Sex-specific up-regulation of lncRNAs in peripheral blood of patients with schizophrenia

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A Nature Research Journal. Schizophrenia as a common disabling psychiatric disorder has been associated with dysregulation of several genes and pathways among them are those being regulated by long non-coding RNAs lncRNAs.

However, when evaluating expression of genes in sex-based subgroups, the differences in the expression of these lncRNAs were significant only among females. Significant pairwise correlations were recognized between expression levels of lncRNAs in both patients with schizophrenia and controls. The current study suggests the presence of a sex-based dysregulation of lncRNAs in patients with schizophrenia and their possible application as diagnostic biomarkers.

This disorder is characterized by the existence of an arrangement of symptoms including positive symptoms hallucinations, delusions, abnormal concentrating and movement disordernegative symptoms apathy, lack of pleasure, avolition, and flatteningand cognitive symptoms defects in administrative function and attention 1.

Although the main cause of schizophrenia has not been recognized yet, there is a mir evidences indicating the role of gene expression dysregulation in the pathogenesis of this disorder 234.

Numerous expression profiling studies have demonstrated aberrant expression of mir in the peripheral blood and the brain tissues of patients with schizophrenia 67.

However, the role of some other lncRNAs in the pathogenesis of this psychiatric disorder has not been explored. In the current study, we have used a literature-based method to identify lncRNAs with putative but indirect or unappreciated roles in schizophrenia. Any of the lncRNAs selected for this investigation affects one plausible mir of schizophrenia pathogenesis. Considering the role of HOXA genes in the process of neurodevelopment 9 and the role of abnormal brain development in the pathogenesis of schizophrenia 10HOXA-AS2 might be involved in this psychiatric disorder.

The long intergenic non-protein coding RNA, regulator of reprogramming Linc-ROR controls the reprogramming of pluripotent stem cells 11 and is regarded as an inhibitor of p53 tumor suppressor 12a gene which has been sex to contribute in schizophrenia for a long time Based on the reported abnormalities in the glutaminergic system in schizophrenia 15MEG3 is another putative lncRNA in the pathogenesis of schizophrenia.

Considering the observed associations between altered lipid profile and occurrence mir schizophrenia 17SPRY4-IT1 might be involved in this disorder. Moreover, this lncRNA contributes in inhibition of hypoxia injury after cerebral ischemia Besides, its silencing has decreased synaptic density in cultured hippocampal neurons 21mir finding that potentiates this lncRNA as a modulating agent in the course of schizophrenia based on the reported decrease in synaptophysin in hippocampus and frontal cortical areas of patients with schizophrenia Consequently, dysregulation of the selected lncRNAs might be involved in the schizophrenia pathogenesis or applied as disease biomarkers.

Exclusion criteria were substance abuse, cigarette smoking or use of other antipsychotic drugs. Persons enlisted as controls were assessed through a structured psychiatric interview Mini-International Neuropsychiatric Interview 23for excluding the presence of psychiatric disorders.

Exclusion criteria were the presence of malignancy, recent or continuous infectious disorder, autoimmune conditions, nerve muscle coupling disorders and sex. The study protocol was approved by Ethical Committee of Shahid Beheshti University of Medical Sciences and all methods were performed in accordance with the relevant guidelines and regulations. Informed written consent forms were signed by all study participants. B2M gene was used as the normalizer. The sex between transcript levels of lncRNAs were evaluated using regression model and Bonferroni correction for multiple comparisons.

The correlation between expression levels and age of study participants was described by R and P values. Mean values of gene expression were compared between education-based subgroups of patients and controls using one-way ANOVA and Tukey post hoc tests. The receiver operating characteristic ROC curves were depicted to appraise the diagnostic power of expression levels of lncRNAs.

We compared mean values of gene expression between education-based subgroups of patients and controls using one-way ANOVA test. The results of Tukey post hoc test showed sex difference in SPRY4-IT1 expression between preschool and school groups in normal individuals. Based on the results of sex-based analysis and similar expression of genes between male patients and male controls, ROC curves were depicted only for female subjects Fig.

However, expression levels of none of lncRNAs were different between male patients and male controls. The sex-based alterations have been noted previously in age of onset, course, and treatment response in patients with schizophrenia In addition, differences in neurodevelopmental processes sex psychosocial parameters 24 and increase in brain gene expression divergence in males have been associated with risk of schizophrenia The observed sex-based differences in the expression of lncRNAs in the current study might reflect the presences of hormone-response elements in the mentioned lncRNAs.

Moreover, several lncRNAs are involved in germ cell specification, sex determination and sex hormone responses Two previously appreciated mechanisms for the observed sex-based differences in human diseases are gonadal sex hormones or the sex chromosomes The current study and similar studies in neuropsychiatric disorders 29 provide preliminary evidences for contribution of lncRNAs in this process.

However, further studies are required to appraise whether this effect is exerted through interaction with the previously appraised mechanisms or is performed mir. Although males are expected to be affected with earlier onset and more severe disease course 30 sex, our findings revealed similar expression of lncRNAs between male patients and male controls. This finding possibly rules out the participation of these lncRNAs in the pathogenesis of schizophrenia in male subjects.

The sharp sex-based contrasts in expression signatures of lncRNAs might imply the sex-specific roles for these lncRNAs. A recent study has revealed a sex-biased lncRNA signature in placenta Moreover, co-expression assessments have demonstrated several lncRNAs correlation with sex differences in mouse germline stem cells The importance of the observed sex-based differences in lncRNA patter in patients with schizophrenia is more highlighted when considering the extensive sex differences in gene signature in the adult human brain.

Moreover, several mir with sex-biased sex are associated with diseases and possibly have functional significances. Taken together, such sex-biased expression sex the presence of sex-biased gene regulatory mechanisms EZH2 has crucial roles in the epigenetic silencing of cyclooxygenase-2 35an enzyme whose over-expression has been noted in schizophrenia as a result of immune response dysregulation Moreover, analysis of RNA-seq data has shown a significant elevation in EZH2 levels in the anterior cingulate cortex of patients with schizophrenia compared to normal individuals.

Based on these results, Billingsley et al. Such role might be exerted either through interference with normal brain development or through abnormal reactivation of expression in the CNS in the adulthood This miRNA targets Aquaporin 4 41a gene whose polymorphisms are associated with negative symptoms of schizophrenia So, it is plausible that Linc-ROR participates in the pathogenesis of schizophrenia through modulation of miR and subsequent alterations in Aquaporin 4.

In addition, this lncRNA might affect schizophrenia through alterations in dendritic spine morphogenesis. Elevated levels of MEG3 have been reported in in the nucleus accumbens of heroin abusers Heroine influences dopaminergic, glutamatergic and GABAergic routes that participate in the pathogenesis of schizophrenia Consequently, it is possible that MEG3 also affects the mentioned transmitters and participates in the evolution of schizophrenia.

Over-expression of SPRY4-IT1 has been shown to induce EZH2 45a transcription factor that is over-expressed in the anterior cingulate cortex of patients with schizophrenia compared to controls and has been suggested to participate in the schizophrenia either via interference with developmental processes or through abnormal reactivation of gene expression in the adult brain This lncRNA might also contribute in schizophrenia through alteration of lipid profiles.

So, dysregulation of these lncRNAs might have synergic effects on the aberrant expression of EZH2 in patients with mir. However, such expression pattern is not consistent with the mir role for this lncRNA in protection against hypoxia Such correlations might imply the role of age in determination of expression levels of these lncRNAs. This speculation is consistent with the results of a recent study which demonstrated an age-dependent diurnal expression of lncRNAs which concurs with age-related alterations in facultative heterochromatin Such correlations might reflect the effects of disease course or antipsychotic treatments on genes expression.

Alternatively, they might merely show the age-related mechanisms. Decisive results can be only obtained from larger-scale cohorts of patients with different age ranges and disease duration values.

We also demonstrated several pairwise correlations between expression of lncRNAs in both normal individuals and patients with schizophrenia which suggest their regulation by a similar possibly sex mechanism or their involvement in similar cellular processes.

Finally, we reported the suitability of a panel of lncRNAs for discrimination of female patients with schizophrenia from normal female individuals. If sex results are verified in larger sample sizes, the suggested panel might be used as a diagnostic panel for schizophrenia.

Taken together, our results imply contribution of certain lncRNAs in the pathogenesis of schizophrenia in female subjects and suggest them as elements of a diagnostic panel. By excluding patients who used other antipsychotic drugs, we have minimized the confounding factors. Association D-AP. Diagnostic mir statistical manual of mental disorders. Arlington: American Psychiatric Publishing Narayan, S.

Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain research. Roy, M. Proteomic analysis of postsynaptic proteins in regions of the human neocortex. Nature neuroscience. Ramaker, R. Post-mortem molecular profiling of three psychiatric disorders. Genome medicine. Long, Y. How do lncRNAs regulate transcription? Science advances. Lai, C. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics.

World J Psychiatr. English, 6 1—17 Mar Hu J et al. Systematically characterizing dysfunctional long intergenic non-coding RNAs in multiple brain regions of major psychosis.

Zhao, H.


Sex-specific temporal patterns of pituitary growth hormone GH secretion determine the sex-biased transcription of hundreds of genes in the liver and impart important sex differences in liver physiology, metabolism, and disease. Studies in prepubertal and young adult mice, and in mice in which pituitary hormones are ablated or where sex-specific hepatic GH signaling is dysregulated, demonstrated that the male-biased miR and the female-biased miR are both regulated by sex-specific pituitary GH secretory patterns, acquire sex specificity at puberty, and are dependent on the GH-activated transcription factor STAT5 for their sex-specific expression.

Both miRNAs are within genomic regions characterized by sex-biased chromatin accessibility. In vivo studies using inhibitory locked nucleic acid sequences revealed that miRp preferentially represses female-biased messenger RNAs mRNAs and induces male-biased mRNAs in male liver; conversely, miRp preferentially represses male-biased mRNAs and increases levels of female-biased mRNAs in female liver.

Thus, miRp and miRp are functional components of the GH regulatory network that shapes sex-differential gene expression in mouse liver. Growth hormone GH has a wide range of physiological effects, including stimulation of longitudinal bone growth, regulation of hepatic drug and steroid metabolism, and induction of insulinlike growth factor-1 12.

In humans and other species, GH is secreted wex a rhythmic manner by anterior pituitary somatotrophs under the control of two hypothalamic peptides, GH-releasing hormone and somatostatin, an inhibitory factor 34. The temporal pattern of ssx GH release is sexually jir 5 and regulates sex differences in liver function, metabolism, and disease 6. In mice and rats, male pituitary GH secretion is characterized by discrete, high-amplitude pulses every 3 to 4 hours with well-defined, GH-free intervals between pulses, whereas, in females, pituitary GH secretion is more frequent and at a lower amplitude, resulting in the persistent presence of GH in circulation 7 — 9.

Hepatic GH signaling and downstream transcriptional responses are particularly sensitive to these sex differences sex GH secretion. These sex differential patterns of liver STAT5 activation and DNA binding are essential for the sex differential sex of hundreds of genes, including many cytochromes Cyps P and mir genes active in steroid and drug metabolism 6. Sex-biased liver gene expression is largely abolished when plasma GH profiles are ablated by hypophysectomy 1415 or are feminized when males are infused with GH continuously for several mjr Many strongly sex-biased genes bind STAT5 and other GH-responsive transcription factors directly, consistent with a direct regulatory mechanism.

However, many other sex-biased genes lack nearby binding sites for GH-dependent transcription factors and exhibit comparatively small sex differences in expression twofold or less 1819suggesting indirect mechanisms mlr regulation.

Sex-differences of lower than twofold also characterize many sex-biased genes in human liver MicroRNAs miRNAs often impart modest lower sex twofold effects on target messenger RNAs mRNAs 21 and could conceivably regulate a subset of the moderately sex-biased genes through posttranscriptional mechanisms, conferring robustness to the sex-biased liver transcriptional networks Comparatively few of the miRNAs cataloged in miRBase database version 21 28 have been validated experimentally and characterized Previous studies used microarrays to identify several sex-biased, developmentally regulated rat liver miRNAs 30 However, the mechanisms regulating the sex-biased expression of these miRNAs were not identified and their functional roles, if any, were not determined.

Finally, we use inhibitory locked nucleic acids LNAs 33 in mouse liver to test the hypothesis that these sex-biased miRNAs regulate a subset of genes that show a sex bias in expression, through posttranscriptional mechanisms. All animal procedures were conducted in accord with accepted standards of humane animal care under protocols approved by the Boston University Institutional Animal Care and Use Committee. Mice were generated by mating mice having a floxed Stat5a-Stat5b locus with mice harboring a Cre recombinase nir regulated by the Albumin promoter Rhonda D.

Kineman University of Illinois at Chicago Statistical significance was determined by Student t test. Raw sequence reads were trimmed by TrimGalore! Coordinates of mature mouse miRNAs were downloaded from MiRBase, version 21 28and the bedtools sex command was used to determine the number of reads at each mature miRNA locus bedtools intersect parameters: -c -f 0.

Whole frozen liver sex 8-week-old untreated male CD1 mice was pulverized to a fine powder with a mortar and pestle on dry ice. Thirty units of DNase Promega; catalog no. These adenoviral constructs were designed and expressed in adenovirus serotype 5 by Applied Biological Materials British Columbia, Canada; control adenovirus, catalog no. Adenovirus seed stocks were propagated in HEKA cells and titered using plaque mr and standard protocols Cells were infected with Adenovirus for 48 to 55 hours to induce a cytopathic effect and strong GFP fluorescence.

A pilot experiment showed that these LNAs did not induce liver mir, as determined by monitoring mouse behavior, body weight, and serum alanine transaminase activity 6 days after treatment of male mice with LNA miRp and female mice with LNA miRp. Alanine transaminase was measured using a colorimetric activity assay kit Cayman Chemical, catalog no. Injections were carried out between 10 am and noon.

Mice sex euthanized on day 3 mir 6, resulting in a total of 3 sex ,ir days of exposure to each LNA. Both male and female mice were injected with LNA-negative control, for both the 3- and the 6-day time points.

Mice were euthanized by cervical dislocation between 10 am and noon, and livers were harvested for RNA extraction and RNA-seq analysis. FeatureCounts 44 was used to quantify the reads within gene bodies of RefSeq genes; EdgeR 40 was used to identify differentially expressed genes.

A total of sex-biased genes male-biased, female-biased and 11, sex-independent genes met these FPKM thresholds Supplemental Table 3A.

Initially, we searched for sex-specific mouse liver miRNAs by screening MiRBase version 21 to identify mouse miRNA loci located within 5 kb of any of the mouse genomic regions that show substantial sex differences in chromatin accessibility in mouse liver, as determined in DHS assays These sex-differential DHS are enriched for key regulatory regions and transcription factor mid sites controlling sex-biased liver gene expression 38 Localization of mor and miR nearby sex-biased DHS and their sex differential expression in mouse liver.

A University of California Santa Cruz browser screenshot of genomic regions surrounding miR top; blue highlight and miR bottom; pink highlight. The sex with the lower expression was set to a y-axis value of 1 for each miRNA. The lowest expression sample group in each time point was set to 1.

Sex-differential expression is first seen after puberty 8 weeks of agewhen miR is upregulated and miR is downregulated in male liver.

Mig, female; M, male; SE, standard error. Small RNA-seq analysis Table 2 confirmed the female-biased expression of miR and the male-biased expression of miRa, miR, and miR in mouse liver. The strong sex-specific chromatin environment surrounding miR and miR suggests these miRNAs are expressed mir a sex-dependent manner.

For qPCR, we used primers targeting mmir mature transcripts of miRp and miRp, which represent the more biologically active guide strand, according to miRBase annotation 28and generated symmetrical, single-product melting srx in our qPCR analysis. Next, mir examined the expression of miRp and miRp sez postnatal liver development. In contrast, neither miRNA showed a substantial change in expression in female liver over this period Fig.

This pattern of a change in gene expression at puberty in male but not female liver characterizes many sex-biased protein coding genes To determine whether pituitary hormones regulate the expression of miR or miR, we measured the levels of each miRNA in livers of hypophysectomized mice. Hypophysectomy i. Following hypophysectomy of male mice, liver miR levels decreased and miR levels increased, indicating that both miRNAs are xex by pituitary hormones in male liver Fig.

In contrast, hypophysectomy of female mice had no impact on the expression of eex miRNA. Further, we examined livers from somatostatin-KO mice 3749 to mir the dependence of miR and miR on the sex-specific pattern of pituitary Mir secretion. Somatostatin, a hypothalamic peptide hormone, antagonizes Sex hormone-stimulated pituitary GH release, thereby ensuring that each pulse of pituitary GH release is followed by a GH-free interval. Loss of somatostatin leads to a persistently elevated basal GH level and, consequently, feminization of male mouse liver In the absence of somatostatin, male liver expression of miR was downregulated to the lower, female liver level, and miR expression was upregulated to female liver levels Fig.

Groups of mir and female livers are marked C to indicate intact or wild-type mice control group or T to indicate hypophysectomized or KO livers treatment group. The lowest expressed group in each analysis was set to 1. STAT5 is a GH-activated transcription factor and major regulator mit a substantial fraction of sex-biased genes in mouse liver. We observed downregulation of miR and upregulation of miR, but no change in miR Fig.

Thus, pituitary hormones, a pulsatile plasma GH pattern, and the GH pulse-activated STAT5 are required in male but not female mouse liver for the sex-biased expression of miR and miR These responses are consistent with miR being a class I male-biased gene 1415 i.

Finally, we examined miR and miR expression in livers of continuous GH-infused male mice, in which exogenous GH infusion using an ALZET osmotic minipump overrides the normal male plasma GH pulses and leads to downregulation of a large fraction of male-biased genes and upregulation sex female-biased genes 16 Consistent with these responses, miR expression was decreased and miR expression was induced in male liver following GH infusion, confirming that both miRNAs are dependent on the temporal pattern of plasma GH Fig.

Together, these studies establish that the sex-dependent expression of miR and miR is primarily regulated in male liver, where it is dependent on the male profile of plasma GH pulse-activated STAT5, which mir at puberty We performed small RNA-seq analysis of 8-week-old male and female mouse liver to identify the global repertoire of sex-biased liver miRNAs.

The elevated expression of miRa in male liver could contribute to the greater predisposition of males to hepatocellular carcinoma These analyses also confirmed the female-biased expression of miRp, whose overexpression sex been implicated in obesity-associated glucose deregulation Thus, all four sex-biased miRNAs are within genomic regions with sex-biased chromatin dex.

Small RNA-seq statistics. Results are shown for the reads mapped to each genomic location using the mir settings of Bowtie 2 see Materials and Methods. Boldface type indicates isoforms of the two major sex-biased miRNAs characterized in this study. The majority of cataloged miRNAs lack functional validation; therefore, it is unclear whether they represent functional genes or fortuitously acquired hairpin RNA structures. Most functional studies have focused on broadly conserved miRNA families, such as that of miRp, whose expression mmir functional role has been confirmed in several studies 52 Computation and experimental validation of miR A Kir of mouse miR and miR Log 2 CPM values are as shown in parentheses.

The sex strands, miRp and miRp, showed much lower expression than the primary strands, miRp and miRp. The 84 nt primary sequence miR is predicted to form a duplex, as shown. D miR and miR associate with Argonaute protein. Mature miR was absent from cells infected with adeno-GFP. Adeno-miR—infected cells contained high levels of correctly processed mature miR with strong 5p over 3p bias, as indicated. NM, no match found; pos, position; SE, standard error. Mouse miR mir within an intron of the male-biased protein coding gene Ttc39c.

Based on the University of California Santa Cruz browser whole genome alignment 54the primary sequence of miR is limited to the mouse lineage, suggesting its relatively recent evolutionary emergence. Supporting the proposal that miR mir functional is its comparatively high expression Fig.

Secondary structure prediction by RNAfold 55 for the precursor sequence of miR indicated a robust hairpin structure Fig. This finding contradicts the annotation in miRBase 28 that miRp is the predominant form. Thus, five mature miRNA isoforms are generated from the miR locus in mouse liver, with miRp contributing most to the heterogeneity Fig. To validate sex authenticity of miR, we examined its association with the Argonaute complex 58 by performing Argonaute RNA immunoprecipitation and found that mature miR and miR are significantly associated with Argonaute Fig.

This finding suggests that both miRNAs are functional. Small RNA-seq analysis of the adeno-miRinfected cells mur in high levels of the mature 22 nt miRp and very low levels of miRp Fig. No miR sequences were detected in HEK cells infected with adenoviral-GFP negative controlconsistent with the mouse and rat lineage-specific nature of miR Fig.

A Nature Research Journal. Schizophrenia as a common disabling psychiatric disorder has been associated with dysregulation of several genes and pathways among them are those being regulated by long non-coding RNAs lncRNAs. However, when evaluating expression of genes in sex-based subgroups, the differences in the expression of these lncRNAs were significant only among females.

Significant pairwise correlations were recognized between expression levels of lncRNAs in both patients with schizophrenia and controls. The current study suggests the presence of a sex-based dysregulation of lncRNAs in patients with schizophrenia and their possible application as diagnostic biomarkers. This disorder is characterized by the existence of an arrangement of symptoms including positive symptoms hallucinations, delusions, abnormal concentrating and movement disorder , negative symptoms apathy, lack of pleasure, avolition, and flattening , and cognitive symptoms defects in administrative function and attention 1.

Although the main cause of schizophrenia has not been recognized yet, there is a bulk evidences indicating the role of gene expression dysregulation in the pathogenesis of this disorder 2 , 3 , 4. Numerous expression profiling studies have demonstrated aberrant expression of lncRNAs in the peripheral blood and the brain tissues of patients with schizophrenia 6 , 7. However, the role of some other lncRNAs in the pathogenesis of this psychiatric disorder has not been explored.

In the current study, we have used a literature-based method to identify lncRNAs with putative but indirect or unappreciated roles in schizophrenia. Any of the lncRNAs selected for this investigation affects one plausible aspect of schizophrenia pathogenesis. Considering the role of HOXA genes in the process of neurodevelopment 9 and the role of abnormal brain development in the pathogenesis of schizophrenia 10 , HOXA-AS2 might be involved in this psychiatric disorder.

The long intergenic non-protein coding RNA, regulator of reprogramming Linc-ROR controls the reprogramming of pluripotent stem cells 11 and is regarded as an inhibitor of p53 tumor suppressor 12 , a gene which has been believed to contribute in schizophrenia for a long time Based on the reported abnormalities in the glutaminergic system in schizophrenia 15 , MEG3 is another putative lncRNA in the pathogenesis of schizophrenia.

Considering the observed associations between altered lipid profile and occurrence of schizophrenia 17 , SPRY4-IT1 might be involved in this disorder. Moreover, this lncRNA contributes in inhibition of hypoxia injury after cerebral ischemia Besides, its silencing has decreased synaptic density in cultured hippocampal neurons 21 , a finding that potentiates this lncRNA as a modulating agent in the course of schizophrenia based on the reported decrease in synaptophysin in hippocampus and frontal cortical areas of patients with schizophrenia Consequently, dysregulation of the selected lncRNAs might be involved in the schizophrenia pathogenesis or applied as disease biomarkers.

Exclusion criteria were substance abuse, cigarette smoking or use of other antipsychotic drugs. Persons enlisted as controls were assessed through a structured psychiatric interview Mini-International Neuropsychiatric Interview 23 , for excluding the presence of psychiatric disorders. Exclusion criteria were the presence of malignancy, recent or continuous infectious disorder, autoimmune conditions, nerve muscle coupling disorders and pregnancy.

The study protocol was approved by Ethical Committee of Shahid Beheshti University of Medical Sciences and all methods were performed in accordance with the relevant guidelines and regulations. Informed written consent forms were signed by all study participants. B2M gene was used as the normalizer. The correlations between transcript levels of lncRNAs were evaluated using regression model and Bonferroni correction for multiple comparisons.

The correlation between expression levels and age of study participants was described by R and P values. Mean values of gene expression were compared between education-based subgroups of patients and controls using one-way ANOVA and Tukey post hoc tests. The receiver operating characteristic ROC curves were depicted to appraise the diagnostic power of expression levels of lncRNAs.

We compared mean values of gene expression between education-based subgroups of patients and controls using one-way ANOVA test. The results of Tukey post hoc test showed significant difference in SPRY4-IT1 expression between preschool and school groups in normal individuals. Based on the results of sex-based analysis and similar expression of genes between male patients and male controls, ROC curves were depicted only for female subjects Fig. However, expression levels of none of lncRNAs were different between male patients and male controls.

The sex-based alterations have been noted previously in age of onset, course, and treatment response in patients with schizophrenia In addition, differences in neurodevelopmental processes and psychosocial parameters 24 and increase in brain gene expression divergence in males have been associated with risk of schizophrenia The observed sex-based differences in the expression of lncRNAs in the current study might reflect the presences of hormone-response elements in the mentioned lncRNAs.

Moreover, several lncRNAs are involved in germ cell specification, sex determination and sex hormone responses Two previously appreciated mechanisms for the observed sex-based differences in human diseases are gonadal sex hormones or the sex chromosomes The current study and similar studies in neuropsychiatric disorders 29 provide preliminary evidences for contribution of lncRNAs in this process.

However, further studies are required to appraise whether this effect is exerted through interaction with the previously appraised mechanisms or is performed independently. Although males are expected to be affected with earlier onset and more severe disease course 30 , our findings revealed similar expression of lncRNAs between male patients and male controls. This finding possibly rules out the participation of these lncRNAs in the pathogenesis of schizophrenia in male subjects.

The sharp sex-based contrasts in expression signatures of lncRNAs might imply the sex-specific roles for these lncRNAs. A recent study has revealed a sex-biased lncRNA signature in placenta Moreover, co-expression assessments have demonstrated several lncRNAs correlation with sex differences in mouse germline stem cells The importance of the observed sex-based differences in lncRNA patter in patients with schizophrenia is more highlighted when considering the extensive sex differences in gene signature in the adult human brain.

Moreover, several genes with sex-biased expression are associated with diseases and possibly have functional significances. Taken together, such sex-biased expression implies the presence of sex-biased gene regulatory mechanisms EZH2 has crucial roles in the epigenetic silencing of cyclooxygenase-2 35 , an enzyme whose over-expression has been noted in schizophrenia as a result of immune response dysregulation Moreover, analysis of RNA-seq data has shown a significant elevation in EZH2 levels in the anterior cingulate cortex of patients with schizophrenia compared to normal individuals.

Based on these results, Billingsley et al. Such role might be exerted either through interference with normal brain development or through abnormal reactivation of expression in the CNS in the adulthood This miRNA targets Aquaporin 4 41 , a gene whose polymorphisms are associated with negative symptoms of schizophrenia So, it is plausible that Linc-ROR participates in the pathogenesis of schizophrenia through modulation of miR and subsequent alterations in Aquaporin 4.

In addition, this lncRNA might affect schizophrenia through alterations in dendritic spine morphogenesis. Elevated levels of MEG3 have been reported in in the nucleus accumbens of heroin abusers Heroine influences dopaminergic, glutamatergic and GABAergic routes that participate in the pathogenesis of schizophrenia Consequently, it is possible that MEG3 also affects the mentioned transmitters and participates in the evolution of schizophrenia.

Over-expression of SPRY4-IT1 has been shown to induce EZH2 45 , a transcription factor that is over-expressed in the anterior cingulate cortex of patients with schizophrenia compared to controls and has been suggested to participate in the schizophrenia either via interference with developmental processes or through abnormal reactivation of gene expression in the adult brain This lncRNA might also contribute in schizophrenia through alteration of lipid profiles.

So, dysregulation of these lncRNAs might have synergic effects on the aberrant expression of EZH2 in patients with schizophrenia. However, such expression pattern is not consistent with the proposed role for this lncRNA in protection against hypoxia Such correlations might imply the role of age in determination of expression levels of these lncRNAs. This speculation is consistent with the results of a recent study which demonstrated an age-dependent diurnal expression of lncRNAs which concurs with age-related alterations in facultative heterochromatin Such correlations might reflect the effects of disease course or antipsychotic treatments on genes expression.

Alternatively, they might merely show the age-related mechanisms. Decisive results can be only obtained from larger-scale cohorts of patients with different age ranges and disease duration values.

We also demonstrated several pairwise correlations between expression of lncRNAs in both normal individuals and patients with schizophrenia which suggest their regulation by a similar possibly epigenetic mechanism or their involvement in similar cellular processes.

Finally, we reported the suitability of a panel of lncRNAs for discrimination of female patients with schizophrenia from normal female individuals. If these results are verified in larger sample sizes, the suggested panel might be used as a diagnostic panel for schizophrenia. Taken together, our results imply contribution of certain lncRNAs in the pathogenesis of schizophrenia in female subjects and suggest them as elements of a diagnostic panel. By excluding patients who used other antipsychotic drugs, we have minimized the confounding factors.

Association D-AP. Diagnostic and statistical manual of mental disorders. Arlington: American Psychiatric Publishing Narayan, S. Molecular profiles of schizophrenia in the CNS at different stages of illness.

Brain research. Roy, M. Proteomic analysis of postsynaptic proteins in regions of the human neocortex. Nature neuroscience. Ramaker, R. Post-mortem molecular profiling of three psychiatric disorders. Genome medicine. Long, Y. How do lncRNAs regulate transcription? Science advances. Lai, C. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World J Psychiatr. English, 6 1 , —17 Mar Hu J et al. Systematically characterizing dysfunctional long intergenic non-coding RNAs in multiple brain regions of major psychosis.

Zhao, H. Journal of cellular biochemistry. Expression of Hox genes in the nervous system of vertebrates. HOX gene expression: Springer, p. Arnold, S. Neurodevelopmental abnormalities in schizophrenia: insights from neuropathology.

Development and psychopathology. Summer 11 3 , — Loewer, S. Nature genetics 42 12 , —7. Zhang, A. Cell research. Ni, X. Human p53 tumor suppressor gene TP53 and schizophrenia: case-control and family studies. Neuroscience letters. Tan, M. Frontiers in cellular neuroscience. Rubio, M. Biomol Ther. English Jan Mazar, J. English Oct Oresic, M. Phospholipids and insulin resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia.

Geng, J. David J. Author information Article notes Copyright and License information Disclaimer. E-mail: ude.

Received Nov 2; Accepted Jan This article has been cited by other articles in PMC. Abstract Sex-specific temporal patterns of pituitary growth hormone GH secretion determine the sex-biased transcription of hundreds of genes in the liver and impart important sex differences in liver physiology, metabolism, and disease. Materials and Methods Experimental animals All animal procedures were conducted in accord with accepted standards of humane animal care under protocols approved by the Boston University Institutional Animal Care and Use Committee.

Results Sex-biased liver expression of miR and miR Initially, we searched for sex-specific mouse liver miRNAs by screening MiRBase version 21 to identify mouse miRNA loci located within 5 kb of any of the mouse genomic regions that show substantial sex differences in chromatin accessibility in mouse liver, as determined in DHS assays Open in a separate window. Figure 1. Table 1. Figure 2.

Figure 3. Table 2. Characterization of miR The majority of cataloged miRNAs lack functional validation; therefore, it is unclear whether they represent functional genes or fortuitously acquired hairpin RNA structures.

Figure 4. Figure 5. Discussion We used small RNA-seq to identify 24 miRNAs that show sex-biased expression in mouse liver, and for two of these miRNAs, miR and miR, we investigated their hormonal regulation and their functional roles in young adult mouse liver. Supplementary Material Supplement Table 1 Click here for additional data file.

References 1. Growth hormone and cell growth. Endocr Dev. Rotwein P. Trends Endocrinol Metab. J Endocrinol. Somatostatin is essential for the sexual dimorphism of GH secretion, corticosteroid-binding globulin production, and corticosterone levels in mice.

Sexual dimorphism in the control of growth hormone secretion. Endocr Rev. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol. Development of a method for the determination of pulsatile growth hormone secretion in mice. Exploring endocrine GH pattern in mice using rank plot analysis and random blood samples. Growth hormone: a newly identified developmental organizer. Mol Cell Biol.

Plasma growth hormone pulse activation of hepatic JAK-STAT5 signaling: developmental regulation and role in male-specific liver gene expression. Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein.

Proposed role as an intracellular regulator of male-specific liver gene transcription. J Biol Chem. Activation of male liver chromatin accessibility and STAT5-dependent gene transcription by plasma growth hormone pulses. Intrinsic sex differences in the early growth hormone responsiveness of sex-specific genes in mouse liver.

Mol Endocrinol. Feminization of male mouse liver by persistent growth hormone stimulation: Activation of sex-biased transcriptional networks and dynamic changes in chromatin states. Impact of CUX2 on the female mouse liver transcriptome: activation of female-biased genes and repression of male-biased genes.

Major molecular differences between mammalian sexes are involved in drug metabolism and renal function. Dev Cell. Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b STAT5b : STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis. Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease.

PLoS One. The impact of microRNAs on protein output. Roles for microRNAs in conferring robustness to biological processes. Bartel DP. MicroRNAs: target recognition and regulatory functions. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs.

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Loss of sexually dimorphic liver gene expression upon hepatocyte-specific deletion of Stat5a-Stat5b locus. Gender-dependent role of endogenous somatostatin in regulating growth hormone-axis function in mice. Unbiased, genome-wide in vivo mapping of transcriptional regulatory elements reveals sex differences in chromatin structure associated with sex-specific liver gene expression.

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Characterization of three growth hormone-responsive transcription factors preferentially expressed in adult female liver. Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet. Analysis of microRNA knockouts in mice. Hum Mol Genet. Vidigal JA, Ventura A. The biological functions of miRNAs: lessons from in vivo studies.

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