic culture dishes in the presence of differentiation medium, and transfected with precursor molecules (pre-miRNA) for miRNA499 (PM11352, 10 nM), miRNA1 (PM10617, 10 nM), and miRNA133 (PM10413, 5 nM) in different combinations or with scrambled miRNA used as a negative CTRL (AM17110, 5 nM) (Supporting Information Table S1). [score:1]
DMSO, scramble miRNA, miRNA1, miRNA133, and miRNA499 + 1; †, p < . [score:1]
In order to confirm the synergic action of miRNA499 with miRNA133, we tested this combination also in AMSC. [score:1]
miRNA499 + 1, p < . [score:1]
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Other miRNAs from this paper: dre-mir-499, hsa-mir-499b, ola-mir-499
Furthermore, our present study demonstrates that medaka miR-499 expression differed from the above-mentioned MYH14expression patterns (see Figure  3). [score:5]
To find out whether miRNA-499 can be expressed despite lacking its host gene, its expression in medaka was examined by in situ hybridization and next-generation sequencing. [score:5]
We observed that medaka miR-499 was expressed at the embryonic stage in the notochord (Figure  3A), miR-499 expression in the notochord has not been previously reported in other animals. [score:5]
Mammalian MYH14 has a microRNA, miR-499, in its 19th intron that suppresses the expression of genes involved in muscle fiber-type specification [7- 11]; thus, miR-499 seemingly acts to support normal slow-muscle formation in mammals. [score:5]
Therefore, these conserved regions in the 5′-flanking sequence may act as a promoter for the spatio-temporal expression of MYH14, and the regulatory sequences are conserved in medaka miR-499 despite the loss of the MYH14 gene. [score:4]
In fact, Matthew et al. [37] reported uncoupled MYH14 and miRNA-499 expression in mice, suggesting the independent transcriptional regulation of miR-499 from MYH14. [score:4]
Furthermore, by using in situ hybridization and small RNA sequencing, miR-499 was expressed in the notochord at the medaka embryonic stage and slow/cardiac muscle at the larval and adult stages. [score:3]
C) Ventral view of miR-499 expression in the heart of a 10-dpf larva. [score:3]
D) Transverse section of cardiac muscle at the position indicated in panel B. E) Transverse section from trunk skeletal muscle at the position indicated in panel B. Arrows indicate miR-499 expression in superficial slow muscle fibers. [score:3]
We also found that medaka miR-499 was even expressed in the absence of its host gene. [score:3]
Unlike the embryonic and larval stages, the adult medaka only exhibited strong miR-499 expression in the cardiac muscle (Figure  3F-H). [score:3]
I) miR-499 expression confirmed by next-generation sequencing. [score:3]
This study reveals the evolutionary history of the MYH14/miRNA-499 locus in teleost fish, indicating divergent distribution and expression of MYH14 and miR-499 genes in different teleost fish lineages. [score:3]
The existence of multiple MYH14 and miR-499 genes in various teleost fish suggests their expressional and functional versatilities. [score:3]
MYH14 contains an intronic microRNA, miR-499, which is expressed in a slow/cardiac muscle specific manner along with its host gene; it plays a key role in muscle fiber-type specification in mammals. [score:3]
In the present study, however, medaka miR-499 was actually expressed in various tissues despite the absence of MYH14 (see Figure  3). [score:3]
miR-499 expression in medaka. [score:3]
This miR-499 expression pattern in the adult stage was also confirmed by next-generation sequencing (Figure  3I). [score:3]
In the present study, we identified MYH14/miR-499 loci on various teleost fish genomes and examined their evolutionary history by sequence and expression analyses. [score:3]
H) Higher magnification of the square indicated in panel G. miR-499 was expressed in cardiac but not in trunk muscle at the adult stage. [score:3]
Recently, Yeung et al. [36] reported promoter activity in a 6.2-kb upstream sequence of mouse MYH14 that mimics endogenous MYH14 and miR-499 expression. [score:3]
At the hatching stage, miR-499 was expressed in cardiac and trunk skeletal muscles (Figure  3B, C). [score:3]
The transverse sections of the medaka larva clearly showed miR-499 expression in the heart (Figure  3D) and the lateral surface of the myotomal muscle (Figure  3E) where slow muscle fibers are present. [score:3]
Abbreviations used: Chr, chromosome; TRPC4AP, transient receptor potential cation channel, subfamily C, member 4 associated protein; EDEM2, ER degradation enhancer, mannosidase alpha-like 2; SLA2, Src-like-adaptor 2; NDRG3, N-myc downstream regulated family member 3; PHF20, PHD finger protein 20; SULF2, sulfatase 2. Phylogenetic analyses based on the MYH14 coding and miR-499 stem-loop sequences were performed to clarify the evolutionary history of the MYH14/miR-499 locus in teleost fish. [score:2]
Comparing the flanking sequences of MYH14/miR-499 loci between torafugu Takifugu rubripes, zebrafish Danio rerio, and medaka revealed some highly conserved regions, suggesting that cis-regulatory elements have been functionally conserved in medaka miR-499 despite the loss of its host gene. [score:2]
Several highly conserved regions were identified at the MYH14/miR-499 5′-flanking and intron, as shown in blue boxes. [score:1]
We used a digoxigenin (DIG)-labeled MiRCURY detection probe (Exiqon, Copenhagen, Denmark), an LNA -modified oligo DNA probe containing the miR-499 mature sequence (5′-AAACATCACTGCAAGTCTTAA-3′), to detect miR-499 transcripts. [score:1]
Using the genomic databases available for different vertebrates, we examined the syntenic organization of human MYH14 and miR-499 with their orthologs. [score:1]
Interestingly, miR-499 was not located in the MYH14 introns of certain teleost fish. [score:1]
miR-499 transcripts were detected in the notochord of the embryo and in cardiac and trunk skeletal muscles in the hatching larva. [score:1]
In tetrapods, however, SULF2 is located in the same chromosome as MYH14/miR-499, but far from the locus. [score:1]
Vertical axis indicates miR-499 read numbers in each tissue. [score:1]
Black circles indicate duplication of the MYH14/miR-499 locus. [score:1]
The torafugu MYH14 intron containing miR-499 is 247 bp in length (see Additional file 2: Figure S2), which is long enough to produce canonical miRNA hairpins to be cut by drosha. [score:1]
In the case of medaka, MYH14 was completely absent, with the exception of miR-499 (Figure  4A and Additional file 2: Figure S2) and an intron immediately downstream of miR-499 (intronic conserved region in Figure  4A, Additional file 3: Figure S3). [score:1]
Secondary structure of the miR-499 stem-loop sequence. [score:1]
Cod and stickleback retained a single MYH14 paralog lacking miR-499 in the other syntenic region that contained SULF2. [score:1]
In medaka, Oryzias latipes, miR-499 is present where MYH14 is completely absent in the genome. [score:1]
Neoteleostei-specific whole genome duplication formed two sets of MYH14/miR-499 pairs. [score:1]
These results combined suggest that miR-499 is not a mirtron but a canonical intronic miRNA. [score:1]
Numbers on the right indicate the positions of the MYH14 (torafugu and zebrafish) start codon and mature miR-499 (medaka) 5′-end. [score:1]
These findings can potentially explain why miR-499 has remained despite the loss of MYH14 in some teleost fish genomes. [score:1]
Figure  4B shows miR-499 predicted stem-loop structures from medaka, torafugu, and the representative mirtron, miR-62, from Caenorhabditis elegans. [score:1]
MYH14 and miR-499 paralogs found in one species are distinguished by numbers (see Table  1). [score:1]
To localize miR-499 transcripts in adult medaka, in situ hybridization was performed with transverse sections of trunk skeletal and cardiac muscles. [score:1]
MYH14 paralogs were separated, except for zebrafish, according to the presence or absence of miR-499 in their introns. [score:1]
Sequence comparison of the intron containing miR-499 among torafugu, zebrafish, and medaka. [score:1]
The torafugu MYH14-1 (MYH [M5]), zebrafish MYH14-1 5′- and 3′-flanking sequences, and the medaka miR-499 stem-loop sequences, which contain Snai1 and TRPC4AP genes, were retrieved from the Ensembl genome browser. [score:1]
It would be interesting to determine whether such differences in MYH14 and miR-499 are related to physiological and ecological variations among teleost fish species. [score:1]
Interestingly, teleost fish genomes contain multiple MYH14 and miR-499 paralogs. [score:1]
MYH14 (A) and miR-499 (B) neighbor-joining (NJ) trees. [score:1]
Our phylogenetic analysis clearly shows duplication of the MYH14/miR-499 locus after the divergence of spotted gar, indicating that the teleostei-specific WGD provided present-day MYH14/miR-499 paralogs in teleost fish. [score:1]
Both zebrafish MYH14 contained miR-499, totaling three MYH14/miR-499 pairs in this species. [score:1]
MYH14 and miR-499 genes were screened from available vertebrate genome databases, and their evolutionary history was examined by synteny and phylogenetic analyses. [score:1]
Figure  5 shows the putative evolutionary history of the MYH14/miR-499 locus in teleost fish. [score:1]
However, the evolutionary history of MYH14 and miR-499 has not been studied in detail. [score:1]
Construction of a physical map around MYH14 and miR-499. [score:1]
Click here for file Sequence comparison of the intron containing miR-499 among torafugu, zebrafish, and medaka. [score:1]
We could also speculate that miR-499 has its own promoter as do some intronic miRNAs. [score:1]
Phylogenetic analysis of MYH14 and miR-499. [score:1]
The aim of this study was to elucidate the evolutionary history of MYH14/miR-499 in fish. [score:1]
Mature miR-499 sequences are boxed. [score:1]
Note that accelerated evolution was clearly observed in MYH14s lacking miR-499 by their large genetic distance from MYH14 possessing miR-499, suggesting a functional relationship between MYH14 and miR-499. [score:1]
Interestingly, in Atlantic cod Gadus morhua, stickleback Gasterosteus aculeatus, platyfish Xiphophorus maculatus, and medaka, miR-499 was present within the expected syntenic region that contained TRPC4AP, NDRG3, SULF2. [score:1]
The sequences with their seed regions (2–8 nucleotides from the 5′-end) showing 100% identity to those of known mature miR-499 sequences were annotated as medaka miR-499. [score:1]
MYH14 (A) and miR-499 (B) maximum-likelihood (ML) trees. [score:1]
An intronic sequence immediately downstream of miR-499 is conserved among zebrafish, torafugu, and medaka, as shown in Figure  4A, which could be the miR-499 promoter. [score:1]
In torafugu, green spotted puffer, and tilapia, redundancy in miR-499 caused the deletion of one of the two miR-499 paralogs. [score:1]
MYH [M5] was located next to TRPC4AP and contained miR-499, whereas MYH [M3383] was located next to sulfatase 2 gene (SULF2) and did not contain miR-499 in its intron. [score:1]
Based on the synteny, two putative MYH14s, one containing miR-499 and the other lacking it, were also found in green spotted puffer Tetraodon nigroviridis and tilapia Oreochromis niloticus. [score:1]
The combined phylogenetic and synteny analyses suggest that the MYH14/miR-499 locus was duplicated early in teleost evolution and one of the duplicated miR-499 genes was lost in the common ancestor to cod and the Acanthopterygii, after the split from the zebrafish lineage. [score:1]
The MYH14 and miR-499 sequence data were retrieved from the available genome databases mentioned above (Table  1). [score:1]
These lines of evidence allowed us to speculate on the existence of a highly varied distribution and function of MYH14 and miR-499 in teleost fish. [score:1]
Interestingly, the torafugu and zebrafish MYH14s 5′-flanking sequences showed clear similarity with those of medaka miR-499 (5′-upstream conserved regions in Figure  4A, Additional file 4: Figure S4). [score:1]
NJ and ML trees were constructed on the basis of the MYH14 coding and miR-499 stem-loop sequences using MEGA5 [39] with 1000 bootstrap replications. [score:1]
Distribution of MYH14 and miR-499 in teleost fish genomes. [score:1]
For medaka, miR-499 is transcribed lacking its host gene MYH14, which suggests the presence of its own promoter for transcription. [score:1]
We speculate that miR-499 is a canonical intronic miRNA produced by drosha cropping (see Figure  4B). [score:1]
Further comparative analyses of MYH14 and miR-499 may shed light on the mechanisms involved in the formation of species-specific musculature evolution. [score:1]
Figure 5 Putative evolutionary history of MYH14 and miR-499 in the fish lineage. [score:1]
In the zebrafish lineage, additional tandem duplication resulted in three MYH14/miR-499 pairs. [score:1]
The common ancestor of amniotes and fish had a single miR-499 containing MYH14. [score:1]
Putative secondary structures of the miR-499 from medaka and torafugu stem-loop sequences and that of the C. elegans mirtron miR-62 (miRBase accession number: MI0000033) were predicted using the RNA fold program CentroidFold (http://www. [score:1]
html) was used to determine the syntenic organization in the region surrounding MYH14 and/or miR-499 in vertebrates. [score:1]
Therefore, further analysis is required to fully reveal MYH14/miR-499 evolution in fish. [score:1]
The Tajima-Nei mo del [41] was employed for the miR-499 NJ tree, whereas the Tamura-Nei mo del [42] was used for the MYH14 and miR-499 ML trees. [score:1]
Figure  4A shows comparisons of torafugu MYH14-1 (MYH [M5]) flanking regions with corresponding regions in zebrafish MYH14-1 and medaka miR-499. [score:1]
However, experimental proof is required to confirm whether miR-499 requires drosha processing. [score:1]
Sequence analysis of MYH14/miR-499 locus flanking regions. [score:1]
Interestingly, sequence comparison analysis showed highly conserved 5′-flanking regions between torafugu MYH [M5] and medaka miR-499 (see Figure  5A). [score:1]
The locations and IDs of MYH14 and miR-499 used in this study are shown in Table  1 and Figure  1. Our results show that the tandem arrayed location of the ER degradation enhancer, mannosidase alpha-like 2 gene (EDEM2), transient receptor potential cation channel subfamily C member 4 associated protein gene (TRPC4AP), and MYH14 containing miR-499 were conserved in humans, chickens, and coelacanths Latimeria chalumnae. [score:1]
In zebrafish Chr11, MYH14 containing miR-499 was located next to TRPC4AP. [score:1]
Synteny and phylogenetic analyses depict the evolutionary history of MYH14/miR-499 loci where teleost specific duplication and several subsequent rounds of species-specific gene loss events took place. [score:1]
Consistent with functional conservation with mammals, Wang et al. [16] showed that the transcriptional network of Sox6/ MYH14/miR-499 plays an essential role in maintaining slow muscle lineage in larval zebrafish muscle. [score:1]
Although the bootstrap value in each node was quite low, three zebrafish miR-499 paralogs, miR-499-1, -2, and −3, were divided into two clades. [score:1]
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Myostatin, a target gene of microRNA-208b and microRNA-499-5p and an inhibitor of muscle growth, is upregulated and inversely correlated with the expression of these microRNAs. [score:10]
Correlation between (C) MYH7 gene expression and microRNA-208b expression and (D) MYH7b gene expression and microRNA-499-5p expression in people with spinal cord injury and able-bodied control subjects. [score:9]
Correlation between (C) myostatin gene expression and microRNA-208b expression and (D) myostatin gene expression and microRNA-499-5p expression in people with spinal cord injury and able-bodied controls. [score:9]
Expression of microRNA-208b and microRNA-499-5p is decreased after spinal cord injury and correlates with expression of host genes MYH7 and MYH7bExpression of microRNA-208b and microRNA-499-5p progressively declined with time after spinal cord injury (Fig. 2). [score:7]
Direct modulation of gene target expression was studied in vivo by gene transfer of microRNA-208b or microRNA-499-5p in intact mouse muscle by electroporation. [score:6]
Our findings corroborate earlier studies describing a feedback loop regulating skeletal muscle mass (McCarthy et al. 2009; van Rooij et al. 2009), whereby decreased expression of MYH7 and MYH7b attenuate the expression of the encoded myomirs, microRNA-208b, and microRNA-499-5p. [score:6]
We also report that in vivo overexpression of microRNA-208b, but not microRNA-499-5p directly reduced myostatin gene expression in mouse skeletal muscle. [score:6]
Relative mRNA expression of myostatin decreased in skeletal muscle overexpressing microRNA-208b, but not microRNA-499-5p (Fig. 4C– D). [score:5]
Myostatin expression was inversely correlated with microRNA-208b and microRNA-499-5p expression in all groups (r =  0.702 and 0.637, respectively, P < 0.001, Fig. 3C– D). [score:5]
Furthermore, expression of both microRNA-208b and microRNA-499-5p correlated with expression of their respective host genes, namely MYH7 and MYH7b (r =  0.810 and 0.656, respectively, P <  0.001 Fig. 2C-D). [score:5]
Expression of microRNA-208b and microRNA-499-5p is decreased after spinal cord injury and correlates with expression of host genes MYH7 and MYH7b. [score:5]
Finally, overexpression of microRNA-208b, but not microRNA-499-5p, in adult rodent skeletal muscle decreased myostatin gene expression. [score:5]
Here, we demonstrate that overexpression of microRNA-208b, though not microRNA-499-5p, in rodent skeletal muscle decreased myostatin gene expression in vivo. [score:5]
Expression of microRNA-208b and microRNA-499-5p progressively declined with time after spinal cord injury (Fig. 2). [score:3]
MicroRNA-208b and microRNA-499-5p have nearly identical seed sequences and therefore share many predicted gene targets. [score:3]
Moreover, myostatin expression was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle following spinal cord injury, coincident with skeletal muscle atrophy. [score:3]
Figure 2MicroRNA-208b (A) and microRNA-499-5p (B) expression in able-bodied control subjects (CON – white bar), and people with complete cervical spinal cord injury studied 1, 3, or 12 months post injury (gray bars) or after long-standing injury (LS – black bar). [score:3]
In conclusion, skeletal muscle expression of microRNA-208b and microRNA-499-5p progressively declined within the first year after cervical spinal cord injury in humans, with changes maintained in long-standing injury. [score:3]
MicroRNA-208b and microRNA-499-5p have similar seed regions that overlap by six bases, indicating that they share several target genes (van Rooij et al. 2009). [score:3]
The genes encoding slow-twitch oxidative type I muscle fiber myosin heavy chains, MYH7 and MYH7b, intronically express microRNA-208b and microRNA-499-5p, respectively (McCarthy et al. 2009). [score:3]
Here, we report that skeletal muscle expression of microRNA-208b and microRNA-499-5p, as well as their host genes MYH7 and MYH7b, decline progressively during the first year after cervical spinal cord injury in humans, with changes maintained in long-standing injury. [score:3]
Although myostatin has been validated as a target of both microRNA-208b (Callis et al. 2009) and microRNA-499-5p by luciferase assay (Bell et al. 2010), the in vivo regulation is unknown. [score:3]
Expression of microRNA-208b and microRNA-499-5p, as well as the slow myosin genes to which these particular microRNAs are intronic, decline progressively within the first year after spinal cord injury. [score:3]
Thus, we determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in skeletal muscle obtained from people with complete spinal cord injury. [score:3]
The myostatin 3′ untranslated region (UTR) includes a mouse to human conserved seed -binding site for microRNA-208b and microRNA-499-5p (Fig. 3A). [score:3]
Hindlimb suspension for 28 days leads to skeletal muscle atrophy, concomitant with decreased expression of microRNA-208b and microRNA-499-5p in rat soleus muscle (McCarthy et al. 2009). [score:3]
In particular, microRNA-208b and microRNA-499-5p play a role in the regulation of skeletal muscle fiber type and skeletal muscle mass (McCarthy et al. 2009; van Rooij et al. 2009). [score:2]
With this method, we achieved an overexpression of microRNA-208b or microRNA-499-5p in predominantly glycolytic, type II, tibialis anterior muscle, respective to control muscle (Fig. 4A– B) that was comparable to levels measured in nontransfected oxidative soleus muscle (data not shown). [score:1]
Figure 3(A) Predicted microRNA seed/mRNA 3′-UTR interaction between microRNA-208b and microRNA-499-5p within the 3′-UTR of the human and mouse myostatin transcripts according to microRNA. [score:1]
Moreover, mice lacking both microRNA-208b and microRNA-499-p5 show a substantial loss of slow-twitch myofibers (van Rooij et al. 2009). [score:1]
MicroRNA-499-5p expression was approximately 33 and 90% lower at months 3 and 12 after injury, respectively, compared to the able-bodied control group (P < 0.05 and <0.001, Fig. 2B). [score:1]
Intact tibialis anterior mouse muscle was electroporated with either a control plasmid or plasmid encoding for pri-microRNA-208b or pri-microRNA-499-5p. [score:1]
Nevertheless, the role of microRNA-208b and microRNA-499-5p in the control of protein synthesis in human skeletal muscle has yet to be determined. [score:1]
The so-called myomir family is a group of microRNAs that includes microRNA-208a, microRNA-208b, and microRNA-499-5p, which fine-tune muscle morphology and function (McCarthy 2011). [score:1]
Tibialis anterior muscles of adult C57Bl/6J mice were electroporated with either a control plasmid or plasmid encoding for pri-microRNA-208b or pri-microRNA-499-5p (Origene, Rockville, MD) as described previously (Kulkarni et al., 2011). [score:1]
In individuals with long-standing injury, level of microRNA-499-5p was 2% of that observed in the able-bodied control group (P < 0.001). [score:1]
Whether microRNA-208b and microRNA-499-5p contribute to skeletal muscle atrophy in spinal cord injury is unknown. [score:1]
Given the known role of microRNA-208b and microRNA-499-5p in determining skeletal muscle size in rodents (van Rooij et al. 2009), we hypothesized that they may be altered, concomitant with skeletal muscle atrophy, in humans after spinal cord injury. [score:1]
In the mouse myostatin gene 3′-UTR there is an additional binding site for microRNA-499-5p (Fig. 3A). [score:1]
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Furthermore, expression of the synthetic mature miR-21 was consistent over the 96 h but suppression of PDCD4 was only apparent at 24 h. This regulation of PDCD4 by miR-499 and miR-21 may be explained by target site accessibility and seed region constraints. [score:8]
The expression levels of miR-21 and miR-499 are known to control the translation of the tumour suppressor PDCD4 and let-7 has been shown to regulate Dicer levels. [score:8]
Some of the upregulated miRNAs included, miR-499, miR-372, miR-18a, miR-21 and miR-30d, while let-7c and miR-198 were downregulated. [score:7]
We also transiently transfected SCC003 cells with PDCD4 with and without the 3’UTR, and as expected, PDCD4 mRNA expression was downregulated by both miR-21 and miR-499 only when the 3’UTR was present (Additional file 1: Figure S5). [score:6]
There was also no significant additive suppressive effect in cells overexpressing both miR-21 and miR-499. [score:5]
Using a wild-type and truncated 3’UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. [score:5]
Fig. 2 a Expression levels of PDCD4, miR-21 and miR-499 in tonsil SCC tissue normalized to expression in adjacent healthy tissue (10 patients were analyzed in this cohort). [score:5]
The delay in miR-499 suppression at 24 h cannot be attributed to miR-499 levels, as overexpression of the mature miR-499 was similar at all-time intervals. [score:5]
PDCD4 protein expression was reduced by miR-21 at 24 and 48 h but returns to basal levels by 72 and 96 h. In contrast, miR-499 decreases PDCD4 expression from 48 h thereafter. [score:5]
Fig. 4 a Expression of PDCD4 mRNA in HEK-293 cells overexpressing miR-21 or miR-499 alone or in combination. [score:5]
We found that miR-21 and miR-499 were not up-regulated in HPV16 positive tonsil SCCs. [score:4]
In line with previous reports of head and neck cancer [10, 11, 26– 34] miR-499, miR-372, miR-18a and miR-21 were upregulated in our series. [score:4]
Taken together these observations suggest that miR-21 and miR-499 can both regulate the expression of PDCD4. [score:4]
Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. [score:3]
In contrast, miR-499 had no affect at 24 h with suppression of PDCD4 only seen at 48 h and being sustained for the duration of the time course. [score:3]
The single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites. [score:3]
Furthermore, we measured the expression of the transfected miRNAs and this indicated consistent high expression of both miR-21 and miR-499 at all-time points (Additional file 1: Figure S6A and B). [score:3]
In contrast, when the 3’UTR was included, PDCD4 mRNA expression was significantly reduced by miR-21 and miR-499 (Fig.   3b). [score:3]
Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites. [score:3]
Given SCC089 cells showed low endogenous levels of PDCD4, these cells were transiently transfected to overexpress PDCD4 with and without the 3’UTR in combination with miR-21 or miR-499. [score:3]
This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. [score:2]
Thus, the deregulation of miR-21 and miR-499 was not influenced by the presence of the virus. [score:2]
Thus, it may be plausible that both miR-21 and miR-499 can regulate PDCD4. [score:2]
More recently, miR-499 was shown to also regulate PDCD4 in colorectal cancer [46]. [score:2]
There appears to be a novel interplay between miR-499 and miR-21 in the regulation of PDCD4. [score:2]
We show that miR-21 and miR-499 directly interact with the 3’UTR of PDCD4 in both HEK-293 and tonsil cancer cell lines. [score:2]
Our study has extended these findings by showing that in tonsillar SCCs, PDCD4 is also regulated by miR-499 and miR-21. [score:2]
To investigate whether miR-21 and miR-499 directly interact with the 3’UTR of PDCD4, the open reading frame (ORF) of PDCD4 with and without a 789 bp section of its 3’UTR which contained the miR-21 and miR-499 sites was cloned into the pCI-neo expression vector (Fig.   3a). [score:2]
One of the miR-499 sites is located within 13 nt of the stop codon, whilst the other two are placed closer to the centre of the UTR. [score:1]
Using the HEK-293-cell line, which expresses stable levels of PDCD4, we transfected, miR-21/miR-499 alone or in combination and levels of PDCD4 were measured over a 96 h time period. [score:1]
The miR-21 site showed a lower free energy value and is interpreted as being more accessible than the other miR-499 sites. [score:1]
In contrast, miR-499 had no effect initially but was effective at the 48 h and beyond. [score:1]
The PDCD4 coding sequence and the first 789 bp of the 3’UTR (NM-014456.3) containing the miR-21 and three miR-499 binding sites were chemically synthesized into the pJ246 vector (DNA 2.0 Inc, USA) with EcoRI, EagI sites at the 5’ start of the UTR and NotI at the 3’ end. [score:1]
In tonsillar SCCs samples, both miR-21 and miR-499 were elevated but the RNA levels for PDCD4 was markedly lower (Fig.   2a). [score:1]
Considering these factors, we propose that may be miRISC/miR-21 initially binds to the miR-21 site to rapidly mediate PDCD4 gene silencing within 24 h. After this initial binding, the miRISC/miR-21 may recruit other factors to expose the downstream miR-499 sites. [score:1]
html) for the first 789 bp 3’UTR of PDCD4 MicroRNA Fold change miR-372 4.82 miR-499 2.89 miR-18a 2.82 miR-200c 2.69 miR-130a 2.59 miR-21 2.29 miR-30d 2.21 miR-409-5p 2.14 miR-20a 2.12 let-7c 0.45 miR-198 0.40 The array data were then confirmed by QRT-PCR of 4 representative miRNAs using ten tumour and adjacent normal samples. [score:1]
These sites would now be accessible to miR-499, which would maintain the silencing of PDCD4. [score:1]
Furthermore, the seed region of miR-21 is a 8mer match while the miR-499 seed is at best a 7mer-1A. [score:1]
c Validation of let-7c, miR-21 and miR-499 was performed using a second UK patient cohort. [score:1]
The 3’UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. [score:1]
The 3’ UTR of PDCD4 contains three binding sites for miR-499 and one for miR-21 (Additional file 1: Figure S2). [score:1]
html) for the first 789 bp 3’UTR of PDCD4 microRNA Position ΔGduplex ΔGopen ΔG miR-21 241 −10.8 −8.1 −2.69 miR-499 466 −9.5 −7.91 −1.58 miR-499 532 −17.6 −16.02 −1.57 miR-499 17 −15 −21.04 6.04 It must also be noted that our tumour samples and cell lines were HPV16 negative. [score:1]
The Locked Nucleic Acid (LNA) miR-21 antisense and LNA negative control (Exiqon, Denmark), pre-miR-21, pre-miR-499 and pre-miR -negative control#1 (Life Technologies, USA) were separately or double transfected into 2.5 x 10 [5] cells per well to a final concentration of 30 pmol per well. [score:1]
b Validation of miR-372, miR-499, miR-21 and let7c in the Australian patient cohort (n = 10). [score:1]
These cells were also co -transfected with either miR-21, miR-499 alone or in combination and harvested 24 h post transfection. [score:1]
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Furthermore, overexpression of miR-499 or -1 results in upregulation of important cardiac myosin heavy-chain genes in embryoid bodies; miR-499 overexpression also causes upregulation of the cardiac transcription factor MEF2C. [score:11]
Compared to controls (WT, LV-BLANK), stable transduction of hESCs by LV-miR-499 or -1 did not affect the transcript expression of pluripotency genes (Oct4, Nanog) or upregulate cardiac genes (α myosin heavy chain or MHC, β myosin heavy chain, troponin T) that are not expressed in the undifferentiated state (p>0.05). [score:7]
We also showed that GATA4 is a probable target of miR-499 but not miR-1. However, our data did not allow us to exclude the possibility that GATA4 down-regulation was merely an indirect or secondary effect. [score:7]
Further analyses suggest that these events were orchestrated consequences of numerous cellular changes directly regulated by miR-499 and -1. Although miR-499 is up-regulated in human mesenchymal stem cells upon in vitro propagation [23], its role and involvement in human cardiogenesis or cardiac differentiation of hESCs has not been demonstrated. [score:6]
Among these, GATA4 is a predicted target of miR-499 but not miR-1. Consistent with this prediction, transduction of hE-CMs by LV-miR-499, but not LV-anti-miR-499, led to a 3-fold downregulation of GATA4 (p<0.05). [score:6]
An inhibitory effect of miR-499 on atrial specification would also lead to an increased percentage yield of ventricular derivatives and cannot be ruled out, although miR overexpression led to neither cytoxicity nor functional changes of atrial CMs. [score:5]
Interestingly, LV-miR-499, but not -anti-499 or –miR1, upregulated MEF2C (by ∼2.5-fold, p<0.05). [score:4]
In another separate study [49], we reported that miR-499 are strongly associated with cardiac differentiation and share many predicted targets with miR-208 that has been previously shown to associate with cardiac development. [score:4]
Consistent with our pre-differentiation transduction experiments already presented, LV-miR-499 transduction of hE-CMs likewise significantly upregulated α-MHC, β-MHC, as well as myosin light chain (MLC) 2v, α-actin and troponin T (p<0.05; Figure 2C). [score:4]
Our finding that pre- and post-differentiation transduction with LV-miR-499 similarly led to β-MHC upregulation hints at the possibility that miR-499 exerts its pro-cardiogenic action after cardiac differentiation is initiated. [score:4]
Similar to the pro-cardiogenic role of miR-1, β-MHC also became significantly upregulated (2.5-fold; p<0.05) in EBs from stably LV-miR-499-transduced hESCs, although α-MHC was unaffected (p>0.05). [score:4]
Indeed, MEF2C that is required for contractile protein activation also remains unchanged even after successful stable suppression of miR-499 by LV-anti-miR-499. [score:3]
Indeed, miR-499 and miR-1 shared a number of overlapping targets including those that are known to play important roles in early cardiogenesis. [score:3]
Most recently, Hosoda et al shows that miR-499 targets Sox6 and Rod1, traverses gap junction channels and translocates to structurally coupled human cardiac stem cells, enhancing their cardiomyogenesis in vitro and after infarction in vivo [48]. [score:3]
Similar to the reciprocal relationship described for normal and failing adult human CMs [14], we identified multiple functional groups of transcripts that were expressed at low levels (i. e. green) in the miR-1 and miR-499 abundant hE-, hF- and hA-VCMs. [score:3]
Indeed, the lack of effect of anti-miR-499 is consistent with its lack of expression in undifferentiated hESCs but a cardiac fate has been acquired. [score:3]
Our present study reports that miR-499 promotes ventricular specification and significantly augments β-MHC expression in hE-CMs, although it has no effect on the electrophysiological and Ca [2+]-handling properties. [score:3]
By contrast, the expression levels of α-MHC and β-MHC were not different between WT and LV-anti-miR-499 hESC-derived EBs. [score:3]
Using an elegant transgenic mouse mo del, they demonstrated that miR-208a is required for expression of β-MHC/miR-499 but its cardiac functions can be replaced by miR-499, suggesting the latter as a downstream mediator. [score:3]
Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p<0.05) and contractile protein expression without affecting their electrophysiological properties (p>0.05). [score:3]
Identification of additional common and distinct targets of miR-499 and -1 requires extensive validation but could help dissect their overlapping and differential roles in cardiac differentiation. [score:3]
This notion is supported by the finding that miR-499 over -expression increases the ventricular yield, although miR-499 per se may not be absolutely necessary for initiating cardiac differentiation. [score:3]
These results suggested that overexpression of miR-499 or -1 alone was insufficient to drive cardiac differentiation or compromise pluripotency. [score:3]
During the course of our manuscript preparation, van Rooij et al reported that a family of miRs encoded by myosin genes, including miR-499, governs myosin expression and muscle performance [46]. [score:3]
According to these analyses, miR-499 is most closely associated with the regulation of embryonic stemness, cell proliferation, cell size and apoptosis; whereas, miR-1 is implicated in control of embryonic stemness, cell cycle, hypertrophy and cell size. [score:2]
As cardiac differentiation continues, ventricular specification occurs following cellular changes in cell proliferation, size and apoptosis that are mediated by miR-499. [score:1]
In the present study, we have identified miR-499 and -1 as determinants of ventricular specification and maturation of human CMs, respectively. [score:1]
We conclude that miR-1 and -499 play differential roles in human cardiac differentiation: While miR-499 promotes ventricular specification in the context of hESC-derived cardiovascular progenitors, miR-1 serves to facilitate their electrophysiological maturation. [score:1]
Our present study focuses on and further demonstrates the functional implications of miR-499 and -1 in the context of cellular electrophysiological and Ca [2+]-handling properties. [score:1]
Specifically, our experiments demonstrate that miR-499 promotes ventricular specification while miR-1 serves to facilitate their electrophysiological maturation. [score:1]
Taken collectively, these independent studies and ours strongly suggest an important biological role of miR-499 in cardiac differentiation. [score:1]
The profiles of miR-1, let-7a, let-7b, miR-26b, miR-30b, miR-125a, miR-126, miR-133a, miR-143, and miR-499 in hE/F/A-VCM were confirmed by qPCR (Figure 1B). [score:1]
A) Representative AP tracings of Control, LV-miR-1- and -miR-499-transduced hESC-derived ventricular derivatives as labeled. [score:1]
Indeed, although stably LV-anti-miR-499-transduced hESCs could differentiate into hE-CMs, our preliminary experiments of injecting zebrafish embryos with miR-499 or -1 anti-sense probes, but not blank or scrambled sequences, led to significant anatomical and functional heart defects, suggestive of an in vivo role. [score:1]
Interestingly, miR-499 is located within intron 20 of MYH7B on chromosome 20 and is highly conserved in vertebrates. [score:1]
This is consistent with the finding that stably LV-anti-miR-499-transduced hESCs were able to efficiently differentiate into hE-CMs with levels of GATA4, α-MHC and β-MHC not different from those of WT EBs. [score:1]
0027417.g003 Figure 3A) Representative AP tracings of Control, LV-miR-1- and -miR-499-transduced hESC-derived ventricular derivatives as labeled. [score:1]
B) The percentage distribution of ventricular, atrial and pacemaker phenotypes before and after LV-miR-1 or -miR-499 transduction. [score:1]
Figure S4 Representative AP tracings of Control, LV-miR-1- and -miR-499-transduced hE-ACMs, and bar graphs summarizing the AP parameters of the groups. [score:1]
In stark contrast, MESP1 was affected by none of LV-miR-1, miR-499 or –anti-miR-499 (p>0.05). [score:1]
We are proposing that upon the initiation of cardiac differentiation, miR-499 serves to promote ventricular specification. [score:1]
While miR-499 promotes ventricular specification of hESCs, miR-1 serves to facilitate electrophysiological maturation. [score:1]
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[+] score: 97
To identify the miRNAs with regulating effect on Gadd45α from these differentially-expressed miRNAs, 20 miRNAs being predicted to regulate Gadd45α by MicroCosm Targets, Targetscan, and Pictar were presented in Table 3. Furthermore, miRNAs microarray results indicated miR-499 was the single differentially-expressed miRNA among these regulating miRNAs of Gadd45α (Fig. 5A). [score:12]
Increased expression of miR-499 in diabetic cardiomyopathy (DCM) and the effect of miR-499 on the expression of Gadd45α. [score:5]
Nonetheless, the differentially-expressed miR-target pair, miR-499 :: Gadd45α, was identified in DCM and DM -induced baroreflex dysfunction by the combination of bioinformatics and biological experiments. [score:5]
In conclusion, increased miR-499 level accompanied with reduced Gadd45α protein expression was observed in the present study, which suggests that miR-499 :: Gadd45α might participate in the process of diabetic heart disease in STZ -induced diabetic rats. [score:5]
These results implied that miR-499 might repress Gadd45α expression by inhibiting transcription. [score:5]
The present study suggests that co-differentially-expressed miR-target pair, miR-499::Gadd45α, might be involved in the tissue-tissue communication between DCM and DM -induced baroreflex dysfunction by an innovative incorporation of bioinformatics, miRNAs microarray analysis and biological experiments, and therefore provides a potential preventive strategy for SCD in DM. [score:5]
However, miR-499 significantly suppressed the protein expression of Gadd45α by 56% (P<0.05, vs NC), which could be partially reversed by co-transfection of AMO-499 (P<0.05, vs miR-499) (Fig. 5F). [score:5]
MiR-499 and Gadd45α, a co-differentially-expressed miR-target pair in heart and NA. [score:5]
In addition, Gadd45α and miR-499 were co-differentially expressed in diabetic heart and NA, and Gadd45α is negatively regulated by miR-499. [score:4]
Among these micoRNAs only miR-499 is computationally predicted to target Gadd45α. [score:3]
These findings suggest that the decreased Gadd45α protein level result from elevated miR-499 expression might potentially contribute to SCD in DM by their congenerous effects on diabetic heart and baroreceptor reflex. [score:3]
In the present study, increased miR-499 expression was verified by both miRNAs microarray analysis and qRT-PCR in diabetic samples. [score:3]
As miR-499 and Gadd45α displayed complementarity (Fig. 5C), luciferase analysis was performed to directly verify the regulating effect of miR-499 on Gadd45α. [score:3]
The 3′UTR of Gadd45α holding miR-499 binding sites were cloned downstream of the luciferase reporter in pMIR-REPORT™ luciferase miRNA expression reporter vector (Ambion, Inc. [score:3]
Consistent with miRNAs microarray results, the subsequent qRT-PCR detection showed that DM led to miR-499 expression increased by 1.61±0.12 folds (P<0.05) and 1.83±0.18 folds (P<0.05) in diabetic heart and NA, respectively (Fig. 5B). [score:3]
Interestingly, inconsistent with our observation of increased miR-499 in left ventricle and NA from 4-week STZ -induced diabetic rats, it is reported miR-499 expression was repressed in the retinas of 3-month STZ -induced diabetic rats [43]. [score:3]
The mRNA (E) and protein (F) expression of Gadd45α in miR-499 treated neonatal cardiac myocytes. [score:3]
In addition, the expression of miR-499 was increased at circulating level after acute myocardial infarction [41], [42]. [score:3]
As demonstrated in Fig. 5E, transfection of miR-499 or AMO-499 showed no significant effect on the Gadd45α expression at mRNA level (P>0.05 vs NC). [score:3]
The reversed alternations in miR-499 expression might be largely attributing to the different time courses (4 weeks vs 3 months) of DM. [score:3]
NR_032141) mimics (sense: 5′-UUAAGACUUGCAGUGAUGUUUGU-3′, antisense: 5′-AAACAUCACUGCAAGUCUUAAAU-3′), and rat miR-499 inhibitors (antisense oligonucleotides of mature miR-499, AMO-499: 5′-+A+C+A+A+ACATCACTGCAAGT+C+T+T+A+A-3′) were synthesized by Integrated DNA Technologies, Inc. [score:3]
For luciferase assay, HEK293 cells were first starved in serum-free medium for 12 h, then transfected with 100 ng the chimeric plasmid (firefly luciferase vector), 20 ng PRL-TK (TK -driven Renilla luciferase expression vector) and 50 nM miR-499, AMO-499 or NC using X-treme GENE siRNA transfection reagent. [score:2]
The expression levels were compared with the value of Gadd45α and miR-499 normalized to the amounts of respective endogeneous controls (β-actin and U6). [score:2]
Rat miR-499 (GenBank acc. [score:1]
MiR-499 negatively regulating Gadd45α. [score:1]
And then, cells (2×10 [5]/well) were transfected with 50 nM miR-499, AMO-499 or negative control (NC) with X-treme GENE siRNA transfection reagent (Roche, Cat. [score:1]
To further investigate the biological effect of miR-499 on the Gadd45α expression, neonatal rat cardiac myocytes were used and transfected with miR-499, AMO-499 or NC. [score:1]
As shown in Fig. 5D, miR-499 transfection resulted in a notable decrease in luciferase activity of the chimeric luciferase vectors of Gadd45α (P<0.05, vs NC), which was significantly alleviated by co -transfected with AMO-499 (P<0.05, vs miR-499). [score:1]
MiR-499 has been established to reflect myocardial damage [35], [36], blunt the cardiac stress response [37], facilitate ventricular specification of human embryonic stem cells (hESCs) [38], be associated with cardiac differentiation [39], and regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells [40]. [score:1]
[1 to 20 of 29 sentences]
[+] score: 47
Other miRNAs from this paper: hsa-mir-208a, hsa-mir-1-2, hsa-mir-1-1, hsa-mir-208b, hsa-mir-499b
Also, overexpression of microRNA-499 enhanced expression of myocyte-specific enhancer factor 2C, the transcription factor which is involved in cardiac morphogenesis and myogenesis and vascular development [4]. [score:6]
Other results suggest that expression of microRNA-499 in human cardiac stem cells (hCSCs) represses the microRNA-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo[5]. [score:5]
Some of those predicted targets of microRNA-499 and microRNA-1 were shown to regulate cardiomyocyte differentiation. [score:4]
It was shown further that microRNA-499 expression increased in human stem cells differentiating into cardiomyocytes. [score:3]
In situ hybridization analysis of mouse heart, brain, spleen, liver, lung, quadriceps muscle, kidney, and gut tissues shows that the mature microRNA-499 is abundantly expressed in cardiac tissue and almost absent in other tissues, including skeletal muscle [10]. [score:3]
Expression of microRNA-499 was observed to be increased a few hundred times during differentiation of human embryonic stem cells into beating clusters [4]. [score:3]
The role of microRNA-499 in heart development in human cardiomyocyte differentiation was previously described [4, 5]. [score:2]
Thus, microRNA-499 appears to play an important role during heart development, although the molecular mechanisms and the microRNA-499 pathways are not well understood at this time. [score:2]
This observation is consistent with earlier publications showing that microRNA-499 plays an important role in cardiac differentiation and cardiogenesis during embryonic development, and it strongly suggests a ubiquitous and conserved mechanism of classic embryonic heart induction [12, 13] and myofibrillogenesis across the spectrum of vertebrate species. [score:2]
Also we screened the online microRNA database, Mirbase [8], and we found homology with a 22 bp miR-499 fragment included in the cloned sequence (Figure  3B). [score:1]
Alignment of the cloned RNA, microRNA-499c, with precursors microRNA-499a and microRNA-499b showed that although they differ in size, they have common and overlapping sequences (Figure  4B). [score:1]
Thus, we conclude that we have discovered a new form of microRNA-499 precursor, which we term microRNA-499c. [score:1]
Alignment showed that a new form of microRNA-499c has 88 common bp with microRNA-499a and 66 common bp with microRNA-499b. [score:1]
Figure 4 Alignment of cloned RNA (microRNA-499c) with (A) microRNA-499a and (B) microRNA-499b. [score:1]
Cardiomyocytes derived from differentiation of hCSCs treated with microRNA-499 appeared to be larger, and their sarcomere striations were more evident [5]. [score:1]
Precursors of the microRNA, microRNA-499a has 122 bp, while microRNA-499b has only 73 bp and the newly discovered form, microRNA-499c has 111 bp. [score:1]
We screened the sequence in Mirbase [8] and found that 22 bp microRNA-499 fragment is included in the cloned sequence (Figure  3B). [score:1]
Underlined area is 22 bp microRNA-499. [score:1]
There are two known forms of the microRNA-499 precursor: microRNA-499a and microRNA-499b. [score:1]
The human microRNA-499 belongs to a family of micro RNAs encoded by the intron of the myosin heavy chain (MHC) genes, referred to as MyomiRs which also include microRNA-208a and microRNA-208b. [score:1]
This cloned RNA matches in partial sequence alignment to human microRNA-499a and b, although it differs in length. [score:1]
The level of microRNA-499 was 400 times higher in cardiomyocytes than in rat cortical stem cells. [score:1]
Also, microRNA-499 transduction by the lentivirus of hESC-derived cardiovascular progenitors significantly increased the yield of stem cell-derived ventricular specified cardiomyocytes [11]. [score:1]
It has been found that microRNA-499 promotes ventricular specification in differentiating human embryonic stem cells [11]. [score:1]
We have concluded that this cloned RNA is unique in its length, but is still related to the microRNA-499 family. [score:1]
All three microRNA-499 precursors apparently originate from the same intron, which is initially the intron of the myosin heavy chain (MHC) genes. [score:1]
[1 to 20 of 26 sentences]
[+] score: 31
Other miRNAs from this paper: hsa-mir-16-1, hsa-mir-16-2
In particular, the study showed that miR-499a-5p overexpression led to a downregulation of the protein expression of the small-conductance calcium-activated potassium channel 3, which may potentially contribute to AF electrical remo deling 37. [score:8]
The observed difference in expression is in agreement with previous results in human atrial tissues from cardiac surgery patients, where miR-499a-5p resulted significantly upregulated in AF 37. [score:6]
Normalized expression for the gene of interest (GOI, miR-499a-5p) with respect to a specific reference gene (RG) was given by E [−dCq], where dC [q] =  C [qGOI]  −  C [qRG]. [score:3]
In the representative example of miR-499a-5p, we showed that normalization by the best reference gene pointed out differences in the expression levels between AF and SR patients, which were lost by applying the wrong normalization strategy. [score:3]
in Fig. 4 show that miR-499a-5p expression levels in the two groups were strongly affected by the normalization process. [score:3]
When normalizing to SNORD48, a significant (p < 0.05) overexpression of miR-499a-5p was observed in the AF versus SR group (left panel). [score:3]
The application of different normalization strategies in the exemplary case of miR-499a-5p assessment pointed out the criticality of the choice of reference genes to obtain reliable information on miRNA deregulation in AF. [score:2]
Normalized expressions of miR-499a-5p in sinus rhythm (SR, green box) versus atrial fibrillation (AF, red box) patients, calculated using the best (SNORD48, left) and the worst (U6, right) reference gene. [score:1]
The effects of normalization strategy on target miRNA profiles were evaluated in the exemplifying case of miR-499a-5p. [score:1]
Impact of normalization strategy on miR-499a-5p profiling. [score:1]
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[+] score: 25
The reported downstream targets of miR-499 are, among others, both the α- and β-isoforms of the calcineurin catalytic subunits, Drp1 and SOX4, among others. [score:3]
For instance, with respect to miR-499, Adachi et al. performed a miRNA array analysis in various human tissues and found that miR-499 is almost specifically expressed in the heart (37). [score:3]
Overall, miR-499 and hs-cTnT provided comparable diagnostic value, with areas under the ROC curves of 0.97. [score:1]
The power of miR-499-5p in discriminating NSTEMI from controls was comparable to cTnT. [score:1]
miR-499, similarly to miR-208, is a mirtron located within an intron of a myosin heavy chain isoform gene, namely the gene Myh7b (109). [score:1]
In patients who presented less than 3 h after pain onset, miR-499 was positive in 93% of patients and hs-cTnT in 88% of patients. [score:1]
As discussed at the end, miRNA-499 bare not only a better diagnostic accuracy over other miRNAs but also showed an interest for the early diagnosis of AMI cases. [score:1]
Actually, miRNAs abundant in the myocardium, known as myomiRs, such as miR-1, miR-133, miR-208a/b, and miR-499a, were reported many times as being strongly increased in the serum or plasma of patients with AMI (36). [score:1]
They also conclude that a reclassification index including miR-499 in a clinical mo del of several risk factors and hs-cTnT was not significant (p = 0.15). [score:1]
For each miRNA, the obtained values were as listed: (i) miR-1: 0.63 and 0.76 (ii) miR-133a: 0.89 and 0.87 (iii) miR-208b: 0.78 and 0.88, and (iv) miR-499: 0.88 and 0.87. [score:1]
The three myosin-related miRNAs, miR-208a/b, and miR-499, together control muscle myosin content, myofiber identity, and muscle performance. [score:1]
More importantly, the accuracy in differentiating NSTEMI from acute heart failure without AMI was higher for miR-499-5p than for cardiac troponins. [score:1]
So in elderly patients, with non-diagnostic electrocardiograms, circulating miR-499-5p holds potential as discriminating biomarker and perhaps could be used to reduce hs-cTnT rate of false positive. [score:1]
Actually, this trans-differentiation has been achieved by Jayawardena et al. in 2015 using the exact same set of miRNAs that stood out in the above-mentioned studies on miRNAs as AMI biomarkers, namely miR-1, miR-133a, miR-208a, and miR-499a (104). [score:1]
Thereby, miR-499 could be helpful as an independent risk factor. [score:1]
However, among the miRNAs set, miR-133a and miR-499 look especially suitable for use as diagnostic biomarkers of AMI. [score:1]
Furthermore, it has brought to the forefront a specific set of miRNAs, namely, miR-1; miR-133; miR-208a/b, and miR-499a. [score:1]
Referring to the aforementioned multiple studies on miRNAs as AMI biomarker, a set of candidates has emerged: the four muscle-specific miRNAs, the myomiRs miR-1, miR-133, miR-208a/b, and miR-499a. [score:1]
Three frequently found miRNAs were chosen for subgroup analysis: miR-1, miR-133, and miR-499. [score:1]
The four miRNAs found repeatedly were miR-1, miR-133a, miR-208b, and miR-499, and these were selected for further processing. [score:1]
The pooled sensitivity and specificity for miRNA-1 resulting from 9 studies were 0.70 and 0.81, for miR-133 resulting from 5 studies were 0.82 and 0.87 and for miR-499 resulting from 10 studies were 0.80 and 0.89. [score:1]
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[+] score: 25
The miR-299a-3p, miR-302b-5p, miR-499 and miR-200c-3p were all up-regulated in EPO-MVs; the up-regulation of miR-499 and miR-200c-3p was significant (p < 0.001, n = 3). [score:7]
Our findings also demonstrate that miR-299, miR-499, miR-302, and miRNA-200 were upregulated in EPO-MVs (Fig.   8c). [score:4]
The miRNA profiles of the MVs revealed that EPO-MVs changed 212 miRNAs (fold-change ≥ 1.5), including miR-299, miR-499, miR-302, and miRNA-200, and that 70.28 % of these changes involved upregulation. [score:4]
d The bar plot shows the top ten enrichment score value of the significant enrichment pathway of the predicted possible target genes of miR-299a-3p, miR-302b-5p, miR-499 and miR-200c-3p. [score:3]
miR-499 plays an inhibitory role in the mitochondrial apoptosis pathway, and protects against H [2]O [2] -induced injury in cardiomyocytes [47]. [score:3]
e The plot shows top ten biologic functions from the predicted possible target genes of miR-299a-3p, miR-302b-5p, miR-499 and miR-200c-3p, P-value cutoff (p < 0.05). [score:3]
Jia Z, Zhang C, Sun M, Wang W, Chen P, Ma K, et al. miR-499 protects cardiomyocytes from H 2O 2 -induced apoptosis via its effects on Pdcd4 and Pacs2. [score:1]
[1 to 20 of 7 sentences]
[+] score: 25
Li M. Zhang S. Wu N. Wu L. Wang C. Lin Y. Overexpression of miR-499–5p inhibits non-small cell lung cancer proliferation and metastasis by targeting VAV3 Sci. [score:7]
Experimental data show that mir-499a-5p overexpression induces apoptosis, and inhibits cell proliferation in vitro and NSCLC metastasis in vivo [25]. [score:5]
Published studies showed that mir-499a-5p is a tumor suppressor miRNA by targeting the VAV3 gene and its reduction correlate with poor clinical outcome in NSCLC. [score:5]
In particular, hsa-mir-520e, hsa-mir-518c-5p, and all six miRNA precursors were, resultingly, downmodulated in the high risk group, while hsa-mir-329-3p, hsa-mir-302d-3p, hsa-mir-520f, hsa-mir-511-5p, hsa-mir-509-3p, hsa-mir-519a-3p, hsa-mir-521, hsa-mir-520h, and hsa-mir-499a-5p were overexpressed. [score:3]
Interestingly, by stratifying patients according to survival status at five years, only two mature miRNAs (hsa-mir-499a-5p and hsa-mir-429) and one miRNA precursor (hsa-mir-212-prec) were found differentially expressed (Supplementary Table S1), being only mir-499a-5p in common with the MSC related signature. [score:3]
On the other hand, other miRNAs were associated with a just a few pathways specific to cancer development: hsa-mir-499a-5p, associated with proliferation signaling, and hsa-mir-511-5p and hsa-mir-520h with EMT (Figure 2). [score:2]
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[+] score: 24
Furthermore, the basic laboratory study also demonstrated that miRNA499 may bind to and reduce the expression of c-MET mRNA, which promotes cell apoptosis and inhibits cell proliferation [39]. [score:5]
In addition, we observed a strong interaction and increased odds ratio for hepatocellular carcinoma development between miRNA499 gene polymorphisms and smoking and alcohol consumption. [score:2]
The distribution of miRNA gene polymorphisms is described in Table 2. In our recruited control group, the frequencies of miRNA146a rs2910164 (χ [2] value: 1.92), miRNA196 rs11614913 (χ [2] value: 0.0005), and miRNA499 rs3746444 (χ [2] value: 0.98) were in Hardy-Weinberg equilibrium, respectively, except for miRNA149 rs2292832 (χ [2] value: 59.86). [score:1]
PCR products of hsa-mir-146a rs2910164 gene polymorphism were subjected SacI to enzymatic digestion by incubation for 4 hr at 37°C and then submitted to electrophoresis in 2% agarose gels; MspI for hsa-mir-196a2 rs2910164 and BclI for hsa-mir-499 rs3746444. [score:1]
Based on the aforementioned reasons, we adopted a case-control research design and 4 pre-miRNA SNPs associated with cancer, namely, has-mir-146a (rs2910164), has-mir-149 (rs2292832), has-mir-196a2 (rs11614913), and has-mir-499 (rs3746444) [25]– [29]. [score:1]
Regarding genotype distribution and environmental risk factors, such as smoking and alcohol consumption, miRNA499 plays a crucial role in hepatocellular carcinoma. [score:1]
Similarly, a significantly higher risk for people who carried the CT (AOR = 6.14, 95% confidence interval [CI] = 1.32–28.56) or CC (AOR = 4.75, 95% CI = 1.32–17.01) genotypes of miRNA499 (rs3746444) was observed in the HBV-infection group (Table S1 in File S1). [score:1]
[2] = 5.293 (3 d. f. ) p = 0.152 miRNA499 rs3746444 TT and non-alcohol intake 163 (48.37) 78 (41.49) Reference Reference CT or CC and non-alcohol intake 38 (11.28) 42 (22.34)2.31 (1.38–3.87, p = 0.001) * 2.43 (1.43–4.12, p = 0.001) * CT or CC and consumer 118 (35.01) 41 (21.81)0.73 (0.47–1.13, p = 0.160)0.66 (0.41–1.06, p = 0.085) CT or CC and alcohol intake 18 (5.34) 27 (14.36)3.14 (1.63–6.03, p<0.001) * 3.44 (1.69–7. [score:1]
People who carry miRNA499 rs3746444 CT or CC genotypes may have a high susceptibility to hepatocellular carcinoma. [score:1]
[2] = 11.175 (3 d. f. ), p = 0.010 * miRNA499 rs3746444 TT and non-smoker 188 (55.79) 74 (39.36) Reference Reference CT or CC and non-smoker 37 (10.98) 34 (18.09)2.34 (1.36–4.00, p = 0.002) * 2.41 (1.36–4.26, p = 0.002) * CT or CC and smoker 93 (27.60) 45 (23.94)1.23 (0.79–1.92, p = 0.364)1.37 (0.85–2.20, p = 0.192) CT or CC and smoker 19 (5.64) 35 (18.62)4.69 (2.52–8.70, p<0.001) * 5.64 (2.87–11. [score:1]
These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. [score:1]
The PCR conditions were 5 min at 94°C followed by 35 cycles of 30 sec at 94°C, 30 sec at 58°C for hsa-mir-146a rs2910164, 30 sec at 63°C for has-mir-196a2 rs11614913, and 30 sec at 67°C for hsa-mir-499 rs3746444, and 1 min at 72°C, and final step at 72°C for 10 min to allow a complete extension of all PCR fragments. [score:1]
In conclusion, we observed a strong relationship between miRNA499 gene polymorphisms and hepatocellular carcinoma. [score:1]
Several studies of Asian populations have reported the same finding; that is, miRNA499 is associated with cancer [36], [37]. [score:1]
Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR were used to analyze miRNA146a (rs2910164), miRNA149 (rs2292832), miRNA196 (rs11614913), and miRNA499 (rs3746444) genetic polymorphisms between the control group and the case group. [score:1]
26, p = 0.544) miRNA499 rs3746444 TT 281 (83.38) 119 (63.30) Reference Reference CT 55 (16.32) 60 (31.91)2.58 (1.69–3.94, p<0.001) * 2.48 (1.62–3.81, p<0.001) * CC 1 (0.30) 9 (4.79)21.2 (2.66–169.55, p = 0.004) * 22.1 (2.73–178.40, p = 0.003) * CT/CC 56 (16.62) 69 (36.70)2.91 (1.93–4.40, p<0.001) * 2.91 (1.93–4. [score:1]
By using a multiple logistic regression mo del to estimate the adjusted odds ratio (AOR), we observed a significantly higher risk for people who carried the CT (AOR = 2.52, 95% confidence interval [CI] = 1.63–3.86) or CC (AOR = 20.7, 95% CI = 2.60–165.90) genotypes of miRNA499 (rs3746444). [score:1]
However, in Caucasian population, miRNA499 has not been associated with cancer [38]. [score:1]
Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility. [score:1]
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[+] score: 23
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-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-20a, hsa-mir-22, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-98, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-15b, mmu-mir-101a, mmu-mir-126a, mmu-mir-130a, mmu-mir-133a-1, mmu-mir-142a, mmu-mir-181a-2, mmu-mir-194-1, hsa-mir-208a, hsa-mir-30c-2, mmu-mir-122, mmu-mir-143, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-122, hsa-mir-130a, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-142, hsa-mir-143, hsa-mir-126, hsa-mir-194-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-208a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-22, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29c, mmu-mir-98, mmu-mir-326, rno-mir-326, rno-let-7d, rno-mir-20a, rno-mir-101b, mmu-mir-101b, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-181b-2, mmu-mir-17, mmu-mir-19a, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-19b-1, mmu-mir-181b-1, mmu-mir-181c, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-101-2, hsa-mir-26a-2, hsa-mir-378a, mmu-mir-378a, hsa-mir-326, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-181b-2, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-15b, rno-mir-16, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19a, rno-mir-22, rno-mir-26a, rno-mir-26b, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30c-2, rno-mir-98, rno-mir-101a, rno-mir-122, rno-mir-126a, rno-mir-130a, rno-mir-133a, rno-mir-142, rno-mir-143, rno-mir-181c, rno-mir-181a-2, rno-mir-181b-1, rno-mir-181b-2, rno-mir-194-1, rno-mir-194-2, rno-mir-208a, rno-mir-181a-1, hsa-mir-423, hsa-mir-18b, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, ssc-mir-122, ssc-mir-15b, ssc-mir-181b-2, ssc-mir-19a, ssc-mir-20a, ssc-mir-26a, ssc-mir-326, ssc-mir-181c, ssc-let-7c, ssc-let-7f-1, ssc-let-7i, ssc-mir-18a, ssc-mir-29c, ssc-mir-30c-2, hsa-mir-484, hsa-mir-181d, rno-mir-1, rno-mir-133b, mmu-mir-484, mmu-mir-20b, rno-mir-20b, rno-mir-378a, rno-mir-499, hsa-mir-378d-2, mmu-mir-423, mmu-mir-499, mmu-mir-181d, mmu-mir-18b, mmu-mir-208b, hsa-mir-208b, rno-mir-17-2, rno-mir-181d, rno-mir-423, rno-mir-484, mmu-mir-1b, ssc-mir-15a, ssc-mir-16-2, ssc-mir-16-1, ssc-mir-17, ssc-mir-130a, ssc-mir-101-1, ssc-mir-101-2, ssc-mir-133a-1, ssc-mir-1, ssc-mir-181a-1, ssc-let-7a-1, ssc-let-7e, ssc-let-7g, ssc-mir-378-1, ssc-mir-133b, ssc-mir-499, ssc-mir-143, ssc-mir-423, ssc-mir-181a-2, ssc-mir-181b-1, ssc-mir-181d, ssc-mir-98, ssc-mir-208b, ssc-mir-142, ssc-mir-19b-1, hsa-mir-378b, ssc-mir-22, rno-mir-126b, rno-mir-208b, rno-mir-133c, hsa-mir-378c, ssc-mir-194b, ssc-mir-133a-2, ssc-mir-484, ssc-mir-30c-1, ssc-mir-126, ssc-mir-378-2, ssc-mir-451, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, mmu-mir-101c, hsa-mir-451b, hsa-mir-499b, ssc-let-7a-2, ssc-mir-18b, hsa-mir-378j, rno-mir-378b, mmu-mir-133c, mmu-let-7j, mmu-mir-378c, mmu-mir-378d, mmu-mir-451b, ssc-let-7d, ssc-let-7f-2, ssc-mir-20b-1, ssc-mir-20b-2, ssc-mir-194a, mmu-let-7k, mmu-mir-126b, mmu-mir-142b, rno-let-7g, rno-mir-15a, ssc-mir-378b, rno-mir-29c-2, rno-mir-1b, ssc-mir-26b
Expression analysis of conserved miRNAs in 14 different tissue types revealed heart-specific expression of miR-499 and miR-208 and liver-specific expression of miR-122. [score:7]
A few notable exceptions are miR-499, an miRNA abundantly expressed in the heart (Figure 2A), which is represented by only one read (Table 2), and the miR-133 family, which is preferentially and abundantly expressed in the heart (Figure 2), and represented by only 7 reads (Table 1). [score:5]
Several miRNAs (miR-1, miR-133, miR-499, miR-208, miR-122, miR-194, miR-18, miR-142-3p, miR-101 and miR-143) have distinct tissue-specific expression patterns. [score:3]
miR-499 is abundantly and specifically expressed only in the heart and could not be detected in other tissues (Figure 2A). [score:3]
Because of their location within the introns of myosin genes and their specific expression in myogenic cells, miR-208 and miR-499 were referred to as MyomiRs [47]. [score:3]
Similar observations have been reported for miR-499 in zebra fish [50]. [score:1]
Similarly, miR-499 is another intronic-derived miRNA located in the Myh7b gene (MHC 7b). [score:1]
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[+] score: 22
Overexpression of miR-499 in human cardiac progenitor cells [75] and hESCs induces expression of cardiac gene markers, including β-MHC [77]. [score:5]
The expression of muscle-specific myosin genes is regulated by a group of intronic miRNAs, including miR-208a, miR-208b and miR-499, which are embedded within the introns of Myh6, Myh7 and Myh7b, respectively [74]. [score:4]
hESC-CMs overexpressing miR-499 show increases in cardiac contractile proteins, including α-MHC and β-MHC, MLC2V, α-actinin and troponin T [77]. [score:3]
Moreover, miR-1, miR-144 and miR-499 are the most differentially expressed miRNAs between hESCs, hESC-CMs, human fetal CMs and human adult CMs [77]. [score:3]
In hESC-CMs the percentage of ventricular CMs in EBs overexpressing miR-499 increases significantly [77]. [score:3]
Although several clusters of miRNA are important for cardiac development and maturation, only miR-1, miR-133 and miR-499 are significantly induced during cardiac differentiation in hESCs [75- 78]. [score:2]
Therefore, while both miR-1 and miR-499 appear to be potent inducers of cardiomyogenic differentiation of stem cells, miR-499 promotes ventricular specificity after initiation of cardiac differentiation while miR-1 induces a more mature ventricular CM phenotype than miR-499 [77]. [score:1]
Overexpression of miR-499 does not induce changes in calcium handling in hESC-CMs that are characteristic of more mature ventricular CMs [77]. [score:1]
[1 to 20 of 8 sentences]
[+] score: 20
It is noteworthy that miR-1, miR-133, miR-30, miR-208a, miR-208b, mir-499, miR-23a, miR-9 and miR-199a have previously been shown to be functionally involved in cardiovascular diseases such as heart failure and hypertrophy [40], [41], [42], [43], [44], and have been proposed as therapeutic- or disease-related drug targets [45], [46]. [score:7]
Although the 3 myomiRs miR-208a/miR-208b/miR-499 contain almost identical seed sequences, miR-499 was considerably less potent at inhibiting luc-Csnk2a2 expression than miR-208a/miR-208b, suggesting a functional role for 3′ compensatory interactions between the myomiRs and Csnk2a2 (Figure 7D and H). [score:5]
In particular, several microRNAs that are preferentially expressed in different types of muscles (e. g. miR-1, miR-133, and the myomiRs miR-208, miR-208b and miR-499) play a pivotal role in maintenance of cardiac function [17], [18], and the ablation of microRNAs-RISC machinery can have dramatic effects on cardiac development [19], [20], [21]. [score:4]
0052442.g007 Figure 7 (A–D) Real-Time RT-PCR of Timp3, Rbm24, Tgfbr2 and Csnk2a2 in HPASM cells transfected with mimics for miR-1, miR-125b-5p, miR-204, miR-499 and miR-208b or with a mimic microRNA negative control. [score:1]
Conserved microRNA signatures were identified in valves (miR-let-7c, miR-125b, miR-127, miR-199a-3p, miR-204, miR-320, miR-99b, miR-328 and miR-744) and in ventricular-specific regions of the myocardium (miR-1, miR-133b, miR-133a, miR-208b, miR-30e, miR-499-5p, miR-30e*) of Wistar rat, Beagle dog and cynomolgus monkey. [score:1]
Furthermore, ventricular microRNAs (miR-1, miR-133, miR-208b and miR-499) have been found to be increased in the plasma of patients with myocardial infarction, and might represent a useful alternative to the classical cardiac troponin (cTnI) biomarker [57], [58], [59], [60], [61]. [score:1]
An assessment of the degree of conservation for structure-specific distribution of microRNAs in Wistar rat, Beagle dog and cynomolgus monkey (see for relative enrichment analysis), revealed high enrichment of nine microRNAs cardiac valves (miR-let7c, mIR-125b, miR-127, mir-199a-3p, miR204, miR-320, miR-99b, miR-328 and miR-744) (Figure 3A) and seven microRNAs in the myocardium (miR-1, mir-133a, miR-133b, miR-208b, miR-30e, miR-499-5p, miR-30e*) (Figure 3A). [score:1]
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[+] score: 20
Thus, miR-129 and miR-499 expression was downregulated upon induction of Aire among mature mTECs, yet both miRNAs were also downregulated in mature mTECs in Aire null mice as compared with WT. [score:8]
In the context of a putative role of miRNA in pGE, it is noteworthy that several mRNAs, upregulated upon mTEC maturation, showed tissue-specific expression patterns, i. e. being restricted to brain (miR-124 and miR-129), heart (miR-499), testis (miR-202), skin (miR-203) or embryo (miR-467 and miR-302). [score:6]
Mir-129, miR-499 and miR-302b were expressed at similar levels in immature mTECs of mutant and control littermates, but were significantly downregulated in mature mTECs of Aire null mutants (Fig. 2B). [score:6]
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[+] score: 17
In addition to myofilament proteins, the expression of four microRNAs (miRNA, miR) involved in cardiac development and function was analysed (Fig. 2B): miR-133a and b, miR-1 and miR-499. [score:4]
3.4In addition to myofilament proteins, the expression of four microRNAs (miRNA, miR) involved in cardiac development and function was analysed (Fig. 2B): miR-133a and b, miR-1 and miR-499. [score:4]
MiR-499 plays a key role in inhibition of cardiomyocyte apoptosis through its suppression of calcineurin -mediated dephosphorylation of dynamin-related protein-1 [11] and has been implicated in myocardial regeneration [12]. [score:4]
MiR-499, which is highly expressed in the late stages of cardiac differentiation [9], was significantly up-regulated at day 4 and 14 post birth compared to adult mouse hearts. [score:4]
The zebrafish genome contains 3 loci encoding miR-499 in contrast to a single mammalian locus [10]. [score:1]
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[+] score: 16
Other miRNAs from this paper: hsa-mir-146a, hsa-mir-499b
Similar to the miR-146a rs2910164, subgroup analysis on Asian population also showed no association of miR-499 rs3746444 polymorphism with susceptibility to HCC. [score:1]
For each study, the departure of frequencies of miR-146a rs2910164 and miR-499 rs3746444 polymorphisms from expectation under Hardy-Weinberg equilibrium (HWE) was assessed by χ [2] test in controls. [score:1]
This meta-analysis suggests that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. [score:1]
To study the relationship between the miR-499 rs3746444 polymorphism and HCC, we made a meta-analysis including 4 case-control studies with 667cases and 1006 controls. [score:1]
Meta-analysis of the Association between miR-499 rs3746444 Polymorphism and Susceptibility to HCC. [score:1]
We carried out a publication search in PubMed, Cochrane Central Register of Controlled Trials, ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI) databases with the following search terms: (“miR-146a” OR “miR-499” OR “rs2910164” OR “rs3746444”) AND (“hepatocellular carcinoma” OR “liver cancer” OR “HCC”) AND (“SNP” OR “mutation” OR “variation” OR “polymorphism”)by two independent investigators (Miao Hu and Lianying Zhao, last search update: Sep 10th, 2012). [score:1]
As for miR-499 rs3746444, there were 3 studies [10], [11], [12] on Asians (Chinese and Korean population) and 1 study on Caucasian population [15](Turkish population). [score:1]
Indeed, the rs3746444 SNP in miRNA-499 and rs291016 SNP in miRNA-146a have been reported to be associated with the susceptibility to squamous cell carcinoma of the head and neck [19], and SNP in miRNA-146a contributes to the genetic predisposition to papillary thyroid carcinoma [20]. [score:1]
Firstly, the sample size is relatively small although we have searched as many eligible literatures as possible, larger sample size and multiple random-control tests are still needed to detect possible minor effects of miR-146a rs2910164 and rs3746444 in miRNA-499 polymorphisms on susceptibility to HCC. [score:1]
A total of 6 studies were identified with 2071 cases and 2350 controls for miR-146a rs2910164 polymorphism, 667 cases and 1006 controls for miR-499 rs3746444 polymorphism. [score:1]
Since a single study with a small sample size may not be enough to detect accurate effects of these SNPs on HCC, we performed this meta-analysis to derive more comprehensive and precise estimation of the associations between the SNPs miR-146a rs2910164 and miR-499 rs11614913 and susceptibility to HCC. [score:1]
We have not found any other research that focused on the relationship between SNP of miRNA-499 and susceptibility of HCC to date. [score:1]
In conclusion, this meta-analysis provides more evidence that miR-146a rs2910164 and miR-499 rs3746444 polymorphisms may not be associated with the risk of HCC, especially for Asian population. [score:1]
miR-499 was reported to play a role of mediator in a wide spectrum of biological processes, such as cellular senescence, apoptosis, immune response, tumorigenesis and metastasis [29], [30], [31]. [score:1]
It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC). [score:1]
Another SNP shown to have potential relationship to the risk for HCC is rs3746444 in miR-499. [score:1]
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[+] score: 15
Other miRNAs from this paper: mmu-mir-208b, hsa-mir-208b
Specifically, HCV was found to regulate expression of two microRNAs (miR-208b and miR-499a-5p) that target the 3′ untranslated region (UTR) of IFNL3 leading to its degradation, allowing for viral persistence. [score:8]
Intriguingly, these same microRNAs also dampen type I IFN signaling in HCV-infected hepatocytes by downregulating expression of IFNAR1, a mechanism distinct from miR-208b and miR-499a-5p regulation of type III IFN (104). [score:7]
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[+] score: 14
Western blotting analysis indicated that LEF1 protein expression levels were indeed downregulated in MDA-MB-231 lacking PI3K-C2β (Figure 5B), suggesting that PI3K-C2β could regulate miR499a by modulating the β catenin/LEF1 pathway. [score:7]
Consistent with the observed upregulation of miR-499a, transient downregulation of β catenin reduced cyclin B1 protein levels in MDA-MB-231 (Figure 5E), as observed in cells lacking PI3K-C2β (Supplementary Figure S3A). [score:7]
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[+] score: 14
Hsa-/mmu-/rno-miR-499a-5p and hsa-499b-3p were plentiful in sheep heart whereas the expression of other forms of miR-499 were low. [score:3]
For the first time we report that not only are the four cardiac-enriched miR-1, miR-133, miR-499 and miR-208 highly expressed in sheep LV, but also provide information on their isomiRs. [score:3]
MiR-499b is the antisense of miR-499a, and it was previously unclear whether miR-499b is expressed in the heart [20]. [score:3]
Four myocardial-enriched miRNAs, miR-1, miR-133, miR-499 and miR-208, were confirmed to be highly expressed in ovine heart tissue. [score:3]
Cardiac-enriched miR-1-3p, miR-133a-3p, miR-133b-3p, miR-208b-3p and miR-499-3p were screened. [score:1]
MiR-1, miR-133, miR-499 and miR-208 are highly enriched myocardial miRNAs 27, 28 and are highly conserved across multiple species including human [29], mouse [30] rat [31] and porcine [32]. [score:1]
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[+] score: 14
Allele comparison showed that the C allele of miR-499 rs3746444 was associated with a higher risk of OSCC with significant odds ratio of 1.453 (95%CI = 1.127–1.874, P = 0.004). [score:1]
393(72.8) 413(78.2) -  G allele 147(27.2) 115(21.8) 1.343(1.015–1.778) 0.039 miR-499 rs3746444  TT(Ref. ) [score:1]
Through an extensive exploring of the databases of the International HapMap Project [15], dbSNP [16], and miRBase registry [17], as well as considering the minor allele frequency of selected SNPs in Asian population, we identified three potential functional polymorphisms in three pre-miRNAs (miR-196a2 rs11614913, miR-146a rs2910164 and miR-499 rs3746444). [score:1]
502(73.8) 528(77.6) -  G allele 178(26.2) 152(22.4) 1.232(0.961–1.579) 0.100 miR-499 rs3746444  TT(Ref. ) [score:1]
These findings suggest that miR-499 rs3746444 and miR-146a rs2910164 polymorphisms may contribute to genetic susceptibility to oral squamous cell cancer. [score:1]
The miR-146a rs2910164 and miR-499 rs3746444 polymorphisms might alter individual susceptibility to oral squamous cell cancer in Chinese. [score:1]
The similar results were found in the relationship between miR-499 rs3746444 polymorphism and OSCC risk in males. [score:1]
Liu et al. reported that miR-146a rs2910164 and miR-196a2 rs11614913 did not affect the risk of head and neck cancers but miR-499 rs3746444 moderately reduced the risk of head and neck cancers [22]. [score:1]
The distribution of demographic factors and tobacco smoking in cases and controls are shown in Table 1. The observed genotype frequencies for the three polymorphisms were all in agreement with that expected under the Hardy-Weinberg equilibrium in the controls (P = 0.530 for miR-146a rs2910164, P = 0.106 for miR-196a2 rs11614913, P = 0.633 for miR-499 rs3746444). [score:1]
54(15.9) 108(31.8) - Never  GC+CC 61(17.9) 67(19.7) 1.811(1.124–2.918) 0.015 Smoking  GG 135(39.7) 99(29.1) 2.719(1.791–4.128) <0.001 Smoking  GC+CC 90(26.5) 65(19.4) 2.713(1.719–4.282) <0.001 miR-499 rs3746444 Never  TT(Ref. ) [score:1]
Our findings suggest that the miR-499 rs3746444 polymorphism is associated with the risk of OSCC in Chinese, particularly among males. [score:1]
109(77.9) 115(75.7) -  G allele 31(22.1) 37(24.3) 0.884(0.513–1.524) 0.657 miR-499 rs3746444  TT(Ref. ) [score:1]
The C allele of miR-499 rs3746444 was associated with a higher risk of oral cancer with significant odds ratio of 1.453. [score:1]
In the stratified analyses by sex, the associations between miR-499 rs3746444 and miR-146a rs2910164 polymorphisms with the susceptibility of oral squamous cell cancer were significant in males. [score:1]
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[+] score: 13
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-mir-15a, hsa-mir-18a, hsa-mir-33a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-mir-27b, mmu-mir-126a, mmu-mir-128-1, mmu-mir-140, mmu-mir-146a, mmu-mir-152, mmu-mir-155, mmu-mir-191, hsa-mir-10a, hsa-mir-211, hsa-mir-218-1, hsa-mir-218-2, mmu-mir-297a-1, mmu-mir-297a-2, hsa-mir-27b, hsa-mir-128-1, hsa-mir-140, hsa-mir-152, hsa-mir-191, hsa-mir-126, hsa-mir-146a, mmu-let-7a-1, mmu-let-7a-2, mmu-mir-15a, mmu-mir-18a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-342, hsa-mir-155, mmu-mir-107, mmu-mir-10a, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-33, mmu-mir-211, hsa-mir-374a, hsa-mir-342, gga-mir-33-1, gga-let-7a-3, gga-mir-155, gga-mir-18a, gga-mir-15a, gga-mir-218-1, gga-mir-103-2, gga-mir-107, gga-mir-128-1, gga-mir-140, gga-let-7a-1, gga-mir-146a, gga-mir-103-1, gga-mir-218-2, gga-mir-126, gga-let-7a-2, gga-mir-27b, mmu-mir-466a, mmu-mir-467a-1, hsa-mir-545, hsa-mir-593, hsa-mir-600, hsa-mir-33b, gga-mir-499, gga-mir-211, gga-mir-466, mmu-mir-675, mmu-mir-677, mmu-mir-467b, mmu-mir-297b, mmu-mir-499, mmu-mir-717, hsa-mir-675, mmu-mir-297a-3, mmu-mir-297a-4, mmu-mir-297c, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-467c, mmu-mir-467d, mmu-mir-466d, hsa-mir-297, mmu-mir-467e, mmu-mir-466l, mmu-mir-466i, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-467f, mmu-mir-466j, mmu-mir-467g, mmu-mir-467h, hsa-mir-664a, hsa-mir-1306, hsa-mir-1307, gga-mir-1306, hsa-mir-103b-1, hsa-mir-103b-2, gga-mir-10a, mmu-mir-1306, mmu-mir-3064, mmu-mir-466m, mmu-mir-466o, mmu-mir-467a-2, mmu-mir-467a-3, mmu-mir-466c-2, mmu-mir-467a-4, mmu-mir-466b-4, mmu-mir-467a-5, mmu-mir-466b-5, mmu-mir-467a-6, mmu-mir-466b-6, mmu-mir-467a-7, mmu-mir-466b-7, mmu-mir-467a-8, mmu-mir-467a-9, mmu-mir-467a-10, mmu-mir-466p, mmu-mir-466n, mmu-mir-466b-8, hsa-mir-466, hsa-mir-3173, hsa-mir-3618, hsa-mir-3064, hsa-mir-499b, mmu-mir-466q, hsa-mir-664b, gga-mir-3064, mmu-mir-126b, gga-mir-33-2, mmu-mir-3618, mmu-mir-466c-3, gga-mir-191
Out of the 26 miRNA/host gene pairs with coordinated expression, 11 have been found to be coordinately expressed in both, human and mouse [19], [27], [59], [61]– [64], [67]– [69], [71], [73]– [79]: mir-103/ PANK3, mir-107/ PANK1, mir-126/ EGFL7, mir-128-1/ R3HDM1, mir-140/ WWP2, mir-211/ TRPM1, mir-218-1/ SLIT2, mir-218-2/ SLIT3, mir-27b/ C9orf3, mir-33/ SREBF2, and mir-499/ MYH7B. [score:5]
For example, we found a link between two independent studies: human MYH7B gene (myosin, heavy chain 7B, cardiac muscle, beta) hosts hsa-mir-499a, a miRNA upregulated in human and murine cardiac hypertrophy and cardiomyopathy [49], which comprises miR-seed-SNP rs3746444 linked with increased risk of dilated cardiomyopathy [50]. [score:4]
Moreover, two miRNA/host gene pairs have been found to have expression patterns associated with the same phenotype in both species: mir-499/ MYH7B with heart development [79] and mir-33/ SREBF2 with cholesterol homeostasis [74], [75], [77]. [score:4]
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[+] score: 12
In addition hsa-mir-371 is predicted to target DNMT3A (miRTar), while DNA-methyl transferase 2 (DNMT2) belongs to the predicted targets of hsa-miR-499 (miRTar). [score:5]
We have demonstrated for the first time that miRNAs (hsa-mir-371, hsa-mir-369-5P, hsa-mir-29c, hsa-mir-499 and hsa-let-7f) are up-regulated upon replicative senescence. [score:4]
SAM analysis identified a group of five significantly up-regulated miRNAs, (FDR<1): hsa-mir-371, hsa-mir-369-5P, hsa-mir-29c, hsa-mir-499 and hsa-mir-217 (signal intensity of hsa-mir-217 was very low and thus not considered for subsequent analysis). [score:3]
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[+] score: 12
5) 7 hsa-mir-19a dbDEMC 32 hsa-mir-30d dbDEMC 8 hsa-mir-92a HMDD, miR2Disease 33 hsa-mir-451 literature 9 hsa-mir-210 miR2Disease 34 hsa-mir-152 dbDEMC 10 hsa-mir-19b dbDEMC, miR2Disease 35 hsa-mir-215 dbDEMC 11 hsa-mir-224 dbDEMC, miR2Disease 36 hsa-mir-130a dbDEMC, HMDD 12 hsa-let-7f dbDEMC, miR2Disease 37 hsa-mir-499 higher RWRMDA (No. [score:11]
Hsa-mir-18a, hsa-mir-18b, hsa-mir-499, and hsa-mir-542 are ranked No. [score:1]
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[+] score: 12
Among these three miRNAs, miR-208a is specifically expressed only in cardiac muscle, whereas miR-208b and miR-499 are also expressed in type I (slow) muscle fibers [67]. [score:5]
Overexpression of miR-499 in skeletal muscle completely converts the fast myofibers of the soleus muscle into slow fibers [67]. [score:3]
Conversely, double knockout of miR-499 and miR-208b in mouse leads to a dramatic loss of type I fibers in the soleus muscle [67]. [score:2]
The two MyomiRs miR-208b and miR-499 have redundant functions in controlling muscle fiber type by repressing fast myofiber genes while activating slow muscle specific genes [67, 68]. [score:1]
These intronic miRNAs, miR-208a, miR-208b, and miR-499, are embedded in three muscle-specific MyHC genes (Myh6, Myh7, and Myh7b, resp. ) [score:1]
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[+] score: 11
Additionally, 9 miRNAs (hsa-miR-484, hsa-miR-499-5p, hsa-miR-126*, hsa-miR-491-5p, hsa-miR-1303, hsa-miR-539, hsa-miR-25*, hsa-let-7e*, and hsa-miR-194*) were upregulated in 10 diseases while not downregulated in any other, as the balloon plot (Figure  3) of all miRNAs significant in at least 8 of 19 diseases (>40%) shows. [score:11]
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[+] score: 10
In G1 (down-regulated), the stages from 35 to 63 dpc showed the most significant differences between breeds, in which miR-20, miR-499, miR-451 and miR-335 had drastic changes. [score:4]
Bhuiyan SS Evolution of the myosin heavy chain gene MYH14 and its intronic microRNA miR-499: muscle-specific miR-499 expression persists in the absence of the ancestral host geneBMC Evol. [score:3]
In G2 (down), the most significant differences between breeds were observed at 2 dpn, when miR-29 and miR-499 showed drastic changes. [score:1]
By contrast, in G1 (down), 35–63 dpc showed the most significant differences between breeds; in this group, miR-20, miR-451, miR-499 and miR-335 showed drastic changes. [score:1]
miR-499 is a muscle-specific miRNA and an intronic miRNA of the myosin heavy chain gene MYH14 that plays a key role in muscle fiber-type specification in mammals [22]. [score:1]
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[+] score: 10
After determining the expression levels of these miRNAs in the same 7 pairs of NSCLC tissues and normal adjacent tissues, we observed that 8 miRNAs (miR-203, miR-30, let-7, miR-132, miR-181, miR-212, miR-101 and miR-9) were downregulated in the NSCLC tissues, while the other 5 miRNAs (miR-125, miR-98, miR-196, miR-23 and miR-499) were upregulated (Fig. S1). [score:9]
A total of 13 miRNAs, including miR-203, miR-30, let-7, miR-132, miR-181, miR-212, miR-101, miR-9, miR-125, miR-98, miR-196, miR-23 and miR-499, were identified as candidate miRNAs by all three computational algorithms (Table S2). [score:1]
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[+] score: 10
They found that upregulation of miR-499a-5p is a common feature of all placental insufficiencies such as preeclampsia (n = 80), gestational hypertension (n = 35), and FGR (n = 35); in addition, they demonstrated an upregulation of miR-1-3p in FGR pregnancies with abnormal umbilical fetal flows (n = 19); finally, they found downregulation of a series of miRNAs (miR-16-5p, miR-26a-5p, miR-100-5p, miR-103a-3p, miR-122-5p, miR-125b-5p, miR-126-3p, miR-143-3p, miR-145-5p, miR-195-5p, miR-199a-5p, miR-221-3p, miR-342-3p, and miR-574-3p) in FGR requiring the delivery before 34 weeks of gestation. [score:10]
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[+] score: 9
Essential amino acids increase microRNA-499, -208b, and -23a and downregulate myostatin and myocyte enhancer factor 2C mRNA expression in human skeletal muscle. [score:6]
In the present study, among the 231 exosomal miRNAs detected in the cattle plasma, muscle-enriched miR-486 and a trace of miR133b were detected, but miR-1, miR-133a, miR-206, miR-208b, and miR-499 were not detected. [score:1]
On the other hand, these muscle-specific miRNAs and miR-499 are present at a very low level in the serum of healthy humans who have not just exercised [30, 39]. [score:1]
Muscle-specific miRNAs such as miR-1, miR-133a, miR-206, miR-208b, and miR-499 were not significantly detected in the plasma exosomes across all samples (i. e., grazing and housed during experiment) except for miR-486 (0.18%) and a trace of miR-133b (< 0.001%). [score:1]
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[+] score: 8
This expression profile was not observed for a group of well-known cardiac or muscle specific miRNAs (miR-1, miR-133a, miR-133b, miR-208a, miR-208b, miR-499-5p and miR-499-3p). [score:3]
Expression profile of (A) miRNA-940; (B) miR-1; (C) miR-133a; (D) miR-133b; (E) miR-499-3p; (F) miR-499-5p; (G) miR-208a; (H) miR-208b in different part of human hearts. [score:3]
Furthermore, compared to well-known cardiac or muscle specific miRNAs (miR-1, miR-133a, miR-133b, miR-208a, miR-208b, miR-499-5p and miR-499-3p), miRNA-940 was the only one which is most highly expressed in the normal human right ventricular out-flow tract comparing to other chambers within the heart (Fig. 3). [score:2]
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[+] score: 8
Specifically, in these studies taken together, miR-1, miR-133a, miR-133b, miR-208, and miR-499 were found upregulated in plasma of AMI patients. [score:4]
More recently, in a systematic review [28] the authors proposed that only cardiomyocyte-enriched miRNAS, miR-1, miR-133a/b, miR-145, miR-208a/b, and miR-499(a) in plasma and/or serum are potential biomarkers for the diagnosis of coronary heart disease. [score:3]
Cheng et al. concluded that miR-499 and miR-133a are possible biomarkers of AMI, showing a sensitivity of 0.88 (95% CI: 0.86–0.90; p = 0.0000); a specificity of 0.87 (95% CI: 0.84–0.90; p = 0.0000) and a sensitivity of 0.89 (95% CI: 0.83–0.94; p = 0.0047); a specificity of 0.87 (95% CI: 0.79–0.92; p = 0.0262), respectively. [score:1]
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[+] score: 7
Fru-miR-206-3p, fru-miR-10b-5p, fru-miR-10d-5p, fru-miR-133b-3p, and fru-miR-133-3p exhibited 434, 77, 60, 17, and 15 times higher levels of expression, respectively, in fast muscle compared with cardiac muscle, while fru-miR-144-5p, fru-miR-499-5p, fru-miR-187-3p, fru-miR-499a-5p, and fru-miR-140-3p exhibited 51-, 41-, 37-, 33-, and 17-fold higher expression levels, respectively, in heart muscle compared with fast muscle. [score:3]
In contrast, fru-miR-126b-5p, fru-miR-194-5p, fru-miR-499-5p, fru-miR-30e-5p, and fru-miR-30c-5p exhibited 121-, 21-, 13-, 11-, and 4-fold higher levels of expression, respectively, in slow muscle compared with fast muscle (Table  1). [score:2]
However, for fru-miR-499-5p, fru-miR-192-5p, fru-miR-196a-5p, fru-miR-202-5p (data not shown) and fru-miR-2478-3p, the results from q-PCR were not consistent with the sequencing results. [score:1]
For example, fru-miR-1-3p was muscle specific, fru-miR-196a-5p was skeletal muscle specific, fru-miR-499-5p was heart and slow muscle specific, fru-miR-204-5p was eye specific, fru-miR-9-3p was brain and eye specific, fru-miR-192-5p was intestine and liver specific, fru-miR-122-5p was liver specific, and fru-miR-202-5p was ovary specific. [score:1]
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[+] score: 7
In M pig, ssc-miR-499 was differentially expressed in four comparison groups. [score:3]
In a previous study, hsa-miR-499 was associated with Duchenne muscular dystrophy and could serve as a promising biomarker for its diagnosis and disease progression [59]. [score:3]
In addition, we identified 199, 127, 140, and 37 DE miRNAs in the 60/120, 120/150, 150/180, and 180/210 dpn comparisons, respectively, in M pig, among which nine miRNAs (ssc-miR-23a, ssc-miR-new-276, ssc-miR-142-3p, ssc-miR-142-5p, ssc-miR-499-5p, ssc-miR-15a, ssc-miR-new-386, ssc-miR-new-421, and ssc-miR-144) were common (S4 Fig and S7 Table). [score:1]
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[+] score: 7
A 10-fold increase in miRNA -mediated murine cardiac fibroblast reprogramming was observed when miRNA-1, miRNA-133, miRNA-208, and miRNA-499 were combined with JAK inhibitor I [30]. [score:3]
miRNA-1, miRNA-133, miRNA-208, and miRNA-499 have been shown to be cardiac- and muscle-specific and play important roles in cardiac development and function. [score:2]
Zhao et al. used a combination of GMHT, miRNA-1, miRNA-133, miRNA-208, miRNA-499, Y-27632, and A83-01 in MEFs and mouse adult fibroblasts to achieve ~60% cardiac troponin T+ and 60% α-actinin+ iCMs [29]. [score:1]
A combination of miRNA-1, miRNA-133, miRNA-208, and miRNA-499 was reported to be sufficient to convert mouse cardiac fibroblasts into iCMs without the addition of other factors in vivo [36]. [score:1]
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In line with these results, we found that miR-208a-3p and miR-499-5p -both cardiac specific and highly abundant in the heart [23]- were either undetectable or very lowly expressed in the circulation of mice. [score:3]
Of the cardiac specific miRNAs, miR-208a-3p was not detectable in the plasma of ischemic heart failure mice and miR-499-5p showed the lowest miRNA expression levels in plasma compared to the other miRNAs (Fig 3 and S4 Table). [score:2]
In addition to the cardiac specific miR-208a-3p and miR-499-5p, we found that the expression of let-7i-5p, miR-16-5p, miR-27a-3p, miR-199a-3p and miR-223-3p was significantly higher in the heart compared to the kidney, independent of the presence of ischemic heart failure (S4 Fig and S5 Table). [score:2]
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[+] score: 7
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-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-26a-1, hsa-mir-99a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-106a, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-99a, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-127, mmu-mir-145a, mmu-mir-146a, mmu-mir-129-1, mmu-mir-206, hsa-mir-129-1, hsa-mir-148a, mmu-mir-122, mmu-mir-143, hsa-mir-139, hsa-mir-221, hsa-mir-222, hsa-mir-223, mmu-let-7d, mmu-mir-106a, hsa-let-7g, hsa-let-7i, hsa-mir-122, hsa-mir-125b-1, hsa-mir-143, hsa-mir-145, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-129-2, hsa-mir-146a, hsa-mir-206, mmu-mir-148a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-21a, mmu-mir-22, mmu-mir-26a-1, mmu-mir-129-2, mmu-mir-103-1, mmu-mir-103-2, rno-let-7d, rno-mir-335, rno-mir-129-2, rno-mir-20a, mmu-mir-107, mmu-mir-17, mmu-mir-139, mmu-mir-223, mmu-mir-26a-2, mmu-mir-221, mmu-mir-222, mmu-mir-125b-1, hsa-mir-26a-2, hsa-mir-335, mmu-mir-335, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-17-1, rno-mir-18a, rno-mir-21, rno-mir-22, rno-mir-26a, rno-mir-99a, rno-mir-101a, rno-mir-103-2, rno-mir-103-1, rno-mir-107, rno-mir-122, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-126a, rno-mir-127, rno-mir-129-1, rno-mir-139, rno-mir-143, rno-mir-145, rno-mir-146a, rno-mir-206, rno-mir-221, rno-mir-222, rno-mir-223, hsa-mir-196b, mmu-mir-196b, rno-mir-196b-1, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, hsa-mir-486-1, mmu-mir-486a, mmu-mir-20b, rno-mir-20b, rno-mir-499, mmu-mir-499, mmu-mir-708, hsa-mir-708, rno-mir-17-2, rno-mir-708, hsa-mir-103b-1, hsa-mir-103b-2, mmu-mir-486b, rno-mir-126b, hsa-mir-451b, hsa-mir-499b, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-130c, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2, mmu-mir-129b, mmu-mir-126b, rno-let-7g, rno-mir-148a, rno-mir-196b-2, rno-mir-486
After 6 and 12 wks of E [2] exposure, 15 miRNAs were down-regulated, e. g., miR-22, miR-99a, miR-106a, miR-127, miR-499, and 19 miRNAs were-up-regulated, e. g., miR-17-5p, miR-20a, miR-21, miR-129-3p, miR-106a, miR-22, and miR-127. [score:7]
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[+] score: 7
Also, miR-499 was found to be significantly upregulated in senescent human mesenchymal stem cells, with the potential to regulate all four of the senescence induction types namely, telomere attrition, oxidative stress, oncogene expression and DNA damage signaling [20]. [score:7]
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[+] score: 7
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-22, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-27a, hsa-mir-31, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-16-2, hsa-mir-192, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-181a-2, hsa-mir-205, hsa-mir-181a-1, hsa-mir-214, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-2, hsa-mir-146a, hsa-mir-184, hsa-mir-186, hsa-mir-193a, hsa-mir-194-1, hsa-mir-155, hsa-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-219a-2, hsa-mir-99b, hsa-mir-26a-2, hsa-mir-365a, hsa-mir-365b, hsa-mir-374a, hsa-mir-148b, hsa-mir-423, hsa-mir-486-1, hsa-mir-532, hsa-mir-590, bta-mir-26a-2, bta-let-7f-2, bta-mir-103-1, bta-mir-148a, bta-mir-16b, bta-mir-21, bta-mir-221, bta-mir-222, bta-mir-27a, bta-mir-499, bta-mir-125b-1, bta-mir-181a-2, bta-mir-205, bta-mir-27b, bta-mir-30b, bta-mir-31, bta-mir-193a, bta-let-7d, bta-mir-148b, bta-mir-186, bta-mir-191, bta-mir-192, bta-mir-200a, bta-mir-214, bta-mir-22, bta-mir-23a, bta-mir-29c, bta-mir-423, bta-let-7g, bta-mir-24-2, bta-let-7a-1, bta-mir-532, bta-let-7f-1, bta-mir-30c, bta-let-7i, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, bta-mir-103-2, bta-mir-125b-2, bta-mir-365-1, bta-mir-374a, bta-mir-99b, hsa-mir-374b, hsa-mir-664a, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-1915, bta-mir-146a, bta-mir-155, bta-mir-16a, bta-mir-184, bta-mir-24-1, bta-mir-194-2, bta-mir-219-1, bta-mir-223, bta-mir-26a-1, bta-mir-365-2, bta-mir-374b, bta-mir-486, bta-mir-763, bta-mir-9-1, bta-mir-9-2, bta-mir-181a-1, bta-mir-2284i, bta-mir-2284s, bta-mir-2284l, bta-mir-2284j, bta-mir-2284t, bta-mir-2284d, bta-mir-2284n, bta-mir-2284g, bta-mir-2339, bta-mir-2284p, bta-mir-2284u, bta-mir-2284f, bta-mir-2284a, bta-mir-2284k, bta-mir-2284c, bta-mir-2284v, bta-mir-2284q, bta-mir-2284m, bta-mir-2284b, bta-mir-2284r, bta-mir-2284h, bta-mir-2284o, bta-mir-664a, bta-mir-2284e, bta-mir-1388, bta-mir-194-1, bta-mir-193a-2, bta-mir-2284w, bta-mir-2284x, bta-mir-148c, hsa-mir-374c, hsa-mir-219b, hsa-mir-499b, hsa-mir-664b, bta-mir-2284y-1, bta-mir-2284y-2, bta-mir-2284y-3, bta-mir-2284y-4, bta-mir-2284y-5, bta-mir-2284y-6, bta-mir-2284y-7, bta-mir-2284z-1, bta-mir-2284aa-1, bta-mir-2284z-3, bta-mir-2284aa-2, bta-mir-2284aa-3, bta-mir-2284z-4, bta-mir-2284z-5, bta-mir-2284z-6, bta-mir-2284z-7, bta-mir-2284aa-4, bta-mir-2284z-2, hsa-mir-486-2, hsa-mir-6516, bta-mir-2284ab, bta-mir-664b, bta-mir-6516, bta-mir-219-2, bta-mir-2284ac, bta-mir-219b, bta-mir-374c, bta-mir-148d
Furthermore, the differential expression pattern of five miRNAs (bta-miR184, miR-24-3p, miR-148, miR-486 and bta-let-7a-5p) were unique to E. coli while four (bta-miR-2339, miR-499, miR-23a and miR-99b) were unique to S. aureus. [score:3]
Five differentially expressed miRNAs (bta-miR-184, miR-24-3p, miR-148, miR-486 and let-7a-5p) were unique to E. coli while four (bta-miR-2339, miR-499, miR-23a and miR-99b) were unique to S. aureus. [score:3]
Interestingly, our study shows that a different set of five miRNAs (miR-184, miR-24-3p, miR-148, miR-486 and let-7a-5p) were unique to E. coli bacteria while another set of four (miR-2339, miR-499, miR-23a and miR-99b) were unique to S. aureus bacteria. [score:1]
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[+] score: 6
Shown in this figure, miR-125a-5p exhibited the highest degree, followed by miR-33a-5p,miR-33b-5p,miR-580-3p,miR-499a-5p and miR-34b-3p In the present study, we employed high-throughput circRNA microarrays to construct profiles of differentially expressed circRNAs in CD28 -associated CD8(+)T cells in the elderly and adult subjects (C1,C2,C3 and C4). [score:3]
Shown in this figure, miR-125a-5p exhibited the highest degree, followed by miR-33a-5p,miR-33b-5p,miR-580-3p,miR-499a-5p and miR-34b-3p In the present study, we employed high-throughput circRNA microarrays to construct profiles of differentially expressed circRNAs in CD28 -associated CD8(+)T cells in the elderly and adult subjects (C1,C2,C3 and C4). [score:3]
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[+] score: 6
An in silico search for putative binding sites of differentially abundant miRNAs was performed using TargetScan 6.0 [26]; note that non-conserved miRNAs (ENSGALT00000042483-3p, ENSGALT00000043002-3p, ENSGALT00000043002-5p, gga-miR-1736-3p) and those with borderline differential abundance (adjusted P-values of 0.0498; ccr-miR-133a-5p, mmu-miR-144-5p, gga-miR-20a, aca-miR-499-3p) were not included in the functional analysis. [score:3]
For example, the three members of the let-7 family (let-7a, let-7f, let-7k) are broadly expressed across tissues [36] and tissue enrichment has been found for miR-499-5p and −3p in heart [37], miR-122-5p in liver [38], miR-202-5p in testis [39] and gga-miR-107-3p in brain tissues [40] (Table 2). [score:3]
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Drummond M. J. Glynn E. L. Fry C. S. Dhanani S. Volpi E. Rasmussen B. B. Essential amino acids increase microRNA-499, -208b, and -23a and downregulate myostatin and myocyte enhancer factor 2C mRNA expression in human skeletal muscleJ. [score:6]
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We then analyzed the GO terms associated to targets of the microRNA families highly expressed in CM, including miR-1 (mir-1 and mir-206), miR-133 (miR-133a and b), miR-208 (miR-208a and b), miR-490, miR-499 and miR-143. [score:5]
Some of these microRNAS have been previously reported and are well-known in the context of cardiac differentiation, such as hsa-mir-1-3p, hsa-mir-499-5p, and the mir-208 and mir-133 families 39, 40. [score:1]
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Wang J. X. Jiao J. Q. Li Q. Long B. Wang K. Liu J. P. Li Y. R. Li P. F. miR-499 regulates mitochondrial dynamics by targeting calcinuerin and dynamin-related protein-1 Nat. [score:4]
However, it was reported in a separated study that a combination of miR-1, miR-133, miR-208, and miR-499 was able to directly induce the cellular reprogramming of fibroblasts into cardiomyocyte-like cells in vitro [18]. [score:2]
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miR-499 is involved in the regulation of genes that codify for IL-17RB, IL-23a, IL-2RB, IL-6, and IL-2. These proteins are related to several biological processes of inflammation, such as the TNF- α signaling pathway, or in the promotion and perpetuation of inflammatory responses [27]. [score:2]
As it is wi dely known, genetic liability is an important factor contributing to the development of RA, and recently SNPs (single-nucleotide polymorphisms) in miRNA genes have been identified to be involved in RA risk in the Caucasian population, with evidence supporting the participation of the rs3746444 polymorphism in miR-499 and RA [26]. [score:2]
El-Shal et al. confirmed that genotypes TC and CC and the allele C of the rs3746444 SNP in miR-499 are independent risk factors for joint erosions in RA. [score:1]
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Essential amino acids increase MicroRNA-499, -208b, and -23a and downregulate myostatin and myocyte enhancer factor 2C mRNA expression in human skeletal muscle. [score:5]
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Furthermore, a comparison was made in their negative regulatory effects on FOXO4 protein expression between miR-150 and several other potential up-stream miRNAs of FOXO4 (miR-421, miR-664a-3p, miR-499a-5p). [score:4]
miR-150, miR-421, miR-664a-3p, miR-499a-5p mimics and miRNA mimic NC were synthesized by Ribobio Technology Co. [score:1]
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When overexpressed in rat BM-MSCs, miR-499 activates the WNT/β-catenin signalling pathway, inducing cardiac differentiation [283]. [score:3]
Similarly, miR-499 is an embedded miRNA present within a ventricular-specific myosin heavy chain gene [282]. [score:1]
Another mechanism of cardiac protection used by miR-499 is calcineurin -mediated dynamin-related protein-1 (Drp1) activation, which prevents cardiomyocyte apoptosis [284]. [score:1]
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[+] score: 5
The mir-499 microRNA has also been implicated in several human malignancies (Table S1). [score:1]
mir-499 rs3746444. [score:1]
Meta-analysis of mir-499 rs3746444 polymorphism. [score:1]
@ miR-499 rs3746444 deviated from HWE in controls. [score:1]
A T>C (rs3746444) polymorphism has been identified in the stem region of the mir-499 gene resulting in A:U to G:U mismatch in the stem structure of miR-499 precursor. [score:1]
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[+] score: 5
Therefore, miRNAs targeting PTEN such as miR-499, miR-26b, and miR-301a are beneficial for improving insulin sensitivity [49, 50, 51]. [score:3]
Wang L. Zhang N. Pan H. P. Wang Z. Cao Z. Y. MiR-499–5p contributes to hepatic insulin resistance by suppressing PTEN Cell. [score:2]
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[+] score: 5
Four of the tested miRNAs (miR-627-5p, miR-379-5p, miR-499-3p, and miR-124-3p) partially or completely lost their potential to suppress their original target due to a SNP in their seed sequence. [score:5]
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[+] score: 5
Other miRNAs from this paper: hsa-mir-499b
In embryonic stem cells, this gene is used as a marker of cardiac cells and its expression is found to be increased with greater expression of miR-499 [30]. [score:5]
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[+] score: 5
Another recent study of serum obtained from DMD boys demonstrated that in addition to the three myomiRs (miR-1, miR-133a/b, and miR-206) being increased in expression, two other muscle-enriched microRNAs, miR-208b and miR-499 were also increased in expression [37] (Table 1). [score:5]
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For example, miR-208 and miR-499 are cardiac-specific miRNAs exclusively expressed in cardiac tissues, while miR-1 and miR-133 are muscle-specific miRNAs preferentially expressed in cardiac and skeletal muscle [37, 38]. [score:5]
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[+] score: 5
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-15a, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, mmu-let-7g, mmu-let-7i, mmu-mir-15b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-130a, mmu-mir-138-2, mmu-mir-181a-2, mmu-mir-182, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10a, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-182, hsa-mir-181a-1, mmu-mir-297a-1, mmu-mir-297a-2, mmu-mir-301a, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, mmu-mir-106a, mmu-mir-106b, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-138-2, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-138-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-26b, mmu-mir-29a, mmu-mir-29c, mmu-mir-34a, rno-mir-301a, rno-let-7d, rno-mir-344a-1, mmu-mir-344-1, rno-mir-346, mmu-mir-346, rno-mir-352, hsa-mir-181b-2, mmu-mir-10a, mmu-mir-181a-1, mmu-mir-29b-2, mmu-mir-138-1, mmu-mir-181b-1, mmu-mir-181c, mmu-mir-125b-1, hsa-mir-106b, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-30e, hsa-mir-362, mmu-mir-362, hsa-mir-369, hsa-mir-374a, mmu-mir-181b-2, hsa-mir-346, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-10a, rno-mir-15b, rno-mir-26b, rno-mir-29b-2, rno-mir-29a, rno-mir-29b-1, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30e, rno-mir-30b, rno-mir-30d, rno-mir-30a, rno-mir-30c-2, rno-mir-34b, rno-mir-34c, rno-mir-34a, rno-mir-106b, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-130a, rno-mir-138-2, rno-mir-138-1, rno-mir-181c, rno-mir-181a-2, rno-mir-181b-1, rno-mir-181b-2, rno-mir-181a-1, hsa-mir-449a, mmu-mir-449a, rno-mir-449a, mmu-mir-463, mmu-mir-466a, hsa-mir-483, hsa-mir-493, hsa-mir-181d, hsa-mir-504, mmu-mir-483, rno-mir-483, mmu-mir-369, rno-mir-493, rno-mir-369, rno-mir-374, hsa-mir-579, hsa-mir-582, hsa-mir-615, hsa-mir-652, hsa-mir-449b, rno-mir-499, hsa-mir-767, hsa-mir-449c, hsa-mir-762, mmu-mir-301b, mmu-mir-374b, mmu-mir-762, mmu-mir-344d-3, mmu-mir-344d-1, mmu-mir-673, mmu-mir-344d-2, mmu-mir-449c, mmu-mir-692-1, mmu-mir-692-2, mmu-mir-669b, mmu-mir-499, mmu-mir-652, mmu-mir-615, mmu-mir-804, mmu-mir-181d, mmu-mir-879, mmu-mir-297a-3, mmu-mir-297a-4, mmu-mir-344-2, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-493, mmu-mir-504, mmu-mir-466d, mmu-mir-449b, hsa-mir-374b, hsa-mir-301b, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-879, mmu-mir-582, rno-mir-181d, rno-mir-182, rno-mir-301b, rno-mir-463, rno-mir-673, rno-mir-652, mmu-mir-466l, mmu-mir-669k, mmu-mir-466i, mmu-mir-669i, mmu-mir-669h, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-466j, mmu-mir-1193, mmu-mir-767, rno-mir-362, rno-mir-504, rno-mir-582, rno-mir-615, mmu-mir-3080, mmu-mir-466m, mmu-mir-466o, mmu-mir-466c-2, mmu-mir-466b-4, mmu-mir-466b-5, mmu-mir-466b-6, mmu-mir-466b-7, mmu-mir-466p, mmu-mir-466n, mmu-mir-344e, mmu-mir-344b, mmu-mir-344c, mmu-mir-344g, mmu-mir-344f, mmu-mir-374c, mmu-mir-466b-8, hsa-mir-466, hsa-mir-1193, rno-mir-449c, rno-mir-344b-2, rno-mir-466d, rno-mir-344a-2, rno-mir-1193, rno-mir-344b-1, hsa-mir-374c, hsa-mir-499b, mmu-mir-466q, mmu-mir-344h-1, mmu-mir-344h-2, mmu-mir-344i, rno-mir-344i, rno-mir-344g, mmu-let-7j, mmu-mir-30f, mmu-let-7k, mmu-mir-692-3, rno-let-7g, rno-mir-15a, rno-mir-762, mmu-mir-466c-3, rno-mir-29c-2, rno-mir-29b-3, rno-mir-344b-3, rno-mir-466b-3, rno-mir-466b-4
1Proliferation, Invasion, Tumor suppression [63– 66] miR-344 ↓2.0 ↓3.2 NA miR-346 ↓2.4Proliferation [67, 68] miR-362 ↓2.3Proliferation, Invasion, Apoptosis [69– 76] miR-369 ↓2.8 ↓2.6 ↓2.1Aerobic glycolysis [77] miR-374 ↑3.0 ↓2.2 NA miR-449 ↑2.7 ↑2.4Proliferation [78– 81] miR-463 ↓2.7 NAmiR-466 [°] ↑2.4 ↑2.1 ↓3.5 NA miR-483 ↓3.2Apoptosis [82] miR-493 ↑2.1 ↓2.2Proliferation [83– 85] miR-499a ↓5.0 ↑2.3Proliferation [86] miR-504 ↓2.6 ↑2.0Proliferation, Apoptosis [87, 88] miR-579 ↑2.8 NAmiR-582 [^] ↑2.4Proliferation [89] miR-615 ↓2.1Proliferation, Invasion [90, 91] miR-652 ↑2.4Proliferation, EMT [92, 93] miR-669b ↓2.1 NA miR-669h ↓3.6 ↑2.3 NA miR-669i ↓2.3 NA miR-669k ↓7.2 ↓5. [score:3]
The identity, fold-change variation, direction of alteration, and biological function of these miRNAs are reported in Table 2. In mice bearing adenomas, 5 miRNAs (miR-34b, miR-106a, miR-499, miR-466, and miR-493) were altered in the blood serum but not in lung. [score:2]
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For example, in previous lung cancer studies, levels of miR-1254, miR-574-5p, miR-486, miR-30d, miR-1, and miR-499 expression were significantly dysregulated in early-stage lung cancer [7], [30]. [score:4]
A number of researchers, including us, have reported the potential clinical application of circulating miRNAs (such as miR-1254, miR-142-3p, miR-24, miR-183, miR-21, miR-221, miR-29c, miR-486, miR-30d, miR-1, miR-499, and miR-210) [7], [8]. [score:1]
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[+] score: 5
The expression level of miR-1471 in small HCC was significantly higher than in large HCC, and the expression level of miR-499-5p and miR-609 in small HCC was significantly lower than in large HCC (Table  3). [score:5]
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In this analysis, we observed that two miRNAs – miR-499-3p and miR-330-5p – were upregulated in cancer samples and followed the enrichment, suggesting they are key miRNAs in male breast cancer. [score:4]
miR-499-3p and miR-330-5p miRNA follow the enrichment, decreasing in the gynecomastia and increasing in the male breast cancer samples. [score:1]
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[+] score: 4
HCV also enhances hepatic expression of miR-208b and miR-499a-5p, two “myomiRs” encoded in the introns of myosin-encoding genes [40]. [score:3]
Nevertheless, the induction of miR-208b or miR-499a-5p by HCV was not observed in our transcriptome analyses. [score:1]
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MiR-13b’s human homologue is miR-499 [57] that expressed in brain region and its polymorphism is associated with ischemic stroke [58]. [score:3]
These results indicate that miR-13b/miR-499 play important roles in pathogenesis of brain insults. [score:1]
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[+] score: 4
To further assess the alterations of mitochondria-related miRNAs in obesity, we examined the expression levels of miR-126a-3p, miR-141-3p, miR-196a-5p, miR-210-3p, miR-378a-3p, miR-484 and miR-499a-5p in mice livers. [score:3]
There was no significant difference of miR-126a-3p, miR-484, miR-499a-5p between HFD mice and SD mice. [score:1]
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Many miRNAs, such as miR-1, miR-133, miR-29, miR-214, miR-206, miR-486, miR-208b, and miR-499 were involved in the regulation of skeletal myogenesis by binding to its target genes 36, 37. [score:4]
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[+] score: 4
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-15a, hsa-mir-16-1, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-96, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, hsa-mir-16-2, hsa-mir-196a-1, hsa-mir-198, hsa-mir-129-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-182, hsa-mir-183, hsa-mir-196a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-204, hsa-mir-210, hsa-mir-211, hsa-mir-212, hsa-mir-181a-1, hsa-mir-214, hsa-mir-215, hsa-mir-216a, hsa-mir-217, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-224, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-23b, hsa-mir-30b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-130a, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-137, hsa-mir-138-2, hsa-mir-140, hsa-mir-141, hsa-mir-142, hsa-mir-143, hsa-mir-145, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-129-2, hsa-mir-138-1, hsa-mir-146a, hsa-mir-150, hsa-mir-184, hsa-mir-185, hsa-mir-195, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-181b-2, hsa-mir-128-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-101-2, hsa-mir-219a-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-99b, hsa-mir-296, hsa-mir-130b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-365a, hsa-mir-365b, hsa-mir-375, hsa-mir-376a-1, hsa-mir-378a, hsa-mir-382, hsa-mir-383, hsa-mir-151a, hsa-mir-148b, hsa-mir-338, hsa-mir-133b, hsa-mir-325, hsa-mir-196b, hsa-mir-424, hsa-mir-20b, hsa-mir-429, hsa-mir-451a, hsa-mir-409, hsa-mir-412, hsa-mir-376b, hsa-mir-483, hsa-mir-146b, hsa-mir-202, hsa-mir-181d, hsa-mir-376a-2, hsa-mir-92b, hsa-mir-33b, hsa-mir-151b, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-301b, hsa-mir-216b, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-378b, hsa-mir-320e, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-219b, hsa-mir-203b, hsa-mir-451b, hsa-mir-499b, hsa-mir-378j
Lineage-restricted expression of miR-499 leads to the establishment and maintenance of slow-twitch muscle fibers through repression of Sox6, which promotes fast-twitch muscle differentiation; this mechanism is conserved among vertebrates (Wang et al. 2011). [score:3]
Xia et al. (2011) miR-1, miR-101a, miR-130b,c, miR-133a, miR-221, and miR-499 Zebrafish NGS, qRT–PCR ? [score:1]
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[+] score: 4
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-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, 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-98, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-192, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-210, hsa-mir-215, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-137, hsa-mir-138-2, hsa-mir-143, hsa-mir-144, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-138-1, hsa-mir-146a, hsa-mir-193a, hsa-mir-194-1, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-194-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-302a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-369, hsa-mir-371a, hsa-mir-340, hsa-mir-335, hsa-mir-133b, hsa-mir-146b, hsa-mir-519e, hsa-mir-519c, hsa-mir-519b, hsa-mir-519d, hsa-mir-519a-1, hsa-mir-519a-2, hsa-mir-504, hsa-mir-421, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-190b, hsa-mir-301b, hsa-mir-302e, hsa-mir-302f, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-320e, hsa-mir-371b, hsa-mir-499b
Loss of stemness has been associated with differential expression of several miRNAs, notably miR-371, miR-369-5p, miR-29c, miR-499 and let-7 in mesenchymal stem cells [88]. [score:3]
Olivieri F. Antonicelli R. Lorenzi M. D’Alessandra Y. Lazzarini R. Santini G. Spazzafumo L. Lisa R. Sala L. L. Galeazzi R. Diagnostic potential of circulating miR-499–5p in elderly patients with acute non ST-elevation myocardial infarction Int. [score:1]
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For example, miR-150 was found to be reduced in serum of patients with arterial fibrillation and miR-1, miR-134, miR-186, miR-208, miR-233 and miR-499 were all found to be significantly upregulated in serum from acute myocardial infarction (AMI) patients [22- 24]. [score:4]
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[+] score: 4
The expression level of miR-499 is similar to that of U6-snRNA. [score:3]
pri-mir499 forward: 5'-gcatgtgaacatcacagcaag-3', pri-mir499 reverse: 5'-ccaaacaccacctaagtcttc-3'. [score:1]
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As to pathological changes, tissue specific miRNAs were analyzed in the blood stream as markers for myocardial injury and drug induced liver injury: A rat mo del of acute myocardial infarction demonstrated that the plasma levels of the cardiac-specific miRNA-208 and miRNA-499 are increased in this disease [50]. [score:3]
Four miRNAs (miRNA-486, miRNA-30d, miRNA-1, and miRNA-499) were confirmed to be associated with patient outcome. [score:1]
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[+] score: 3
Very low but specific expression of the members of the mir-302 family and miR-367 and miR-499 (group V, r = 0.995) was detected in different parts of the heart. [score:3]
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[+] score: 3
The miR-208a/b family and miR-499, designated as MyomiRs, are located in the introns of three myosin genes, Myh6, Myh7, and Myh7b, respectively, and play critical roles in the control of pathological cardiac hypertrophy, heart failure and myocardial infarction in humans and mouse mo dels of heart disease [10, 136]. [score:3]
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Additionally, we have also found that the miRNAs involved in reducing hypoxic damage (miR-100 and miR-199a) and promoting slow muscle formation (miR-499 and miR-208b) are highly expressed in PMM 53 54. [score:3]
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[+] score: 3
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-21, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-99a, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-16-2, hsa-mir-192, hsa-mir-148a, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181a-1, hsa-mir-215, hsa-mir-223, hsa-mir-224, hsa-mir-200b, hsa-mir-15b, hsa-mir-27b, hsa-mir-125b-1, hsa-mir-141, hsa-mir-143, hsa-mir-152, hsa-mir-125b-2, hsa-mir-126, hsa-mir-146a, hsa-mir-184, hsa-mir-200c, hsa-mir-155, hsa-mir-29c, hsa-mir-200a, hsa-mir-99b, hsa-mir-296, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-378a, hsa-mir-342, hsa-mir-148b, hsa-mir-451a, ssc-mir-125b-2, ssc-mir-148a, ssc-mir-15b, ssc-mir-184, ssc-mir-224, ssc-mir-23a, ssc-mir-24-1, ssc-mir-26a, ssc-mir-29b-1, ssc-let-7f-1, ssc-mir-103-1, ssc-mir-21, ssc-mir-29c, hsa-mir-486-1, hsa-mir-671, hsa-mir-378d-2, bta-mir-26a-2, bta-mir-29a, bta-let-7f-2, bta-mir-103-1, bta-mir-148a, bta-mir-16b, bta-mir-21, bta-mir-499, bta-mir-99a, bta-mir-125b-1, bta-mir-126, bta-mir-181a-2, bta-mir-27b, bta-mir-31, bta-mir-15b, bta-mir-215, bta-mir-30e, bta-mir-148b, bta-mir-192, bta-mir-200a, bta-mir-200c, bta-mir-23a, bta-mir-29b-2, bta-mir-29c, bta-mir-10b, bta-mir-24-2, bta-mir-30a, bta-mir-200b, bta-let-7a-1, bta-mir-342, bta-let-7f-1, bta-let-7a-2, bta-let-7a-3, bta-mir-103-2, bta-mir-125b-2, bta-mir-15a, bta-mir-99b, hsa-mir-664a, ssc-mir-99b, hsa-mir-103b-1, hsa-mir-103b-2, ssc-mir-15a, ssc-mir-16-2, ssc-mir-16-1, bta-mir-141, bta-mir-143, bta-mir-146a, bta-mir-152, bta-mir-155, bta-mir-16a, bta-mir-184, bta-mir-24-1, bta-mir-223, bta-mir-224, bta-mir-26a-1, bta-mir-296, bta-mir-29d, bta-mir-378-1, bta-mir-451, bta-mir-486, bta-mir-671, bta-mir-29e, bta-mir-29b-1, bta-mir-181a-1, ssc-mir-181a-1, ssc-mir-215, ssc-mir-30a, bta-mir-2318, bta-mir-2339, bta-mir-2430, bta-mir-664a, bta-mir-378-2, ssc-let-7a-1, ssc-mir-378-1, ssc-mir-29a, ssc-mir-30e, ssc-mir-499, ssc-mir-143, ssc-mir-10b, ssc-mir-486-1, ssc-mir-152, ssc-mir-103-2, ssc-mir-181a-2, ssc-mir-27b, ssc-mir-24-2, ssc-mir-99a, ssc-mir-148b, ssc-mir-664, ssc-mir-192, ssc-mir-342, ssc-mir-125b-1, oar-mir-21, oar-mir-29a, oar-mir-125b, oar-mir-181a-1, hsa-mir-378b, hsa-mir-378c, ssc-mir-296, ssc-mir-155, ssc-mir-146a, bta-mir-148c, ssc-mir-126, ssc-mir-378-2, ssc-mir-451, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-451b, hsa-mir-499b, ssc-let-7a-2, ssc-mir-486-2, hsa-mir-664b, hsa-mir-378j, ssc-let-7f-2, ssc-mir-29b-2, ssc-mir-31, ssc-mir-671, bta-mir-378b, bta-mir-378c, hsa-mir-486-2, oar-let-7a, oar-let-7f, oar-mir-103, oar-mir-10b, oar-mir-143, oar-mir-148a, oar-mir-152, oar-mir-16b, oar-mir-181a-2, oar-mir-200a, oar-mir-200b, oar-mir-200c, oar-mir-23a, oar-mir-26a, oar-mir-29b-1, oar-mir-30a, oar-mir-99a, bta-mir-664b, chi-let-7a, chi-let-7f, chi-mir-103, chi-mir-10b, chi-mir-125b, chi-mir-126, chi-mir-141, chi-mir-143, chi-mir-146a, chi-mir-148a, chi-mir-148b, chi-mir-155, chi-mir-15a, chi-mir-15b, chi-mir-16a, chi-mir-16b, chi-mir-184, chi-mir-192, chi-mir-200a, chi-mir-200b, chi-mir-200c, chi-mir-215, chi-mir-21, chi-mir-223, chi-mir-224, chi-mir-2318, chi-mir-23a, chi-mir-24, chi-mir-26a, chi-mir-27b, chi-mir-296, chi-mir-29a, chi-mir-29b, chi-mir-29c, chi-mir-30a, chi-mir-30e, chi-mir-342, chi-mir-378, chi-mir-451, chi-mir-499, chi-mir-671, chi-mir-99a, chi-mir-99b, bta-mir-378d, ssc-mir-378b, oar-mir-29b-2, ssc-mir-141, ssc-mir-200b, ssc-mir-223, bta-mir-148d
Similarly, Jin et al. (2014a) demonstrated a differential expression of nine miRNAs (bta-miR-184, miR-24-3p, miR-148, miR-486, and let-7a-5p, miR-2339, miR-499, miR-23a, and miR-99b) upon challenge of MACT-cells (bovine mammary epithelia cell line) with heat inactivated E. coli and S. aureus bacteria. [score:3]
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From the 7 microRNAs assessed, miR-133a, miR-21 and miR-19b were detected both in myocardial and serum samples from AS patients and control subjects, whereas the expression of miR-29b, miR-1, miR-208a and miR-499-5p was under the limit of detection in serum samples from AS patients and control subjects. [score:3]
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A total of 22 miRNAs (Additional file 6: Figure S5) were selected for qPCR validation including the following 14 biomarker candidates of organ toxicity: liver (cfa-miR-122 and -885), pancreas (cfa-miR-216a/b); heart (cfa-miR-499); muscle (cfa-miR-206); heart/muscle (cfa-miR-1, -133a/b, and -208); testis (cfa-miR-34b/c); and brain and sciatic nervous tissues (cfa-miR-212, -432, and -885), and 5 miRNAs reported in the literature (cfa-miR-21, -192, -193a/b, and -200). [score:1]
Enrichment of miR-499 in the heart has been demonstrated in rat, monkey, and human [36, 37]. [score:1]
A single HTE miRNA was identified in the dog heart (cfa-miR-499) and in skeletal muscle (cfa-miR-206), and both tissues had the same 5 TE miRNAs (cfa-miR-1, -133a-5p, -133a-3p, -133b, and -208) (Fig.   3). [score:1]
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Interestingly, a recent paper by Anversa and co-workers shows that microRNA typically associated to adult cardiomyocytes (such as miR-1, mir-499 and mir-133) are expressed in cardiovascular precursors, but at lower levels than in adult cardiomyocytes [49]. [score:3]
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Interventional cardiologists have already provided evidence that cardiac expressed miRs (miR-1, miR-133a, miR-133b, miR-208a, miR-208b, and miR-499) increase in the blood acutely following a myocardial infarction (MI) and some of these studies have additionally scrutinized the diagnostic potential of miRs by comparisons with cTns[15– 17]. [score:3]
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Some of these microRNAs that exhibit specific patterns of muscle expression are dubbed “myomiRs”; these include members of the bicistronic miR-1/133a and miR206/133b families [20], and a group of microRNAs, namely miR-208, miR-208b, and miR-499, that are embedded in genes encoding the myosin heavy chain [21]. [score:3]
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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-21, hsa-mir-148a, hsa-let-7g, hsa-let-7i, hsa-mir-122, hsa-mir-34c, hsa-mir-148b, dre-mir-430a-1, dre-mir-430b-1, dre-mir-430c-1, dre-let-7a-1, dre-let-7a-2, dre-let-7a-3, dre-let-7a-4, dre-let-7a-5, dre-let-7a-6, dre-let-7b, dre-let-7c-1, dre-let-7c-2, dre-let-7d-1, dre-let-7d-2, dre-let-7e, dre-let-7f, dre-let-7g-1, dre-let-7g-2, dre-let-7h, dre-let-7i, dre-mir-10c, dre-mir-21-1, dre-mir-21-2, dre-mir-122, dre-mir-135c-1, dre-mir-135c-2, dre-mir-148, dre-mir-430c-2, dre-mir-430c-3, dre-mir-430c-4, dre-mir-430c-5, dre-mir-430c-6, dre-mir-430c-7, dre-mir-430c-8, dre-mir-430c-9, dre-mir-430c-10, dre-mir-430c-11, dre-mir-430c-12, dre-mir-430c-13, dre-mir-430c-14, dre-mir-430c-15, dre-mir-430c-16, dre-mir-430c-17, dre-mir-430c-18, dre-mir-430a-2, dre-mir-430a-3, dre-mir-430a-4, dre-mir-430a-5, dre-mir-430a-6, dre-mir-430a-7, dre-mir-430a-8, dre-mir-430a-9, dre-mir-430a-10, dre-mir-430a-11, dre-mir-430a-12, dre-mir-430a-13, dre-mir-430a-14, dre-mir-430a-15, dre-mir-430a-16, dre-mir-430a-17, dre-mir-430a-18, dre-mir-430i-1, dre-mir-430i-2, dre-mir-430i-3, dre-mir-430b-2, dre-mir-430b-3, dre-mir-430b-4, dre-mir-430b-6, dre-mir-430b-7, dre-mir-430b-8, dre-mir-430b-9, dre-mir-430b-10, dre-mir-430b-11, dre-mir-430b-12, dre-mir-430b-13, dre-mir-430b-14, dre-mir-430b-15, dre-mir-430b-16, dre-mir-430b-17, dre-mir-430b-18, dre-mir-430b-5, dre-mir-430b-19, dre-mir-430b-20, dre-mir-459, dre-let-7j, dre-mir-499, dre-mir-34c, dre-mir-734, hsa-mir-499b, dre-mir-7146, dre-mir-7147, dre-mir-7148
For example, miRNAs such as : dre-miR-135c and dre-miR-734 were found to be highly expressed in brain, dre-miR-122 was found to be associated to liver, and dre-miR-499 was found to be highly enriched in heart. [score:3]
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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-15a, hsa-mir-17, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-32, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-106a, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30a, mmu-mir-30b, mmu-mir-126a, mmu-mir-9-2, mmu-mir-135a-1, mmu-mir-137, mmu-mir-140, mmu-mir-150, mmu-mir-155, mmu-mir-24-1, mmu-mir-193a, mmu-mir-194-1, mmu-mir-204, mmu-mir-205, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-143, mmu-mir-30e, hsa-mir-34a, hsa-mir-204, hsa-mir-205, hsa-mir-222, mmu-let-7d, mmu-mir-106a, mmu-mir-106b, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-137, hsa-mir-140, hsa-mir-143, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-150, hsa-mir-193a, hsa-mir-194-1, mmu-mir-19b-2, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-23a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-31, mmu-mir-92a-2, mmu-mir-34a, rno-mir-322-1, mmu-mir-322, rno-let-7d, rno-mir-329, mmu-mir-329, rno-mir-140, rno-mir-350-1, mmu-mir-350, hsa-mir-200c, hsa-mir-155, mmu-mir-17, mmu-mir-25, mmu-mir-32, mmu-mir-200c, mmu-mir-33, mmu-mir-222, mmu-mir-135a-2, mmu-mir-19b-1, mmu-mir-92a-1, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-7b, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-106b, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-30e, hsa-mir-375, mmu-mir-375, mmu-mir-133b, hsa-mir-133b, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-7b, rno-mir-9a-1, rno-mir-9a-3, rno-mir-9a-2, rno-mir-17-1, rno-mir-19b-1, rno-mir-19b-2, rno-mir-23a, rno-mir-24-1, rno-mir-24-2, rno-mir-25, rno-mir-27b, rno-mir-29a, rno-mir-30c-1, rno-mir-30e, rno-mir-30b, rno-mir-30d, rno-mir-30a, rno-mir-30c-2, rno-mir-31a, rno-mir-32, rno-mir-33, rno-mir-34a, rno-mir-92a-1, rno-mir-92a-2, rno-mir-106b, rno-mir-126a, rno-mir-135a, rno-mir-137, rno-mir-143, rno-mir-150, rno-mir-193a, rno-mir-194-1, rno-mir-194-2, rno-mir-200c, rno-mir-200a, rno-mir-204, rno-mir-205, rno-mir-222, hsa-mir-196b, mmu-mir-196b, rno-mir-196b-1, mmu-mir-410, hsa-mir-329-1, hsa-mir-329-2, mmu-mir-470, hsa-mir-410, hsa-mir-486-1, rno-mir-133b, mmu-mir-486a, hsa-mir-33b, rno-mir-499, mmu-mir-499, mmu-mir-467d, hsa-mir-891a, hsa-mir-892a, hsa-mir-890, hsa-mir-891b, hsa-mir-888, hsa-mir-892b, rno-mir-17-2, rno-mir-375, rno-mir-410, mmu-mir-486b, rno-mir-31b, rno-mir-9b-3, rno-mir-9b-1, rno-mir-126b, rno-mir-9b-2, hsa-mir-499b, mmu-let-7j, mmu-mir-30f, mmu-let-7k, hsa-mir-486-2, mmu-mir-126b, rno-mir-155, rno-let-7g, rno-mir-15a, rno-mir-196b-2, rno-mir-322-2, rno-mir-350-2, rno-mir-486, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Similarly, miR-133b, miR-137, miR-155, and miR499 were exclusively expressed in the caudal region of the mouse epididymis but were wi dely distributed throughout the rat and/or human epididymis (S4 Table). [score:3]
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Nat Commun 4. 16 Qin H, Chen GX, Liang MY, Rong J, Yao JP, et al (2013) The altered expression profile of microRNAs in cardiopulmonary bypass canine mo dels and the effects of mir-499 on myocardial ischemic reperfusion injury. [score:3]
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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-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-30a, hsa-mir-31, hsa-mir-98, hsa-mir-99a, hsa-mir-101-1, hsa-mir-16-2, hsa-mir-192, hsa-mir-197, hsa-mir-199a-1, hsa-mir-208a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-187, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-211, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-224, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-138-2, hsa-mir-140, hsa-mir-142, hsa-mir-143, hsa-mir-144, hsa-mir-145, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-138-1, hsa-mir-146a, hsa-mir-200c, hsa-mir-155, hsa-mir-128-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-101-2, hsa-mir-219a-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-99b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-375, hsa-mir-328, hsa-mir-337, hsa-mir-338, hsa-mir-339, hsa-mir-384, hsa-mir-424, hsa-mir-429, hsa-mir-449a, hsa-mir-485, hsa-mir-146b, hsa-mir-494, hsa-mir-497, hsa-mir-498, hsa-mir-520a, hsa-mir-518f, hsa-mir-509-1, hsa-mir-574, hsa-mir-582, hsa-mir-606, hsa-mir-629, hsa-mir-449b, hsa-mir-449c, hsa-mir-509-2, hsa-mir-874, hsa-mir-744, hsa-mir-208b, hsa-mir-509-3, hsa-mir-1246, hsa-mir-1248, hsa-mir-219b, hsa-mir-203b, hsa-mir-499b
Trinh H. K. T. Pham D. L. Kim S. C. Kim R. Y. Park H. S. Kim S. H. Association of the miR-196a2, miR-146a, and miR-499 polymorphisms with asthma phenotypes in a Korean populationMol. [score:1]
Toraih E. A. Hussein M. H. Al Ageeli E. Riad E. AbdAllah N. B. Helal G. M. Fawzy M. S. Structure and functional impact of seed region variant in MIR-499 gene family in bronchial asthmaRespir. [score:1]
Another candidate miRNA in atopic asthma is miR-499. [score:1]
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Corsten M. F. Dennert R. Jochems S. Kuznetsova T. Devaux Y. Hofstra L. Wagner D. R. Staessen J. A. Heymans S. Schroen B. Circulating microRNA-208b and microRNA-499 reflect myocardial damage in cardiovascular disease Circ. [score:3]
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MiR-499a-5p was present in 33% of samples, whereas miR-499a-3p was present in only 2% of samples. [score:1]
They include miR-1, miR-133, miR-206 (skeletal muscle only), miR-208, miR-486 and miR-499 [27]. [score:1]
MyomiRs (miR-1, miR-133, miR-206, miR-208, miR-486 and miR-499) are highly enriched in cardiac and skeletal muscle, miR-1 being the most abundant miRNA in the heart [44]. [score:1]
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miR-208b/miR-499, also named myomiRs because of their muscle-restricted expression, are produced from the introns of two myosin genes, β-MHC and Myh7b. [score:3]
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We determined the expression of angiogenesis-related miRNAs (miR-20a, miR-126, miR-210, miR-221, miR-222, miR-328; Dews et al., 2006; Poliseno et al., 2006; Kuehbacher et al., 2007; Fasanaro et al., 2008; Soeki et al., 2016), inflammation-related miRNAs (miR-21, miR-146a, miR-155; Taganov et al., 2006; Urbich et al., 2008; Wang et al., 2017) and cardiac or muscle-specific/enriched miRNAs (miR-1, miR-133a, miR-133b, miR-208a, miR-208b, miR-378, miR-486, miR-499, miR-940; Chen et al., 2006; Soci et al., 2016; Xu et al., 2016). [score:3]
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In addition to expression analysis, microRNA single nucleotide polymorphism (SNP) analysis has revealed a correlation between SNPs in miR-146a (rs2910164) and miR-499 (rs3746444) and increased pulmonary tuberculosis susceptibility in certain populations (Li et al., 2011). [score:3]
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Database 2015, pbav29 (doi:10.1093/database/bav029) 23 Cai T et al. 2017 Polymorphisms in MIR499A and MIR125A gene are associated with autoimmune thyroid diseases. [score:3]
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Other miRNAs from this paper: mmu-mir-499, mmu-mir-208b, hsa-mir-208b, hsa-mir-499b
However, unlike Myh7 which was hypermethylated, regions within the promoter for both miR-208b and miR499 were hypomethylated. [score:1]
Of the miRNA promoter regions with DMRs, two were related to cardiac hypertrophy including miR-208b and miR-499 (Table 8) [49], [50]. [score:1]
MiR-208b is located within intron 31 of the Myh7 gene which is also differentially methylated and miR-499 is located in intron 19 of Myh7b. [score:1]
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The analysis of miRNA expression in cardiomyocyte progenitor cells (CMPCs) showed that 188 miRNAs were detectable in proliferating CMPCs and 195 in differentiated CMPCs such as miR1, miR1-2, miR499, miR322, miR503, miR208, miR133, and miR26b [30, 31, 32, 33, 34]. [score:3]
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Levels of miR-208, miR-208b and miR-499 were higher in human endomyocardial samples of DCM patients than in controls. [score:1]
An increased risk of DCM was also found in people with genetic polymorphisms in the pre-stages of miR-196a and miR-499 [51]. [score:1]
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A series of studies have demonstrated that cardiomyocytes specific miRNAs (miR-1, miR-208, miR-499, miR-133, etc. ) [score:1]
It was reported that cardiomyocytes-derived miRNAs (miR-1, miR-208, miR-499, miR-133, miR-30c, miR-181, etc. ) [score:1]
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Other miRNAs from this paper: hsa-mir-499b
A small subset of disease genes had very small loci (e. g. miR499) and were not considered in the analysis. [score:2]
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In addition, circulating miR-1, miR-133a, miR-328, miR-499, and miR-208b levels also increase in patients who present with acute myocardial infarction [82, 83]. [score:1]
During the I/R injury, plasma levels of miR-1, miR-133a, miR-499-5p, and cardiac-specific miR-208b rapidly increase in both rodent mo dels and in human patients presenting with ST-elevation myocardial infarction (STEMI). [score:1]
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1504/fig-3 Figure 3Furthermore, nine representative DE miRNAs (miR-133a-5p, miR-181a-1-3p, miR-499-5p, miR-320-3p, miR-24-1-3p, miR-214-3p, let-7g-5p, miR-23a-3p, and miR-10b-3p) were chosen for validation by the stem–loop real time (RT)-PCR -based method using three independent samples. [score:1]
1504/fig-3 Figure 3 Furthermore, nine representative DE miRNAs (miR-133a-5p, miR-181a-1-3p, miR-499-5p, miR-320-3p, miR-24-1-3p, miR-214-3p, let-7g-5p, miR-23a-3p, and miR-10b-3p) were chosen for validation by the stem–loop real time (RT)-PCR -based method using three independent samples. [score:1]
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Du W. Ma X. L. Zhao C. Liu T. Du Y. L. Kong W. Q. Wei B. L. Yu J. Y. Li Y. Y. Huang J. W. Associations of single nucleotide polymorphisms in miR-146a, miR-196a, miR-149 and miR-499 with colorectal cancer susceptibility Asian Pac. [score:1]
Chen C. Yang S. Chaugai S. Wang Y. Wang D. W. Meta-analysis of Hsa-mir-499 polymorphism (rs3746444) for cancer risk: Evidence from 31 case-control studies BMC Med. [score:1]
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Functional SNPs can occur in mature miRNAs outside the seed region, as recently demonstrated by the finding of a rare variant at nt 17 of miR-499 [27]. [score:1]
Evaluation of the effects of this variant in transgenic mice showed that it protected against the cardiomyopathy that developed with overexpression of the wildtype form of miR-499. [score:1]
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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-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-23a, hsa-mir-25, hsa-mir-26a-1, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-96, hsa-mir-99a, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-16-2, hsa-mir-198, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-182, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-204, hsa-mir-210, hsa-mir-212, hsa-mir-181a-1, hsa-mir-214, hsa-mir-215, hsa-mir-216a, hsa-mir-217, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-224, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-27b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-130a, hsa-mir-132, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-142, hsa-mir-145, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-134, hsa-mir-146a, hsa-mir-150, hsa-mir-186, hsa-mir-188, hsa-mir-193a, hsa-mir-194-1, hsa-mir-320a, hsa-mir-155, hsa-mir-181b-2, hsa-mir-128-2, hsa-mir-194-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-219a-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-99b, hsa-mir-130b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-362, hsa-mir-369, hsa-mir-375, hsa-mir-378a, hsa-mir-382, hsa-mir-340, hsa-mir-328, hsa-mir-342, hsa-mir-151a, hsa-mir-148b, hsa-mir-331, hsa-mir-339, hsa-mir-335, hsa-mir-345, hsa-mir-196b, hsa-mir-424, hsa-mir-425, hsa-mir-20b, hsa-mir-451a, hsa-mir-409, hsa-mir-484, hsa-mir-486-1, hsa-mir-487a, hsa-mir-511, hsa-mir-146b, hsa-mir-496, hsa-mir-181d, hsa-mir-523, hsa-mir-518d, hsa-mir-501, hsa-mir-532, hsa-mir-487b, hsa-mir-551a, hsa-mir-92b, hsa-mir-572, hsa-mir-580, hsa-mir-550a-1, hsa-mir-550a-2, hsa-mir-590, hsa-mir-599, hsa-mir-612, hsa-mir-624, hsa-mir-625, hsa-mir-627, hsa-mir-629, hsa-mir-33b, hsa-mir-633, hsa-mir-638, hsa-mir-644a, hsa-mir-650, hsa-mir-548d-1, hsa-mir-449b, hsa-mir-550a-3, hsa-mir-151b, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-454, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-708, hsa-mir-216b, hsa-mir-1290, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-378b, hsa-mir-3151, hsa-mir-320e, hsa-mir-378c, hsa-mir-550b-1, hsa-mir-550b-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-219b, hsa-mir-203b, hsa-mir-451b, hsa-mir-499b, hsa-mir-378j, hsa-mir-486-2
Among them, eight are located at six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6) and three at miRNA genes (miR-612, miR-499, and miR-449b). [score:1]
Interestingly, miRNA-612 and miRNA-499 have significant correlations with ALL susceptibility [57]. [score:1]
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An increasing number of miRNAs with different functions in heart development have also been identified, including miR-1, miR-208, miR-133, miR-206, miR-126, miR-143, miR-145, and miR-499; from this group, we analyzed the 7 miRNAs most relevant to postnatal heart growth. [score:2]
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Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. [score:2]
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