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Sample records for mir-124 regulates adult

  1. Regulation of Nuclear Receptor Nur77 by miR-124

    PubMed Central

    Tenga, Alexa; Beard, Jordan A.; Takwi, Apana; Wang, Yue-Ming; Chen, Taosheng

    2016-01-01

    The nuclear receptor Nur77 is commonly upregulated in adult cancers and has oncogenic functions. Nur77 is an immediate-early response gene that acts as a transcription factor to promote proliferation and protect cells from apoptosis. Conversely, Nur77 can translocate to the mitochondria and induce apoptosis upon treatment with various cytotoxic agents. Because Nur77 is upregulated in cancer and may have a role in cancer progression, it is of interest to understand the mechanism controlling its expression. MicroRNAs (miRNAs) are responsible for inhibiting translation of their target genes by binding to the 3ʹUTR and either degrading the mRNA or preventing it from being translated into protein, thereby making these non-coding endogenous RNAs vital regulators of every cellular process. Several miRNAs have been predicted to target Nur77; however, strong evidence showing the regulation of Nur77 by any miRNA is lacking. In this study, we used a luciferase reporter assay containing the 3ʹUTR of Nur77 to screen 296 miRNAs and found that miR-124, which is the most abundant miRNA in the brain and has a role in promoting neuronal differentiation, caused the greatest reduction in luciferase activity. Interestingly, we discovered an inverse relationship in Daoy medulloblastoma cells and undifferentiated granule neuron precursors in which Nur77 is upregulated and miR-124 is downregulated. Exogenous expression to further elevate Nur77 levels in Daoy cells increased proliferation and viability, but knocking down Nur77 via siRNA resulted in the opposite phenotype. Importantly, exogenous expression of miR-124 reduced Nur77 expression, cell viability, proliferation, and tumor spheroid size in 3D culture. In all, we have discovered miR-124 to be downregulated in instances of medulloblastoma in which Nur77 is upregulated, resulting in a proliferative state that abets cancer progression. This study provides evidence for increasing miR-124 expression as a potential therapy for cancers

  2. Expression of Flotilin-2 and Acrosome Biogenesis Are Regulated by MiR-124 during Spermatogenesis

    PubMed Central

    Zheng, Haoyu; Jiang, Min; Xia, Zhengrong; Yu, Jinjin; Chen, Ling; Huang, Xiaoyan

    2015-01-01

    MicroRNAs (miRNAs) are a class of short non-coding RNA molecules, which diversely regulate gene expression in organisms. Although the regulatory role of these small RNA molecules has been recently explored in animal spermatogenesis, the role of miR-124 in male germ cells is poorly defined. In our previous study, flotillin-2 was investigated as a novel Golgi-related protein involved in sperm acrosome biogenesis. The current study was designed to analyze the contribution of miR-124 in the regulation of flotillin-2 expression during mouse acrosome biogenesis. Luciferase assays revealed the target effects of miR-124 on flotillin-2 expression. Following intratesticular injection of miR-124 in 3-week-old male mice, quantitative real-time RT-PCR and western blot analysis were employed to confirm the function of miR-124 in regulating flotillin-2 after 48 hours. Sperm abnormalities were assessed 3 weeks later by ordinary optical microscopy, the acrosome abnormalities were also assessed by PNA staining and transmission electron microscopy. The results showed the proportion of sperm acrosome abnormalities was significantly higher than that of the control group. The expression of flotillin-2 and caveolin-1 was significantly downregulated during acrosome biogenesis. These results indicated that miR-124 could potentially play a role in caveolin-independent vesicle trafficking and modulation of flotillin-2 expression in mouse acrosome biogenesis. PMID:26313572

  3. miR-124 Regulates the Phase of Drosophila Circadian Locomotor Behavior

    PubMed Central

    Lamba, Pallavi; Guo, Peiyi

    2016-01-01

    Animals use circadian rhythms to anticipate daily environmental changes. Circadian clocks have a profound effect on behavior. In Drosophila, for example, brain pacemaker neurons dictate that flies are mostly active at dawn and dusk. miRNAs are small, regulatory RNAs (≈22 nt) that play important roles in posttranscriptional regulation. Here, we identify miR-124 as an important regulator of Drosophila circadian locomotor rhythms. Under constant darkness, flies lacking miR-124 (miR-124KO) have a dramatically advanced circadian behavior phase. However, whereas a phase defect is usually caused by a change in the period of the circadian pacemaker, this is not the case in miR-124KO flies. Moreover, the phase of the circadian pacemaker in the clock neurons that control rhythmic locomotion is not altered either. Therefore, miR-124 modulates the output of circadian clock neurons rather than controlling their molecular pacemaker. Circadian phase is also advanced under temperature cycles, but a light/dark cycle partially corrects the defects in miR-124KO flies. Indeed, miR-124KO shows a normal evening phase under the latter conditions, but morning behavioral activity is suppressed. In summary, miR-124 controls diurnal activity and determines the phase of circadian locomotor behavior without affecting circadian pacemaker function. It thus provides a potent entry point to elucidate the mechanisms by which the phase of circadian behavior is determined. SIGNIFICANCE STATEMENT In animals, molecular circadian clocks control the timing of behavioral activities to optimize them with the day/night cycle. This is critical for their fitness and survival. The mechanisms by which the phase of circadian behaviors is determined downstream of the molecular pacemakers are not yet well understood. Recent studies indicate that miRNAs are important regulators of circadian outputs. We found that miR-124 shapes diurnal behavioral activity and has a striking impact on the phase of circadian

  4. miR-124 negatively regulates osteogenic differentiation and in vivo bone formation of mesenchymal stem cells.

    PubMed

    Qadir, Abdul S; Um, Soyoun; Lee, Heesu; Baek, Kyunghwa; Seo, Byoung Moo; Lee, Gene; Kim, Gwan-Shik; Woo, Kyung Mi; Ryoo, Hyun-Mo; Baek, Jeong-Hwa

    2015-05-01

    MicroRNAs are novel key regulators of cellular differentiation. Dlx transcription factors play an important role in osteoblast differentiation, and Dlx5 and Dlx2 are known targets of miR-124. Therefore, in the present study, we investigated the regulatory effects of miR-124 on the osteogenic differentiation and in vivo bone formation of mesenchymal stem cells (MSCs). During osteogenic induction by BMP2, the expression levels of miR-124 were inversely correlated with those of osteogenic differentiation marker genes in human and mouse bone marrow-derived MSCs, MC3T3-E1 cells and C2C12 cells. The overexpression of a miR-124 mimic significantly decreased the expression levels of Dlx5, Dlx3, and Dlx2, whereas the silencing of miR-124 with hairpin inhibitors significantly increased the expression of these Dlx genes. Luciferase reporter assays demonstrated that miR-124 directly targets the 3'UTRs of Dlx3, Dlx5, and Dlx2. The overexpression of a miR-124 mimic suppressed the osteogenic marker gene expression levels, alkaline phosphatase activity and matrix mineralization, which were all significantly increased by the overexpression of a miR-124 inhibitor. When ectopic bone formation was induced by the subcutaneous transplantation of human bone marrow-derived MSCs in nude mice, MSCs overexpressing a miR-124 inhibitor significantly enhanced woven bone formation compared with control MSCs. However, MSCs overexpressing a miR-124 mimic exhibited increased adipocyte differentiation at the expense of ectopic bone formation. These results suggest that miR-124 is a negative regulator of osteogenic differentiation and in vivo bone formation and that the targeting of Dlx5, Dlx3, and Dlx2 genes partly contributes to this inhibitory effect exerted by miR-124. PMID:25424317

  5. miR-124 regulates cell apoptosis and autophagy in dopaminergic neurons and protects them by regulating AMPK/mTOR pathway in Parkinson’s disease

    PubMed Central

    Gong, Xin; Wang, Huiqing; Ye, Yongyi; Shu, Yugao; Deng, Yongwen; He, Xiaozheng; Lu, Guohui; Zhang, Shizhong

    2016-01-01

    The important roles of miR-124 in the development and progression of various diseases are being increasing recognized. This study was aimed to investigate the potential roles of miR-124 in dopaminergic (DA) neuronal apoptosis and autophagy in Parkinson’s disease (PD) and to explore their mechanisms. Human SH-SY5Y cells that are treated with MPTP were transfected with mature miR-124 vector and control empty vector. The effect of MPTP on miR-124 mRNA level was analyzed using RT-PCR analysis. Furthermore, the effects of miR-124 expression on neuronal apoptosis and autophagy, as well as the expression of proteins in the AMPK/mTOR pathway, were analyzed using RT-PCR and western blotting. This study found that miR-124 was down-regulated in the MPTP-treated (100 μM) neurons, and miR-124 suppression significantly increased cell apoptosis and induced autophagy-associated protein expression, including that of Beclin 1 and increased the ratio of LC3 II/LC3 I compared with that in controls. In addition, in vitro rescue of miR-124 significantly decreased the percentage of apoptotic cells and the ratio of LC3 II/LC3 I, findings that were approximately equal to the controls. Moreover, miR-124 suppression increased p-AMPK but decreased p-mTOR levels in neurons. Our study suggested that miR-124 functions as a protector of DA neurons during PD through the involvement of cell apoptosis and autophagy by regulating the AMPK/mTOR pathway. PMID:27347320

  6. miR-124-regulated RhoG reduces neuronal process complexity via ELMO/Dock180/Rac1 and Cdc42 signalling

    PubMed Central

    Franke, Kristin; Otto, Wolfgang; Johannes, Sascha; Baumgart, Jan; Nitsch, Robert; Schumacher, Stefan

    2012-01-01

    The small GTPase RhoG plays a central role in actin remodelling during diverse biological processes such as neurite outgrowth, cell migration, phagocytosis of apoptotic cells, and the invasion of pathogenic bacteria. Although it is known that RhoG stimulates neurite outgrowth in the rat pheochromocytoma PC12 cell line, neither the physiological function nor the regulation of this GTPase in neuronal differentiation is clear. Here, we identify RhoG as an inhibitor of neuronal process complexity, which is regulated by the microRNA miR-124. We find that RhoG inhibits dendritic branching in hippocampal neurons in vitro and in vivo. RhoG also inhibits axonal branching, acting via an ELMO/Dock180/Rac1 signalling pathway. However, RhoG inhibits dendritic branching dependent on the small GTPase Cdc42. Finally, we show that the expression of RhoG in neurons is suppressed by the CNS-specific microRNA miR-124 and connect the regulation of RhoG expression by miR-124 to the stimulation of neuronal process complexity. Thus, RhoG emerges as a cellular conductor of Rac1 and Cdc42 activity, in turn regulated by miR-124 to control axonal and dendritic branching. PMID:22588079

  7. miR-124-regulated RhoG reduces neuronal process complexity via ELMO/Dock180/Rac1 and Cdc42 signalling.

    PubMed

    Franke, Kristin; Otto, Wolfgang; Johannes, Sascha; Baumgart, Jan; Nitsch, Robert; Schumacher, Stefan

    2012-06-29

    The small GTPase RhoG plays a central role in actin remodelling during diverse biological processes such as neurite outgrowth, cell migration, phagocytosis of apoptotic cells, and the invasion of pathogenic bacteria. Although it is known that RhoG stimulates neurite outgrowth in the rat pheochromocytoma PC12 cell line, neither the physiological function nor the regulation of this GTPase in neuronal differentiation is clear. Here, we identify RhoG as an inhibitor of neuronal process complexity, which is regulated by the microRNA miR-124. We find that RhoG inhibits dendritic branching in hippocampal neurons in vitro and in vivo. RhoG also inhibits axonal branching, acting via an ELMO/Dock180/Rac1 signalling pathway. However, RhoG inhibits dendritic branching dependent on the small GTPase Cdc42. Finally, we show that the expression of RhoG in neurons is suppressed by the CNS-specific microRNA miR-124 and connect the regulation of RhoG expression by miR-124 to the stimulation of neuronal process complexity. Thus, RhoG emerges as a cellular conductor of Rac1 and Cdc42 activity, in turn regulated by miR-124 to control axonal and dendritic branching. PMID:22588079

  8. miR-124 downregulation leads to breast cancer progression via LncRNA-MALAT1 regulation and CDK4/E2F1 signal activation

    PubMed Central

    Feng, Tongbao; Shao, Fang; Wu, Qiyong; Zhang, Xiaohang; Xu, Dongqin; Qian, Keqing; Xie, Yewen; Wang, Shizhong; Xu, Ning; Wang, Yong; Qi, Chunjian

    2016-01-01

    The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recently shown to be dysregulated in several cancers. However, the mechanisms underlying the role of MALAT1 in breast cancer remain unclear. Herein, we showed that MALAT1 was aberrantly increased in breast cancer tissues and cells. MALAT1-siRNA inhibited breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Furthermore, MALAT1 acted as an endogenous potent regulator by directly binding to miR-124 and down-regulating miR-124 expression. In addition, MALAT1 reversed the inhibitory effect of miR-124 on breast cancer proliferation and was involved in the cyclin-dependent kinase 4 (CDK4) expression. Taken together, our data highlight the pivotal role of MALAT1 in breast cancer tumorigenesis. Moreover, the present study elucidated the MALAT1-miR-124-CDK4/E2F1 signaling pathway in breast cancer, which might provide a new approach for tackling breast cancer. PMID:26918449

  9. miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3β pathway by targeting Rap2a

    PubMed Central

    Xue, Qian; Yu, Caiyong; Wang, Yan; Liu, Ling; Zhang, Kun; Fang, Chao; Liu, Fangfang; Bian, Ganlan; Song, Bing; Yang, Angang; Ju, Gong; Wang, Jian

    2016-01-01

    A single microRNA (miRNA) can regulate expression of multiple proteins, and expression of an individual protein may be controlled by numerous miRNAs. This regulatory pattern strongly suggests that synergistic effects of miRNAs play critical roles in regulating biological processes. miR-9 and miR-124, two of the most abundant miRNAs in the mammalian nervous system, have important functions in neuronal development. In this study, we identified the small GTP-binding protein Rap2a as a common target of both miR-9 and miR-124. miR-9 and miR-124 together, but neither miRNA alone, strongly suppressed Rap2a, thereby promoting neuronal differentiation of neural stem cells (NSCs) and dendritic branching of differentiated neurons. Rap2a also diminished the dendritic complexity of mature neurons by decreasing the levels of pAKT and pGSK3β. Our results reveal a novel pathway in which miR-9 and miR-124 synergistically repress expression of Rap2a to sustain homeostatic dendritic complexity during neuronal development and maturation. PMID:27221778

  10. miR-124 Contributes to the functional maturity of microglia.

    PubMed

    Svahn, Adam J; Giacomotto, Jean; Graeber, Manuel B; Rinkwitz, Silke; Becker, Thomas S

    2016-05-01

    During early development of the central nervous system (CNS), a subset of yolk-sac derived myeloid cells populate the brain and provide the seed for the microglial cell population, which will self-renew throughout life. As development progresses, individual microglial cells transition from a phagocytic amoeboid state through a transitional morphing phase into the sessile, ramified, and normally nonphagocytic microglia observed in the adult CNS under healthy conditions. The molecular drivers of this tissue-specific maturation profile are not known. However, a survey of tissue resident macrophages identified miR-124 to be expressed in microglia. In this study, we used transgenic zebrafish to overexpress miR-124 in the mpeg1 expressing yolk-sac-derived myeloid cells that seed the microglia. In addition, a systemic sponge designed to neutralize the effects of miR-124 was used to assess microglial development in a miR-124 loss-of-function environment. Following the induction of miR-124 overexpression, microglial motility and phagocytosis of apoptotic cells were significantly reduced. miR-124 overexpression in microglia resulted in the accumulation of residual apoptotic cell bodies in the optic tectum, which could not be achieved by miR-124 overexpression in differentiated neurons. Conversely, expression of the miR-124 sponge caused an increase in the motility of microglia and transiently rescued motility and phagocytosis functions when activated simultaneously with miR-124 overexpression. This study provides in vivo evidence that miR-124 activity has a key role in the development of functionally mature microglia. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 507-518, 2016. PMID:26184457

  11. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA

    SciTech Connect

    Lang, Qingbo; Ling, Changquan

    2012-09-21

    Highlights: Black-Right-Pointing-Pointer PIK3CA is a novel target of miR-124 in HepG2 cells. Black-Right-Pointing-Pointer MiR-124 suppresses cell proliferation by downregulating PIK3CA expression. Black-Right-Pointing-Pointer MiR-124 regulates the PI3K/Akt pathway in HepG2 cells. Black-Right-Pointing-Pointer MiR-124 overexpression inhibits the tumorigenesis in nude mice. -- Abstract: MicroRNAs (miRNAs) have crucial roles in the development and progression of human cancers, including hepatocellular carcinoma (HCC). Recent studies have shown that microRNA-124 (miR-124) was downregulated in HCC; however, the underlying mechanisms by which miR-124 suppresses tumorigenesis in HCC are largely unknown. In this study, we report that phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA) is a novel target of miR-124 in HepG2 cells. Overexpression of miR-124 resulted in decreased expression of PIK3CA at both mRNA and protein levels. We found that miR-124 overexpression markedly suppressed cell proliferation by inducing G1-phase cell-cycle arrest in vitro. Consistent with the restoring miR-124 expression, PIK3CA knockdown suppressed cell proliferation, whereas overexpression of PIK3CA abolished the suppressive effect of miR-124. Mechanistic studies showed that miR-124-mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. The expressions of Akt and mTOR, key components of the PI3K/Akt pathway, were all downregulated. Moreover, we found overexpressed miR-124 effectively repressed tumor growth in xenograft animal experiments. Taken together, our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA.

  12. miR-124 radiosensitizes human esophageal cancer cell TE-1 by targeting CDK4.

    PubMed

    Zhang, Y H; Wang, Q Q; Li, H; Ye, T; Gao, F; Liu, Y C

    2016-01-01

    Radiotherapy is one of the most important treatments for esophageal cancer, but radioresistance remains a major challenge. Previous studies have shown that microRNAs (miRNAs or miRs) are involved in human cancers. miR-124 has been widely reported in various cancers and it is intimately involved in proliferation, cell cycle regulation, apoptosis, migration, and invasion of cancer cells. The aim of this study was to explore the relationship between the miR-124/cyclin-dependent kinase 4 (CDK4) axis and the radiosensitivity of esophageal cancer cells. In this study, we identified the reduced expression of miR-124 in 18 paired esophageal cancer tissues compared to their matched normal tissues. In order to investigate the physiological role of miR-124 in esophageal cancer, the cell counting kit-8 (CCK-8) assay and wound healing assay were performed, and the results suggest that miR-124 overexpression decreases tumor growth and aggression. Next, we detected the effects of ectopic miR-124 expression on the apoptosis of an esophageal cancer cell line (TE-1) following radiotherapy. Using the CCK-8 assay and Hoechst 332528 stain, we found that ectopic expression of miR-124 led to a higher percentage of apoptotic cells. Finally, we identified that CDK4 is a direct target of miR-124 in TE-1 cells using target prediction algorithms and a luciferase reporter assay. Moreover, western blot assay confirmed that CDK4 was downregulated during miR-124 transfection. Taken together, we illustrate that the miR-124/CDK4 axis plays an important role in radiation sensitivity of human esophageal cancer cells by targeting CDK4. PMID:27323123

  13. MiR-124 Radiosensitizes Human Colorectal Cancer Cells by Targeting PRRX1

    PubMed Central

    Huang, Jing; Gao, Fei; Lin, Xiaoshan; He, Lian; Li, Dan; Li, Zhijun; Ding, Yi; Chen, Longhua

    2014-01-01

    One of the challenges in the treatment of colorectal cancer patients is that these tumors show resistance to radiation. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cellular response to ionizing radiation (IR). In this study, we found that miR-124 was significantly down-regulated both in CRC-derived cell lines and clinical CRC samples compared with adjacent non-tumor colorectal tissues, MiR-124 could sensitize human colorectal cancer cells to IR in vitro and in vivo. We identified PRRX1, a new EMT inducer and stemness regulator as a novel direct target of miR-124 by using target prediction algorithms and luciferase assay. PRRX1 knockdown could sensitize CRC cells to IR similar to the effects caused by miR-124. Overexpression of PRRX1 in stably overexpressed-miR-124 cell lines could rescue the effects of radiosensitivity enhancement brought by miR-124. Taking these observations into consideration, we illustrated that miR-124 could increase the radiosensitivity of CRC cells by blocking the expression of PRRX1, which indicated miR-124 could act as a great therapeutic target for CRC patients. PMID:24705396

  14. MiR-124 inhibits myogenic differentiation of mesenchymal stem cells via targeting Dlx5.

    PubMed

    Qadir, Abdul S; Woo, Kyung Mi; Ryoo, Hyun-Mo; Yi, TacGhee; Song, Sun U; Baek, Jeong-Hwa

    2014-09-01

    MicroRNAs (miRNAs), including miR-1, miR-133, and miR-206, play a crucial role in muscle development by regulating muscle cell proliferation and differentiation. The aim of the present study was to define the effect of miR-124 on myogenic differentiation of mesenchymal stem cells (MSCs). The expression level of miR-124 in skeletal muscles was much lower than those in primary cultured bone marrow-derived MSCs and the bone, fat and brain tissues obtained from C57BL/6 mice. Myogenic stimuli significantly decreased the expression levels of miR-124 in mouse bone marrow-derived MSCs and C2C12 cells. Forced expression of miR-124 suppressed the expression of myogenic marker genes such as Myf5, Myod1, myogenin and myosin heavy chain and multinucleated myotube formation. Blockade of endogenous miR-124 with a hairpin inhibitor enhanced myogenic marker gene expression and myotube formation. During myogenic differentiation of MSCs and C2C12 cells, the levels of Dlx5, a known target of miR-124, were inversely regulated with those of miR-124. Furthermore, overexpression of Dlx5 increased myogenic differentiation, whereas knockdown of Dlx5 using siRNA inhibited myogenesis in C2C12 cells. These results suggest that miR-124 is a negative regulator of myogenic differentiation of MSCs and that upregulation of Dlx5 accompanied with downregulation of miR-124 by myogenic stimuli is necessary for the proper progression of myogenic differentiation. PMID:24733577

  15. miR-124 interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer.

    PubMed

    Jiang, Lei; Lin, Tiesu; Xu, Chaochao; Hu, Sunkuan; Pan, Yangyang; Jin, Rong

    2016-02-01

    Aberrant Notch signalling plays an important role in cancer progression. However, little is known about the interaction between miRNA and the Notch signalling pathway and its role in gastric cancer (GC). In this study, we found that miR-124 was down-regulated in GC compared with adjacent normal tissue. Forced expression of miR-124 inhibited GC cell growth, migration and invasion, and induced cell cycle arrest. miR-124 negatively regulated Notch1 signalling by targeting JAG1. miR-124 levels were also shown to be inversely correlated with JAG1 expression in GC. Furthermore, we found that the overexpression of the intracellular domain of Notch1 repressed miR-124 expression, promoted GC cell growth, migration and invasion. Conversely, blocking Notch1 using a γ-secretase inhibitor up-regulated miR-124 expression, inhibited GC cell growth, migration and invasion. In conclusion, our data demonstrates a regulatory feedback loop between miR-124 and Notch1 signalling in GC cells, suggesting that the miR-124/Notch axis may be a potential therapeutic target against GC. PMID:26612211

  16. Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference.

    PubMed

    Chandrasekar, Vijay; Dreyer, Jean-Luc

    2011-05-01

    Molecular adaptations underlying drug seeking and relapse remain largely unknown. Studies highlight post-transcriptional modifications mediated by microRNAs (miRNAs) in addiction and other neurological disorders. We have previously shown that chronic cocaine suppresses miR-124 and let-7d and induces the expression of miR-181a in mesolimbic pathway. To further address the role and target gene regulation network of these miRNAs in vivo in cocaine addiction, we developed lentiviral vector (LV)-expressing miRNAs and their corresponding silencers for stable and regulatable miRNA expression. We tested in vivo miRNA gain and loss of function on cocaine-induced conditioned place preference (CPP) by localized LV-miRNA regulation in the nucleus accumbens (NAc). LV-miR-124 and let-7d expression in the NAc attenuates cocaine CPP, whereas LV-miR-181a enhances it. Silencing miRNAs by corresponding LV-miRNA silencers expressing perfect miRNA target sequences inversed this effect on cocaine CPP. Doxycycline treatment for switching off silencer expression abolished the observed behavioral changes. Behavioral changes mediated by LV-miRNA regulation resulted in dynamic alterations in transcription factors, receptors, and other effector genes involved in cocaine-induced plasticity. Our results describe a complex regulatory pathway mediated by miRNAs in cocaine-mediated neuronal adaptations. PMID:21307844

  17. MiR-124 Promote Neurogenic Transdifferentiation of Adipose Derived Mesenchymal Stromal Cells Partly through RhoA/ROCK1, but Not ROCK2 Signaling Pathway

    PubMed Central

    Wang, Ye; Wang, Desheng; Guo, Dawen

    2016-01-01

    Objective Some recent studies suggest that multiple miRNAs might regulate neurogenic transdifferentiation of mesenchymal stromal cells (MSCs). In the present study, we hypothesized that the miR-124 can repress the expression of RhoA upon the neurogenesis of adipose derived MSCs (ADMSCs). Methods MiRNA expression dynamics during neurogenic transdifferentiation of ADMSCs were measured. The expression of neuron-specific enolase (NSE), Tuj-1 (Neuron-specific class III beta-tubulin) and glial fibrillary acidic protein (GFAP), as well as electrophysiological properties, were detected after neurogenic transdifferentiation. The targeting of miR-124 over RhoA was verified by dual luciferase assay, qRT-PCR and western blot. The functions of miR-124 and the RhoA/ROCK signaling pathway were studied using gain and loss of function experiments in vitro. Results MiR-124 is significantly upregulated during neurogenic transdifferentiation of ADMSCs. Knockdown of endogenous miR-124 hampered neurogenic transdifferentiation and the acquired electrophysiological properties. MiR-124 could directly target RHOA mRNA and repress its expression, through which it increased the proportion of transdifferentiated (transdiff.) cells with positive NSE, Tuj-1 and GFAP. RhoA/ROCK1, but not ROCK2 is a downstream signaling pathway of miR-124 in the process of transdifferentiation. Conclusion MiR-124 is an important miRNA modulating neurogenic transdifferentiation of ADMSCs at least partly via the miR-124/RhoA/ROCK1 signaling pathway. These findings provided some fundamental information for future use of ADMSCs as an agent for regenerative medicine and cell therapy for neurological diseases. PMID:26745800

  18. TCF4-Targeting miR-124 is Differentially Expressed amongst Dendritic Cell Subsets

    PubMed Central

    Han, Sun Murray; Na, Hye Young; Ham, Onju; Choi, Wanho; Sohn, Moah; Ryu, Seul Hye; In, Hyunju; Hwang, Ki-Chul

    2016-01-01

    Dendritic cells (DCs) are professional antigen-presenting cells that sample their environment and present antigens to naïve T lymphocytes for the subsequent antigen-specific immune responses. DCs exist in a range of distinct subpopulations including plasmacytoid DCs (pDCs) and classical DCs (cDCs), with the latter consisting of the cDC1 and cDC2 lineages. Although the roles of DC-specific transcription factors across the DC subsets have become understood, the posttranscriptional mechanisms that regulate DC development are yet to be elucidated. MicroRNAs (miRNAs) are pivotal posttranscriptional regulators of gene expression in a myriad of biological processes, but their contribution to the immune system is just beginning to surface. In this study, our in-house probe collection was screened to identify miRNAs possibly involved in DC development and function by targeting the transcripts of relevant mouse transcription factors. Examination of DC subsets from the culture of mouse bone marrow with Flt3 ligand identified high expression of miR-124 which was able to target the transcript of TCF4, a transcription factor critical for the development and homeostasis of pDCs. Further expression profiling of mouse DC subsets isolated from in vitro culture as well as via ex vivo purification demonstrated that miR-124 was outstandingly expressed in CD24+ cDC1 cells compared to in pDCs and CD172α+ cDC2 cells. These results imply that miR-124 is likely involved in the processes of DC subset development by posttranscriptional regulation of a transcription factor(s). PMID:26937233

  19. Atorvastatin increases miR-124a expression: a mechanism of Gamt modulation in liver cells.

    PubMed

    Phulukdaree, Alisa; Moodley, Devapregasan; Khan, Sajidah; Chuturgoon, Anil A

    2015-11-01

    Atorvastatin is used to control cholesterol and lipid levels in hyperlipidaemic and hypercholesterolaemic patients. Myopathy and hepatotoxicity, however, have been reported as side effects in a small percentage of statin users. This study aimed to investigate the cytotoxicity and the effect of atorvastatin on microRNA expression in HepG2 cells. The methylthiazol tetrazolium assay was used to assess hepatocyte viability and at 20 μM atorvastatin (24 h) treatment were 82 ± 1.5% viable (P = 0.0002). Levels of intracellular ATP in cells treated with 20 μM atorvastatin were reduced by 1.25-fold, P = 0.002. Cytotoxicity, measured by the release of intracellular lactate dehydrogenase, was increased from 0.95 ± 0.29 units in control cells to 1.12 ± 0.02 units (P = 0.002) in atorvastatin treated cells. A panel of 84-miRNA species was used to evaluate the effect of atorvastatin on miRNA expression. MiR-124a was significantly up-regulated by atorvastatin (12.94-fold). A significant decrease in GAMT expression (3.54-fold) was observed in atorvastatin treated cells following quantitative PCR analysis. In addition, western blotting data showed GAMT protein levels were significantly lower than the controls (3.02-fold) and analysis of creatine levels in treated cells showed a significant decrease in the atorvastatin treated culture supernatant compared to control culture supernatant (32.33 ± 3.51 μM/l vs. 59.67 ± 1.52μM/l, P = 0.0056). This is the first study to show that atorvastatin up-regulates miR-124a levels and consequently modulates GAMT expression in hepatocytes. PMID:25926069

  20. MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity

    PubMed Central

    Hou, Qingming; Ruan, Hongyu; Gilbert, James; Wang, Guan; Ma, Qi; Yao, Wei-Dong; Man, Heng-Ye

    2015-01-01

    Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3′-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity. PMID:26620774

  1. Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression

    PubMed Central

    Watari, Hidemichi; Hanley, Sharon J.B.; Yamada, Takahiro; Hosaka, Masayoshi; Kudo, Masataka; Yue, Junming; Sakuragi, Noriaki

    2016-01-01

    Overexpression of IQGAP1 and microRNA (miRNA) dysregulation are frequent in human tumors, but little is known about the role of IQGAP1 and its relationship to miRNA in endometrial carcinogenesis. We demonstrate that IQGAP1 activates the epithelial–mesenchymal transition (EMT) program and that miR-124 directly represses IQGAP1 expression in endometrial cancer (EC) cells. The overexpression of IQGAP1 stimulates EMT features and enhances migration, invasion and proliferation of EC cells, whereas knocking down IQGAP1 expression reverses EMT and inhibits these malignant properties. Using miRNA microarray profiling, we identified 29 miRNAs (let-7b, let-7f, miR-10b, miR-15b, miR-23a, miR-24, miR-25, miR-27a, miR-29b, miR-30a-5p, miR-34a, miR-124, miR-127, miR-130b, miR-148a, miR-155, miR-191*, miR-194, miR-224, miR-362, miR-409-3p, miR-422b, miR-424, miR-453, miR-497, miR-518d, miR-518f*, miR-526a and miR-656) that are significantly down-regulated in an in vitro-selected highly invasive derivative cell line (HEC-50-HI) relative to the parental HEC-50 cells. We further identified miR-124 as a direct regulator of IQGAP1 in EC cells. Enforced expression of miR-124 suppresses EC cell invasion and proliferation. The expression of IQGAP1 mRNA was significantly elevated in EC tissues, while the expression of miR-124 was decreased. The downregulation of miR-124 correlates with a poor survival outcome for patients with EC. Treating EC cells with the demethylating agent 5-aza-2′-deoxycytidine increased miR-124 expression and down-regulated IQGAP1 levels. Our data suggest that IQGAP1 promotes EMT, migration and invasion of EC cells. MiR-124, a novel tumor suppressor miRNA that is epigenetically silenced in EC, can reverse EMT and the invasive properties, by attenuating the expression of the IQGAP1 oncogene. PMID:26934121

  2. A functional MiR-124 binding-site polymorphism in IQGAP1 affects human cognitive performance.

    PubMed

    Yang, Lixin; Zhang, Rui; Li, Ming; Wu, Xujun; Wang, Jianhong; Huang, Lin; Shi, Xiaodong; Li, Qingwei; Su, Bing

    2014-01-01

    As a product of the unique evolution of the human brain, human cognitive performance is largely a collection of heritable traits. Rather surprisingly, to date there have been no reported cases to highlight genes that underwent adaptive evolution in humans and which carry polymorphisms that have a marked effect on cognitive performance. IQ motif containing GTPase activating protein 1 (IQGAP1), a scaffold protein, affects learning and memory in a dose-dependent manner. Its expression is regulated by miR-124 through the binding sites in the 3'UTR, where a SNP (rs1042538) exists in the core-binding motif. Here we showed that this SNP can influence the miR-target interaction both in vitro and in vivo. Individuals carrying the derived T alleles have higher IQGAP1 expression in the brain as compared to the ancestral A allele carriers. We observed a significant and male-specific association between rs1042538 and tactile performances in two independent cohorts. Males with the derived allele displayed higher tactual performances as compared to those with the ancestral allele. Furthermore, we found a highly diverged allele-frequency distribution of rs1042538 among world human populations, likely caused by natural selection and/or recent population expansion. These results suggest that current human populations still carry sequence variations that affect cognitive performances and that these genetic variants may likely have been subject to comparatively recent natural selection. PMID:25222038

  3. Converging miRNA functions in diverse brain disorders: A case for miR-124 and miR-126

    PubMed Central

    Sonntag, Kai C.; Woo, Tsung-Ung W.; Krichevsky, Anna M.

    2012-01-01

    A growing body of information on the biology of miRNAs has revealed new insight into their roles in normal homeostasis and pathology of disease. miRNAs control all steps of the cellular expression machinery acting through a “single miRNA/multiple targets” or “multiple miRNAs/single target” mechanism. They have profound impact on the regulation of signaling pathways, which govern common and specific functions across different cellular phenotypes. There is increasing evidence that various diseases share similar disturbances in gene expression networks. Since miRNAs have both common and varying effects in different cellular contexts, they might also influence overlapping signaling pathways in different organs and disease entities. Here, we review this concept for two miRNAs highly abundant in the brain, miR-124 and miR-126, and their potential role in diseases of the brain. PMID:22178324

  4. The feedback loop between miR-124 and TGF-β pathway plays a significant role in non-small cell lung cancer metastasis.

    PubMed

    Zu, Lidong; Xue, Yunjing; Wang, Jinglong; Fu, Yujie; Wang, Xiumin; Xiao, Gang; Hao, Mingang; Sun, Xueqing; Wang, Yingying; Fu, Guohui; Wang, Jianhua

    2016-03-01

    Increasing evidence shows that micro RNAs (miRNAs) play a critical role in tumor development. However, the role of miRNAs in non-small cell lung cancer (NSCLC) metastasis remains largely unknown. Here, we found that miR-124 expression was significantly impaired in NSCLC tissues and associated with its metastasis. In vitro and in vivo experiments indicate that restoring miR-124 expression in NSCLC cells had a marked effect on reducing cell migration, invasion and metastasis. Mechanistic analyses show that Smad4, a cobinding protein in transforming growth factor-β (TGF-β) pathway, was identified as a new target gene of miR-124. Restoring Smad4 expression in miR-124-infected cells could partially rescue miR-124-induced abolition of cell migration and invasion. Notably, upon TGF-β stimulation, phosphorylation of Smad2/3 was modulated by alteration of miR-124 or Smad4 expression, followed by inducing some special transcription of downstream genes including Snail, Slug and ZEB2, all of which may trigger epithelial-mesenchymal transition and be associated with NSCLC metastasis. Moreover, activation of TGF-β pathway may enhance expression of DNMT3a, leading to hypermethylation on miR-124 promoter. Therefore, heavily loss of miR-124 expression further enhances Smad4 level by this feedback loop. Taken together, our data show for the first time that the feedback loop between miR-124 and TGF-β pathway may play a significant role in NSCLC metastasis. Targeting the loop may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for NSCLC. PMID:26818357

  5. MicroRNA-124 negatively regulates LPS-induced TNF-α production in mouse macrophages by decreasing protein stability

    PubMed Central

    Sun, Yang; Qin, Zhen; Li, Qi; Wan, Jing-jing; Cheng, Ming-he; Wang, Peng-yuan; Su, Ding-feng; Yu, Jian-guang; Liu, Xia

    2016-01-01

    Aim: MicroRNAs play pivotal roles in regulation of both innate and adaptive immune responses. In the present study, we investigated the effects of microRNA-124 (miR-124) on production of the pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-treated mouse macrophages. Methods: Mouse macrophage cell line RAW264.7 was stimulated with LPS (100 ng/mL). The levels of miR-124 and TNF-α mRNA were evaluated using q-PCR. ELISA and Western blotting were used to detect TNF-α protein level in cell supernatants and cells, respectively. 3′-UTR luciferase reporter assays were used to analyze the targets of miR-124. For in vivo experiments, mice were injected with LPS (30 mg/kg, ip). Results: LPS stimulation significantly increased the mRNA level of miR-124 in RAW264.7 macrophages in vitro and mice in vivo. In RAW264.7 macrophages, knockdown of miR-124 with miR-124 inhibitor dose-dependently increased LPS-stimulated production of TNF-α protein and prolonged the half-life of TNF-α protein, but did not change TNF-α mRNA levels, whereas overexpression of miR-124 with miR-124 mimic produced the opposite effects. Furthermore, miR-124 was found to directly target two components of deubiquitinating enzymes: ubiquitin-specific proteases (USP) 2 and 14. Knockdown of USP2 or USP14 accelerated protein degradation of TNF-α, and abolished the effect of miR-124 on TNF-α protein stability. Conclusion: miR-124, targeting USP2 and USP14, negatively regulates LPS-induced TNF-α production in mouse macrophages, suggesting miR-124 as a new therapeutic target in inflammation-related diseases. PMID:27063215

  6. MiR-124 is differentially expressed in derivatives of the sympathoadrenal cell lineage and promotes neurite elongation in chromaffin cells.

    PubMed

    Shtukmaster, Stella; Narasimhan, Priyanka; El Faitwri, Tehani; Stubbusch, Jutta; Ernsberger, Uwe; Rohrer, Hermann; Unsicker, Klaus; Huber, Katrin

    2016-08-01

    The neural-crest-derived sympathoadrenal cell lineage gives rise to sympathetic neurons and to endocrine chromaffin cells of the adrenal medulla. Both cell types express a largely overlapping set of genes, including those coding for the molecular machinery related to the synthesis and exocytotic release of catecholamines. During their early development, sympathetic neurons and chromaffin cells rely on a shared transcription factor network that controls the establishment of these common features. Despite many similarities, mature sympathetic neurons and chromaffin cells significantly differ regarding their morphology and function. Most prominently, sympathetic neurons possess axons that are absent in mammalian adrenal chromaffin cells. The molecular mechanism underlying the divergent development of sympathoadrenal cells into neuronal and endocrine cells remains elusive. Mutational inactivation of the ribonuclease dicer hints at the importance of microRNAs in this diversification. We show here that miR-124 is detectable in developing sympathetic neurons but absent in chromaffin cell precursors. We further demonstrate that miR-124 promotes neurite elongation when transfected into cultured chromaffin cells indicating its capability to support the establishment of a neuronal morphology in non-neuronal sympathoadrenal cells. Our results also show that treatment of PC12 cells with the neurotrophin nerve growth factor leads to an upregulation of miR-124 expression and that inhibition of miR-124 reduces nerve-growth-factor-induced neurite outgrowth in PC12 cells. Thus, our data indicate that miR-124 contributes to the establishment of specific neuronal features in developing sympathoadrenal cells. PMID:27094431

  7. Editor's Highlight: Plasma miR-183/96/182 Cluster and miR-124 are Promising Biomarkers of Rat Retinal Toxicity.

    PubMed

    Peng, Qinghai; Collette, Walter; Giddabasappa, Anand; David, John; Twamley, Michelle; Kalabat, Dalia; Aguirre, Shirley A; Huang, Wenhu

    2016-08-01

    Retinal toxicity is one of the leading causes of attrition in drug development, and drug-induced retinal toxicity remains an issue in both drug discovery and postmarketed drugs. Derisking strategies to help with early identification of retinal injury utilizing a predictive retinal miRNA biomarker would greatly benefit decision-making in drug discovery programs, ultimately reducing attrition due to retinal toxicity. Our previous work demonstrated elevation of circulating retina-enriched miRNAs in a retinal toxicity model. To further validate our previous observation, 2 additional rat retinal injury models were utilized in this study: NaIO3-induced retinal injury and laser-induced choroidal neovascularization (CNV) injury model. Following induction of retina tissue injuries, circulating miR-183/96/182 cluster (miR-183 cluster), and miR-124 was investigated, as well as evaluations using an electroretinogram (ERG) and histopathology analysis. Data revealed that circulating miR-183/96/182 cluster was significantly increased (2- to 15-fold) compared with baseline/control in both laser-induced CNV and NaIO3-induced retinal injury models. Moreover, the severity of the retinal injury evaluated by ERG and histopathology correlated highly with elevation of these retina-enriched miRNAs in plasma. MiR-124 was also significantly increased in comparison with baseline/control by ∼25-fold postrepeat-doses of 30 mg/kg NaIO3 treatment. Increased level of these plasma miRNA biomarkers appeared to be dose- and time-dependent upon NaIO3 or laser treatment. The results suggest that the retina-enriched miRNAs (miR-183/96/182 cluster and miR-124) could serve as convenient and predictive biomarkers of retinal toxicity in drug development. PMID:27208084

  8. MicroRNA-124-3p regulates cell proliferation, invasion, apoptosis, and bioenergetics by targeting PIM1 in astrocytoma.

    PubMed

    Deng, Danni; Wang, Lei; Chen, Yao; Li, Bowen; Xue, Lian; Shao, Naiyuan; Wang, Qiang; Xia, Xiwei; Yang, Yilin; Zhi, Feng

    2016-07-01

    The PIM1 protein is an important regulator of cell proliferation, the cell cycle, apoptosis, and metabolism in various human cancers. MicroRNAs (miRNAs) are powerful post-transcriptional gene regulators that function through translational repression or transcript destabilization. Therefore, we aimed to identify whether a close relationship exists between PIM1 and miRNAs. PIM1 protein levels and mRNA levels were significantly upregulated in astrocytoma tissues, indicating the oncogenic role of PIM1 in astrocytoma. Further bioinformatics analysis indicated that miR-124-3p targeted the 3'-UTR of PIM1. We also observed an inverse correlation between the miR-124-3p levels and PIM1 protein or mRNA levels in astrocytoma samples. Next, we experimentally confirmed that miR-124-3p directly recognizes the 3'-UTR of the PIM1 transcript and regulates PIM1 expression at both the protein and mRNA levels. Furthermore, we examined the biological consequences of miR-124-3p targeting PIM1 in vitro. We showed that the repression of PIM1 in astrocytoma cancer cells by miR-124-3p suppressed proliferation, invasion, and aerobic glycolysis and promoted apoptosis. We observed that the restoration or inhibition of PIM1 activity resulted in effects that were similar to those induced by miR-124-3p inhibitors or mimics in cancer cells. Finally, overexpression of PIM1 rescued the inhibitory effects of miR-124-3p. In summary, these findings aid in understanding the tumor-suppressive role of miR-124-3p in astrocytoma pathogenesis through the inhibition of PIM1 translation. PMID:27088547

  9. Adult neurogenesis in the short-lived teleost Nothobranchius furzeri: localization of neurogenic niches, molecular characterization and effects of aging

    PubMed Central

    Tozzini, Eva Terzibasi; Baumgart, Mario; Battistoni, Giorgia; Cellerino, Alessandro

    2012-01-01

    We studied adult neurogenesis in the short-lived annual fish Nothobranchius furzeri and quantified the effects of aging on the mitotic activity of the neuronal progenitors and the expression of glial fibrillary acid protein (GFAP) in the radial glia. The distribution of neurogenic niches is substantially similar to that of zebrafish and adult stem cells generate neurons, which persist in the adult brain. As opposed to zebrafish, however, the N. furzeri genome contains a doublecortin (DCX) gene. Doublecortin is transiently expressed by newly generated neurons in the telencephalon and optic tectum (OT). We also analyzed the expression of the microRNA miR-9 and miR-124 and found that they have complementary expression domains: miR-9 is expressed in the neurogenic niches of the telencephalon and the radial glia of the OT, while miR-124 is expressed in differentiated neurons. The main finding of this paper is the demonstration of an age-dependent decay in adult neurogenesis. Using unbiased stereological estimates of cell numbers, we detected an almost fivefold decrease in the number of mitotically active cells in the OT between young and old age. This reduced mitotic activity is paralleled by a reduction in DCX labeling. Finally, we detected a dramatic up-regulation of GFAP in the radial glia of the aged brain. This up-regulation is not paralleled by a similar up-regulation of S100B and Musashi-1, two other markers of the radial glia. In summary, the brain of N. furzeri replicates two typical hallmarks of mammalian aging: gliosis and reduced adult neurogenesis. PMID:22171971

  10. Affection of Single-Nucleotide Polymorphisms in miR-27a, miR-124a, and miR-146a on Susceptibility to Type 2 Diabetes Mellitus in Chinese Han People

    PubMed Central

    Wang, Tong-Tong; Chen, Yong-Jie; Sun, Lu-Lu; Zhang, Si-Jia; Zhou, Zhong-Yu; Qiao, Hong

    2015-01-01

    inhibitors that directly regulate miRNA expression present novel and promising therapeutic targets. PMID:25673459

  11. Validation of the FAM19A4/mir124-2 DNA methylation test for both lavage- and brush-based self-samples to detect cervical (pre)cancer in HPV-positive women

    PubMed Central

    De Strooper, Lise M.A.; Verhoef, Viola M.J.; Berkhof, Johannes; Hesselink, Albertus T.; de Bruin, Helena M.E.; van Kemenade, Folkert J.; Bosgraaf, Remko P.; Bekkers, Ruud L.M.; Massuger, Leon F.A.G.; Melchers, Willem J.G.; Steenbergen, Renske D.M.; Snijders, Peter J.F.; Meijer, Chris J.L.M.; Heideman, Daniëlle A.M.

    2016-01-01

    Objectives DNA methylation analysis of cancer-related genes is a promising tool for HPV-positive women to identify those with cervical (pre)cancer (CIN3+) in need of treatment. However, clinical performance of methylation markers can be influenced by the sample type utilized. We describe a multiplex quantitative methylation-specific PCR that targets FAM19A4 and mir124-2 loci, to detect CIN3+ using both HPV-positive lavage- and brush self-samples. Methods We determined methylation thresholds for clinical classification using HPV-positive training sets comprising lavage self-samples of 182 women (including 40 with CIN3+) and brush self-samples of 224 women (including 61 with CIN3+). Subsequently, independent HPV-positive validation sets of 389 lavage self-samples (including 78 with CIN3+), and 254 brush self-samples (including 72 with CIN3+) were tested using the preset thresholds. Furthermore, the clinical performance of combined methylation analysis and HPV16/18 genotyping was determined. Results Training set analysis revealed similar FAM19A4 and mir124-2 thresholds for both self-sample types to yield highest CIN3+ sensitivity at 70% specificity. Validation set analysis resulted in a CIN3+ sensitivity of 70.5% (95%CI: 60.4–80.6) at a specificity of 67.8% (95%CI: 62.7–73.0) for lavage self-samples, and a CIN3+ sensitivity of 69.4% (95%CI: 58.8–80.1) at a 76.4% (95%CI: 70.2–82.6) specificity for brush self-samples. In combination with HPV16/18 genotyping, CIN3+ sensitivity and specificity were 88.5% (95%CI: 81.4–95.6) and 46.0% (95%CI: 40.4–51.5) for lavage self-samples, and 84.7% (95%CI: 76.4–93.0) and 54.9% (95%CI: 47.7–62.2) for brush self-samples. Conclusions FAM19A4/mir124-2 methylation analysis performs equally well in HPV-positive lavage- and brush self-samples to identify women with CIN3+. In combination with HPV16/18 genotyping, significantly higher CIN3+ sensitivities are obtained, at decreased specificity. PMID:26921784

  12. MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation.

    PubMed

    Doeppner, Thorsten R; Doehring, Maria; Bretschneider, Eva; Zechariah, Anil; Kaltwasser, Britta; Müller, Barbara; Koch, Jan C; Bähr, Mathias; Hermann, Dirk M; Michel, Uwe

    2013-08-01

    MicroRNAs (miRNAs) are highly conserved non-coding RNAs modulating gene expression via mRNA binding. Recent work suggests an involvement of miRNAs in cardiovascular diseases including stroke. As such, the brain-abundant miR-124 and its transcriptional repressor RE1-silencing transcription factor (REST) do not only have elementary roles in the developing and the adult brain, but also alter expression upon cerebral ischemia. However, the therapeutic potential of miR-124 against stroke and the mechanisms involved remain elusive. Here, we analyzed the therapeutic potential of ectopic miR-124 against stroke and its underlying mechanisms with regard to the interaction between miR-124 and REST. Our results show that viral vector-mediated miR-124 delivery increased the resistance of cultured oxygen-glucose-deprived cortical neurons in vitro and reduced brain injury as well as functional impairment in mice submitted to middle cerebral artery occlusion. Likewise, miR-124 induced enhanced neurovascular remodeling leading to increased angioneurogenesis 8 weeks post-stroke. While REST abundance increased upon stroke, the increase was prevented by miR-124 despite a so far unknown negative feedback loop between miR-124 and REST. Rather, miR-124 decreased the expression of the deubiquitinating enzyme Usp14, which has two conserved miR-124-binding sites in the 3'UTR of its mRNA, and thereby mediated reduced REST levels. The down-regulation of REST by miR-124 was also mimicked by the Usp14 inhibitor IU-1, suggesting that miR-124 promotes neuronal survival under ischemic conditions via Usp14-dependent REST degradation. Ectopic miR-124 expression, therefore, appears as an attractive and novel tool in stroke treatment, mediating neuroprotection via a hitherto unknown mechanism that involves Usp14-dependent REST degradation. PMID:23754622

  13. Nitric oxide negatively regulates mammalian adult neurogenesis

    NASA Astrophysics Data System (ADS)

    Packer, Michael A.; Stasiv, Yuri; Benraiss, Abdellatif; Chmielnicki, Eva; Grinberg, Alexander; Westphal, Heiner; Goldman, Steven A.; Enikolopov, Grigori

    2003-08-01

    Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system.

  14. Emotion Regulation and Impulsivity in Young Adults

    PubMed Central

    Schreiber, Liana R.N.; Grant, Jon E.; Odlaug, Brian L.

    2012-01-01

    Past research has linked both emotion regulation and impulsivity with the development and maintenance of addictions. However, no research has investigated the relationship between emotion regulation and impulsivity within young adults. In the present study, we analyzed 194 young adults (27.8% female; 21.3 ± 3.32 years old; 91.8% single; 85.1% Caucasian), grouping them as low, average, or high emotionally dysregulated, and compared self-reported impulsivity, impulsive behaviors (such as alcohol and substance use and gambling) and cognitive impulsivity. We hypothesized that those with high levels of emotion dysregulation would score higher on self-reported and cognitive impulsivity, and report more impulsive behaviors. Analysis indicated that compared to low, the high emotion dysregulation group scored significantly higher on two self-report measures of impulsivity, harm avoidance, and cognitive reasoning. No significant differences were found between groups in impulsive behaviors and cognitive impulsivity. Overall, this study highlights the relationship between emotion dysregulation and impulsivity, suggesting that emotion regulation may be an important factor to consider when assessing individuals at a higher risk for developing an addiction. PMID:22385661

  15. Epigenetic regulation in adult stem cells and cancers

    PubMed Central

    2013-01-01

    Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells. PMID:24172544

  16. Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs.

    PubMed

    Lovis, Pascal; Gattesco, Sonia; Regazzi, Romano

    2008-03-01

    Fine-tuning of insulin secretion from pancreatic beta-cells participates in blood glucose homeostasis. Defects in this process can lead to chronic hyperglycemia and diabetes mellitus. Several proteins controlling insulin exocytosis have been identified, but the mechanisms regulating their expression remain poorly understood. Here, we show that two non-coding microRNAs, miR124a and miR96, modulate the expression of proteins involved in insulin exocytosis and affect secretion of the beta-cell line MIN6B1. miR124a increases the levels of SNAP25, Rab3A and synapsin-1A and decreases those of Rab27A and Noc2. Inhibition of Rab27A expression is mediated by direct binding to the 3'-untranslated region of Rab27A mRNA. The effect on the other genes is indirect and linked to changes in mRNA levels. Over-expression of miR124a leads to exaggerated hormone release under basal conditions and a reduction in glucose-induced secretion. miR96 increases mRNA and protein levels of granuphilin, a negative modulator of insulin exocytosis, and decreases the expression of Noc2, resulting in lower capacity of MIN6B1 cells to respond to secretagogues. Our data identify miR124a and miR96 as novel regulators of the expression of proteins playing a critical role in insulin exocytosis and in the release of other hormones and neurotransmitters. PMID:18177263

  17. Signaling mechanisms regulating adult neural stem cells and neurogenesis

    PubMed Central

    Faigle, Roland; Song, Hongjun

    2012-01-01

    Background Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain. Scope of review Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity. Major conclusions Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies. General significance A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. PMID:22982587

  18. Immunological regulation of neurogenic niches in the adult brain

    PubMed Central

    Gonzalez-Perez, Oscar; Gutierrez-Fernandez, Fernando; Lopez-Virgen, Veronica; Collas-Aguilar, Jorge; Quinones-Hinojosa, Alfredo; Garcia-Verdugo, Jose M.

    2012-01-01

    In mammals, neurogenesis and oligodendrogenesis are germinal processes that occur in the adult brain throughout life. The subventricular (SVZ) and subgranular (SGZ) zones are the main neurogenic regions in adult brain. Therein, it resides a subpopulation of astrocytes that act as neural stem cells. Increasing evidence indicates that pro-inflammatory and other immunological mediators are important regulators of neural precursors into the SVZ and the SGZ. There are a number of inflammatory cytokines that regulate the function of neural stem cells. Some of the most studied include: interleukin-1, interleukin-6, tumor necrosis factor-alpha, insulin-like growth factor-1, growth-regulated oncogene-alpha, leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, interferon-gamma, monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. This plethora of immunological mediators can control the migration, proliferation, quiescence, cell-fate choices and survival of neural stem cells and their progeny. Thus, systemic or local inflammatory processes represent important regulators of germinal niches in the adult brain. In this review, we summarized the current evidence regarding the effects of pro-inflammatory cytokines involved in the regulation of adult neural stem cells under in vitro and in vivo conditions. Additionally, we described the role of proinflammatory cytokines in neurodegenerative diseases and some therapeutical approaches for the immunomodulation of neural progenitor cells. PMID:22986164

  19. Selectivity as an Emotion Regulation Strategy: Lessons from Older Adults

    PubMed Central

    Sims, Tamara; Hogan, Candice; Carstensen, Laura

    2015-01-01

    Findings based on studies of daily life consistently associate older ages with relatively positive emotional experience, suggesting that older adults may regulate emotions more effectively than younger adults. Findings from laboratory studies are equivocal, however, with mixed evidence for age-related improvements in use of emotion regulatory strategies. In the current paper, we propose that findings may reflect a failure of laboratory-based experiments to capture the regulatory strategies that older people use in their everyday lives. We argue that the advantages older people have are likely due to antecedent emotion regulation as opposed to response-focused strategies. Understanding the regulatory approaches that older people actually use may inform developmental models of emotion regulation throughout adulthood as well as interventions for improving emotional experience across the life span. PMID:25914897

  20. Regulation and Function of Adult Neurogenesis. From Genes to Cognition

    DOE PAGESBeta

    Aimone, J. B.; Li, Y.; Lee, S. W.; Clemenson, G. D.; Deng, W.; Gage, F. H.

    2014-10-01

    Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. Our review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages ofmore » maturation, ultimately integrating into the adult dentate gyrus network. Furthermore, the increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.« less

  1. Regulation and Function of Adult Neurogenesis. From Genes to Cognition

    SciTech Connect

    Aimone, J. B.; Li, Y.; Lee, S. W.; Clemenson, G. D.; Deng, W.; Gage, F. H.

    2014-10-01

    Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. Our review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. Furthermore, the increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.

  2. Regulation and Function of Adult Neurogenesis: From Genes to Cognition

    PubMed Central

    Aimone, James B.; Li, Yan; Lee, Star W.; Clemenson, Gregory D.; Deng, Wei; Gage, Fred H.

    2014-01-01

    Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders. PMID:25287858

  3. Dietary glucose regulates yeast consumption in adult Drosophila males.

    PubMed

    Lebreton, Sébastien; Witzgall, Peter; Olsson, Marie; Becher, Paul G

    2014-01-01

    The adjustment of feeding behavior in response to hunger and satiety contributes to homeostatic regulation in animals. The fruit fly Drosophila melanogaster feeds on yeasts growing on overripe fruit, providing nutrients required for adult survival, reproduction and larval growth. Here, we present data on how the nutritional value of food affects subsequent yeast consumption in Drosophila adult males. After a period of starvation, flies showed intensive yeast consumption. In comparison, flies stopped feeding after having access to a nutritive cornmeal diet. Interestingly, dietary glucose was equally efficient as the complex cornmeal diet. In contrast, flies fed with sucralose, a non-metabolizable sweetener, behaved as if they were starved. The adipokinetic hormone and insulin-like peptides regulate metabolic processes in insects. We did not find any effect of the adipokinetic hormone pathway on this modulation. Instead, the insulin pathway was involved in these changes. Flies lacking the insulin receptor (InR) did not respond to nutrient deprivation by increasing yeast consumption. Together these results show the importance of insulin in the regulation of yeast consumption in response to starvation in adult D. melanogaster males. PMID:25566097

  4. Dietary glucose regulates yeast consumption in adult Drosophila males

    PubMed Central

    Lebreton, Sébastien; Witzgall, Peter; Olsson, Marie; Becher, Paul G.

    2014-01-01

    The adjustment of feeding behavior in response to hunger and satiety contributes to homeostatic regulation in animals. The fruit fly Drosophila melanogaster feeds on yeasts growing on overripe fruit, providing nutrients required for adult survival, reproduction and larval growth. Here, we present data on how the nutritional value of food affects subsequent yeast consumption in Drosophila adult males. After a period of starvation, flies showed intensive yeast consumption. In comparison, flies stopped feeding after having access to a nutritive cornmeal diet. Interestingly, dietary glucose was equally efficient as the complex cornmeal diet. In contrast, flies fed with sucralose, a non-metabolizable sweetener, behaved as if they were starved. The adipokinetic hormone and insulin-like peptides regulate metabolic processes in insects. We did not find any effect of the adipokinetic hormone pathway on this modulation. Instead, the insulin pathway was involved in these changes. Flies lacking the insulin receptor (InR) did not respond to nutrient deprivation by increasing yeast consumption. Together these results show the importance of insulin in the regulation of yeast consumption in response to starvation in adult D. melanogaster males. PMID:25566097

  5. Motor regulation problems and pain in adults diagnosed with ADHD

    PubMed Central

    2013-01-01

    Background Most children who are diagnosed with attention deficit-hyperactivity disorder (ADHD) have moderate-to-severe motor problems using the Motor Function Neurological Assessment battery (MFNU). The MFNU focuses on specific muscle adjustment problems associated with ADHD, especially motor inhibition problems and high muscle tone. Here we investigated whether adults with ADHD/hyperkinetic disorder (HKD) have similar motor problems. In our clinical experience, adults with ADHD often complain about back, shoulder, hip, and leg pain. We also investigate reported pain in adults with ADHD. Methods Twenty-five adult outpatients diagnosed with ADHD/HKD who were responders to methylphenidate (MPH) were compared to 23 non-ADHD controls on 16 MFNU subtests and using a ‘total score’ (‘TS’) parameter. The MFNU test leader was blinded to group identity. The two groups were also compared using the Pain Drawing and Numerical Pain Rating Scale. Results The adult ADHD group had significantly (p < .001) more motor problems (higher TS) than controls. On the muscle regulation subtests, 36–96% of the ADHD group showed ‘moderate’ to ‘severe’ problems compared to 13–52% of the control group, and 80% of the ADHD group reported widespread pain. Highly significant differences were found between the ADHD and control groups for the variables ‘pain level’ (p < .001) and ‘pain location’ (p < .001). Significant correlations were found between TS and ‘pain location’ and between TS and ‘pain level’. Conclusions These findings suggest that similar to children with ADHD, adults diagnosed with ADHD also have motor inhibition problems and heightened muscle tone. The presence of significantly higher pain levels and more widespread pain in the ADHD group compared to non-ADHD controls might indicate that pain is a long-term secondary effect of heightened muscle tone and restricted movement that can be demonstrated in children and adults by the MFNU

  6. Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling

    PubMed Central

    Ashton, Randolph S.; Conway, Anthony; Pangarkar, Chinmay; Bergen, Jamie; Lim, Kwang-Il; Shah, Priya; Bissell, Mina; Schaffer, David V.

    2012-01-01

    Neurogenesis in the adult hippocampus involves activation of quiescent neural stem cells (NSCs) to yield transiently amplifying NSCs and progenitors, and ultimately neurons that affect learning and memory. This process is tightly controlled by microenvironmental cues, though few endogenous factors are known to regulate neuronal differentiation. While astrocytes have been implicated, their role in juxtacrine (i.e. cell-cell contact-dependent) signaling within NSC niches has not been investigated. We show that ephrin-B2 presented from rodent hippocampal astrocytes regulates neurogenesis in vivo. Furthermore, clonal analysis in NSC fate-mapping studies reveals a novel role for ephrin-B2 in instructing neuronal differentiation. Additionally, ephrin-B2 signaling, transduced by EphB4 receptors on NSCs, activates β-catenin in vitro and in vivo independent of Wnt signaling and upregulates proneural transcription factors. Ephrin-B2+ astrocytes thus promote neuronal differentiation of adult NSCs through juxtacrine signaling, findings that advance our understanding of adult neurogenesis and may have future regenerative medicine implications. PMID:22983209

  7. Exosomes as Novel Regulators of Adult Neurogenic Niches

    PubMed Central

    Bátiz, Luis Federico; Castro, Maite A.; Burgos, Patricia V.; Velásquez, Zahady D.; Muñoz, Rosa I.; Lafourcade, Carlos A.; Troncoso-Escudero, Paulina; Wyneken, Ursula

    2016-01-01

    Adult neurogenesis has been convincingly demonstrated in two regions of the mammalian brain: the sub-granular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, and the sub-ventricular zone (SVZ) of the lateral ventricles (LV). SGZ newborn neurons are destined to the granular cell layer (GCL) of the DG, while new neurons from the SVZ neurons migrate rostrally into the olfactory bulb (OB). The process of adult neurogenesis persists throughout life and is supported by a pool of neural stem cells (NSCs), which reside in a unique and specialized microenvironment known as “neurogenic niche”. Neurogenic niches are structured by a complex organization of different cell types, including the NSC-neuron lineage, glial cells and vascular cells. Thus, cell-to-cell communication plays a key role in the dynamic modulation of homeostasis and plasticity of the adult neurogenic process. Specific cell-cell contacts and extracellular signals originated locally provide the necessary support and regulate the balance between self-renewal and differentiation of NSCs. Furthermore, extracellular signals originated at distant locations, including other brain regions or systemic organs, may reach the niche through the cerebrospinal fluid (CSF) or the vasculature and influence its nature. The role of several secreted molecules, such as cytokines, growth factors, neurotransmitters, and hormones, in the biology of adult NSCs, has been systematically addressed. Interestingly, in addition to these well-recognized signals, a novel type of intercellular messengers has been identified recently: the extracellular vesicles (EVs). EVs, and particularly exosomes, are implicated in the transfer of mRNAs, microRNAs (miRNAs), proteins and lipids between cells and thus are able to modify the function of recipient cells. Exosomes appear to play a significant role in different stem cell niches such as the mesenchymal stem cell niche, cancer stem cell niche and pre-metastatic niche; however, their

  8. Alpha-Defensin 5 Expression is Regulated by microRNAs in the Caco-2 Intestinal Epithelial Cell Line

    PubMed Central

    Miles, Donald R B; Shen, Jun; Chuang, Alice Y.; Dong, Fenshi; Wu, Feng; Kwon, John

    2016-01-01

    Background In inflammatory bowel disease (IBD), an inappropriate immune response leads to chronic mucosal inflammation. This response may be partly due to dysregulation of defensins, which are endogenously produced antimicrobial peptides. This study determined whether microRNAs (miRNAs) regulate α-defensin 5 (DEFA5), which could further implicate both in IBD pathogenesis. Methods Induction of DEFA5 mRNA and protein expression was determined in Caco-2 cells. An in silico analysis identified putative miRNA binding sites of DEFA5. Expression of these miRNAs was assessed in Caco-2 cells. Regulation of DEFA5 expression by these miRNAs was measured by luciferase assays. Caco-2 cells were transfected with miR-124 and miR-924 mimics, and DEFA5 mRNA and protein expression was measured. Results DEFA5 mRNA and protein expression was inducible in Caco-2 cells. Fifteen putative miRNA binding sites were found in DEFA5. The expression of miR-124 and miR-924 decreased following induction. Transfection of a luciferase construct containing the DEFA5 miRNA binding sites resulted in a decrease in luciferase activity compared to transfection of the empty vector. Transfection of a reporter construct containing mismatched miRNA binding sites resulted in restoration of luciferase activities. Transfection of miRNA mimics decreased DEFA5 mRNA expression and protein expression. Conclusions miR-124 and miR-924 negatively regulate DEFA5 mRNA and protein expression. These data implicate miRNAs in intestinal innate immune regulation and IBD pathogenesis. PMID:27525335

  9. AHCYL1 is mediated by estrogen-induced ERK1/2 MAPK cell signaling and microRNA regulation to effect functional aspects of the avian oviduct.

    PubMed

    Jeong, Wooyoung; Kim, Jinyoung; Ahn, Suzie E; Lee, Sang In; Bazer, Fuller W; Han, Jae Yong; Song, Gwonhwa

    2012-01-01

    S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1), also known as IP(3) receptor-binding protein released with IP(3) (IRBIT), regulates IP(3)-induced Ca(2+) release into the cytoplasm of cells. AHCYL1 is a critical regulator of early developmental stages in zebrafish, but little is known about the function of AHCYL1 or hormonal regulation of expression of the AHCYL1 gene in avian species. Therefore, we investigated differential expression profiles of the AHCYL1 gene in various adult organs and in oviducts from estrogen-treated chickens. Chicken AHCYL1 encodes for a protein of 540 amino acids that is highly conserved and has considerable homology to mammalian AHCYL1 proteins (>94% identity). AHCYL1 mRNA was expressed abundantly in various organs of chickens. Further, the synthetic estrogen agonist induced AHCYL1 mRNA and protein predominantly in luminal and glandular epithelial cells of the chick oviduct. In addition, estrogen activated AHCYL1 through the ERK1/2 signal transduction cascade and that activated expression of AHCYL1 regulated genes affecting oviduct development in chicks as well as calcium release in epithelial cells of the oviduct. Also, microRNAs, miR-124a, miR-1669, miR-1710 and miR-1782 influenced AHCYL1 expression in vitro via its 3'-UTR which suggests that post-transcriptional events are involved in the regulation of AHCYL1 expression in the chick oviduct. In conclusion, these results indicate that AHCYL1 is a novel estrogen-stimulated gene expressed in epithelial cells of the chicken oviduct that likely affects growth, development and calcium metabolism of the mature oviduct of hens via an estrogen-mediated ERK1/2 MAPK cell signaling pathway. PMID:23145124

  10. Fgf regulates dedifferentiation during skeletal muscle regeneration in adult zebrafish.

    PubMed

    Saera-Vila, Alfonso; Kish, Phillip E; Kahana, Alon

    2016-09-01

    Fibroblast growth factors (Fgfs) regulate critical biological processes such as embryonic development, tissue homeostasis, wound healing, and tissue regeneration. In zebrafish, Fgf signaling plays an important role in the regeneration of the spinal cord, liver, heart, fin, and photoreceptors, although its exact mechanism of action is not fully understood. Utilizing an adult zebrafish extraocular muscle (EOM) regeneration model, we demonstrate that blocking Fgf receptor function using either a chemical inhibitor (SU5402) or a dominant-negative transgenic construct (dnFGFR1a:EGFP) impairs muscle regeneration. Adult zebrafish EOMs regenerate through a myocyte dedifferentiation process, which involves a muscle-to-mesenchyme transition and cell cycle reentry by differentiated myocytes. Blocking Fgf signaling reduced cell proliferation and active caspase 3 levels in the regenerating muscle with no detectable levels of apoptosis, supporting the hypothesis that Fgf signaling is involved in the early steps of dedifferentiation. Fgf signaling in regenerating myocytes involves the MAPK/ERK pathway: inhibition of MEK activity with U0126 mimicked the phenotype of the Fgf receptor inhibition on both muscle regeneration and cell proliferation, and activated ERK (p-ERK) was detected in injured muscles by immunofluorescence and western blot. Interestingly, following injury, ERK2 expression is specifically induced and activated by phosphorylation, suggesting a key role in muscle regeneration. We conclude that the critical early steps of myocyte dedifferentiation in EOM regeneration are dependent on Fgf signaling. PMID:27267062

  11. An Expanded Notch-Delta Model Exhibiting Long-Range Patterning and Incorporating MicroRNA Regulation

    PubMed Central

    Chen, Jerry S.; Gumbayan, Abygail M.; Zeller, Robert W.; Mahaffy, Joseph M.

    2014-01-01

    Notch-Delta signaling is a fundamental cell-cell communication mechanism that governs the differentiation of many cell types. Most existing mathematical models of Notch-Delta signaling are based on a feedback loop between Notch and Delta leading to lateral inhibition of neighboring cells. These models result in a checkerboard spatial pattern whereby adjacent cells express opposing levels of Notch and Delta, leading to alternate cell fates. However, a growing body of biological evidence suggests that Notch-Delta signaling produces other patterns that are not checkerboard, and therefore a new model is needed. Here, we present an expanded Notch-Delta model that builds upon previous models, adding a local Notch activity gradient, which affects long-range patterning, and the activity of a regulatory microRNA. This model is motivated by our experiments in the ascidian Ciona intestinalis showing that the peripheral sensory neurons, whose specification is in part regulated by the coordinate activity of Notch-Delta signaling and the microRNA miR-124, exhibit a sparse spatial pattern whereby consecutive neurons may be spaced over a dozen cells apart. We perform rigorous stability and bifurcation analyses, and demonstrate that our model is able to accurately explain and reproduce the neuronal pattern in Ciona. Using Monte Carlo simulations of our model along with miR-124 transgene over-expression assays, we demonstrate that the activity of miR-124 can be incorporated into the Notch decay rate parameter of our model. Finally, we motivate the general applicability of our model to Notch-Delta signaling in other animals by providing evidence that microRNAs regulate Notch-Delta signaling in analogous cell types in other organisms, and by discussing evidence in other organisms of sparse spatial patterns in tissues where Notch-Delta signaling is active. PMID:24945987

  12. Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia.

    PubMed

    Bellon, Marcia; Lu, Ling; Nicot, Christophe

    2016-05-19

    Human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia and T-cell lymphoma (ATL) are aggressive diseases with poor prognoses, limited therapeutic options, and no curative treatment. In this study, we used a mouse model of ATL and restored expression of the microRNA, miR-124a, to identify in vivo downstream effectors responsible for its tumor-suppressive functions in ATL cells. Our results revealed that STAT3, a direct target of miR-124a, is constitutively activated in HTLV-I-transformed cells and ATL cells, and activating STAT3 mutations were detected in 25.5% of primary ATL patients. Interestingly, we found that the STAT3 downstream kinase effector, Pim1, is constitutively activated in ATL cells. The dependence of ATL cells to Pim1 activity was demonstrated using 2 Pim1 small inhibitors, SMI-4a and AZD1208. These studies indicated that HTLV-I-transformed and ATL cells, but not normal peripheral blood mononuclear cells, are highly sensitive to AZD1208, and the inhibition of Pim1 signaling triggers an apoptotic signal in leukemic cells. Finally, preclinical testing of AZD1208 in a mouse model of ATL resulted in significant prevention of tumor growth in vivo. In conclusion, our studies suggest that constitutive activation of the STAT3-Pim1 pathway represents a novel therapeutic target for the treatment of ATL. PMID:26813676

  13. Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

    PubMed

    Levinthal, D J; Bielefeldt, K

    2014-08-01

    Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse-all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management ("mind-body") interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS. PMID:24736863

  14. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

    PubMed Central

    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  15. Reduced facial reactivity as a contributor to preserved emotion regulation in older adults.

    PubMed

    Pedder, David J; Terrett, Gill; Bailey, Phoebe E; Henry, Julie D; Ruffman, Ted; Rendell, Peter G

    2016-02-01

    This study investigated whether differences in the type of strategy used, or age-related differences in intensity of facial reactivity, might contribute to preserved emotion regulation ability in older adults. Young (n = 35) and older (n = 33) adults were instructed to regulate their emotion to positive and negative pictures under 3 conditions (watch, expressive suppression, cognitive 'detached' reappraisal). Participants were objectively monitored using facial electromyography (EMG) and assessed on memory performance. Both age groups were effectively, and equivalently, able to reduce their facial expressions. In relation to facial reactivity, the percentage increase of older adults' facial muscle EMG activity in the watch condition was significantly reduced relative to young adults. Recall of pictures following regulation was similar to the watch condition, and there was no difference in memory performance between the 2 regulation strategies for both groups. These findings do not support the proposal that the type of strategy used explains preserved emotion regulation ability in older adults. Coupled with the lack of memory costs following regulation, these data instead are more consistent with the suggestion that older adults may retain emotion regulation capacity partly because they exhibit less facial reactivity to begin with. (PsycINFO Database Record PMID:26691303

  16. GABA regulates synaptic integration of newly generated neurons in the adult brain

    NASA Astrophysics Data System (ADS)

    Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

    2006-02-01

    Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

  17. Intravesical treatment of advanced urothelial bladder cancers with oncolytic HSV-1 co-regulated by differentially expressed microRNAs.

    PubMed

    Zhang, K-X; Matsui, Y; Lee, C; Osamu, O; Skinner, L; Wang, J; So, A; Rennie, P S; Jia, W W

    2016-05-01

    Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers. PMID:26905370

  18. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs

    PubMed Central

    Zheng, Qiupeng; Bao, Chunyang; Guo, Weijie; Li, Shuyi; Chen, Jie; Chen, Bing; Luo, Yanting; Lyu, Dongbin; Li, Yan; Shi, Guohai; Liang, Linhui; Gu, Jianren; He, Xianghuo; Huang, Shenglin

    2016-01-01

    Circular RNAs (circRNAs) represent a class of widespread and diverse endogenous RNAs that may regulate gene expression in eukaryotes. However, the regulation and function of human circRNAs remain largely unknown. Here we generate ribosomal-depleted RNA sequencing data from six normal tissues and seven cancers, and detect at least 27,000 circRNA candidates. Many of these circRNAs are differently expressed between the normal and cancerous tissues. We further characterize one abundant circRNA derived from Exon2 of the HIPK3 gene, termed circHIPK3. The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth. Via a luciferase screening assay, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites. Specifically, we show that circHIPK3 directly binds to miR-124 and inhibits miR-124 activity. Our results provide evidence that circular RNA produced from precursor mRNA may have a regulatory role in human cells. PMID:27050392

  19. Adult Antisocial Behavior and Affect Regulation among Primary Crack/Cocaine-Using Women

    ERIC Educational Resources Information Center

    Litt, Lisa Caren; Hien, Denise A.; Levin, Deborah

    2003-01-01

    The relationship between deficits in affect regulation and Adult Antisocial Behavior (ASB) in primary crack/cocaine-using women was explored in a sample of 80 inner-city women. Narrative early memories were coded for two components of affect regulation, Affect Tolerance and Affect Expression, using the Epigenetic Assessment Rating Scale (EARS;…

  20. Driving Skills of Young Adults with Developmental Coordination Disorder: Regulating Speed and Coping with Distraction

    ERIC Educational Resources Information Center

    de Oliveira, Rita F.; Wann, John P.

    2011-01-01

    In two experiments, we used an automatic car simulator to examine the steering control, speed regulation and response to hazards of young adults with developmental coordination disorder (DCD) and limited driving experience. In Experiment 1 participants either used the accelerator pedal to regulate their speed, or used the brake pedal when they…

  1. Endocrine and social regulation of adult neurogenesis in songbirds.

    PubMed

    Balthazart, Jacques; Ball, Gregory F

    2016-04-01

    The identification of pronounced seasonal changes in the volume of avian song control nuclei stimulated the discovery of adult neurogenesis in songbirds as well as renewed studies in mammals including humans. Neurogenesis in songbirds is modulated by testosterone and other factors such as photoperiod, singing activity and social environment. Adult neurogenesis has been widely studied by labeling, with tritiated thymidine or its analog BrdU, cells duplicating their DNA in anticipation of their last mitotic division and following their fate as new neurons. New methods based on endogenous markers of cell cycling or of various stages of neuronal life have allowed for additional progress. In particular immunocytochemical visualization of the microtubule-associated protein doublecortin has provided an integrated view of neuronal replacement in the song control nucleus HVC. Multiple questions remain however concerning the specific steps in the neuronal life cycle that are modulated by various factors and the underlying cellular mechanisms. PMID:26996818

  2. Phagocytic activity of neuronal progenitors regulates adult neurogenesis.

    PubMed

    Lu, Zhenjie; Elliott, Michael R; Chen, Yubo; Walsh, James T; Klibanov, Alexander L; Ravichandran, Kodi S; Kipnis, Jonathan

    2011-09-01

    Whereas thousands of new neurons are generated daily during adult life, only a fraction of them survive and become part of neural circuits; the rest die, and their corpses are presumably cleared by resident phagocytes. How the dying neurons are removed and how such clearance influences neurogenesis are not well understood. Here, we identify an unexpected phagocytic role for the doublecortin (DCX)-positive neuronal progenitor cells during adult neurogenesis. Our in vivo and ex vivo studies demonstrate that DCX(+) cells comprise a significant phagocytic population within the neurogenic zones. Intracellular engulfment protein ELMO1, which promotes Rac activation downstream of phagocytic receptors, was required for phagocytosis by DCX(+) cells. Disruption of engulfment in vivo genetically (in Elmo1-null mice) or pharmacologically (in wild-type mice) led to reduced uptake by DCX(+) cells, accumulation of apoptotic nuclei in the neurogenic niches and impaired neurogenesis. Collectively, these findings indicate a paradigm wherein DCX(+) neuronal precursors also serve as phagocytes, and that their phagocytic activity critically contributes to neurogenesis in the adult brain. PMID:21804544

  3. Eating Pathology, Emotion Regulation, and Emotional Overeating in Obese Adults with Binge Eating Disorder

    PubMed Central

    Gianini, Loren M.; White, Marney A.; Masheb, Robin M.

    2013-01-01

    Objective The purpose of the current study was to examine the relationship among emotional regulation, emotional overeating, and general eating pathology in a treatment seeking sample of adults with Binge Eating Disorder (BED). Method The sample was composed of 326 adults (248 women, 78 men) who were obese and met DSM-IV-TR criteria for BED. Prior to treatment, participants completed the Difficulties in Emotion Regulation Scale (DERS), Emotional Overeating Questionnaire (EOQ), Beck Depression Inventory (BDI), and Eating Disorder Examination-Questionnaire (EDE-Q) as part of a larger assessment battery. Results A series of hierarchical regression analyses indicated that difficulties with emotion regulation accounted for unique variance in both emotional overeating and general eating pathology above and beyond sex and negative affect. Discussion Emotion regulation may play a significant role in the maintenance of emotional overeating and eating pathology in obese adults with BED. PMID:23910772

  4. Functional genomics identifies regulators of the phototransduction machinery in the Drosophila larval eye and adult ocelli.

    PubMed

    Mishra, Abhishek Kumar; Bargmann, Bastiaan O R; Tsachaki, Maria; Fritsch, Cornelia; Sprecher, Simon G

    2016-02-15

    Sensory perception of light is mediated by specialized Photoreceptor neurons (PRs) in the eye. During development all PRs are genetically determined to express a specific Rhodopsin (Rh) gene and genes mediating a functional phototransduction pathway. While the genetic and molecular mechanisms of PR development is well described in the adult compound eye, it remains unclear how the expression of Rhodopsins and the phototransduction cascade is regulated in other visual organs in Drosophila, such as the larval eye and adult ocelli. Using transcriptome analysis of larval PR-subtypes and ocellar PRs we identify and study new regulators required during PR differentiation or necessary for the expression of specific signaling molecules of the functional phototransduction pathway. We found that the transcription factor Krüppel (Kr) is enriched in the larval eye and controls PR differentiation by promoting Rh5 and Rh6 expression. We also identified Camta, Lola, Dve and Hazy as key genes acting during ocellar PR differentiation. Further we show that these transcriptional regulators control gene expression of the phototransduction cascade in both larval eye and adult ocelli. Our results show that PR cell type-specific transcriptome profiling is a powerful tool to identify key transcriptional regulators involved during several aspects of PR development and differentiation. Our findings greatly contribute to the understanding of how combinatorial action of key transcriptional regulators control PR development and the regulation of a functional phototransduction pathway in both larval eye and adult ocelli. PMID:26769100

  5. GABA-CREB signalling regulates maturation and survival of newly generated neurons in the adult hippocampus

    PubMed Central

    Jagasia, Ravi; Steib, Kathrin; Englberger, Elisabeth; Herold, Sabine; Faus-Kessler, Theresa; Saxe, Michael; Gage, Fred H.; Song, Hongjun; Lie, D. Chichung

    2009-01-01

    Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signalling pathways. Here, we investigate the role of CREB signalling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous fashion impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule associated protein, DCX, and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects following loss of GABA-mediated excitation can be compensated by enhanced CREB signalling. These results indicate that CREB signalling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation. PMID:19553437

  6. TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation.

    PubMed

    Hillje, A-L; Pavlou, M A S; Beckmann, E; Worlitzer, M M A; Bahnassawy, L; Lewejohann, L; Palm, T; Schwamborn, J C

    2013-01-01

    In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process. PMID:24357807

  7. Dual transcriptional activator and repressor roles of TBX20 regulate adult cardiac structure and function

    PubMed Central

    Sakabe, Noboru J.; Aneas, Ivy; Shen, Tao; Shokri, Leila; Park, Soo-Young; Bulyk, Martha L.; Evans, Sylvia M.; Nobrega, Marcelo A.

    2012-01-01

    The ongoing requirement in adult heart for transcription factors with key roles in cardiac development is not well understood. We recently demonstrated that TBX20, a transcriptional regulator required for cardiac development, has key roles in the maintenance of functional and structural phenotypes in adult mouse heart. Conditional ablation of Tbx20 in adult cardiomyocytes leads to a rapid onset and progression of heart failure, with prominent conduction and contractility phenotypes that lead to death. Here we describe a more comprehensive molecular characterization of the functions of TBX20 in adult mouse heart. Coupling genome-wide chromatin immunoprecipitation and transcriptome analyses (RNA-Seq), we identified a subset of genes that change expression in Tbx20 adult cardiomyocyte-specific knockout hearts which are direct downstream targets of TBX20. This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor, and that each of these functions regulates genes with very specialized and distinct molecular roles. We also show how TBX20 binds to its targets genome-wide in a context-dependent manner, using various cohorts of co-factors to either promote or repress distinct genetic programs within adult heart. Our integrative approach has uncovered several novel aspects of TBX20 and T-box protein function within adult heart. Sequencing data accession number (http://www.ncbi.nlm.nih.gov/geo): GSE30943. PMID:22328084

  8. Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells

    PubMed Central

    Smrt, Richard D.; Johnson, Eric B.; Li, Xuekun; Pfeiffer, Rebecca L.; Szulwach, Keith E.; Duan, Ranhui; Barkho, Basam Z.; Li, Wendi; Liu, Changmei; Jin, Peng; Zhao, Xinyu

    2010-01-01

    Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis. PMID:20386739

  9. A Common Language: How Neuroimmunological Cross Talk Regulates Adult Hippocampal Neurogenesis

    PubMed Central

    Leiter, Odette; Kempermann, Gerd; Walker, Tara L.

    2016-01-01

    Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus—a region crucial for learning and memory. PMID:27143977

  10. Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1

    PubMed Central

    Chau, You-Ying; Brownstein, David; Mjoseng, Heidi; Lee, Wen-Chin; Buza-Vidas, Natalija; Nerlov, Claus; Jacobsen, Sten Eirik; Perry, Paul; Berry, Rachel; Thornburn, Anna; Sexton, David; Morton, Nik; Hohenstein, Peter; Freyer, Elisabeth; Samuel, Kay; van't Hof, Rob; Hastie, Nicholas

    2011-01-01

    There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal–epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover. PMID:22216009

  11. Syndecan-3 and Notch cooperate in regulating adult myogenesis

    PubMed Central

    Pisconti, Addolorata; Cornelison, D.D.W.; Olguín, Hugo C.; Antwine, Tiffany L.

    2010-01-01

    Skeletal muscle postnatal growth and repair depend on satellite cells and are regulated by molecular signals within the satellite cell niche. We investigated the molecular and cellular events that lead to altered myogenesis upon genetic ablation of Syndecan-3, a component of the satellite cell niche. In the absence of Syndecan-3, satellite cells stall in S phase, leading to reduced proliferation, increased cell death, delayed onset of differentiation, and markedly reduced numbers of Pax7+ satellite cells accompanied by myofiber hypertrophy and an increased number of centrally nucleated myofibers. We show that the aberrant cell cycle and impaired self-renewal of explanted Syndecan-3–null satellite cells are rescued by ectopic expression of the constitutively active Notch intracellular domain. Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-α–converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. PMID:20696709

  12. Syndecan-3 and Notch cooperate in regulating adult myogenesis.

    PubMed

    Pisconti, Addolorata; Cornelison, D D W; Olguín, Hugo C; Antwine, Tiffany L; Olwin, Bradley B

    2010-08-01

    Skeletal muscle postnatal growth and repair depend on satellite cells and are regulated by molecular signals within the satellite cell niche. We investigated the molecular and cellular events that lead to altered myogenesis upon genetic ablation of Syndecan-3, a component of the satellite cell niche. In the absence of Syndecan-3, satellite cells stall in S phase, leading to reduced proliferation, increased cell death, delayed onset of differentiation, and markedly reduced numbers of Pax7(+) satellite cells accompanied by myofiber hypertrophy and an increased number of centrally nucleated myofibers. We show that the aberrant cell cycle and impaired self-renewal of explanted Syndecan-3-null satellite cells are rescued by ectopic expression of the constitutively active Notch intracellular domain. Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. PMID:20696709

  13. Social regulation of adult neurogenesis in a eusocial mammal.

    PubMed

    Peragine, D E; Simpson, J A; Mooney, S J; Lovern, M B; Holmes, M M

    2014-05-30

    The present study examined the effects of social status on adult neurogenesis in an extreme cooperative breeder: the naked mole rat. These animals live in large colonies of up to 300 individuals, with a strict reproductive dominance hierarchy; one female and one to three males breed, and all other members are socially subordinate and reproductively suppressed. We examined the effects of social and gonadal cues on doublecortin (DCX; a marker for immature neurons) immunoreactivity in the dentate gyrus (DG), piriform cortex (PCx) and basolateral amygdala (BLA) by comparing dominant breeding animals to non-breeding subordinates from intact colonies. We also examined DCX expression in subordinate animals that had been removed from their colony and paired with an opposite- or same-sex conspecific for 6months. Compared to subordinates, dominant breeders had significantly reduced DCX immunoreactivity in all brain areas, with BLA effects confined to females. By contrast, the effects of same- versus opposite-sex housing were region-specific. In the DG and PCx, more DCX immunoreactivity was observed for opposite- than same-sex-paired subordinates. Conversely, same-sex-paired females had more DCX immunoreactivity than opposite-sex-paired females in the BLA. Gonadectomy did not affect DCX expression in opposite-sex-paired animals, and no significant relationships between gonadal steroids and DCX immunoreactivity were detected, suggesting that group differences in neurogenesis are independent of gonadal hormones. The apparent lower neurogenic capacity displayed by breeders contrasts previous reports on neurogenesis and social rank, challenging the conventional view that subordination is stressful and impairs neurogenesis. Future work will clarify whether the present findings can be attributed to status-dependent differences in stress, behavioral plasticity, or life stage. PMID:24607322

  14. Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes.

    PubMed

    Li, Xiaoheng; Wang, Zhao; Jiang, Zhenming; Guo, Jingjing; Zhang, Yuxi; Li, Chenhao; Chung, Jinyong; Folmer, Janet; Liu, June; Lian, Qingquan; Ge, Renshan; Zirkin, Barry R; Chen, Haolin

    2016-03-01

    Testicular Leydig cells are the primary source of testosterone in males. Adult Leydig cells have been shown to arise from stem cells present in the neonatal testis. Once established, adult Leydig cells turn over only slowly during adult life, but when these cells are eliminated experimentally from the adult testis, new Leydig cells rapidly reappear. As in the neonatal testis, stem cells in the adult testis are presumed to be the source of the new Leydig cells. As yet, the mechanisms involved in regulating the proliferation and differentiation of these stem cells remain unknown. We developed a unique in vitro system of cultured seminiferous tubules to assess the ability of factors from the seminiferous tubules to regulate the proliferation of the tubule-associated stem cells, and their subsequent entry into the Leydig cell lineage. The proliferation of the stem Leydig cells was stimulated by paracrine factors including Desert hedgehog (DHH), basic fibroblast growth factor (FGF2), platelet-derived growth factor (PDGF), and activin. Suppression of proliferation occurred with transforming growth factor β (TGF-β). The differentiation of the stem cells was regulated positively by DHH, lithium- induced signaling, and activin, and negatively by TGF-β, PDGFBB, and FGF2. DHH functioned as a commitment factor, inducing the transition of stem cells to the progenitor stage and thus into the Leydig cell lineage. Additionally, CD90 (Thy1) was found to be a unique stem cell surface marker that was used to obtain purified stem cells by flow cytometry. PMID:26929346

  15. Stress Regulation in Adolescents: Physiological Reactivity during the Adult Attachment Interview and Conflict Interaction

    ERIC Educational Resources Information Center

    Beijersbergen, Marielle D.; Bakermans-Kranenburg, Marian J.; van IJzendoorn, Marinus H.; Juffer, Femmie

    2008-01-01

    The current study examined whether adolescents' attachment representations were associated with differences in emotion regulation during the Adult Attachment Interview (AAI; C. George, N. Kaplan, & M. Main, 1996) and during a mother-adolescent conflict interaction task (Family Interaction Task [FIT]; J. P. Allen et al., 2003). Participants were…

  16. Affective Self-Regulation Trajectories during Secondary School Predict Substance Use among Urban Minority Young Adults

    ERIC Educational Resources Information Center

    Griffin, Kenneth W.; Lowe, Sarah R.; Acevedo, Bianca P.; Botvin, Gilbert J.

    2015-01-01

    This study explored the relationship between trajectories of affective self-regulation skills during secondary school and young adult substance use in a large multiethnic, urban sample (N = 995). During secondary school, participants completed a measure of cognitive and behavioral skills used to control negative, unpleasant emotions or perceived…

  17. Self-Regulation, Self-Efficacy and Health Behavior Change in Older Adults.

    ERIC Educational Resources Information Center

    Purdie, Nola; McCrindle, Andrea

    2002-01-01

    Presents an overview of self-regulation models: theory of planned behavior, protection motivation theory, health belief model, action control theory, transtheoretical model of behavior change, health action process, and precaution adoption process. Applies models to health behavior change in older adults with cardiovascular disease or diabetes.…

  18. SomethiNG 2 talk about-Transcriptional regulation in embryonic and adult oligodendrocyte precursors.

    PubMed

    Küspert, Melanie; Wegner, Michael

    2016-05-01

    Glial cells that express the chondroitin sulfate proteoglycan NG2 represent an inherently heterogeneous population. These so-called NG2-glia are present during development and in the adult CNS, where they are referred to as embryonic oligodendrocyte precursors and adult NG2-glia, respectively. They give rise to myelinating oligodendrocytes at all times of life. Over the years much has been learnt about the transcriptional network in embryonic oligodendrocyte precursors, and several transcription factors from the HLH, HMG-domain, zinc finger and homeodomain protein families have been identified as main constituents. Much less is known about the corresponding network in adult NG2-glia. Here we summarize and discuss current knowledge on functions of each of these transcription factor families in NG2-glia, and where possible compare transcriptional regulation in embryonic oligodendrocyte precursors and adult NG2-glia. This article is part of a Special Issue entitled SI:NG2-glia (Invited only). PMID:26232072

  19. Regulation of leptin synthesis and secretion before birth: implications for the early programming of adult obesity.

    PubMed

    McMillen, I C; Edwards, L J; Duffield, J; Muhlhausler, B S

    2006-03-01

    A series of epidemiological, clinical and experimental studies have shown that there are associations between the fetal and neonatal nutritional environment and the amount and distribution of adipose tissue in adult life. This review considers the evidence for these relationships and discusses the potential impact of the prenatal nutritional experience on the development of the endocrine and neuroendocrine systems that regulate energy balance, with a particular emphasis on the role of the adipocyte-derived hormone, leptin. In the rodent, leptin derived from the mother may exert an important influence on the development of the appetite regulatory neural network and on the subsequent regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, there is also recent evidence that the synthesis and secretion of adipocyte-derived hormones, such as leptin, are regulated in fetal life. Furthermore, the hypothalamic neuropeptides that regulate energy intake and expenditure in adult life are also present within the fetal brain and may be regulated by the prevailing level of maternal and hence fetal nutrient and hormonal signals, including leptin. This work is important in determining those initiating mechanisms within the 'fat-brain' axis in early life that precede the development of adult obesity. PMID:16514185

  20. Comprehensive expression map of transcription regulators in the adult zebrafish telencephalon reveals distinct neurogenic niches.

    PubMed

    Diotel, Nicolas; Rodriguez Viales, Rebecca; Armant, Olivier; März, Martin; Ferg, Marco; Rastegar, Sepand; Strähle, Uwe

    2015-06-01

    The zebrafish has become a model to study adult vertebrate neurogenesis. In particular, the adult telencephalon has been an intensely studied structure in the zebrafish brain. Differential expression of transcriptional regulators (TRs) is a key feature of development and tissue homeostasis. Here we report an expression map of 1,202 TR genes in the telencephalon of adult zebrafish. Our results are summarized in a database with search and clustering functions to identify genes expressed in particular regions of the telencephalon. We classified 562 genes into 13 distinct patterns, including genes expressed in the proliferative zone. The remaining 640 genes displayed unique and complex patterns of expression and could thus not be grouped into distinct classes. The neurogenic ventricular regions express overlapping but distinct sets of TR genes, suggesting regional differences in the neurogenic niches in the telencephalon. In summary, the small telencephalon of the zebrafish shows a remarkable complexity in TR gene expression. The adult zebrafish telencephalon has become a model to study neurogenesis. We established the expression pattern of more than 1200 transcription regulators (TR) in the adult telencephalon. The neurogenic regions express overlapping but distinct sets of TR genes suggesting regional differences in the neurogenic potential. PMID:25556858

  1. GATAe regulates intestinal stem cell maintenance and differentiation in Drosophila adult midgut.

    PubMed

    Okumura, Takashi; Takeda, Koji; Kuchiki, Megumi; Akaishi, Marie; Taniguchi, Kiichiro; Adachi-Yamada, Takashi

    2016-02-01

    Adult intestinal tissues, exposed to the external environment, play important roles including barrier and nutrient-absorption functions. These functions are ensured by adequately controlled rapid-cell metabolism. GATA transcription factors play essential roles in the development and maintenance of adult intestinal tissues both in vertebrates and invertebrates. We investigated the roles of GATAe, the Drosophila intestinal GATA factor, in adult midgut homeostasis with its first-generated knock-out mutant as well as cell type-specific RNAi and overexpression experiments. Our results indicate that GATAe is essential for proliferation and maintenance of intestinal stem cells (ISCs). Also, GATAe is involved in the differentiation of enterocyte (EC) and enteroendocrine (ee) cells in both Notch (N)-dependent and -independent manner. The results also indicate that GATAe has pivotal roles in maintaining normal epithelial homeostasis of the Drosophila adult midgut through interaction of N signaling. Since recent reports showed that mammalian GATA-6 regulates normal and cancer stem cells in the adult intestinal tract, our data also provide information on the evolutionally conserved roles of GATA factors in stem-cell regulation. PMID:26719127

  2. [Regulation of neurogenesis: factors affecting of new neurons formation in adult mammals brain].

    PubMed

    Respondek, Michalina; Buszman, Ewa

    2015-01-01

    Neurogenesis is a complex and multi-step process of generating completely functional neurons. This process in adult brain is based on pluripotentional neuronal stem cells (NSC), which are able to proliferation and differentiation into mature neurons or glial cells. NSC are located in subgranular zone inside hippocampus and in subventricular zone. The new neurons formation depends on many endo- and exogenous factors which modulate each step of neurogenesis. This article describes the most important regulators of adult neurogenesis, mainly: neurotrophins, growth factors, hormones, neurotransmitters and microenvironment of NSC. Some drugs, especially antipsychotics, antidepressants and normothymics may affect the neurogenic properties of adult brain. Moreover pathological processes such as neuroinflammation, stroke or epilepsy are able to induce proliferation of NSC. The proneurogenic effects of psychotropic drugs and pathological processes are associated with their ability to increase some hormones and neurotrophins level, as well as with rising the expression of antiapoptotic Bcl-2 protein and metalloproteinase MMP-2. Additionaly, some drugs, for example haloperidol, are able to block prolactin and dopaminergic neuroblasts receptors. Down-regulation of adult neurogenesis is associated with alcohol abuse and high stress level. Negative effect of many drugs, such as cytostatics, COX-2 inhibitors and opioides was also observed. The proneurogenic effect of described factors suggest their broad therapeutic potential and gives a new perspective on an effective and modern treatment of many neuropsychiatric disorders. This effect can also help to clarify the pathogenesis of disorders associated with proliferation and degeneration of adult brain cells. PMID:27259217

  3. The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans

    PubMed Central

    Block, Dena H. S.; Twumasi-Boateng, Kwame; Kang, Hae Sung; Carlisle, Jolie A.; Hanganu, Alexandru; Lai, Ty Yu-Jen; Shapira, Michael

    2015-01-01

    GATA transcription factors play critical roles in cellular differentiation and development. However, their roles in mature tissues are less understood. In C. elegans larvae, the transcription factor ELT-2 regulates terminal differentiation of the intestine. It is also expressed in the adult intestine, where it was suggested to maintain intestinal structure and function, and where it was additionally shown to contribute to infection resistance. To study the function of elt-2 in adults we characterized elt-2-dependent gene expression following its knock-down specifically in adults. Microarray analysis identified two ELT-2-regulated gene subsets: one, enriched for hydrolytic enzymes, pointed at regulation of constitutive digestive functions as a dominant role of adult elt-2; the second was enriched for immune genes that are induced in response to Pseudomonas aeruginosa infection. Focusing on the latter, we used genetic analyses coupled to survival assays and quantitative RT-PCR to interrogate the mechanism(s) through which elt-2 contributes to immunity. We show that elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1. This demonstrates a mechanism through which the constitutively nuclear elt-2 can impact induced responses, and play a dominant role in C. elegans immunity. PMID:26016853

  4. Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms.

    PubMed

    Mahmoud, Rand; Wainwright, Steven R; Galea, Liisa A M

    2016-04-01

    Neurogenesis within the adult hippocampus is modulated by endogenous and exogenous factors. Here, we review the role of sex hormones in the regulation of adult hippocampal neurogenesis in males and females. The review is framed around the potential functional implications of sex hormone regulation of adult hippocampal neurogenesis, with a focus on cognitive function and mood regulation, which may be related to sex differences in incidence and severity of dementia and depression. We present findings from preclinical studies of endogenous fluctuations in sex hormones relating to reproductive function and ageing, and from studies of exogenous hormone manipulations. In addition, we discuss the modulating roles of sex, age, and reproductive history on the relationship between sex hormones and neurogenesis. Because sex hormones have diverse targets in the central nervous system, we overview potential mechanisms through which sex hormones may influence hippocampal neurogenesis. Lastly, we advocate for a more systematic consideration of sex and sex hormones in studying the functional implications of adult hippocampal neurogenesis. PMID:26988999

  5. Sterilization Effects of Adult-targeted Baits Containing Insect Growth Regulators on Delia antiqua.

    PubMed

    Zhou, Fangyuan; Zhu, Guodong; Zhao, Haipeng; Wang, Zheng; Xue, Ming; Li, Xianxian; Xu, Huaqiang; Ma, Xiaodan; Liu, Yanyan

    2016-01-01

    The onion maggot, Delia antiqua, is a devastating pest of liliaceous crops and current control measures fail to avert pesticide residues, threats to agroecosystem, and costly expenditures. Insect growth regulators (IGRs) are used as trypetid pest chemosterilants for their suppression on adult fertility and fecundity, but their effects on onion flies are unknown. Here, three IGRs (lufenuron, cyromazine, pyriproxyfen) were incorporated into baits to evaluate their effects on onion fly survival, fecundity, fertility, susceptibility of adults in different ages and offspring development. Lufenuron and cyromazine did not affect survival of new-emerged adults, but lufenuron inhibited adult fertility without affecting fecundity, and cyromazine reduced fertility and fecundity. Differently, pyriproxyfen enhanced fecundity within 10 days after treatment, while it reduced adult survival without affecting fertility. The fertility of younger adults was affected by lufenuron and cyromazine whereas the fecundity was affected with cyromazine and pyriproxyfen. For offspring of onion flies treated with lufenuron or cyromazine, most of larvae died within 5 days after hatch, but surviving larvae pupated and emerged normally. Pyriproxyfen did not affect offspring larval survival or pupation but affected pupal emergence. Thus, lufenuron and cyromazine could be potential chemosterilants for onion flies. PMID:27619006

  6. A Sodium Leak Current Regulates Pacemaker Activity of Adult Central Pattern Generator Neurons in Lymnaea Stagnalis

    PubMed Central

    Lu, Tom Z.; Feng, Zhong-Ping

    2011-01-01

    The resting membrane potential of the pacemaker neurons is one of the essential mechanisms underlying rhythm generation. In this study, we described the biophysical properties of an uncharacterized channel (U-type channel) and investigated the role of the channel in the rhythmic activity of a respiratory pacemaker neuron and the respiratory behaviour in adult freshwater snail Lymnaea stagnalis. Our results show that the channel conducts an inward leak current carried by Na+ (ILeak-Na). The ILeak-Na contributed to the resting membrane potential and was required for maintaining rhythmic action potential bursting activity of the identified pacemaker RPeD1 neurons. Partial knockdown of the U-type channel suppressed the aerial respiratory behaviour of the adult snail in vivo. These findings identified the Na+ leak conductance via the U-type channel, likely a NALCN-like channel, as one of the fundamental mechanisms regulating rhythm activity of pacemaker neurons and respiratory behaviour in adult animals. PMID:21526173

  7. Adult Hippocampal Neurogenesis: Regulation, Functional Implications, And Contribution to Disease Pathology

    PubMed Central

    Balu, Darrick T.; Lucki, Irwin

    2009-01-01

    It is now well established that the mammalian brain has the capacity to produce new neurons into adulthood. One such region that provides the proper milieu to sustain progenitor cells and is permissive to neuronal fate determination is located in the dentate gyrus of the hippocampus. This review will discuss in detail the complex process of adult hippocampal neurogenesis, including proliferation, differentiation, survival, and incorporation into neuronal networks. The regulation of this phenomenon by a number of factors is described, including neurotransmitter systems, growth factors, paracrine signaling molecules, neuropeptides, transcription factors, endogenous psychotropic systems, sex hormones, stress, and others. This review also addresses the functional significance of adult born hippocampal granule cells with regard to hippocampal circuitry dynamics and behavior. Furthermore, the relevance of perturbations in adult hippocampal neurogenesis to the pathophysiology of various disease states, including depression, schizophrenia, epilepsy, and diabetes are examined. Finally, this review discusses the potential of using hippocampal neurogenesis as a therapeutic target for these disorders. PMID:18786562

  8. Regulation of plasma lipid homeostasis by hepatic lipoprotein lipase in adult mice.

    PubMed

    Liu, Gan; Xu, Jun-Nan; Liu, Dong; Ding, Qingli; Liu, Meng-Na; Chen, Rong; Fan, Mengdi; Zhang, Ye; Zheng, Chao; Zou, Da-Jin; Lyu, Jianxin; Zhang, Weiping J

    2016-07-01

    LPL is a pivotal rate-limiting enzyme to catalyze the hydrolysis of TG in circulation, and plays a critical role in regulating lipid metabolism. However, little attention has been paid to LPL in the adult liver due to its relatively low expression. Here we show that endogenous hepatic LPL plays an important physiological role in plasma lipid homeostasis in adult mice. We generated a mouse model with the Lpl gene specifically ablated in hepatocytes with the Cre/LoxP approach, and found that specific deletion of hepatic Lpl resulted in a significant decrease in plasma LPL contents and activity. As a result, the postprandial TG clearance was markedly impaired, and plasma TG and cholesterol levels were significantly elevated. However, deficiency of hepatic Lpl did not change the liver TG and cholesterol contents or glucose homeostasis. Taken together, our study reveals that hepatic LPL is involved in the regulation of plasma LPL activity and lipid homeostasis. PMID:27234787

  9. Protein kinase LKB1 regulates polarized dendrite formation of adult hippocampal newborn neurons.

    PubMed

    Huang, Wei; She, Liang; Chang, Xing-ya; Yang, Rong-rong; Wang, Liang; Ji, Hong-bin; Jiao, Jian-wei; Poo, Mu-ming

    2014-01-01

    Adult-born granule cells in the dentate gyrus of the rodent hippocampus are important for memory formation and mood regulation, but the cellular mechanism underlying their polarized development, a process critical for their incorporation into functional circuits, remains unknown. We found that deletion of the serine-threonine protein kinase LKB1 or overexpression of dominant-negative LKB1 reduced the polarized initiation of the primary dendrite from the soma and disrupted its oriented growth toward the molecular layer. This abnormality correlated with the dispersion of Golgi apparatus that normally accumulated at the base and within the initial segment of the primary dendrite, and was mimicked by disrupting Golgi organization via altering the expression of Golgi structural proteins GM130 or GRASP65. Thus, besides its known function in axon formation in embryonic pyramidal neurons, LKB1 plays an additional role in regulating polarized dendrite morphogenesis in adult-born granule cells in the hippocampus. PMID:24367100

  10. The Wnt Adaptor Protein ATP6AP2 Regulates Multiple Stages of Adult Hippocampal Neurogenesis

    PubMed Central

    Han, Jinju; Pena, Monique; von Bohlen und Halbach, Oliver; Peters, Jörg; Gage, Fred H.

    2015-01-01

    In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/β-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non-canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/β-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts. PMID:25810528

  11. The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis.

    PubMed

    Schafer, Simon T; Han, Jinju; Pena, Monique; von Bohlen Und Halbach, Oliver; Peters, Jörg; Gage, Fred H

    2015-03-25

    In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/β-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non-canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/β-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts. PMID:25810528

  12. miR-17-92 Cluster Regulates Adult Hippocampal Neurogenesis, Anxiety, and Depression.

    PubMed

    Jin, Junghee; Kim, Seung-Nam; Liu, Xuqing; Zhang, Haijun; Zhang, Chao; Seo, Ji-Seon; Kim, Yong; Sun, Tao

    2016-08-01

    Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors. PMID:27477270

  13. Cortisol-treated zebrafish embryos develop into pro-inflammatory adults with aberrant immune gene regulation.

    PubMed

    Hartig, Ellen I; Zhu, Shusen; King, Benjamin L; Coffman, James A

    2016-01-01

    Chronic early-life stress increases adult susceptibility to numerous health problems linked to chronic inflammation. One way that this may occur is via glucocorticoid-induced developmental programming. To gain insight into such programming we treated zebrafish embryos with cortisol and examined the effects on both larvae and adults. Treated larvae had elevated whole-body cortisol and glucocorticoid signaling, and upregulated genes associated with defense response and immune system processes. In adulthood the treated fish maintained elevated basal cortisol levels in the absence of exogenous cortisol, and constitutively mis-expressed genes involved in defense response and its regulation. Adults derived from cortisol-treated embryos displayed defective tailfin regeneration, heightened basal expression of pro-inflammatory genes, and failure to appropriately regulate those genes following injury or immunological challenge. These results support the hypothesis that chronically elevated glucocorticoid signaling early in life directs development of a pro-inflammatory adult phenotype, at the expense of immunoregulation and somatic regenerative capacity. PMID:27444789

  14. Cortisol-treated zebrafish embryos develop into pro-inflammatory adults with aberrant immune gene regulation

    PubMed Central

    Hartig, Ellen I.; Zhu, Shusen; King, Benjamin L.

    2016-01-01

    ABSTRACT Chronic early-life stress increases adult susceptibility to numerous health problems linked to chronic inflammation. One way that this may occur is via glucocorticoid-induced developmental programming. To gain insight into such programming we treated zebrafish embryos with cortisol and examined the effects on both larvae and adults. Treated larvae had elevated whole-body cortisol and glucocorticoid signaling, and upregulated genes associated with defense response and immune system processes. In adulthood the treated fish maintained elevated basal cortisol levels in the absence of exogenous cortisol, and constitutively mis-expressed genes involved in defense response and its regulation. Adults derived from cortisol-treated embryos displayed defective tailfin regeneration, heightened basal expression of pro-inflammatory genes, and failure to appropriately regulate those genes following injury or immunological challenge. These results support the hypothesis that chronically elevated glucocorticoid signaling early in life directs development of a pro-inflammatory adult phenotype, at the expense of immunoregulation and somatic regenerative capacity. PMID:27444789

  15. Regulation of brain water during acute glucose-induced hyperosmolality in ovine fetuses, lambs, and adults.

    PubMed

    Stonestreet, Barbara S; Petersson, Katherine H; Sadowska, Grazyna B; Patlak, Clifford S

    2004-02-01

    We tested the hypothesis that, during acute glucose-induced hyperosmolality, the brain shrinks less than predicted on the basis of an ideal osmometer and that brain volume regulation is present in fetuses, premature and newborn lambs. Brain water responses to glucose-induced hyperosmolality were measured in the cerebral cortex, cerebellum, and medulla of fetuses at 60% of gestation, premature ventilated lambs at 90% of gestation, newborn lambs, and adult sheep. After exposure of the sheep to increases in osmolality with glucose plus NaCl, brain water and electrolytes were measured. The ideal osmometer is a system in which impermeable solutes do not enter or leave in response to an osmotic stress. In the absence of volume regulation, brain solute remains constant as osmolality changes. The osmotically active solute demonstrated direct linear correlations with plasma osmolality in the cerebral cortex of the fetuses at 60% of gestation (r = 0.72, n = 24, P = 0.0001), premature lambs (r = 0.58, n = 22, P = 0.005), newborn lambs (r = 0.57, n = 24, P = 0.004), and adult sheep (r = 0.70, n = 18, P = 0.001). Similar findings were observed in the cerebellum and medulla. Increases in the quantity of osmotically active solute over the range of plasma osmolalities indicate that volume regulation was present in the brain regions of the fetuses, premature lambs, newborn lambs, and adult sheep during glucose-induced hyperosmolality. We conclude that, during glucose-induced hyperosmolality, the brain shrinks less than predicted on the basis of an ideal osmometer and exhibits volume regulation in fetuses at 60% of gestation, premature lambs, newborn lambs, and adult sheep. PMID:14578364

  16. Dietary and sex-specific factors regulate hypothalamic neurogenesis in young adult mice

    PubMed Central

    Lee, Daniel A.; Yoo, Sooyeon; Pak, Thomas; Salvatierra, Juan; Velarde, Esteban; Aja, Susan; Blackshaw, Seth

    2014-01-01

    The hypothalamus is the central regulator of a broad range of homeostatic and instinctive physiological processes, such as the sleep-wake cycle, food intake, and sexually dimorphic behaviors. These behaviors can be modified by various environmental and physiological cues, although the molecular and cellular mechanisms that mediate these effects remain poorly understood. Recently, it has become clear that both the juvenile and adult hypothalamus exhibit ongoing neurogenesis, which serve to modify homeostatic neural circuitry. In this report, we share new findings on the contributions of sex-specific and dietary factors to regulating neurogenesis in the hypothalamic mediobasal hypothalamus, a recently identified neurogenic niche. We report that high fat diet (HFD) selectively activates neurogenesis in the median eminence (ME) of young adult female but not male mice, and that focal irradiation of the ME in HFD-fed mice reduces weight gain in females but not males. These results suggest that some physiological effects of high fat diet are mediated by the stimulation of ME neurogenesis in a sexually dimorphic manner. We discuss these results in the context of recent advances in understanding the cellular and molecular mechanisms that regulate neurogenesis in postnatal and adult hypothalamus. PMID:24982613

  17. Professionalisation as development and as regulation: Adult education in Germany, the United Kingdom and India

    NASA Astrophysics Data System (ADS)

    Doyle, Lesley; Egetenmeyer, Regina; Singai, Chetan; Devi, Uma

    2016-06-01

    In this paper, the authors seek to disentangle what they see as contradictory uses of the term "professionalisation" with reference to adult educator development and training (AEDT). They set out to distinguish professionalisation from professionalism, and to identify the locus of control of AEDT in Germany, the UK and India. In these three countries, all of which have a long tradition of adult education, "professionalisation" and "professionalism" are used interchangeably to describe conflicting purposes. The authors aim to identify and critically explore the organisations and policies which control and support AEDT in their own countries using American sociologist Eliot Freidson's "third logic" model, and drawing on his juxtaposition of "professions", "the market" and "bureaucracy". Applying Freidson's models to the organisations highlights the role of bureaucracy and that where adult education is concerned, national governments, the European Union and aid organisations not only serve bureaucracy but also support the market rather than operating separately from it. While the term "professionalisation" continues to be used to mean professional development, either by adult educators and representative organisations (as in the UK) or by organisations acting on their behalf (as in Germany and India), it is also used to denote regulation and standardisation issuing from bureaucratic institutions and adult education provider organisations in the interests of the market. The authors suggest that Freidson's model provides a useful tool for adult educators in other countries to reflect on their professional position and to engage in the development of their own professional standards, both in their own interests and in the interests of those they educate.

  18. Hepatitis C virus suppresses Hepatocyte Nuclear Factor 4 alpha, a key regulator of hepatocellular carcinoma.

    PubMed

    Vallianou, Ioanna; Dafou, Dimitra; Vassilaki, Niki; Mavromara, Penelope; Hadzopoulou-Cladaras, Margarita

    2016-09-01

    Hepatitis C Virus (HCV) infection presents with a disturbed lipid profile and can evolve to hepatic steatosis and hepatocellular carcinoma (HCC). Hepatocyte Nuclear Factor 4 alpha (HNF4α) is the most abundant transcription factor in the liver, a key regulator of hepatic lipid metabolism and a critical determinant of Epithelial to Mesenchymal Transition and hepatic development. We have previously shown that transient inhibition of HNF4α initiates transformation of immortalized hepatocytes through a feedback loop consisting of miR-24, IL6 receptor (IL6R), STAT3, miR-124 and miR-629, suggesting a central role of HNF4α in HCC. However, the role of HNF4α in Hepatitis C Virus (HCV)-related hepatocarcinoma has not been evaluated and remains controversial. In this study, we provide strong evidence suggesting that HCV downregulates HNF4α expression at both transcriptional and translational levels. The observed decrease of HNF4α expression correlated with the downregulation of its downstream targets, HNF1α and MTP. Ectopic overexpression of HCV proteins also exhibited an inhibitory effect on HNF4α levels. The inhibition of HNF4α expression by HCV appeared to be mediated at transcriptional level as HCV proteins suppressed HNF4α gene promoter activity. HCV also up-regulated IL6R, activated STAT3 protein phosphorylation and altered the expression of acute phase genes. Furthermore, as HCV triggered the loss of HNF4α a consequent change of miR-24, miR-629 or miR-124 was observed. Our findings demonstrated that HCV-related HCC could be mediated through HNF4α-microRNA deregulation implying a possible role of HNF4α in HCV hepatocarcinogenesis. HCV inhibition of HNF4α could be sustained to promote HCC. PMID:27477312

  19. Reelin Exerts Structural, Biochemical and Transcriptional Regulation Over Presynaptic and Postsynaptic Elements in the Adult Hippocampus

    PubMed Central

    Bosch, Carles; Muhaisen, Ashraf; Pujadas, Lluís; Soriano, Eduardo; Martínez, Albert

    2016-01-01

    Reelin regulates neuronal positioning and synaptogenesis in the developing brain, and adult brain plasticity. Here we used transgenic mice overexpressing Reelin (Reelin-OE mice) to perform a comprehensive dissection of the effects of this protein on the structural and biochemical features of dendritic spines and axon terminals in the adult hippocampus. Electron microscopy (EM) revealed both higher density of synapses and structural complexity of both pre- and postsynaptic elements in transgenic mice than in WT mice. Dendritic spines had larger spine apparatuses, which correlated with a redistribution of Synaptopodin. Most of the changes observed in Reelin-OE mice were reversible after blockade of transgene expression, thus supporting the specificity of the observed phenotypes. Western blot and transcriptional analyses did not show major changes in the expression of pre- or postsynaptic proteins, including SNARE proteins, glutamate receptors, and scaffolding and signaling proteins. However, EM immunogold assays revealed that the NMDA receptor subunits NR2a and NR2b, and p-Cofilin showed a redistribution from synaptic to extrasynaptic pools. Taken together with previous studies, the present results suggest that Reelin regulates the structural and biochemical properties of adult hippocampal synapses by increasing their density and morphological complexity and by modifying the distribution and trafficking of major glutamatergic components. PMID:27303269

  20. Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

    PubMed

    Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

    2016-03-15

    Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. PMID:26851220

  1. Regulation of adult hematopoiesis by the a disintegrin and metalloproteinase 10 (ADAM10).

    PubMed

    Weber, Silvio; Wetzel, Sebastian; Prox, Johannes; Lehmann, Tobias; Schneppenheim, Janna; Donners, Marjo; Saftig, Paul

    2013-12-13

    Adult hematopoiesis requires tightly regulated cell-cell interactions between hematopoietic cells and the bone marrow stromal microenvironment. We addressed the question if the ectodomain sheddase ADAM10 is essential to regulate adult hematopoiesis. Induced ADAM10 deletion in hematopoietic cells resulted in morphological and histological abnormalities that resemble an unclassified myeloproliferative disorder (MPD). The MPD was characterized by an expansion of granulocytic subpopulations and their infiltration of peripheral hematopoietic tissues, the development of hepatosplenomegaly with extramedullary erythropoiesis, lymphnodepathy and death of the mice around 20weeks after induction. ADAM10 expression analysis during the different stages of the MPD revealed that non-targeted hematopoietic cells repopulated the immune system of the ADAM10-deficient mice. Examination of mice with a myeloid- or epidermis-specific deletion of ADAM10 and bone marrow transplantation (BMT) experiments indicated that the development of the MPD can be triggered by non-cell autonomous effects. We found that plasma levels of clinical markers for MPD such as G-CSF, TIMP-1 and IL-16 were significantly elevated in ADAM10-deficient mice. Our findings indicate that a tightly controlled ADAM10 expression is needed to balance hematopoietic cell-fate decisions in adult mice. PMID:24239882

  2. Self-Regulation, Metacognition and Child- and Adult-Initiated Activity: Does It Matter Who Initiates the Task?

    ERIC Educational Resources Information Center

    Robson, Sue

    2016-01-01

    Debate about the balance between child- and adult-initiated activities in early childhood settings is long standing. This article reports a study of 29 children aged 4-5 years in a London state school, on the influences of child- and adult-initiated activities on children's self-regulation and metacognition. Whilst both contexts were supportive,…

  3. The role of CD44 in fetal and adult hematopoietic stem cell regulation

    PubMed Central

    Cao, Huimin; Heazlewood, Shen Y.; Williams, Brenda; Cardozo, Daniela; Nigro, Julie; Oteiza, Ana; Nilsson, Susan K.

    2016-01-01

    Throughout development, hematopoietic stem cells migrate to specific microenvironments, where their fate is, in part, extrinsically controlled. CD44 standard as a member of the cell adhesion molecule family is extensively expressed within adult bone marrow and has been previously reported to play important roles in adult hematopoietic regulation via CD44 standard-ligand interactions. In this manuscript, CD44 expression and function are further assessed and characterized on both fetal and adult hematopoietic stem cells. Using a CD44−/− mouse model, conserved functional roles of CD44 are revealed throughout development. CD44 is critical in the maintenance of hematopoietic stem and progenitor pools, as well as in hematopoietic stem cell migration. CD44 expression on hematopoietic stem cells as well as other hematopoietic cells within the bone marrow microenvironment is important in the homing and lodgment of adult hematopoietic stem cells isolated from the bone/bone marrow interface. CD44 is also involved in fetal hematopoietic stem cell migration out of the liver, via a process involving stromal cell-derived factor-1α. The absence of CD44 in neonatal bone marrow has no impact on the size of the long-term reconstituting hematopoietic stem cell pool, but results in an enhanced long-term engraftment potential of hematopoietic stem cells. PMID:26546504

  4. Adult plant development in triticale (× triticosecale wittmack) is controlled by dynamic genetic patterns of regulation.

    PubMed

    Würschum, Tobias; Liu, Wenxin; Alheit, Katharina V; Tucker, Matthew R; Gowda, Manje; Weissmann, Elmar A; Hahn, Volker; Maurer, Hans Peter

    2014-09-01

    Many biologically and agronomically important traits are dynamic and show temporal variation. In this study, we used triticale (× Triticosecale Wittmack) as a model crop to assess the genetic dynamics underlying phenotypic plasticity of adult plant development. To this end, a large mapping population with 647 doubled haploid lines derived from four partially connected families from crosses among six parents was scored for developmental stage at three different time points. Using genome-wide association mapping, we identified main effect and epistatic quantitative trait loci (QTL) at all three time points. Interestingly, some of these QTL were identified at all time points, whereas others appear to only contribute to the genetic architecture at certain developmental stages. Our results illustrate the temporal contribution of QTL to the genetic control of adult plant development and more generally, the temporal genetic patterns of regulation that underlie dynamic traits. PMID:25237110

  5. TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration.

    PubMed

    Nicklas, Sarah; Otto, Anthony; Wu, Xiaoli; Miller, Pamela; Stelzer, Sandra; Wen, Yefei; Kuang, Shihuan; Wrogemann, Klaus; Patel, Ketan; Ding, Hao; Schwamborn, Jens C

    2012-01-01

    Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H. PMID:22299041

  6. [Emotional experience and regulation across the adult lifespan: comparative analysis in three age groups].

    PubMed

    Márquez-González, María; Izal Fernández de Trocóniz, María; Montorio Cerrato, Ignacio; Losada Baltar, Andrés

    2008-11-01

    The studies focused on age-related differences in emotional experience are still scarce, and most of them have been conducted with North-American samples. This study explores the presence of age-related differences in some facets of emotional experience (subjective well-being and emotional intensity), as well as in variables related to emotion regulation (subjective emotional control and three emotion-regulation mechanisms: situation selection, emotion suppression, rumination) in the Spanish population. One hundred and sixty people from three age groups (younger, middle-aged and older adults) participated in the study. Older participants reported lower levels of life satisfaction and positive emotional intensity than younger ones, as well as higher levels of perceived emotional control, emotional maturity and leveling of positive affect, and more use of emotion suppression. The results partially support the emotional maturity hypothesis of emotional functioning in old age, but also suggest that older adults' emotional regulation may present important peculiarities which have not yet been addressed in the extant literature, such as the moderation or limitation of emotional experience, especially positive emotions. PMID:18940059

  7. MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3

    SciTech Connect

    Lu, Yanxin; Yue, Xupeng; Cui, Yuanyuan; Zhang, Jufeng; Wang, KeWei

    2013-11-29

    Highlights: •miR-124 is down-regulated in hepatocellular carcinoma HepG2 cells. •Over-expression of miR-124 suppresses proliferation and induces apoptosis in HepG2 cells. •miR-124 inhibits xenograft tumor growth in nude mice implanted with HepG2 cells by reducing STAT3 expression. •STATs function as a novel target of miR-124 in HCC HepG2 cells. -- Abstract: The aberrant expression of microRNAs is associated with development and progression of cancers. Down-regulation of miR-124 has been demonstrated in the hepatocellular carcinoma (HCC), but the underlying mechanism by which miR-124 suppresses tumorigenesis in HCC remains elusive. In this study, we found that miR-124 suppresses the tumor growth of HCC through targeting the signal transducers and activators of transcription 3 (STAT3). Overexpression of miR-124 suppressed proliferation and induced apoptosis in HepG-2 cells. Luciferase assay confirmed that miR-124 binding to the 3′-UTR region of STAT3 inhibited the expression of STAT3 and phosphorylated STAT3 proteins in HepG-2 cells. Knockdown of STAT3 by siRNA in HepG-2 cells mimicked the effect induced by miR-124. Overexpression of STAT3 in miR-124-transfected HepG-2 cells effectively rescued the inhibition of cell proliferation caused by miR-124. Furthermore, miR-124 suppressed xenograft tumor growth in nude mice implanted with HepG-2 cells by reducing STAT3 expression. Taken together, our findings show that miR-124 functions as tumor suppressor in HCC by targeting STAT3, and miR-124 may therefore serve as a biomarker for diagnosis and therapeutics in HCC.

  8. Lipoprotein Receptor LRP1 Regulates Leptin Signaling and Energy Homeostasis in the Adult Central Nervous System

    PubMed Central

    Liu, Qiang; Zhang, Juan; Zerbinatti, Celina; Zhan, Yan; Kolber, Benedict J.; Herz, Joachim; Muglia, Louis J.; Bu, Guojun

    2011-01-01

    Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system. PMID:21264353

  9. An Annotated Bibliography: Using Theories of Self-Regulation to Understand How Adults Learn in Various Contexts

    ERIC Educational Resources Information Center

    Artino, Anthony R., Jr.

    2007-01-01

    The present report presents an annotated bibliography of peer-reviewed articles that employed theories of self-regulation to understand how adults learn in various contexts. Seven scholarly articles, published between 2000 and 2006, were reviewed and summarized. Articles reviewed include (1) Self-regulation in a Web-based Course: A Case Study (J.…

  10. New Tools for the Identification of Developmentally Regulated Enhancer Regions in Embryonic and Adult Zebrafish

    PubMed Central

    Krauss, Jana; Koehler, Carla; Boden, Cindy; Harris, Matthew P.

    2013-01-01

    Abstract We have conducted a screen to identify developmentally regulated enhancers that drive tissue-specific Gal4 expression in zebrafish. We obtained 63 stable transgenic lines with expression patterns in embryonic or adult zebrafish. The use of a newly identified minimal promoter from the medaka edar locus resulted in a relatively unbiased set of expression patterns representing many tissue types derived from all germ layers. Subsequent detailed characterization of selected lines showed strong and reproducible Gal4-driven GFP expression in diverse tissues, including neurons from the central and peripheral nervous systems, pigment cells, erythrocytes, and peridermal cells. By screening adults for GFP expression, we also isolated lines expressed in tissues of the adult zebrafish, including scales, fin rays, and joints. The new and efficient minimal promoter and large number of transactivating driver-lines we identified will provide the zebrafish community with a useful resource for further enhancer trap screening, as well as precise investigation of tissue-specific processes in vivo. PMID:23461416

  11. Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation

    PubMed Central

    Lei, Jinzhi; Levin, Simon A.; Nie, Qing

    2014-01-01

    Adult stem cells, which exist throughout the body, multiply by cell division to replenish dying cells or to promote regeneration to repair damaged tissues. To perform these functions during the lifetime of organs or tissues, stem cells need to maintain their populations in a faithful distribution of their epigenetic states, which are susceptible to stochastic fluctuations during each cell division, unexpected injury, and potential genetic mutations that occur during many cell divisions. However, it remains unclear how the three processes of differentiation, proliferation, and apoptosis in regulating stem cells collectively manage these challenging tasks. Here, without considering molecular details, we propose a genetic optimal control model for adult stem cell regeneration that includes the three fundamental processes, along with cell division and adaptation based on differential fitnesses of phenotypes. In the model, stem cells with a distribution of epigenetic states are required to maximize expected performance after each cell division. We show that heterogeneous proliferation that depends on the epigenetic states of stem cells can improve the maintenance of stem cell distributions to create balanced populations. A control strategy during each cell division leads to a feedback mechanism involving heterogeneous proliferation that can accelerate regeneration with less fluctuation in the stem cell population. When mutation is allowed, apoptosis evolves to maximize the performance during homeostasis after multiple cell divisions. The overall results highlight the importance of cross-talk between genetic and epigenetic regulation and the performance objectives during homeostasis in shaping a desirable heterogeneous distribution of stem cells in epigenetic states. PMID:24501127

  12. Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence

    PubMed Central

    Parkash, Jyoti; Messina, Andrea; Langlet, Fanny; Cimino, Irene; Loyens, Anne; Mazur, Danièle; Gallet, Sarah; Balland, Eglantine; Malone, Samuel A.; Pralong, François; Cagnoni, Gabriella; Schellino, Roberta; De Marchis, Silvia; Mazzone, Massimiliano; Pasterkamp, R. Jeroen; Tamagnone, Luca; Prevot, Vincent; Giacobini, Paolo

    2015-01-01

    Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic–pituitary–gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle. PMID:25721933

  13. Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence.

    PubMed

    Parkash, Jyoti; Messina, Andrea; Langlet, Fanny; Cimino, Irene; Loyens, Anne; Mazur, Danièle; Gallet, Sarah; Balland, Eglantine; Malone, Samuel A; Pralong, François; Cagnoni, Gabriella; Schellino, Roberta; De Marchis, Silvia; Mazzone, Massimiliano; Pasterkamp, R Jeroen; Tamagnone, Luca; Prevot, Vincent; Giacobini, Paolo

    2015-01-01

    Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic-pituitary-gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle. PMID:25721933

  14. Energy Density, Energy Intake, and Body Weight Regulation in Adults12345

    PubMed Central

    Karl, J. Philip; Roberts, Susan B.

    2014-01-01

    The role of dietary energy density (ED) in the regulation of energy intake (EI) is controversial. Methodologically, there is also debate about whether beverages should be included in dietary ED calculations. To address these issues, studies examining the effects of ED on EI or body weight in nonelderly adults were reviewed. Different approaches to calculating dietary ED do not appear to alter the direction of reported relations between ED and body weight. Evidence that lowering dietary ED reduces EI in short-term studies is convincing, but there are currently insufficient data to determine long-term effectiveness for weight loss. The review also identified key barriers to progress in understanding the role of ED in energy regulation, in particular the absence of a standard definition of ED, and the lack of data from multiple long-term clinical trials examining the effectiveness of low-ED diet recommendations for preventing both primary weight gain and weight regain in nonobese individuals. Long-term clinical trials designed to examine the impact of dietary ED on energy regulation, and including multiple ED calculation methods within the same study, are still needed to determine the importance of ED in the regulation of EI and body weight. PMID:25398750

  15. Differential neurotrophic regulation of sodium and calcium channels in an adult sympathetic neuron.

    PubMed

    Ford, Christopher P; Wong, Kenneth V; Lu, Van B; Posse de Chaves, Elena; Smith, Peter A

    2008-03-01

    Adult neuronal phenotype is maintained, at least in part, by the sensitivity of individual neurons to a specific selection of neurotrophic factors and the availability of such factors in the neurons' environment. Nerve growth factor (NGF) increases the functional expression of Na(+) channel currents (I(Na)) and both N- and L-type Ca(2+) currents (I(Ca,N) and I(Ca,L)) in adult bullfrog sympathetic ganglion (BFSG) B-neurons. The effects of NGF on I(Ca) involve the mitogen-activated protein kinase (MAPK) pathway. Prolonged exposure to the ganglionic neurotransmitter luteinizing hormone releasing hormone (LHRH) also increases I(Ca,N) but the transduction mechanism remains to be elucidated as does the transduction mechanism for NGF regulation of Na(+) channels. We therefore exposed cultured BFSG B-neurons to chicken II LHRH (0.45 microM; 6-9 days) or to NGF (200 ng/ml; 9-10 days) and used whole cell recording, immunoblot analysis, and ras or rap-1 pulldown assays to study effects of various inhibitors and activators of transduction pathways. We found that 1) LHRH signals via ras-MAPK to increase I(Ca,N), 2) this effect is mediated via protein kinase C-beta (PKC-beta-IotaIota), 3) protein kinase A (PKA) is necessary but not sufficient to effect transduction, 4) NGF signals via phosphatidylinositol 3-kinase (PI3K) to increase I(Na), and 5) long-term exposure to LHRH fails to affect I(Na). Thus downstream signaling from LHRH has access to the ras-MAPK pathway but not to the PI3K pathway. This allows for differential retrograde and anterograde neurotrophic regulation of sodium and calcium channels in an adult sympathetic neuron. PMID:18216230

  16. Executive function and self-regulated exergaming adherence among older adults.

    PubMed

    Anderson-Hanley, Cay; Arciero, Paul J; Barcelos, Nicole; Nimon, Joseph; Rocha, Tracey; Thurin, Marisa; Maloney, Molly

    2014-01-01

    The rise in dementia and the evidence of cognitive benefits of exercise for the older adult population together make salient the research into variables affecting cognitive benefit and exercise behavior. One promising avenue for increasing exercise participation has been the introduction of exergaming, a type of exercise that works in combination with virtual reality to enhance both the exercise experience and health outcomes. Past research has revealed that executive function (EF) was related to greater use of self-regulatory strategies, which in turn was related to greater adherence to exercise following an intervention (McAuley et al., 2011). Best et al. (2014) found improvement in EF related to adherence to exercise post- intervention. Anderson-Hanley et al. (2012) found that for older adults aerobic exergaming yielded greater cognitive benefit than traditional exercise alone; however, questions remain as to the possible impact of greater cognitive benefit and other factors on participants' involvement in exercise following the end of an intervention. The current study presents follow-up data exploring the relationship between EF, self-regulation, and exercise behavior in the post-intervention (naturalistic) period. Herein, it was predicted that higher EF at the start of the naturalistic window, would predict subsequent exercise with an exergame. Contrary to expectations, results suggest that those with poorer EF are likely to exergame more frequently. The results of this study contradict previous literature, but suggest an interesting relationship between EF, self-regulation, and exercise behaviors when exergaming is employed, particularly with older adults with some cognitive decline. We hypothesize that other factors may be at work, perhaps expectation of cognitive benefit might act as a unique motivator. PMID:25538608

  17. Executive function and self-regulated exergaming adherence among older adults

    PubMed Central

    Anderson-Hanley, Cay; Arciero, Paul J.; Barcelos, Nicole; Nimon, Joseph; Rocha, Tracey; Thurin, Marisa; Maloney, Molly

    2014-01-01

    The rise in dementia and the evidence of cognitive benefits of exercise for the older adult population together make salient the research into variables affecting cognitive benefit and exercise behavior. One promising avenue for increasing exercise participation has been the introduction of exergaming, a type of exercise that works in combination with virtual reality to enhance both the exercise experience and health outcomes. Past research has revealed that executive function (EF) was related to greater use of self-regulatory strategies, which in turn was related to greater adherence to exercise following an intervention (McAuley et al., 2011). Best et al. (2014) found improvement in EF related to adherence to exercise post- intervention. Anderson-Hanley et al. (2012) found that for older adults aerobic exergaming yielded greater cognitive benefit than traditional exercise alone; however, questions remain as to the possible impact of greater cognitive benefit and other factors on participants’ involvement in exercise following the end of an intervention. The current study presents follow-up data exploring the relationship between EF, self-regulation, and exercise behavior in the post-intervention (naturalistic) period. Herein, it was predicted that higher EF at the start of the naturalistic window, would predict subsequent exercise with an exergame. Contrary to expectations, results suggest that those with poorer EF are likely to exergame more frequently. The results of this study contradict previous literature, but suggest an interesting relationship between EF, self-regulation, and exercise behaviors when exergaming is employed, particularly with older adults with some cognitive decline. We hypothesize that other factors may be at work, perhaps expectation of cognitive benefit might act as a unique motivator. PMID:25538608

  18. Drebrin A regulates hippocampal LTP and hippocampus-dependent fear learning in adult mice.

    PubMed

    Kojima, N; Yasuda, H; Hanamura, K; Ishizuka, Y; Sekino, Y; Shirao, T

    2016-06-01

    Structural plasticity of dendritic spines, which underlies higher brain functions including learning and memory, is dynamically regulated by the actin cytoskeleton and its associated proteins. Drebrin A is an F-actin-binding protein preferentially expressed in the brain and localized in the dendritic spines of mature neurons. Isoform conversion from drebrin E to drebrin A and accumulation of the latter in dendritic spines occurs during synapse maturation. We have previously demonstrated that drebrin A plays a pivotal role in spine morphogenesis and plasticity. However, it is unclear whether drebrin A plays a specific role in processes required for structural plasticity, and whether drebrin E can substitute in this role. To answer these questions, we analyzed mutant mice (named DAKO mice), in which isoform conversion from drebrin E to drebrin A is disrupted. In DAKO mouse brain, drebrin E continues to be expressed throughout life instead of drebrin A. Electrophysiological studies using hippocampal slices revealed that long-term potentiation of CA1 synapses was impaired in adult DAKO mice, but not in adolescents. In parallel with this age-dependent impairment, DAKO mice exhibited impaired hippocampus-dependent fear learning in an age-dependent manner; the impairment was evident in adult mice, but not in adolescents. In addition, histological investigation revealed that the spine length of the apical dendrite of CA1 pyramidal cells was significantly longer in adult DAKO mice than in wild-type mice. Our data indicate that the roles of drebrin E and drebrin A in brain function are different from each other, that the isoform conversion of drebrin is critical, and that drebrin A is indispensable for normal synaptic plasticity and hippocampus-dependent fear memory in the adult brain. PMID:26970584

  19. Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity

    PubMed Central

    Rusanescu, Gabriel; Mao, Jianren

    2015-01-01

    Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long-term increase in the number of spinal cord laminae I–II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long-term nociception. TrkB agonists, well-known promoters of nociception in the short-term, significantly inhibit long-term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain. PMID:26223362

  20. NeuroD modulates opioid agonist-selective regulation of adult neurogenesis and contextual memory extinction.

    PubMed

    Zheng, Hui; Zhang, Yue; Li, Wen; Loh, Horace H; Law, Ping-Yee

    2013-04-01

    Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP, but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus before CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190-virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse. PMID:23303051

  1. Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins

    PubMed Central

    Cui, Xiaofeng; Lu, Yao Wei; Lee, Vivian; Kim, Diana; Dorsey, Taylor; Wang, Qingjie; Lee, Young; Vincent, Peter; Schwarz, John; Dai, Guohao

    2015-01-01

    Arteries and veins have very different susceptibility to certain vascular diseases such as atherosclerosis and vascular calcification. The molecular mechanisms of these differences are not fully understood. In this study, we discovered that COUP-TFII, a transcription factor critical for establishing the venous identity during embryonic vascular development, also regulates the pathophysiological functions of adult blood vessels, especially those directly related to vascular diseases. Specifically, we found that suppression of COUP-TFII in venous ECs switched its phenotype toward pro-atherogenic by up-regulating the expression of inflammatory genes and down-regulating anti-thrombotic genes. ECs with COUP-TFII knockdown also readily undergo endothelial-to-mesenchymal transition (EndoMT) and subsequent osteogenic differentiation with dramatically increased osteogenic transcriptional program and calcium deposition. Consistently, over-expression of COUP-TFII led to the completely opposite effects. In vivo validation of these pro-atherogenic and osteogenic genes also demonstrates a broad consistent differential expression pattern in mouse aorta vs. vena cava ECs, which cannot be explained by the difference in hemodynamic flow. These data reveal phenotypic modulation by different levels of COUP-TFII in arterial and venous ECs, and suggest COUP-TFII may play an important role in the different susceptibilities of arteries and veins to vascular diseases such as atherosclerosis and vascular calcification. PMID:26537113

  2. The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila.

    PubMed

    Wang, Zhenghan; Tian, Ai; Benchabane, Hassina; Tacchelly-Benites, Ofelia; Yang, Eungi; Nojima, Hisashi; Ahmed, Yashi

    2016-05-15

    Wnt/β-catenin signaling controls intestinal stem cell (ISC) proliferation, and is aberrantly activated in colorectal cancer. Inhibitors of the ADP-ribose polymerase Tankyrase (Tnks) have become lead therapeutic candidates for Wnt-driven cancers, following the recent discovery that Tnks targets Axin, a negative regulator of Wnt signaling, for proteolysis. Initial reports indicated that Tnks is important for Wnt pathway activation in cultured human cell lines. However, the requirement for Tnks in physiological settings has been less clear, as subsequent studies in mice, fish and flies suggested that Tnks was either entirely dispensable for Wnt-dependent processes in vivo, or alternatively, had tissue-specific roles. Here, using null alleles, we demonstrate that the regulation of Axin by the highly conserved Drosophila Tnks homolog is essential for the control of ISC proliferation. Furthermore, in the adult intestine, where activity of the Wingless pathway is graded and peaks at each compartmental boundary, Tnks is dispensable for signaling in regions where pathway activity is high, but essential where pathway activity is relatively low. Finally, as observed previously for Wingless pathway components, Tnks activity in absorptive enterocytes controls the proliferation of neighboring ISCs non-autonomously by regulating JAK/STAT signaling. These findings reveal the requirement for Tnks in the control of ISC proliferation and suggest an essential role in the amplification of Wnt signaling, with relevance for development, homeostasis and cancer. PMID:27190037

  3. The thioredoxin TRX-1 regulates adult lifespan extension induced by dietary restriction in Caenorhabditis elegans

    SciTech Connect

    Fierro-Gonzalez, Juan Carlos; Gonzalez-Barrios, Maria; Miranda-Vizuete, Antonio

    2011-03-18

    Highlights: {yields} First in vivo data for thioredoxin in dietary-restriction-(DR)-induced longevity. {yields} Thioredoxin (trx-1) loss suppresses longevity of eat-2 mutant, a genetic DR model. {yields} trx-1 overexpression extends wild-type longevity, but not that of eat-2 mutant. {yields} Longevity by dietary deprivation (DD), a non-genetic DR model, requires trx-1. {yields} trx-1 expression in ASJ neurons of aging adults is increased in response to DD. -- Abstract: Dietary restriction (DR) is the only environmental intervention known to extend adult lifespan in a wide variety of animal models. However, the genetic and cellular events that mediate the anti-aging programs induced by DR remain elusive. Here, we used the nematode Caenorhabditis elegans to provide the first in vivo evidence that a thioredoxin (TRX-1) regulates adult lifespan extension induced by DR. We found that deletion of the gene trx-1 completely suppressed the lifespan extension caused by mutation of eat-2, a genetic surrogate of DR in the worm. However, trx-1 deletion only partially suppressed the long lifespan caused by mutation of the insulin-like receptor gene daf-2 or by mutation of the sensory cilia gene osm-5. A trx-1::GFP translational fusion expressed from its own promoter in ASJ neurons (Ptrx-1::trx-1::GFP) rescued the trx-1 deletion-mediated suppression of the lifespan extension caused by mutation of eat-2. This rescue was not observed when trx-1::GFP was expressed from the ges-1 promoter in the intestine. In addition, overexpression of Ptrx-1::trx-1::GFP extended lifespan in wild type, but not in eat-2 mutants. trx-1 deletion almost completely suppressed the lifespan extension induced by dietary deprivation (DD), a non-genetic, nutrient-based model of DR in the worm. Moreover, DD upregulated the expression of a trx-1 promoter-driven GFP reporter gene (Ptrx-1::GFP) in ASJ neurons of aging adults, but not that of control Pgpa-9::GFP (which is also expressed in ASJ neurons). We propose

  4. MicroRNAs: regulators of neuronal fate

    PubMed Central

    Sun, Alfred X; Crabtree, Gerald R; Yoo, Andrew S

    2013-01-01

    Mammalian neural development has been traditionally studied in the context of evolutionarily conserved signaling pathways and neurogenic transcription factors. Recent studies suggest that microRNAs, a group of highly conserved non-coding regulatory small RNAs also play essential roles in neural development and neuronal function. A part of their action in the developing nervous system is to regulate subunit compositions of BAF complexes (ATP-dependent chromatin remodeling complexes), which appear to have dedicated functions during neural development. Intriguingly, ectopic expression of a set of brain-enriched microRNAs, miR-9/9* and miR-124 that promote the assembly of neuron-specific BAF complexes, convert the nonneuronal fate of human dermal fibroblasts towards post-mitotic neurons, thereby revealing a previously unappreciated instructive role of these microRNAs. In addition to these global effects, accumulating evidence indicate that many microRNAs could also function locally, such as at the growth cone or at synapses modulating synaptic activity and neuronal connectivity. Here we discuss some of the recent findings about microRNAs’ activity in regulating various developmental stages of neurons. PMID:23374323

  5. Regulation of adult cardiocyte growth: effects of active and passive mechanical loading

    NASA Technical Reports Server (NTRS)

    Decker, M. L.; Janes, D. M.; Barclay, M. M.; Harger, L.; Decker, R. S.

    1997-01-01

    Fluctuations in hemodynamic load have been documented to modulate contractile protein turnover and myofibrillar structure in the heart; however, the relative importance of active and passive loading in regulating adult cardiocyte growth remains unresolved. To address this issue at the cellular level, adult feline cardiocytes were cultured either on Silastic membranes or plastic surfaces. Cardiocyte-laden membranes were stretched 10% of their rest length to enhance passive loading, whereas heart cells cultured on plastic or Silastic were field stimulated at 1 Hz to mimic active loading. Turnover of contractile proteins and structural integrity of the contractile-cytoskeletal apparatus were monitored for periods ranging from 4 to 72 h. Active and passive loading elevated contractile protein synthesis nearly equally (approximately 50%) and promoted the attachment of remodeled myofibrils to vinculin-positive focal contacts and/or costameres during the first 24 h of loading. Thereafter, rates of contractile protein synthesis returned to control values in passively stretched heart cells but remained elevated in field-stimulated cultures. The fractional rate of growth was increased significantly (approximately 8%/day) in electrically paced cells, whereas in passively stretched cardiocytes the growth rate rose only modestly (approximately 2%/day). Changes in the rate of myocyte growth appeared more closely correlated with the development of focal contacts and myofibril remodeling than with changes in myofibrillar protein turnover per se. 2,3-Butanedione monoxime, nifedipine, and, to a lesser extent, ryanodine blocked field-stimulated contractile protein synthesis and myofibrillar remodeling but had no impact on protein turnover or myofibril reassembly in passively loaded cardiocytes. The results of these experiments imply that both active and passive loading stimulate contractile protein turnover and myofibril remodeling, but the generation of active tension accelerates

  6. Fragile X Mental Retardation Protein Regulates New Neuron Differentiation in the Adult Olfactory Bulb

    PubMed Central

    Scotto-Lomassese, Sophie; Nissant, Antoine; Mota, Tatiana; Néant-Féry, Marie; Oostra, Ben A.; Greer, Charles A.; Lledo, Pierre-Marie; Trembleau, Alain; Caillé, Isabelle

    2013-01-01

    The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis. PMID:21307257

  7. Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation.

    PubMed

    Lucassen, Paul J; Oomen, Charlotte A; Naninck, Eva F G; Fitzsimons, Carlos P; van Dam, Anne-Marie; Czeh, Boldizsár; Korosi, Aniko

    2015-09-01

    Exposure to stress is one of the best-known negative regulators of adult neurogenesis (AN). We discuss changes in neurogenesis in relation to exposure to stress, glucocorticoid hormones, and inflammation, with a particular focus on early development and on lasting effects of stress. Although the effects of acute and mild stress on AN are generally brief and can be quickly overcome, chronic exposure or more severe forms of stress can induce longer lasting reductions in neurogenesis that can, however, in part, be overcome by subsequent exposure to exercise, drugs targeting the stress system, and some antidepressants. Exposure to stress, particularly during the sensitive period of early life, may (re)program brain plasticity, in particular, in the hippocampus. This may increase the risk to develop cognitive or anxiety symptoms, common to brain diseases like dementia and depression in which plasticity changes occur, and a normalization of neurogenesis may be required for a successful treatment response and recovery. PMID:26330520

  8. Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis

    PubMed Central

    Ferrón, S. R.; Radford, E. J.; Domingo-Muelas, A.; Kleine, I.; Ramme, A.; Gray, D.; Sandovici, I.; Constancia, M.; Ward, A.; Menheniott, T. R.; Ferguson-Smith, A. C.

    2015-01-01

    Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Here we address the importance of Igf2 imprinting for murine adult neurogenesis in the subventricular zone (SVZ) and in the subgranular zone (SGZ) of the hippocampus in vivo. In the SVZ, paracrine IGF2 is a cerebrospinal fluid and endothelial-derived neurogenic factor requiring biallelic expression, with mutants having reduced activation of the stem cell pool and impaired olfactory bulb neurogenesis. In contrast, Igf2 is imprinted in the hippocampus acting as an autocrine factor expressed in neural stem cells (NSCs) solely from the paternal allele. Conditional mutagenesis of Igf2 in blood vessels confirms that endothelial-derived IGF2 contributes to NSC maintenance in SVZ but not in the SGZ, and that this is regulated by the biallelic expression of IGF2 in the vascular compartment. Our findings indicate that a regulatory decision to imprint or not is a functionally important mechanism of transcriptional dosage control in adult neurogenesis. PMID:26369386

  9. Low dose 4-MBC effect on neuroendocrine regulation of reproductive axis in adult male rats.

    PubMed

    Carou, Maria E; Ponzo, Osvaldo J; Cardozo Gutierrez, Romina P; Szwarcfarb, Berta; Deguiz, Maria L; Reynoso, Roxana; Carbone, Silvia; Moguilevsky, Jaime A; Scacchi, Pablo

    2008-09-01

    4-Methylbenzylidene camphor (4-MBC) is an ultraviolet absorbent. The objective of this paper was to evaluate the effect of 4-MBC low-dose exposure on the neuroendocrine reproductive regulation in male rats. Wistar male adult rats were injected sc. with 4-MBC during 5 days with a dose of 2 and 10mg/kg or during 2 days with a dose of 2 and 20mg/kg. In all rats serum prolactin, LH and FSH concentration were assayed. The hypothalamus of rats injected during 2 days were also dissected to study GnRH release. Rats that received 2 and 10mg/kg of 4-MBC during 5 days showed a decrease in the LH and FSH serum concentration. In rats injected during 2 days, serum LH decreased with 2 and 20mg/kg and FSH decreased with 2mg/kg of 4-MBC. In vitro hypothalamic GnRH release also decreased in these animals. These results show that low doses of 4-MBC inhibit the reproductive axis in adult male rats. PMID:21783915

  10. Sox8 is a critical regulator of adult Sertoli cell function and male fertility.

    PubMed

    O'Bryan, Moira K; Takada, Shuji; Kennedy, Claire L; Scott, Greg; Harada, Shun-ichi; Ray, Manas K; Dai, Qunsheng; Wilhelm, Dagmar; de Kretser, David M; Eddy, E Mitch; Koopman, Peter; Mishina, Yuji

    2008-04-15

    Sox8 encodes a high-mobility group transcription factor that is widely expressed during development. Sox8, -9 and -10 form group E of the Sox gene family which has been implicated in several human developmental disorders. In contrast to other SoxE genes, the role of Sox8 is unclear and Sox8 mouse mutants reportedly showed only idiopathic weight loss and reduced bone density. The careful analysis of our Sox8 null mice, however, revealed a progressive male infertility phenotype. Sox8 null males only sporadically produced litters of reduced size at young ages. We have shown that SOX8 protein is a product of adult Sertoli cells and its elimination results in an age-dependent deregulation of spermatogenesis, characterized by sloughing of spermatocytes and round spermatids, spermiation failure and a progressive disorganization of the spermatogenic cycle, which resulted in the inappropriate placement and juxtaposition of germ cell types within the epithelium. Those sperm that did enter the epididymides displayed abnormal motility. These data show that SOX8 is a critical regulator of adult Sertoli cell function and is required for both its cytoarchitectural and paracrine interactions with germ cells. PMID:18342849

  11. Neuregulin 1 as an endogenous regulator of nicotinic acetylcholine receptors in adult major pelvic ganglion neurons.

    PubMed

    Kim, Han-Gyu; Cho, Sung-Min; Lee, Choong-Ku; Jeong, Seong-Woo

    2015-08-01

    We investigated whether endogenous neuregulin 1 (NRG1) is released in a soluble form (called sNRG1) and upregulates expression of nicotinic acetylcholine receptor (nAChR) in autonomic major pelvic ganglion (MPG) neurons of adult rats. To elicit the release of sNRG1, either the hypogastric nerve or the pelvic nerve was electrically stimulated. Then, the MPG-conditioned medium (CM) was subjected to western blotting using an antibody directed against the N-terminal ectodomain of NRG1. Both sympathetic and parasympathetic nerve activation elicited the release of sNRG1 from MPG neurons in a frequency-dependent manner. The sNRG1 release was also induced by treatment of MPG neurons with either high KCl or neurotrophic factors. The biological activity of the released sNRG1 was detected by tyrosine phosphorylation (p185) of the ErbB2 receptors in MPG neurons. When MPG neurons were incubated for 6 h in the CM, the protein level of the nAChR α3 subunit and ACh-induced current (IACh) density were significantly increased. The CM-induced changes in IACh was abolished by a selective ErbB2 tyrosine kinase inhibitor. Taken together, these data suggest that NRG1 functions as an endogenous regulator of nAChR expression in adult MPG neurons. PMID:26043693

  12. Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis.

    PubMed

    Ferrón, S R; Radford, E J; Domingo-Muelas, A; Kleine, I; Ramme, A; Gray, D; Sandovici, I; Constancia, M; Ward, A; Menheniott, T R; Ferguson-Smith, A C

    2015-01-01

    Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Here we address the importance of Igf2 imprinting for murine adult neurogenesis in the subventricular zone (SVZ) and in the subgranular zone (SGZ) of the hippocampus in vivo. In the SVZ, paracrine IGF2 is a cerebrospinal fluid and endothelial-derived neurogenic factor requiring biallelic expression, with mutants having reduced activation of the stem cell pool and impaired olfactory bulb neurogenesis. In contrast, Igf2 is imprinted in the hippocampus acting as an autocrine factor expressed in neural stem cells (NSCs) solely from the paternal allele. Conditional mutagenesis of Igf2 in blood vessels confirms that endothelial-derived IGF2 contributes to NSC maintenance in SVZ but not in the SGZ, and that this is regulated by the biallelic expression of IGF2 in the vascular compartment. Our findings indicate that a regulatory decision to imprint or not is a functionally important mechanism of transcriptional dosage control in adult neurogenesis. PMID:26369386

  13. Subacute toxicity assessment of diflubenzuron, an insect growth regulator, in adult male rats.

    PubMed

    de Barros, Aline Lima; Cavalheiro, Gabriela Finoto; de Souza, Alexsandra Vila Maior; Traesel, Giseli Karenina; Anselmo-Franci, Janete A; Kassuya, Cândida Aparecida Leite; Arena, Arielle Cristina

    2016-04-01

    Diflubenzuron (DFB), an insecticide and acaricide insect growth regulator, can be used in agriculture against insect predators and in public health programs, to control insects and vectors, mainly Aedes aegypti larvae. Due to the lack of toxicological assessments of this compound, the objective of the present study was to evaluate the toxicological effects of subacute exposure to the DFB insecticide in adult male rats. Adult male rats were exposed (gavage) to 0, 2, 4, or 8 mg/kg of DFB for 28 days. No clinical signs of toxicity were observed in the DFB-treated animals of the experimental groups. However, there was an increase in serum levels of alanine aminotransferase in the group that received 8 mg/kg/DFB/day and urea at doses of 4 and 8 mg/kg/DFB/day, without altering other biochemical or hematological parameters. The subacute exposure to the lowest dose of DFB caused significant decrease in testis weight, daily sperm production, and in number of sperm in the epididymis in relation to the control group. However, no alterations were observed in the sperm morphology, testicular, epididymis, liver and kidney histology, or testosterone levels. These findings unveiled the hazardous effects of DFB on male reproduction after the subacute exposure and special attention should be addressed to the effects of low doses of this pesticide. PMID:25266294

  14. Emotion Regulation Difficulties, Youth-Adult Relationships, and Suicide Attempts Among High School Students in Underserved Communities

    PubMed Central

    Pisani, Anthony R.; Wyman, Peter A.; Petrova, Mariya; Schmeelk-Cone, Karen; Goldston, David B.; Xia, Yinglin; Gould, Madelyn S.

    2013-01-01

    To develop and refine interventions to prevent youth suicide, knowledge is needed about specific processes that reduce risk at a population level. Using a cross-sectional design, the present study tested hypotheses regarding associations between self-reported suicide attempts, emotion regulation difficulties, and positive youth-adult relationships among 7,978 high-school students (48.6% male, 49.9% female) in 30 high schools from predominantly rural, low-income communities. 683 students (8.6%) reported a past-year suicide attempt. Emotion regulation difficulties and a lack of trusted adults at home and school were associated with increased risk for making a past-year suicide attempt, above and beyond the effects of depressive symptoms and demographic factors. The association between emotion regulation difficulties and suicide attempts was modestly lower among students who perceived themselves as having higher levels of trusted adults in the family, consistent with a protective effect. Having a trusted adult in the community (outside of school and family) was associated with fewer suicide attempts in models that controlled only for demographic covariates, but not when taking symptoms of depression into account. These findings point to adolescent emotion regulation and relationships with trusted adults as complementary targets for suicide prevention that merit further intervention studies. Reaching these targets in a broad population of adolescents will require new delivery systems and “option rich” intervention designs. PMID:23666604

  15. Emotion regulation difficulties, youth-adult relationships, and suicide attempts among high school students in underserved communities.

    PubMed

    Pisani, Anthony R; Wyman, Peter A; Petrova, Mariya; Schmeelk-Cone, Karen; Goldston, David B; Xia, Yinglin; Gould, Madelyn S

    2013-06-01

    To develop and refine interventions to prevent youth suicide, knowledge is needed about specific processes that reduce risk at a population level. Using a cross-sectional design, the present study tested hypotheses regarding associations between self-reported suicide attempts, emotion regulation difficulties, and positive youth-adult relationships among 7,978 high-school students (48.6% male, 49.9% female) in 30 high schools from predominantly rural, low-income communities. 683 students (8.6%) reported a past-year suicide attempt. Emotion regulation difficulties and a lack of trusted adults at home and school were associated with increased risk for making a past-year suicide attempt, above and beyond the effects of depressive symptoms and demographic factors. The association between emotion regulation difficulties and suicide attempts was modestly lower among students who perceived themselves as having higher levels of trusted adults in the family, consistent with a protective effect. Having a trusted adult in the community (outside of school and family) was associated with fewer suicide attempts in models that controlled only for demographic covariates, but not when taking symptoms of depression into account. These findings point to adolescent emotion regulation and relationships with trusted adults as complementary targets for suicide prevention that merit further intervention studies. Reaching these targets in a broad population of adolescents will require new delivery systems and "option rich" (OR) intervention designs. PMID:23666604

  16. Eating regulation styles, appearance schemas, and body satisfaction predict changes in body fat for emerging adults.

    PubMed

    Morgan, Ali Zaremba; Keiley, Margaret K; Ryan, Aubrey E; Radomski, Juliana Groves; Gropper, Sareen S; Connell, Lenda Jo; Simmons, Karla P; Ulrich, Pamela V

    2012-09-01

    . Overall, males and females with high autonomous regulation and high motivational salience are likely to maintain (instead of increase) percent body fat over the college years. Knowing the influence of these predictors can be useful for promoting health and intervening with young adults in the college setting and other emerging adults who are not enrolled in postsecondary institutions. PMID:22447394

  17. Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets.

    PubMed

    Sun, Xingshen; Olivier, Alicia K; Liang, Bo; Yi, Yaling; Sui, Hongshu; Evans, Turan I A; Zhang, Yulong; Zhou, Weihong; Tyler, Scott R; Fisher, John T; Keiser, Nicholas W; Liu, Xiaoming; Yan, Ziying; Song, Yi; Goeken, J Adam; Kinyon, Joann M; Fligg, Danielle; Wang, Xiaoyan; Xie, Weiliang; Lynch, Thomas J; Kaminsky, Paul M; Stewart, Zoe A; Pope, R Marshall; Frana, Timothy; Meyerholz, David K; Parekh, Kalpaj; Engelhardt, John F

    2014-03-01

    Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets. PMID:24074402

  18. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation

    PubMed Central

    Kolf, Catherine M; Cho, Elizabeth; Tuan, Rocky S

    2007-01-01

    Recent advances in understanding the cellular and molecular signaling pathways and global transcriptional regulators of adult mesenchymal stem cells have provided new insights into their biology and potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal and regulation of lineage-specific differentiation of mesenchymal stem cells. In addition we review recent research on the concept of stem cell niche, and its relevance to adult mesenchymal stem cells. PMID:17316462

  19. Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow.

    PubMed

    Yue, Rui; Zhou, Bo O; Shimada, Issei S; Zhao, Zhiyu; Morrison, Sean J

    2016-06-01

    Skeletal stem cells (SSCs) that are the major source of osteoblasts and adipocytes in adult bone marrow express leptin receptor (LepR). To test whether LepR regulates SSC function, we conditionally deleted Lepr from limb bone marrow stromal cells, but not from the axial skeleton or hypothalamic neurons, using Prx1-Cre. Prx1-Cre;Lepr(fl/fl) mice exhibited normal body mass and normal hematopoiesis. However, limb bones from Prx1-Cre;Lepr(fl/fl) mice exhibited increased osteogenesis, decreased adipogenesis, and accelerated fracture healing. Leptin increased adipogenesis and reduced osteogenesis by activating Jak2/Stat3 signaling in bone marrow stromal cells. A high-fat diet increased adipogenesis and reduced osteogenesis in limb bones from wild-type mice, but not from Prx1-Cre;Lepr(fl/fl) mice. This reflected local effects of LepR on osteogenesis and adipogenesis by bone marrow stromal cells and systemic effects on bone resorption. Leptin/LepR signaling regulates adipogenesis and osteogenesis by mesenchymal stromal cells in the bone marrow in response to diet and adiposity. PMID:27053299

  20. Protein kinase C regulates mood-related behaviors and adult hippocampal cell proliferation in rats.

    PubMed

    Abrial, Erika; Etievant, Adeline; Bétry, Cécile; Scarna, Hélène; Lucas, Guillaume; Haddjeri, Nasser; Lambás-Señas, Laura

    2013-06-01

    The neurobiological mechanisms underlying the pathophysiology and therapeutics of bipolar disorder are still unknown. In recent years, protein kinase C (PKC) has emerged as a potential key player in mania. To further investigate the role of this signaling system in mood regulation, we examined the effects of PKC modulators in behavioral tests modeling several facets of bipolar disorder and in adult hippocampal cell proliferation in rats. Our results showed that a single injection of the PKC inhibitors tamoxifen (80 mg/kg, i.p.) and chelerythrine (3 mg/kg, s.c.) attenuated amphetamine-induced hyperlocomotion and decreased risk-taking behavior, supporting the efficacy of PKC blockade in acute mania. Moreover, chronic exposure to tamoxifen (10 mg/kg/day, i.p., for 14 days) or chelerythrine (0.3 mg/kg/day, s.c., for 14 days) caused depressive-like behavior in the forced swim test, and resulted in a reduction of cell proliferation in the dentate gyrus of the hippocampus. Finally, we showed that, contrary to the PKC inhibitors, the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced risk-taking behavior and induced an antidepressant-like effect. Taken together, these findings support the involvement of PKC in regulating opposite facets of bipolar disorder, and emphasize a major role for PKC in this disease. PMID:23228462

  1. Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals.

    PubMed

    Zhou, Hongyi; Lei, Xinnuo; Benson, Tyler; Mintz, James; Xu, Xiaojing; Harris, Ruth B; Weintraub, Neal L; Wang, Xiaoling; Chen, Weiqin

    2015-10-01

    Mutations in BSCL2/SEIPIN cause Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), but the mechanisms whereby Bscl2 regulates adipose tissue function are unclear. Here, we generated adipose tissue (mature) Bscl2 knockout (Ad-mKO) mice, in which Bscl2 was specifically ablated in adipocytes of adult animals, to investigate the impact of acquired Bscl2 deletion on adipose tissue function and energy balance. Ad-mKO mice displayed reduced adiposity and were protected against high fat diet-induced obesity, but not insulin resistance or hepatic steatosis. Gene expression profiling and biochemical assays revealed increased lipolysis and fatty acid oxidation in white adipose tissue (WAT) and brown adipose tissue , as well as browning of WAT, owing to induction of cAMP/protein kinase A signaling upon Bscl2 deletion. Interestingly, Bscl2 deletion reduced food intake and downregulated adipose β3-adrenergic receptor (ADRB3) expression. Impaired ADRB3 signaling partially offsets upregulated browning-induced energy expenditure and thermogenesis in Ad-mKO mice housed at ambient temperature. However, this counter-regulatory response was abrogated under thermoneutral conditions, resulting in even greater body mass loss in Ad-mKO mice. These findings suggest that Bscl2 regulates adipocyte lipolysis and β-adrenergic signaling to produce complex effects on adipose tissues and whole-body energy balance. PMID:26269358

  2. Transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues

    PubMed Central

    Ecco, Gabriela; Cassano, Marco; Kauzlaric, Annamaria; Duc, Julien; Coluccio, Andrea; Offner, Sandra; Imbeault, Michaël; Rowe, Helen M.; Turelli, Priscilla; Trono, Didier

    2016-01-01

    Summary KRAB-containing zinc finger proteins (KRAB-ZFPs) are early embryonic controllers of transposable elements (TEs), which they repress with their cofactor KAP1 through histone and DNA methylation, a process thought to result in irreversible silencing. Using a target-centered functional screen, we matched murine TEs with their cognate KRAB-ZFP. We found the paralogs ZFP932 and Gm15446 to bind overlapping but distinguishable subsets of ERVK (endogenous retrovirus K), to repress these elements in embryonic stem cells, and to regulate secondarily the expression of neighboring genes. Most importantly, we uncovered that these KRAB-ZFPs and KAP1 control TEs in adult tissues, in cell culture and in vivo, where they partner up to modulate cellular genes. Therefore, TEs and KRAB-ZFPs establish transcriptional networks that regulate not only development but probably many physiological events. Given the high degree of species-specificity of TEs and KRAB-ZFPs, these results have important implications for understanding the biology of higher vertebrates, including humans. PMID:27003935

  3. Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells

    PubMed Central

    Shin, Jae-Won; Spinler, Kyle R.; Swift, Joe; Chasis, Joel A.; Mohandas, Narla; Discher, Dennis E.

    2013-01-01

    Hematopoietic stem and progenitor cells, as well as nucleated erythroblasts and megakaryocytes, reside preferentially in adult marrow microenvironments whereas other blood cells readily cross the endothelial barrier into the circulation. Because the nucleus is the largest organelle in blood cells, we hypothesized that (i) cell sorting across microporous barriers is regulated by nuclear deformability as controlled by lamin-A and -B, and (ii) lamin levels directly modulate hematopoietic programs. Mass spectrometry-calibrated intracellular flow cytometry indeed reveals a lamin expression map that partitions human blood lineages between marrow and circulating compartments (P = 0.00006). B-type lamins are highly variable and predominate only in CD34+ cells, but migration through micropores and nuclear flexibility in micropipette aspiration both appear limited by lamin-A:B stoichiometry across hematopoietic lineages. Differentiation is also modulated by overexpression or knockdown of lamins as well as retinoic acid addition, which regulates lamin-A transcription. In particular, erythroid differentiation is promoted by high lamin-A and low lamin-B1 expression whereas megakaryocytes of high ploidy are inhibited by lamin suppression. Lamins thus contribute to both trafficking and differentiation. PMID:24191023

  4. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα. PMID:25533124

  5. Fluid cognitive ability is a resource for successful emotion regulation in older and younger adults.

    PubMed

    Opitz, Philipp C; Lee, Ihno A; Gross, James J; Urry, Heather L

    2014-01-01

    The Selection, Optimization, and Compensation with Emotion Regulation (SOC-ER) framework suggests that (1) emotion regulation (ER) strategies require resources and that (2) higher levels of relevant resources may increase ER success. In the current experiment, we tested the specific hypothesis that individual differences in one internal class of resources, namely cognitive ability, would contribute to greater success using cognitive reappraisal (CR), a form of ER in which one reinterprets the meaning of emotion-eliciting situations. To test this hypothesis, 60 participants (30 younger and 30 older adults) completed standardized neuropsychological tests that assess fluid and crystallized cognitive ability, as well as a CR task in which participants reinterpreted the meaning of sad pictures in order to alter (increase or decrease) their emotions. In a control condition, they viewed the pictures without trying to change how they felt. Throughout the task, we indexed subjective emotional experience (self-reported ratings of emotional intensity), expressive behavior (corrugator muscle activity), and autonomic physiology (heart rate and electrodermal activity) as measures of emotional responding. Multilevel models were constructed to explain within-subjects variation in emotional responding as a function of ER contrasts comparing increase or decrease conditions with the view control condition and between-subjects variation as a function of cognitive ability and/or age group (older, younger). As predicted, higher fluid cognitive ability-indexed by perceptual reasoning, processing speed, and working memory-was associated with greater success using reappraisal to alter emotional responding. Reappraisal success did not vary as a function of crystallized cognitive ability or age group. Collectively, our results provide support for a key tenet of the SOC-ER framework that higher levels of relevant resources may confer greater success at emotion regulation. PMID:24987387

  6. Fluid cognitive ability is a resource for successful emotion regulation in older and younger adults

    PubMed Central

    Opitz, Philipp C.; Lee, Ihno A.; Gross, James J.; Urry, Heather L.

    2014-01-01

    The Selection, Optimization, and Compensation with Emotion Regulation (SOC-ER) framework suggests that (1) emotion regulation (ER) strategies require resources and that (2) higher levels of relevant resources may increase ER success. In the current experiment, we tested the specific hypothesis that individual differences in one internal class of resources, namely cognitive ability, would contribute to greater success using cognitive reappraisal (CR), a form of ER in which one reinterprets the meaning of emotion-eliciting situations. To test this hypothesis, 60 participants (30 younger and 30 older adults) completed standardized neuropsychological tests that assess fluid and crystallized cognitive ability, as well as a CR task in which participants reinterpreted the meaning of sad pictures in order to alter (increase or decrease) their emotions. In a control condition, they viewed the pictures without trying to change how they felt. Throughout the task, we indexed subjective emotional experience (self-reported ratings of emotional intensity), expressive behavior (corrugator muscle activity), and autonomic physiology (heart rate and electrodermal activity) as measures of emotional responding. Multilevel models were constructed to explain within-subjects variation in emotional responding as a function of ER contrasts comparing increase or decrease conditions with the view control condition and between-subjects variation as a function of cognitive ability and/or age group (older, younger). As predicted, higher fluid cognitive ability—indexed by perceptual reasoning, processing speed, and working memory—was associated with greater success using reappraisal to alter emotional responding. Reappraisal success did not vary as a function of crystallized cognitive ability or age group. Collectively, our results provide support for a key tenet of the SOC-ER framework that higher levels of relevant resources may confer greater success at emotion regulation. PMID:24987387

  7. Two Measures of Self-Regulation for Young Adults and Late Adolescents in the Academic and Social Domains

    ERIC Educational Resources Information Center

    Geldhof, John; Little, Todd D.; Hawley, Patricia H.

    2012-01-01

    In this paper we present domain-specific measures of academic and social self-regulation in young adults. We base our scales on Baltes and colleagues' Selection, Optimization, and Compensation (SOC) model, and establish the factor structure of our new measures using data collected from a sample of 152 college students. We then compare the…

  8. Self-Regulation and Metacognition in Young Children: Does It Matter if Adults Are Present or Not?

    ERIC Educational Resources Information Center

    Robson, Sue

    2016-01-01

    This paper brings together two areas of considerable interest to researchers, practitioners and policy makers: young children's developing self-regulation and metacognition, and the impact of adult (practitioner) presence or absence on their behaviour and learning. One hundred and twenty-eight observations of 29 children aged 4-5 years in a…

  9. Emotion Regulation Difficulties, Youth-Adult Relationships, and Suicide Attempts among High School Students in Underserved Communities

    ERIC Educational Resources Information Center

    Pisani, Anthony R.; Wyman, Peter A.; Petrova, Mariya; Schmeelk-Cone, Karen; Goldston, David B.; Xia, Yinglin; Gould, Madelyn S.

    2013-01-01

    To develop and refine interventions to prevent youth suicide, knowledge is needed about specific processes that reduce risk at a population level. Using a cross-sectional design, the present study tested hypotheses regarding associations between self-reported suicide attempts, emotion regulation difficulties, and positive youth-adult relationships…

  10. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins

    PubMed Central

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang; Zhang, Dongfeng; Duan, Haiping; Tan, Qihua; Hjelmborg, Jacob; Kruse, Torben; Dalgård, Christine

    2016-01-01

    Objective The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic, cultural, social-economic backgrounds and geographical environments. Materials and Methods The study covered a relatively large sample of 502 pairs of Danish adult twins followed up for a long period of 12 years with a mean age at intake of 38 years (range: 18–65) and a total of 181 Chinese adult twin pairs traced for about 7 years with a mean baseline age of 39.5 years (range: 23–64). The classical twin models were fitted to the longitudinal change in each phenotype (Δphenotype) to estimate the genetic and environmental contributions to the variation in Δphenotype. Results Moderate to high contributions by the unique environment were estimated for all phenotypes in both Danish (from 0.51 for low density lipoprotein cholesterol up to 0.72 for triglycerides) and Chinese (from 0.41 for triglycerides up to 0.73 for diastolic blood pressure) twins; low to moderate genetic components were estimated for long-term change in most of the phenotypes in Danish twins except for triglycerides and hip circumference. Compared with Danish twins, the Chinese twins tended to have higher genetic control over the longitudinal changes in lipids (except high density lipoprotein cholesterol) and glucose, higher unique environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. Conclusion Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples. PMID:26862898

  11. Cav1.1 controls frequency-dependent events regulating adult skeletal muscle plasticity.

    PubMed

    Jorquera, Gonzalo; Altamirano, Francisco; Contreras-Ferrat, Ariel; Almarza, Gonzalo; Buvinic, Sonja; Jacquemond, Vincent; Jaimovich, Enrique; Casas, Mariana

    2013-03-01

    An important pending question in neuromuscular biology is how skeletal muscle cells decipher the stimulation pattern coming from motoneurons to define their phenotype as slow or fast twitch muscle fibers. We have previously shown that voltage-gated L-type calcium channel (Cav1.1) acts as a voltage sensor for activation of inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃]-dependent Ca(2+) signals that regulates gene expression. ATP released by muscle cells after electrical stimulation through pannexin-1 channels plays a key role in this process. We show now that stimulation frequency determines both ATP release and Ins(1,4,5)P₃ production in adult skeletal muscle and that Cav1.1 and pannexin-1 colocalize in the transverse tubules. Both ATP release and increased Ins(1,4,5)P₃ was seen in flexor digitorum brevis fibers stimulated with 270 pulses at 20 Hz, but not at 90 Hz. 20 Hz stimulation induced transcriptional changes related to fast-to-slow muscle fiber phenotype transition that required ATP release. Addition of 30 µM ATP to fibers induced the same transcriptional changes observed after 20 Hz stimulation. Myotubes lacking the Cav1.1-α1 subunit released almost no ATP after electrical stimulation, showing that Cav1.1 has a central role in this process. In adult muscle fibers, ATP release and the transcriptional changes produced by 20 Hz stimulation were blocked by both the Cav1.1 antagonist nifedipine (25 µM) and by the Cav1.1 agonist (-)S-BayK 8644 (10 µM). We propose a new role for Cav1.1, independent of its calcium channel activity, in the activation of signaling pathways allowing muscle fibers to decipher the frequency of electrical stimulation and to activate specific transcriptional programs that define their phenotype. PMID:23321639

  12. Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function.

    PubMed

    Modi, Honey; Jacovetti, Cecile; Tarussio, David; Metref, Salima; Madsen, Ole D; Zhang, Fu-Ping; Rantakari, Pia; Poutanen, Matti; Nef, Serge; Gorman, Tracy; Regazzi, Romano; Thorens, Bernard

    2015-12-01

    Insulin-like growth factor 2 (IGF2), produced and secreted by adult β-cells, functions as an autocrine activator of the β-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in β-cell and whole-body physiology is not known. Here, we studied mice with β-cell-specific inactivation of Igf2 (βIGF2KO mice) and assessed β-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female βIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female βIGF2KO mice displayed lower GSIS compared with control mice, but reduced β-cell mass was observed only in female βIGF2KO mice. During pregnancy, there was no increase in β-cell proliferation and mass in βIGF2KO mice. Finally, β-cell mass expansion in response to acute induction of insulin resistance was lower in βIGF2KO mice than in control mice. Thus, the autocrine action of IGF2 regulates adult β-cell mass and function to preserve in vivo GSIS in aging and to adapt β-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance. PMID:26384384

  13. Adult rat brain is sensitive to thyroid hormone. Regulation of RC3/neurogranin mRNA.

    PubMed Central

    Iñiguez, M A; Rodriguez-Peña, A; Ibarrola, N; Morreale de Escobar, G; Bernal, J

    1992-01-01

    The mammalian brain is considered to be poorly responsive to thyroid hormone after the so called "critical periods" of brain development, which occur in the rat before postnatal days 15-20. In a previous work (Muñoz, A., A. Rodriguez-Peña, A. Perez-Castillo, B. Ferreiro, J.G. Sutcliffe, and J. Bernal. 1991. Mol. Endocrinol. 5:273-280) we have identified one neuronal gene, RC3, whose expression is influenced by early neonatal hypothyroidism and thyroid hormone treatment. In the present work we show that adult-onset hypothyroidism leads to a reversible decrease of RC3 mRNA. Rats thyroidectomized on postnatal day 40 and killed three months later showed a decreased RC3 mRNA concentration in the cerebral cortex and striatum. The same effect was observed in animals made hypothyroid on postnatal day 32 and killed on postnatal day 52. RC3 expression was normal when hypothyroid animals were treated with T4 five days before being killed. In contrast, the mRNA encoding myelin proteolipid protein showed no changes in either experimental situation. RC3 mRNA levels were not affected by food restriction demonstrating that the effect of hypothyroidism was not related to the lack of weight gain. The control of RC3 mRNA is so far the only molecular event known to be regulated by thyroid hormone once the critical periods of brain development are over and could represent a molecular correlate for the age-independent, reversible alterations induced by hypothyroidism in the adult brain. Images PMID:1379612

  14. Gain-of-function microRNA screens identify miR-193a regulating proliferation and apoptosis in epithelial ovarian cancer cells

    PubMed Central

    NAKANO, HARUO; YAMADA, YOJI; MIYAZAWA, TATSUYA; YOSHIDA, TETSUO

    2013-01-01

    MicroRNAs (miRNAs) are a small class of non-coding RNAs that negatively regulate gene expression, and are considered as new therapeutic targets for treating cancer. In this study, we performed a gain-of-function screen using miRNA mimic library (319 miRNA species) to identify those affecting cell proliferation in human epithelial ovarian cancer cells (A2780). We discovered a number of miRNAs that increased or decreased the cell viability of A2780 cells. Pro-proliferative and anti-proliferative miRNAs include oncogenic miR-372 and miR-373, and tumor suppressive miR-124a, miR-7, miR-192 and miR-193a, respectively. We found that overexpression of miR-124a, miR-192, miR-193a and miR-193b inhibited BrdU incorporation in A2780 cells, indicating that these miRNAs affected the cell cycle. Overexpression of miR-193a and miR-193b induced an activation of caspase 3/7, and resulted in apoptotic cell death in A2780 cells. A genome-wide gene expression analysis with miR-193a-transfected A2780 cells led to identification of ARHGAP19, CCND1, ERBB4, KRAS and MCL1 as potential miR-193a targets. We demonstrated that miR-193a decreased the amount of MCL1 protein by binding 3′UTR of its mRNA. Our study suggests the potential of miRNA screens to discover miRNAs as therapeutic tools to treat ovarian cancer. PMID:23588298

  15. Coping, emotion regulation, and self-blame as mediators of sexual abuse and psychological symptoms in adult sexual assault.

    PubMed

    Ullman, Sarah E; Peter-Hagene, Liana C; Relyea, Mark

    2014-01-01

    This study examined whether coping, emotion regulation, and self-blame mediate relationships of trauma histories with post-traumatic stress disorder and depression in adult sexual assault victims (N = 1863). A path analysis showed that theorized mediators partially mediated associations between trauma history variables and psychological symptoms. Specifically, child sexual abuse severity was related to greater post-traumatic stress disorder and depression indirectly through maladaptive coping and decreased emotion regulation but not self-blame. Other traumas had direct relationships with symptoms and partially mediated effects through maladaptive coping and emotion regulation. Child sexual abuse was unrelated to self-blame, but other traumas were related to greater self-blame. Results differed according to whether women had counseling post-assault. Implications are drawn for future research and clinical treatment of adult sexual assault victims. PMID:24393091

  16. YAP Regulates Cell Proliferation, Migration, and Steroidogenesis in Adult Granulosa Cell Tumors

    PubMed Central

    Fu, David; Lv, Xiangmin; Hua, Guohua; He, Chunbo; Dong, Jixin; Lele, Subodh M.; Li, David Wan-Cheng; Zhai, Qiongli; Davis, John S.; Wang, Cheng

    2014-01-01

    The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of ovary, excess production of estrogen, high frequency of recurrence and potential of malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild-type YAP or a constitutively active YAP mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in regulating GCT cell proliferation, migration and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT. PMID:24389730

  17. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain

    PubMed Central

    Guo, Junjie U.; Su, Yijing; Shin, Joo Heon; Shin, Jaehoon; Li, Hongda; Xie, Bin; Zhong, Chun; Hu, Shaohui; Le, Thuc; Fan, Guoping; Zhu, Heng; Chang, Qiang; Gao, Yuan; Ming, Guo-li; Song, Hongjun

    2014-01-01

    DNA methylation plays critical roles in the nervous system and has been traditionally considered to be restricted to CpG dinucleotides in metazoan genomes. Here we show that the single-base resolution DNA methylome from adult mouse dentate neurons consists of both CpG (~75%) and CpH (~25%) methylation (H = A/C/T). Neuronal CpH methylation is conserved in human brains, enriched in low CpG-density regions, depleted at protein-DNA interaction sites, and anti-correlated with gene expression. Functionally, both mCpGs and mCpHs can repress transcription in vitro and are recognized by MeCP2 in neurons in vivo. Unlike most CpG methylation, CpH methylation is established de novo during neuronal maturation and requires DNMT3A for active maintenance in post-mitotic neurons. These characteristics of CpH methylation suggest a significantly expanded proportion of the neuronal genome under cytosine methylation regulation and provide a new foundation for understanding the role of this key epigenetic modification in the nervous system. PMID:24362762

  18. Hormonal regulation of epidermal growth factor and protease in the submandibular gland of the adult mouse.

    PubMed

    Gresik, E W; Schenkein, I; van der Noen, H; Barka, T

    1981-09-01

    The structure of the granular convoluted tubules of the mouse submandibular gland is influenced by androgens, adrenal steroids, and thyroid hormones. We wished to investigate the effects of variations in hormonal status on the quantitative and qualitative distribution of two secretory products of these tubules, epidermal growth factor (EGF) and protease. The effects of the thyroid and adrenal glands on EGF content and protease activity of the submandibular glands of adult female mice were studied by RIAs (EGF), enzyme assays (protease), and immunocytochemical methods. In animals rendered chronically hypothyroid by propylthiouracil (4 months) or in animals which were adrenalectomized and ovariectomized (3 weeks), protease activity and EGF levels were reduced by 81-97%. The administration of testosterone induced these polypeptides even in hypothyroid animals. Daily administration of L-T4 (T4; 1 micrograms/g BW) for 7 days increased EGF and protease activity 3.6-fold in intact mice and reversed the effect of hypothyroidism. EGF and protease were also induced by T4 in adrenalectomized and ovariectomized mice, although to a lesser degree than in intact animals. Immunocytochemical stainings of submandibular glands indicated that the number of granular convoluted tubule cells immunoreactive for EGF correlated with the levels of EGF determined by RIAs. With respect to immunostaining for protease, such a correlation was not observed. The data indicate multihormonal regulation of EGF and protease in the mouse submandibular gland. PMID:7021131

  19. FGF-2 regulation of neurogenesis in adult hippocampus after brain injury

    PubMed Central

    Yoshimura, Shinichi; Takagi, Yasushi; Harada, Jun; Teramoto, Tetsuyuki; Thomas, Sunu S.; Waeber, Christian; Bakowska, Joanna C.; Breakefield, Xandra O.; Moskowitz, Michael A.

    2001-01-01

    Fibroblast growth factor-2 (FGF-2) promotes proliferation of neuroprogenitor cells in culture and is up-regulated within brain after injury. Using mice genetically deficient in FGF-2 (FGF-2−/− mice), we addressed the importance of endogenously generated FGF-2 on neurogenesis within the hippocampus, a structure involved in spatial, declarative, and contextual memory, after seizures or ischemic injury. BrdUrd incorporation was used to mark dividing neuroprogenitor cells and NeuN expression to monitor their differentiation into neurons. In the wild-type strain, hippocampal FGF-2 increased after either kainic acid injection or middle cerebral artery occlusion, and the numbers of BrdUrd/NeuN-positive cells significantly increased on days 9 and 16 as compared with the controls. In FGF-2−/− mice, BrdUrd labeling was attenuated after kainic acid or middle cerebral artery occlusion, as was the number of neural cells colabeled with both BrdUrd and NeuN. After FGF-2−/− mice were injected intraventricularly with a herpes simplex virus-1 amplicon vector carrying FGF-2 gene, the number of BrdUrd-labeled cells increased significantly to values equivalent to wild-type littermates after kainate seizures. These results indicate that endogenously synthesized FGF-2 is necessary and sufficient to stimulate proliferation and differentiation of neuroprogenitor cells in the adult hippocampus after brain insult. PMID:11320217

  20. Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis.

    PubMed

    Pallas-Bazarra, Noemí; Jurado-Arjona, Jerónimo; Navarrete, Marta; Esteban, Jose A; Hernández, Félix; Ávila, Jesús; Llorens-Martín, María

    2016-07-01

    Tau is a microtubule-associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress-induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau(-/-) mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau(-/-) mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli. PMID:27198172

  1. Continuous up-regulation of heat shock proteins in larvae, but not adults, of a polar insect

    PubMed Central

    Rinehart, Joseph P.; Hayward, Scott A. L.; Elnitsky, Michael A.; Sandro, Luke H.; Lee, Richard E.; Denlinger, David L.

    2006-01-01

    Antarctica's terrestrial environment is a challenge to which very few animals have adapted. The largest, free-living animal to inhabit the continent year-round is a flightless midge, Belgica antarctica. Larval midges survive the lengthy austral winter encased in ice, and when the ice melts in summer, the larvae complete their 2-yr life cycle, and the wingless adults form mating aggregations while subjected to surprisingly high substrate temperatures. Here we report a dichotomy in survival strategies exploited by this insect at different stages of its life cycle. Larvae constitutively up-regulate their heat shock proteins (small hsp, hsp70, and hsp90) and maintain a high inherent tolerance to temperature stress. High or low temperature exposure does not further up-regulate these genes nor does it further enhance thermotolerance. Such “preemptive” synthesis of hsps is sufficient to prevent irreversible protein aggregation in response to a variety of common environmental stresses. Conversely, adults exhibit no constitutive up-regulation of their hsps and have a lower intrinsic tolerance to high temperatures, but their hsps can be thermally activated, resulting in enhanced thermotolerance. Thus, the midge larvae, but not the adults, have adopted the unusual strategy of expressing hsps continuously, possibly to facilitate proper protein folding in a cold habitat that is more thermally stable than that of the adults but a habitat subjected frequently to freeze-thaw episodes and bouts of pH, anoxic, and osmotic stress. PMID:16968769

  2. Emotion regulation in disordered eating: Psychometric properties of the Difficulties in Emotion Regulation Scale among Spanish adults and its interrelations with personality and clinical severity

    PubMed Central

    Wolz, Ines; Agüera, Zaida; Granero, Roser; Jiménez-Murcia, Susana; Gratz, Kim L.; Menchón, José M.; Fernández-Aranda, Fernando

    2015-01-01

    Objective: The aims of the study were to (1) validate the Difficulties in Emotion Regulation Scale (DERS) in a sample of Spanish adults with and without eating disorders, and (2) explore the role of emotion regulation difficulties in eating disorders (ED), including its mediating role in the relation between key personality traits and ED severity. Methods: One hundred and thirty four patients (121 female, mean age = 29 years) with anorexia nervosa (n = 30), bulimia nervosa (n = 54), binge eating (n = 20), or Other Specified Feeding or Eating Disorders (n = 30) and 74 healthy control participants (51 female, mean age = 21 years) reported on general psychopathology, ED severity, personality traits and difficulties in emotion regulation. Exploratory and confirmatory factor analyses were conducted to examine the psychometrics of the DERS in this Spanish sample (Aim 1). Additionally, to examine the role of emotion regulation difficulties in ED (Aim 2), differences in emotion regulation difficulties across eating disorder subgroups were examined and structural equation modeling was used to explore the interrelations among emotion regulation, personality traits, and eating disorder severity. Results: Results support the validity and reliability of the DERS within this Spanish adult sample and suggest that this measure has a similar factor structure in this sample as in the original sample. Moreover, emotion regulation difficulties were found to differ as a function of eating disorder subtype and to mediate the relation between two specific personality traits (i.e., high harm avoidance and low self-directedness) and ED severity. Conclusions: Personality traits of high harm avoidance and low self-directedness may increase vulnerability to ED pathology indirectly, through emotion regulation difficulties. PMID:26175710

  3. MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells.

    PubMed

    Wissink, Erin M; Smith, Norah L; Spektor, Roman; Rudd, Brian D; Grimson, Andrew

    2015-11-01

    Immunological memory, which protects organisms from re-infection, is a hallmark of the mammalian adaptive immune system and the underlying principle of vaccination. In early life, however, mice and other mammals are deficient at generating memory CD8+ T cells, which protect organisms from intracellular pathogens. The molecular basis that differentiates adult and neonatal CD8+ T cells is unknown. MicroRNAs (miRNAs) are both developmentally regulated and required for normal adult CD8+ T cell functions. We used next-generation sequencing to identify mouse miRNAs that are differentially regulated in adult and neonatal CD8+ T cells, which may contribute to the impaired development of neonatal memory cells. The miRNA profiles of adult and neonatal cells were surprisingly similar during infection; however, we observed large differences prior to infection. In particular, miR-29 and miR-130 have significant differential expression between adult and neonatal cells before infection. Importantly, using RNA-Seq, we detected reciprocal changes in expression of messenger RNA targets for both miR-29 and miR-130. Moreover, targets that we validated include Eomes and Tbx21, key genes that regulate the formation of memory CD8+ T cells. Notably, age-dependent changes in miR-29 and miR-130 are conserved in human CD8+ T cells, further suggesting that these developmental differences are biologically relevant. Together, these results demonstrate that miR-29 and miR-130 are likely important regulators of memory CD8+ T cell formation and suggest that neonatal cells are committed to a short-lived effector cell fate prior to infection. PMID:26416483

  4. MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells

    PubMed Central

    Wissink, Erin M.; Smith, Norah L.; Spektor, Roman; Rudd, Brian D.; Grimson, Andrew

    2015-01-01

    Immunological memory, which protects organisms from re-infection, is a hallmark of the mammalian adaptive immune system and the underlying principle of vaccination. In early life, however, mice and other mammals are deficient at generating memory CD8+ T cells, which protect organisms from intracellular pathogens. The molecular basis that differentiates adult and neonatal CD8+ T cells is unknown. MicroRNAs (miRNAs) are both developmentally regulated and required for normal adult CD8+ T cell functions. We used next-generation sequencing to identify mouse miRNAs that are differentially regulated in adult and neonatal CD8+ T cells, which may contribute to the impaired development of neonatal memory cells. The miRNA profiles of adult and neonatal cells were surprisingly similar during infection; however, we observed large differences prior to infection. In particular, miR-29 and miR-130 have significant differential expression between adult and neonatal cells before infection. Importantly, using RNA-Seq, we detected reciprocal changes in expression of messenger RNA targets for both miR-29 and miR-130. Moreover, targets that we validated include Eomes and Tbx21, key genes that regulate the formation of memory CD8+ T cells. Notably, age-dependent changes in miR-29 and miR-130 are conserved in human CD8+ T cells, further suggesting that these developmental differences are biologically relevant. Together, these results demonstrate that miR-29 and miR-130 are likely important regulators of memory CD8+ T cell formation and suggest that neonatal cells are committed to a short-lived effector cell fate prior to infection. PMID:26416483

  5. A self-regulation resource model of self-compassion and health behavior intentions in emerging adults

    PubMed Central

    Sirois, Fuschia M.

    2015-01-01

    Objective This study tested a self-regulation resource model (SRRM) of self-compassion and health-promoting behavior intentions in emerging adults. The SRRM posits that positive and negative affect in conjunction with health self-efficacy serve as valuable self-regulation resources to promote health behaviors. Methods An online survey was completed by 403 emerging adults recruited from the community and a Canadian University in late 2008. Multiple meditation analyses with bootstrapping controlling for demographics and current health behaviors tested the proposed explanatory role of the self-regulation resource variables (affect and self-efficacy) in linking self-compassion to health behavior intentions. Results Self-compassion was positively associated with intentions to engage in health-promoting behaviors. The multiple mediation model explained 23% of the variance in health behavior intentions, with significant indirect effects through health self-efficacy and low negative affect. Conclusion Interventions aimed at increasing self-compassion in emerging adults may help promote positive health behaviors, perhaps through increasing self-regulation resources. PMID:26844074

  6. Dietary adenine controls adult lifespan via adenosine nucleotide biosynthesis and AMPK, and regulates the longevity benefit of caloric restriction

    PubMed Central

    Stenesen, Drew; Suh, Jae Myoung; Seo, Jin; Yu, Kweon; Lee, Kyu-Sun; Kim, Jong-Seok; Min, Kyung-Jin; Graff, Jonathan M.

    2012-01-01

    SUMMARY A common thread among conserved lifespan regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of adenosine monophosphate (AMP) biosynthetic enzymes extend Drosophila lifespan. The lifespan benefit of these mutations depends upon increased AMP to adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended lifespan, while AMPK RNAi reduced lifespan. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed lifespan extension. Remarkably, this simple change in diet also blocked the pro-longevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult lifespan, provide a mechanistic link between cellular anabolism and energy sensing pathways, and indicate that dietary adenine manipulations might alter metabolism to influence animal lifespan. PMID:23312286

  7. Seasonal regulation of structural plasticity and neurogenesis in the adult mammalian brain: focus on the sheep hypothalamus.

    PubMed

    Migaud, Martine; Butrille, Lucile; Batailler, Martine

    2015-04-01

    To cope with variations in the environment, most mammalian species exhibit seasonal cycles in physiology and behaviour. Seasonal plasticity during the lifetime contributes to seasonal physiology. Over the years, our ideas regarding adult brain plasticity and, more specifically, hypothalamic plasticity have greatly evolved. Along with the two main neurogenic regions, namely the hippocampal subgranular and lateral ventricle subventricular zones, the hypothalamus, which is the central homeostatic regulator of numerous physiological functions that comprise sexual behaviours, feeding and metabolism, also hosts neurogenic niches. Both endogenous and exogenous factors, including the photoperiod, modulate the hypothalamic neurogenic capacities. The present review describes the effects of season on adult morphological plasticity and neurogenesis in seasonal species, for which the photoperiod is a master environmental cue for the successful programming of seasonal functions. In addition, the potential functional significance of adult neurogenesis in the mediation of the seasonal control of reproduction and feeding is discussed. PMID:25462590

  8. Influence of short time exposure to an insect growth regulator, hexaflumuron, on mortality and adult emergence of vector mosquitoes.

    PubMed

    Vasuki, V; Rajavel, A R

    1992-01-01

    Hexaflumuron, an insect growth regulator (IGR), was found to greatly affect the development of immatures and emergence of adults of three species of vector mosquitoes, Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi, when larvae were subjected to short time exposure of < or = 1 h. This IGR could completely prevent adult emergence even at a minimum exposure time of 10 min at 0.001, 0.01 and 0.1 mg/l. On treatment, larval and pupal mortality as well as varying degrees of morphogenetic abnormalities were induced in immatures and adults of the three species. Four weeks of control achieved in a slow moving sullage canal breeding Culex quinquefasciatus indicates that this IGR can be of use in such breeding habitats. PMID:1308571

  9. Emotion regulation and mental representation of attachment in patients with systemic lupus erythematosus: a study using the Adult Attachment Interview.

    PubMed

    Barbasio, Chiara; Granieri, Antonella

    2013-04-01

    Mental representations of attachment and emotion regulation influence individual patterns of stress response and vulnerability to illness. The present study investigates the adult attachment states of mind of 40 women with systemic lupus erythematosus (SLE) using the Adult Attachment Interview. We also assessed alexithymia using the Toronto Alexithymia Scale and dissociation using the Dissociative Experiences Scale. The results showed a high prevalence of the unresolved state of mind (13 patients, 32.5%) and the entangled state of mind (10 patients, 25%). The alexithymia score also varied significantly as a function of the mental representation of attachment and was modulated by amnestic dissociation. These findings suggest that adult attachment in patients with SLE influences the presence of alexithymic features. Moreover, these also indicate that dissociative states mediate the perception of painful memories and feelings, thus contributing to the partial avoidance of emotions and the failure to fully experience and recognize them. The clinical implications of these findings are also discussed. PMID:23538975

  10. Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory.

    PubMed

    Lieberwirth, Claudia; Pan, Yongliang; Liu, Yan; Zhang, Zhibin; Wang, Zuoxin

    2016-08-01

    Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk). PMID:27174001

  11. Regulation by equilibrative nucleoside transporter of adenosine outward currents in adult rat spinal dorsal horn neurons.

    PubMed

    Liu, Tao; Fujita, Tsugumi; Kawasaki, Yasuhiko; Kumamoto, Eiichi

    2004-07-30

    A current response induced by superfusing adenosine was examined in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. In 78% of the neurons examined, adenosine induced an outward current at -70 mV [18.8 +/- 1.1 pA (n = 98) at 1mM] in a dose-dependent manner (EC(50) = 177 microM). A similar current was induced by A(1) agonist N(6)-cyclopentyladenosine (1 microM), whereas A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 microM) reversed the adenosine action. The adenosine current reversed its polarity at a potential being close to the equilibrium potential for K(+), and was attenuated by Ba(2+) (100 microM) and 4-aminopyridine (5mM) but not tetraethylammonium (5mM). The adenosine current was enhanced in duration by equilibrative nucleoside-transport (rENT1) inhibitor S-(4-nitrobenzyl)-6-thioinosine (1 microM) and adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (1 microM), and slowed in falling phase by adenosine kinase (AK) inhibitor iodotubercidine (1 microM). We conclude that a Ba(2+)- and 4-aminopyridine-sensitive K(+) channel in SG neurons is opened via the activation of A(1) receptors by adenosine whose level is possibly regulated by rENT1, adenosine deaminase and adenosine kinase. Considering that intrathecally-administered adenosine analogues produce antinociception, the regulatory systems of adenosine may serve as targets for antinociceptive drugs. PMID:15275960

  12. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action.

    PubMed

    Lucassen, P J; Meerlo, P; Naylor, A S; van Dam, A M; Dayer, A G; Fuchs, E; Oomen, C A; Czéh, B

    2010-01-01

    Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to the etiology of depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in antidepressant action. PMID:19748235

  13. Eating frequency and energy regulation in free-living adults consuming self-selected diets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The relative importance of eating frequency to weight control is poorly understood. This review examines the evidence to date on the role of eating frequency in weight control in free-living adults. The majority of cross-sectional studies in free-living adults show an inverse relationship between ea...

  14. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

    PubMed Central

    Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

    2016-01-01

    The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

  15. SUMO regulates somatic cyst stem cell maintenance and directly targets the Hedgehog pathway in adult Drosophila testis.

    PubMed

    Lv, Xiangdong; Pan, Chenyu; Zhang, Zhao; Xia, Yuanxin; Chen, Hao; Zhang, Shuo; Guo, Tong; Han, Hui; Song, Haiyun; Zhang, Lei; Zhao, Yun

    2016-05-15

    SUMO (Small ubiquitin-related modifier) modification (SUMOylation) is a highly dynamic post-translational modification (PTM) that plays important roles in tissue development and disease progression. However, its function in adult stem cell maintenance is largely unknown. Here, we report the function of SUMOylation in somatic cyst stem cell (CySC) self-renewal in adult Drosophila testis. The SUMO pathway cell-autonomously regulates CySC maintenance. Reduction of SUMOylation promotes premature differentiation of CySCs and impedes the proliferation of CySCs, which leads to a reduction in the number of CySCs. Consistent with this, CySC clones carrying a mutation of the SUMO-conjugating enzyme are rapidly lost. Furthermore, inhibition of the SUMO pathway phenocopies disruption of the Hedgehog (Hh) pathway, and can block the proliferation of CySCs induced by Hh activation. Importantly, the SUMO pathway directly regulates the SUMOylation of Hh pathway transcription factor Cubitus interruptus (Ci), which is required for promoting CySC proliferation. Thus, we conclude that SUMO directly targets the Hh pathway and regulates CySC maintenance in adult Drosophila testis. PMID:27013244

  16. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain.

    PubMed

    Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

    2016-01-01

    The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

  17. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults.

    PubMed

    Kilpinen, S; Hulkkonen, J; Wang, X Y; Hurme, M

    2001-03-01

    In the promoter region of the IL-6 gene there is a single base exchange (G --> C) polymorphism at position -174. Recent findings suggest that this polymorphism may affect the transcription rate of the IL-6 gene and IL-6 plasma levels. To analyse its biological significance, we examined IL-6 plasma levels in cord blood and IL-6 production by neonatal cells after LPS-stimulation in relation to the presence of the IL-6G and IL-6C alleles. We hypothesized that since healthy neonates lack a previous exposure to exogenous antigens, their cytokine production could be genetically regulated. We also assumed that the normal labour-related stress could provide a physiological stimulus for IL-6 production. Cord blood was collected from 50 healthy, full-term neonates after normal vaginal delivery (VD) and from 42 healthy, full-term neonates after elective caesarean section (ECS). Adult samples were obtained from 450 healthy adult controls. The -174 polymorphism was analysed using PCR. IL-6 plasma levels and in vitro IL-6 production were measured using an ELISA method. Generally, IL-6 plasma levels in neonates were significantly higher than those in adults (neonates born by VD versus adults p < 0.001 and neonates born by ECS versus adults p < 0.001); the median value for neonates born by VD was 11.4 pg/ml (4.5-45.9), for neonates born by ECS 2.9 pg/ml (1.9-6.4) and for adults, 1.2 pg/ml (0.7-2.0). Surprisingly, cord blood IL-6 levels after VD differed significantly from those after ECS (p < 0.001). An analysis was carried out to ascertain if there was a genetic association between different IL-6 genotypes and IL-6 plasma levels in neonates. In the group of VD neonates with the CC genotype, non-carriers of the G allele, secreted significantly more IL-6 than carriers of the G allele (p < 0.03); 21.4 pg/ml (9.5-81.3) and 9.6 pg/ml (3.5-36.2) respectively. In line with this, ECS newborns with the CC genotype had higher IL-6 plasma levels than carriers of the G allele (p < 0

  18. Effects of tamoxifen on autosomal genes regulating ovary maintenance in adult mice.

    PubMed

    Yu, Mingxi; Liu, Wei; Wang, Jingyun; Qin, Junwen; Wang, Yongan; Wang, Yu

    2015-12-01

    Environmental endocrine-disrupting chemicals (EDCs), known to bind to estrogen/androgen receptors and mimic native estrogens, have been implicated as a main source for increasing human reproductive and developmental deficiencies and diseases. Tamoxifen (TAM) is one of the most well-known antiestrogens with defined adverse effects on the female reproductive tract, but the mechanisms related to autosomal gene regulation governing ovary maintenance in mammals remain unclear. The expression pattern and levels of key genes and proteins involved in maintaining the ovarian phenotype in mice were analyzed. The results showed that TAM induced significant upregulation of Sox9, which is the testis-determining factor gene. The results showed that TAM induced significant upregulation of Sox9, the testis-determining factor gene, and the expression level of Sox9 mRNA in the ovaries of mice exposed to 75 or 225 mg/kg bw TAM was 2- and 10-fold that in the control group, respectively (p < 0.001). Furthermore, the testicular fibroblast growth factor gene, Fgf9, was also elevated in TAM-treated ovaries. Accordingly, expression of the ovary development marker, forkhead transcription factor (FOXL2), and WNT4/FST signaling, were depressed. The levels of protein expression changed consistently with the target genes. Moreover, the detection of platelet/endothelial cell adhesion molecule 1 (PECAM-1) in TAM-treated ovaries suggested the formation of vascular endothelial cells, which is a further evidence for the differentiation of the ovaries to a testis-like phenotype. During this period, the level of 17β-estradiol, progesterone, and luteinizing hormone decreased, while that of testosterone increased by 3.3-fold (p = 0.013). The activation of a testis-specific molecular signaling cascade was a potentially important mechanism contributing to the gender disorder induced by TAM, which resulted in the differentiation of the ovaries to a testis-like phenotype in adult mice. Limited with

  19. Expression and Regulation of the Fkbp5 Gene in the Adult Mouse Brain

    PubMed Central

    Scharf, Sebastian H.; Liebl, Claudia; Binder, Elisabeth B.

    2011-01-01

    Background Chronic stress has been found to be a major risk factor for various human pathologies. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated via, among others, the glucocorticoid receptor (GR). The activity of the GR is modulated by a variety of proteins, including the co-chaperone FK506 binding protein 51 (FKBP5). Although FKBP5 has been associated with risk for affective disorders and has been implicated in GR sensitivity, previous studies focused mainly on peripheral blood, while information about basal distribution and induction in the central nervous system are sparse. Methodology/Principal Findings In the present study, we describe the basal expression pattern of Fkbp5 mRNA in the brain of adult male mice and show the induction of Fkbp5 mRNA via dexamethasone treatment or different stress paradigms. We could show that Fkbp5 is often, but not exclusively, expressed in regions also known for GR expression, for example the hippocampus. Furthermore, we were able to induce Fkbp5 expression via dexamethasone in the CA1 and DG subregions of the hippocampus, the paraventricular nucleus (PVN) and the central amygdala (CeA). Increase of Fkbp5 mRNA was also found after restrained stress and 24 hours of food deprivation in the PVN and the CeA, while in the hippocampus only food deprivation caused an increase in Fkbp5 mRNA. Conclusions/Significance Interestingly, regions with a low basal expression showed higher increase in Fkbp5 mRNA following induction than regions with high basal expression, supporting the hypothesis that GR sensitivity is, at least partly, mediated via Fkbp5. In addition, this also supports the use of Fkbp5 gene expression as a marker for GR sensitivity. In summary, we were able to give an overview of the basal expression of fkbp5 mRNA as well as to extend the findings of induction of Fkbp5 and its regulatory influence on GR sensitivity from peripheral blood to the brain. PMID:21347384

  20. GONADAL STEROIDS REGULATED THE EXPRESSION OF GLIAL FIBRILLARY ACIDIC PROTEIN IN THE ADULT MALE RAT HIPPOCAMPUS

    EPA Science Inventory

    This study demonstrates that gonadal steroids (estradiol, testosterone, dihydrotestosterone) can inhibit the expression of glial fibrillary acidic protein and it MRNA in the adult male rat brain. esticular hormones may influence the activity of astrocytes in the intact and lesion...

  1. The COP1 ortholog PPS regulates the juvenile-adult and vegetative-reproductive phase changes in rice.

    PubMed

    Tanaka, Nobuhiro; Itoh, Hironori; Sentoku, Naoki; Kojima, Mikiko; Sakakibara, Hitoshi; Izawa, Takeshi; Itoh, Jun-Ichi; Nagato, Yasuo

    2011-06-01

    Because plant reproductive development occurs only in adult plants, the juvenile-to-adult phase change is an indispensable part of the plant life cycle. We identified two allelic mutants, peter pan syndrome-1 (pps-1) and pps-2, that prolong the juvenile phase in rice (Oryza sativa) and showed that rice PPS is an ortholog of Arabidopsis thaliana CONSTITUTIVE PHOTOMORPHOGENIC1. The pps-1 mutant exhibits delayed expression of miR156 and miR172 and the suppression of GA biosynthetic genes, reducing the GA(3) content in this mutant. In spite of its prolonged juvenile phase, the pps-1 mutant flowers early, and this is associated with derepression of RAP1B expression in pps-1 plants independently of the Hd1-Hd3a/RFT1 photoperiodic pathway. PPS is strongly expressed in the fourth and fifth leaves, suggesting that it regulates the onset of the adult phase downstream of MORI1 and upstream of miR156 and miR172. Its ability to regulate the vegetative phase change and the time of flowering suggests that rice PPS acquired novel functions during the evolution of rice/monocots. PMID:21705640

  2. Type 1 inositol trisphosphate receptor regulates cerebellar circuits by maintaining the spine morphology of purkinje cells in adult mice.

    PubMed

    Sugawara, Takeyuki; Hisatsune, Chihiro; Le, Tung Dinh; Hashikawa, Tsutomu; Hirono, Moritoshi; Hattori, Mitsuharu; Nagao, Soichi; Mikoshiba, Katsuhiko

    2013-07-24

    The structural maintenance of neural circuits is critical for higher brain functions in adulthood. Although several molecules have been identified as regulators for spine maintenance in hippocampal and cortical neurons, it is poorly understood how Purkinje cell (PC) spines are maintained in the mature cerebellum. Here we show that the calcium channel type 1 inositol trisphosphate receptor (IP3R1) in PCs plays a crucial role in controlling the maintenance of parallel fiber (PF)-PC synaptic circuits in the mature cerebellum in vivo. Significantly, adult mice lacking IP3R1 specifically in PCs (L7-Cre;Itpr1(flox/flox)) showed dramatic increase in spine density and spine length of PCs, despite having normal spines during development. In addition, the abnormally rearranged PF-PC synaptic circuits in mature cerebellum caused unexpectedly severe ataxia in adult L7-Cre;Itpr1(flox/flox) mice. Our findings reveal a specific role for IP3R1 in PCs not only as an intracellular mediator of cerebellar synaptic plasticity induction, but also as a critical regulator of PF-PC synaptic circuit maintenance in the mature cerebellum in vivo; this mechanism may underlie motor coordination and learning in adults. PMID:23884927

  3. Timing of Expression of a Gene in the Adult Drosophila Is Regulated by Mechanisms Independent of Temperature and Metabolic Rate

    PubMed Central

    Rogina, B.; Helfand, S. L.

    1996-01-01

    The examination of β-galactosidase (β-gal) expression in the third segment of the antenna of the 2216 enhancer trap line in Drosophila melanogaster reveals two distinct spatial and temporal regulatory patterns of expression during adult life. Type I expression is characterized by a decline in the level of β-gal expression with increasing age. Starting from a maximal level of expression at the time of adult emergence, there is a decrease in the number of cells that express β-gal so that by 40-50 days of adult life few cells express β-gal. Varying the ambient temperature and using hyperactivity mutants (Hyperkinetic(1), Shaker(5)) demonstrates that the rate of this decline is independent of temperature and metabolic rate. Type II expression is distinctly different in spatial distribution and temporal regulation from the first pattern. Type II expression is restricted in the antenna to a small (<20-30) set of cells whose level of expression changes in a periodic manner with time. The regulation of this periodicity appears to be linked to ambient temperature. PMID:8844152

  4. A Case Study on the Impacts of Connective Technology on Self-Efficacy and Self-Regulated Learning of Female Adult Students Managing Work-Life Balance

    ERIC Educational Resources Information Center

    Sheetz, Tracey L.

    2014-01-01

    Adults frequently define their lives as "hectic" and "overextended;" yet, many make the decision to return to school and add the role of student into their busy lives. This research study explored and explained the impact of connective technology on self-efficacy and self-regulated learning of female adult students balancing…

  5. Site-specific regulation of adult neurogenesis by dietary fatty acid content, vitamin E and flight exercise in European starlings.

    PubMed

    Hall, Zachary J; Bauchinger, Ulf; Gerson, Alexander R; Price, Edwin R; Langlois, Lillie A; Boyles, Michelle; Pierce, Barbara; McWilliams, Scott R; Sherry, David F; Macdougall-Shackleton, Scott A

    2014-03-01

    Exercise is known to have a strong effect on neuroproliferation in mammals ranging from rodents to humans. Recent studies have also shown that fatty acids and other dietary supplements can cause an upregulation of neurogenesis. It is not known, however, how exercise and diet interact in their effects on adult neurogenesis. We examined neuronal recruitment in multiple telencephalic sites in adult male European starlings (Sturnus vulgaris) exposed to a factorial combination of flight exercise, dietary fatty acids and antioxidants. Experimental birds were flown in a wind tunnel following a training regime that mimicked the bird's natural flight behaviour. In addition to flight exercise, we manipulated the composition of dietary fatty acids and the level of enrichment with vitamin E, an antioxidant reported to enhance neuronal recruitment. We found that all three factors - flight exercise, fatty acid composition and vitamin E enrichment - regulate neuronal recruitment in a site-specific manner. We also found a robust interaction between flight training and vitamin E enrichment at multiple sites of neuronal recruitment. Specifically, flight training was found to enhance neuronal recruitment across the telencephalon, but only in birds fed a diet with a low level of vitamin E. Conversely, dietary enrichment with vitamin E upregulated neuronal recruitment, but only in birds not flown in the wind tunnel. These findings indicate conserved modulation of adult neurogenesis by exercise and diet across vertebrate taxa and indicate possible therapeutic interventions in disorders characterized by reduced adult neurogenesis. PMID:24372878

  6. Regulation of netrin-1 receptors by amphetamine in the adult brain.

    PubMed

    Yetnikoff, L; Labelle-Dumais, C; Flores, C

    2007-12-19

    Netrin-1 is a guidance cue molecule fundamental to the organization of neuronal connectivity during development. Netrin-1 and its receptors, deleted in colorectal cancer (DCC) and UNC-5 homologues (UNC-5), continue to be expressed in the adult brain, although neither their function nor the kinds of events that activate their expression are known. Two lines of evidence suggest a role for netrin-1 in amphetamine-induced dopamine plasticity in the adult. First, DCC is highly expressed by adult dopamine neurons. Second, adult mice with reduced DCC levels do not develop amphetamine-induced behavioral sensitization. To explore the role of netrin-1 in amphetamine-induced plasticity, we examined the effects of sensitizing treatment regimens of amphetamine on DCC and/or UNC-5 protein expression in the adult rat. These treatments produced striking and enduring increases in DCC and UNC-5 expression in the cell body, but not terminal regions, of the mesocorticolimbic dopamine system. Notably, neuroadaptations in the cell body region of mesocorticolimbic dopamine neurons underlie the development of sensitization to the effects of amphetamine. Furthermore, these localized amphetamine-induced changes were prevented by co-treatment with an N-methyl-d-aspartate receptor antagonist, a treatment known to block the development of amphetamine-induced sensitization of behavioral activation, dopamine release and motivated behavior. Using immunohistochemistry, we showed that both DCC and UNC-5 receptors are highly expressed by adult mesocorticolimbic dopamine neurons. These results provide the first evidence that repeated exposure to a stimulant drug such as amphetamine affects netrin-1 receptor expression in the adult brain. Taken together, our findings suggest that changes in netrin-1 receptor expression may play a role in the lasting effects of exposure to amphetamine and other stimulant drugs. PMID:17996376

  7. REGULATION OF NETRIN-1 RECEPTORS BY AMPHETAMINE IN THE ADULT BRAIN

    PubMed Central

    YETNIKOFF, L.; LABELLE-DUMAIS, C.; FLORES, C.

    2016-01-01

    Netrin-1 is a guidance cue molecule fundamental to the organization of neuronal connectivity during development. Netrin-1 and its receptors, deleted in colorectal cancer (DCC) and UNC-5 homologues (UNC-5), continue to be expressed in the adult brain, although neither their function nor the kinds of events that activate their expression are known. Two lines of evidence suggest a role for netrin-1 in amphetamine-induced dopamine plasticity in the adult. First, DCC is highly expressed by adult dopamine neurons. Second, adult mice with reduced DCC levels do not develop amphetamine-induced behavioral sensitization. To explore the role of netrin-1 in amphetamine-induced plasticity, we examined the effects of sensitizing treatment regimens of amphetamine on DCC and/or UNC-5 protein expression in the adult rat. These treatments produced striking and enduring increases in DCC and UNC-5 expression in the cell body, but not terminal regions, of the mesocorticolimbic dopamine system. Notably, neuroadaptations in the cell body region of mesocorticolimbic dopamine neurons underlie the development of sensitization to the effects of amphetamine. Furthermore, these localized amphetamine-induced changes were prevented by co-treatment with an N-methyl-D-aspartate receptor antagonist, a treatment known to block the development of amphetamine-induced sensitization of behavioral activation, dopamine release and motivated behavior. Using immunohistochemistry, we showed that both DCC and UNC-5 receptors are highly expressed by adult mesocorticolimbic dopamine neurons. These results provide the first evidence that repeated exposure to a stimulant drug such as amphetamine affects netrin-1 receptor expression in the adult brain. Taken together, our findings suggest that changes in netrin-1 receptor expression may play a role in the lasting effects of exposure to amphetamine and other stimulant drugs. PMID:17996376

  8. Astroglial β-Arrestin1-mediated Nuclear Signaling Regulates the Expansion of Neural Precursor Cells in Adult Hippocampus

    PubMed Central

    Tao, Yezheng; Ma, Li; Liao, Zhaohui; Le, Qiumin; Yu, Jialing; Liu, Xing; Li, Haohong; Chen, Yuejun; Zheng, Ping; Yang, Zhengang; Ma, Lan

    2015-01-01

    Adult hippocampal neurogenesis is crucial for preserving normal brain function, but how it is regulated by niche cells is uncertain. Here we show that β-arrestin 1 (β-arr1) in dentate gyrus (DG) regulates neural precursor proliferation. β-arr1 knockout (KO) mice show reduced neural precursor proliferation in subgranular zone (SGZ) which could be rescued by selective viral expression of β-arr1 but not its nuclear-function-deficient mutants under control of hGFAP promotor in DG. Compared with wild type astrocytes, β-arr1 KO astrocytes nurture less neurospheres, and this may be attributed to changed activity of soluble, heat-sensitive excretive factors, such as BMP2. RNA-sequencing reveals that β-arr1 KO DG astrocytes exhibit an aberrant gene expression profile of niche factors, including elevated transcription of Bmp2. Taken together, our data suggest that β-arr1 mediated nuclear signaling regulates the production of excretive factors derived from niche astrocytes and expansion of neural precursors in DG, thus maintaining homeostasis of adult hippocampal neurogenesis. PMID:26500013

  9. Transcription factors and miRNAs that regulate fetal to adult CFTR expression change are new targets for cystic fibrosis.

    PubMed

    Viart, Victoria; Bergougnoux, Anne; Bonini, Jennifer; Varilh, Jessica; Chiron, Raphaël; Tabary, Olivier; Molinari, Nicolas; Claustres, Mireille; Taulan-Cadars, Magali

    2015-01-01

    The CFTR gene displays a tightly regulated tissue-specific and temporal expression. Mutations in this gene cause cystic fibrosis (CF). In this study we wanted to identify trans-regulatory elements responsible for CFTR differential expression in fetal and adult lung, and to determine the importance of inhibitory motifs in the CFTR-3'UTR with the aim of developing new tools for the correction of disease-causing mutations within CFTR. We show that lung development-specific transcription factors (FOXA, C/EBP) and microRNAs (miR-101, miR-145, miR-384) regulate the switch from strong fetal to very low CFTR expression after birth. By using miRNome profiling and gene reporter assays, we found that miR-101 and miR-145 are specifically upregulated in adult lung and that miR-101 directly acts on its cognate site in the CFTR-3'UTR in combination with an overlapping AU-rich element. We then designed miRNA-binding blocker oligonucleotides (MBBOs) to prevent binding of several miRNAs to the CFTR-3'UTR and tested them in primary human nasal epithelial cells from healthy individuals and CF patients carrying the p.Phe508del CFTR mutation. These MBBOs rescued CFTR channel activity by increasing CFTR mRNA and protein levels. Our data offer new understanding of the control of the CFTR gene regulation and new putative correctors for cystic fibrosis. PMID:25186262

  10. Adult longevity of certain mosquito species after larval and pupal exposure to sublethal concentration of an insect growth regulator, hexaflumuron.

    PubMed

    Vasuki, V

    1992-03-01

    Longevity of the adults of three vector species, Culex quinquefasciatus, Anopheles stephensi, and Aedes aegypti was drastically reduced when they were exposed at larval and pupal stages to sublethal concentrations of an insect growth regulator hexaflumuron. When the three species were exposed to 0.05 mg/l at the pupal stage, males and females of Cx. quinquefasciatus suffered a more shortened life span than other species. Among the females whose feeding activity was adversely affected by IGR treatment at the pupal stage, Ae. aegypti showed the minimum survival duration with LT50 of 2.74 days. PMID:1523463

  11. The Association among Difficulties in Emotion Regulation, Hostility, and Empathy in a Sample of Young Italian Adults.

    PubMed

    Contardi, Anna; Imperatori, Claudio; Penzo, Ilaria; Del Gatto, Claudia; Farina, Benedetto

    2016-01-01

    The aim of the present study was to assess the role of empathy in mediating the association between difficulties in emotion regulation and hostility. Three hundred and sixty young Italian adults (220 women and 140 men) were enrolled in the study. Psychopathological assessments included the Difficulties in Emotion Regulation Scale (DERS), the Interpersonal Reactivity Index and the Buss-Durkee Hostility Inventory (BDHI). Perspective taking (PT) and Personal distress (PD) are significantly associated with both DERS total score and BDHI total score. A mediational model analyzing the direct and indirect effects of DERS on BDHI through the mediating role of PT and PD showed that the relation between DERS and BDHI was partially mediated by PT total score (b = 0.16; se = 0.01; p = 0.02). Taken together our findings support the possibility that PT skills could play a crucial role in inhibiting hostility behaviors. PMID:27486417

  12. The Association among Difficulties in Emotion Regulation, Hostility, and Empathy in a Sample of Young Italian Adults

    PubMed Central

    Contardi, Anna; Imperatori, Claudio; Penzo, Ilaria; Del Gatto, Claudia; Farina, Benedetto

    2016-01-01

    The aim of the present study was to assess the role of empathy in mediating the association between difficulties in emotion regulation and hostility. Three hundred and sixty young Italian adults (220 women and 140 men) were enrolled in the study. Psychopathological assessments included the Difficulties in Emotion Regulation Scale (DERS), the Interpersonal Reactivity Index and the Buss–Durkee Hostility Inventory (BDHI). Perspective taking (PT) and Personal distress (PD) are significantly associated with both DERS total score and BDHI total score. A mediational model analyzing the direct and indirect effects of DERS on BDHI through the mediating role of PT and PD showed that the relation between DERS and BDHI was partially mediated by PT total score (b = 0.16; se = 0.01; p = 0.02). Taken together our findings support the possibility that PT skills could play a crucial role in inhibiting hostility behaviors. PMID:27486417

  13. The use and evaluation of self-regulation techniques can predict health goal attainment in adults: an explorative study.

    PubMed

    Plaete, Jolien; De Bourdeaudhuij, Ilse; Verloigne, Maite; Crombez, Geert

    2016-01-01

    Background. Self-regulation tools are not always used optimally, and implementation intention plans often lack quality. Therefore, this study explored participants' use and evaluation of self-regulation techniques and their impact on goal attainment. Methods. Data were obtained from 452 adults in a proof of concept (POC) intervention of 'MyPlan', an eHealth intervention using self-regulation techniques to promote three healthy behaviours (physical activity (PA), fruit intake, or vegetable intake). Participants applied self-regulation techniques to a self-selected health behaviour, and evaluated the self-regulation techniques. The quality of implementation intentions was rated by the authors as a function of instrumentality (instrumental and non-instrumental) and specificity (non-specific and medium to highly specific). Logistic regression analyses were conducted to predict goal attainment. Results. Goal attainment was significantly predicted by the motivational value of the personal advice (OR:1.86), by the specificity of the implementation intentions (OR:3.5), by the motivational value of the action plan (OR:1.86), and by making a new action plan at follow-up (OR:4.10). Interaction-effects with behaviour showed that the specificity score of the implementation intention plans (OR:4.59), the motivational value of the personal advice (OR:2.38), selecting hindering factors and solutions(OR:2.00) and making a new action plan at follow-up (OR:7.54) were predictive of goal attainment only for fruit or vegetable intake. Also, when participants in the fruit and vegetable group made more than three plans, they were more likely to attain their goal (OR:1.73), whereas the reverse was the case in the PA group (OR:0.34). Discussion. The chance that adults reach fruit and vegetable goals can be increased by including motivating personal advice, self-formulated action plans, and instructions/strategies to make specific implementation intentions into eHealth interventions. To

  14. The use and evaluation of self-regulation techniques can predict health goal attainment in adults: an explorative study

    PubMed Central

    De Bourdeaudhuij, Ilse; Verloigne, Maite; Crombez, Geert

    2016-01-01

    Background. Self-regulation tools are not always used optimally, and implementation intention plans often lack quality. Therefore, this study explored participants’ use and evaluation of self-regulation techniques and their impact on goal attainment. Methods. Data were obtained from 452 adults in a proof of concept (POC) intervention of ‘MyPlan’, an eHealth intervention using self-regulation techniques to promote three healthy behaviours (physical activity (PA), fruit intake, or vegetable intake). Participants applied self-regulation techniques to a self-selected health behaviour, and evaluated the self-regulation techniques. The quality of implementation intentions was rated by the authors as a function of instrumentality (instrumental and non-instrumental) and specificity (non-specific and medium to highly specific). Logistic regression analyses were conducted to predict goal attainment. Results. Goal attainment was significantly predicted by the motivational value of the personal advice (OR:1.86), by the specificity of the implementation intentions (OR:3.5), by the motivational value of the action plan (OR:1.86), and by making a new action plan at follow-up (OR:4.10). Interaction-effects with behaviour showed that the specificity score of the implementation intention plans (OR:4.59), the motivational value of the personal advice (OR:2.38), selecting hindering factors and solutions(OR:2.00) and making a new action plan at follow-up (OR:7.54) were predictive of goal attainment only for fruit or vegetable intake. Also, when participants in the fruit and vegetable group made more than three plans, they were more likely to attain their goal (OR:1.73), whereas the reverse was the case in the PA group (OR:0.34). Discussion. The chance that adults reach fruit and vegetable goals can be increased by including motivating personal advice, self-formulated action plans, and instructions/strategies to make specific implementation intentions into eHealth interventions

  15. The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity

    PubMed Central

    Chen, Shiau-Mei; Chou, Wen-Cheng; Hu, Ling-Yueh; Hsiung, Chia-Ni; Chu, Hou-Wei; Huang, Yuan-Ling; Hsu, Huan-Ming; Yu, Jyh-Cherng; Shen, Chen-Yang

    2015-01-01

    MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair–related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair–related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents. PMID:26115122

  16. Circadian regulation gene polymorphisms are associated with sleep disruption and duration, and circadian phase and rhythm in adults with HIV.

    PubMed

    Lee, Kathryn A; Gay, Caryl; Byun, Eeeseung; Lerdal, Anners; Pullinger, Clive R; Aouizerat, Bradley E

    2015-01-01

    Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep-wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72 h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST

  17. Relaxation therapy and anxiety, self-esteem, and emotional regulation among adults with intellectual disabilities: A randomized controlled trial.

    PubMed

    Bouvet, Cyrille; Coulet, Aurélie

    2016-09-01

    This pilot study is a randomized controlled trial on the effects of relaxation on anxiety, self-esteem, and emotional regulation in adults with intellectual disabilities (ID) working in a center of supported employment in France. We studied 30 adults with mild or moderate ID who were split at random into a relaxation group (RG, 15 subjects), who completed 10 sessions of relaxation therapy, and a control group (CG, 15 subjects), who were on a waiting list. The method used is the pretest and posttest. Variables were assessed by the State-Trait Anxiety Inventory form Y scale, the Rosenberg Self-Esteem scale, and the Emotion Regulation Questionnaire. We found that in the RG, relaxation significantly reduced state anxiety, t(14, 15) = 17.8***, d = -0.72, and improved self-esteem, t(14, 15) = -7.7***, d = 1.03, and cognitive reappraisal, t(14, 15) = -6.3***, d = 1.3, while the CG showed no change for these variables. We conclude that relaxation seems to be an interesting therapeutic option for reducing anxiety in people with ID in a supported employment setting. PMID:26420821

  18. Brief Report: The Deletion of the Phosphatase Regulator NIPP1 Causes Progenitor Cell Expansion in the Adult Liver.

    PubMed

    Boens, Shannah; Verbinnen, Iris; Verhulst, Stefaan; Szekér, Kathelijne; Ferreira, Monica; Gevaert, Thomas; Baes, Myriam; Roskams, Tania; van Grunsven, Leo A; Van Eynde, Aleyde; Bollen, Mathieu

    2016-08-01

    The Ppp1r8 gene encodes NIPP1, a nuclear interactor of protein phosphatase PP1. The deletion of NIPP1 is embryonic lethal at the gastrulation stage, which has hampered its functional characterization in adult tissues. Here, we describe the effects of a conditional deletion of NIPP1 in mouse liver epithelial cells. Ppp1r8(-/-) livers developed a ductular reaction, that is, bile-duct hyperplasia with associated fibrosis. The increased proliferation of biliary epithelial cells was at least partially due to an expansion of the progenitor cell compartment that was independent of liver injury. Gene-expression analysis confirmed an upregulation of progenitor cell markers in the liver knockout livers but showed no effect on the expression of liver-injury associated regulators of cholangiocyte differentiation markers. Consistent with an inhibitory effect of NIPP1 on progenitor cell proliferation, Ppp1r8(-/-) livers displayed an increased sensitivity to diet-supplemented 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which also causes bile-duct hyperplasia through progenitor cell expansion. In contrast, the liver knockouts responded normally to injuries (partial hepatectomy, single CCl4 administration) that are restored through proliferation of differentiated parenchymal cells. Our data indicate that NIPP1 does not regulate the proliferation of hepatocytes but is a suppressor of biliary epithelial cell proliferation, including progenitor cells, in the adult liver. Stem Cells 2016;34:2256-2262. PMID:27068806

  19. Genetic regulators of a pluripotent adult stem cell system in planarians identified by RNAi and clonal analysis

    PubMed Central

    Wagner, Daniel E.; Ho, Jaclyn J.

    2012-01-01

    Summary Pluripotency is a central, well-studied feature of embryonic development, but the role of pluripotent cell regulation in somatic tissue regeneration remains poorly understood. In planarians, regeneration of entire animals from tissue fragments is promoted by the activity of adult pluripotent stem cells (cNeoblasts). We utilized transcriptional profiling to identify planarian genes expressed in adult proliferating, regenerative cells (neoblasts). We also developed quantitative clonal analysis methods for expansion and differentiation of cNeoblast descendants that, together with RNAi, revealed gene roles in stem cell biology. Genes encoding two zinc finger proteins, Vasa, a LIM domain protein, Sox and Jun-like transcription factors, two candidate RNA-binding proteins, a Setd8-like protein, and PRC2 (Polycomb) were required for proliferative expansion and/or differentiation of cNeoblast-derived clones. These findings suggest that planarian stem cells utilize molecular mechanisms found in germ cells and other pluripotent cell types, and identify novel genetic regulators of the planarian stem cell system. PMID:22385657

  20. Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression

    PubMed Central

    Marqués-Torrejón, M. Ángeles; Porlan, Eva; Banito, Ana; Gómez-Ibarlucea, Esther; Fernández-Capetillo, Óscar; Vidal, Anxo; Gil, Jesús; Torres, Josema; Fariñas, Isabel

    2013-01-01

    Summary In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a novel function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21-null cells induces replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19Arf and p53. Our results show a novel regulation of NSC expansion driven by a p21/Sox2/p53 axis. PMID:23260487

  1. Gender difference in older adult's utilization of gravitational and ground reaction force in regulation of angular momentum during stair descent.

    PubMed

    Singhal, Kunal; Kim, Jemin; Casebolt, Jeffrey; Lee, Sangwoo; Han, Ki-Hoon; Kwon, Young-Hoo

    2015-06-01

    Angular momentum of the body is a highly controlled quantity signifying stability, therefore, it is essential to understand its regulation during stair descent. The purpose of this study was to investigate how older adults use gravity and ground reaction force to regulate the angular momentum of the body during stair descent. A total of 28 participants (12 male and 16 female; 68.5 years and 69.0 years of mean age respectively) performed stair descent from a level walk in a step-over-step manner at a self-selected speed over a custom made three-step staircase with embedded force plates. Kinematic and force data were used to calculate angular momentum, gravitational moment, and ground reaction force moment about the stance foot center of pressure. Women show a significantly greater change in normalized angular momentum (0.92Nms/Kgm; p=.004) as compared to men (0.45Nms/Kgm). Women produce higher normalized GRF (p=.031) during the double support phase. The angular momentum changes show largest backward regulation for Step 0 and forward regulation for Step 2. This greater difference in overall change in the angular momentum in women may explain their increased risk of fall over the stairs. PMID:25846952

  2. Localization and regulation of PML bodies in the adult mouse brain.

    PubMed

    Hall, Małgorzata H; Magalska, Adriana; Malinowska, Monika; Ruszczycki, Błażej; Czaban, Iwona; Patel, Satyam; Ambrożek-Latecka, Magdalena; Zołocińska, Ewa; Broszkiewicz, Hanna; Parobczak, Kamil; Nair, Rajeevkumar R; Rylski, Marcin; Pawlak, Robert; Bramham, Clive R; Wilczyński, Grzegorz M

    2016-06-01

    PML is a tumor suppressor protein involved in the pathogenesis of promyelocytic leukemia. In non-neuronal cells, PML is a principal component of characteristic nuclear bodies. In the brain, PML has been implicated in the control of embryonic neurogenesis, and in certain physiological and pathological phenomena in the adult brain. Yet, the cellular and subcellular localization of the PML protein in the brain, including its presence in the nuclear bodies, has not been investigated comprehensively. Because the formation of PML bodies appears to be a key aspect in the function of the PML protein, we investigated the presence of these structures and their anatomical distribution, throughout the adult mouse brain. We found that PML is broadly expressed across the gray matter, with the highest levels in the cerebral and cerebellar cortices. In the cerebral cortex PML is present exclusively in neurons, in which it forms well-defined nuclear inclusions containing SUMO-1, SUMO 2/3, but not Daxx. At the ultrastructural level, the appearance of neuronal PML bodies differs from the classic one, i.e., the solitary structure with more or less distinctive capsule. Rather, neuronal PML bodies have the form of small PML protein aggregates located in the close vicinity of chromatin threads. The number, size, and signal intensity of neuronal PML bodies are dynamically influenced by immobilization stress and seizures. Our study indicates that PML bodies are broadly involved in activity-dependent nuclear phenomena in adult neurons. PMID:25956166

  3. Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice.

    PubMed

    Knapp, Amy E; Goldberg, Daniel; Delavar, Hamid; Trisko, Breanna M; Tang, Kechun; Hogan, Michael C; Wagner, Peter D; Breen, Ellen C

    2016-07-01

    A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P < 0.05) and endurance capacity (-47%; P < 0.05), which did not persist after 8 wk. In skmVEGF-/- mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity. PMID:27225953

  4. MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity.

    PubMed

    Moretti, Irene; Ciciliot, Stefano; Dyar, Kenneth A; Abraham, Reimar; Murgia, Marta; Agatea, Lisa; Akimoto, Takayuki; Bicciato, Silvio; Forcato, Mattia; Pierre, Philippe; Uhlenhaut, N Henriette; Rigby, Peter W J; Carvajal, Jaime J; Blaauw, Bert; Calabria, Elisa; Schiaffino, Stefano

    2016-01-01

    The myogenic regulatory factor MRF4 is highly expressed in adult skeletal muscle but its function is unknown. Here we show that Mrf4 knockdown in adult muscle induces hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and widespread activation of muscle-specific genes, many of which are targets of MEF2 transcription factors. MEF2-dependent genes represent the top-ranking gene set enriched after Mrf4 RNAi and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The Mrf4 RNAi-dependent increase in fibre size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofibre hypertrophy. The nuclear localization of the MEF2 corepressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. These findings open new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia. PMID:27484840

  5. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages.

    PubMed

    Pearson, Bret J; Sánchez Alvarado, Alejandro

    2010-01-01

    The functions of adult stem cells and tumor suppressor genes are known to intersect. However, when and how tumor suppressors function in the lineages produced by adult stem cells is unknown. With a large population of stem cells that can be manipulated and studied in vivo, the freshwater planarian is an ideal system with which to investigate these questions. Here, we focus on the tumor suppressor p53, homologs of which have no known role in stem cell biology in any invertebrate examined thus far. Planaria have a single p53 family member, Smed-p53, which is predominantly expressed in newly made stem cell progeny. When Smed-p53 is targeted by RNAi, the stem cell population increases at the expense of progeny, resulting in hyper-proliferation. However, ultimately the stem cell population fails to self-renew. Our results suggest that prior to the vertebrates, an ancestral p53-like molecule already had functions in stem cell proliferation control and self-renewal. PMID:20040488

  6. Neural stem cells in the adult ciliary epithelium express GFAP and are regulated by Wnt signaling

    SciTech Connect

    Das, Ani V.; Zhao Xing; James, Jackson; Kim, Min; Cowan, Kenneth H.; Ahmad, Iqbal . E-mail: iahmad@unmc.edu

    2006-01-13

    The identification of neural stem cells with retinal potential in the ciliary epithelium (CE) of the adult mammals is of considerable interest because of their potential for replacing or rescuing degenerating retinal neurons in disease or injury. The evaluation of such a potential requires characterization of these cells with regard to their phenotypic properties, potential, and regulatory mechanisms. Here, we demonstrate that rat CE stem cells/progenitors in neurosphere culture display astrocytic nature in terms of expressing glial intermediate neurofilament protein, GFAP. The GFAP-expressing CE stem cells/progenitors form neurospheres in proliferating conditions and generate neurons when shifted to differentiating conditions. These cells express components of the canonical Wnt pathway and its activation promotes their proliferation. Furthermore, we demonstrate that the activation of the canonical Wnt pathway influences neuronal differentiation of CE stem cells/progenitors in a context dependent manner. Our observations suggest that CE stem cells/progenitors share phenotypic properties and regulatory mechanism(s) with neural stem cells elsewhere in the adult CNS.

  7. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family

    PubMed Central

    Porrello, Enzo R.; Mahmoud, Ahmed I.; Simpson, Emma; Johnson, Brett A.; Grinsfelder, David; Canseco, Diana; Mammen, Pradeep P.; Rothermel, Beverly A.; Olson, Eric N.; Sadek, Hesham A.

    2013-01-01

    We recently identified a brief time period during postnatal development when the mammalian heart retains significant regenerative potential after amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-old mice and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal heart mounted a robust regenerative response, through proliferation of preexisting cardiomyocytes, resulting in full functional recovery within 21 d. Moreover, we show that the miR-15 family of microRNAs modulates neonatal heart regeneration through inhibition of postnatal cardiomyocyte proliferation. Finally, we demonstrate that inhibition of the miR-15 family from an early postnatal age until adulthood increases myocyte proliferation in the adult heart and improves left ventricular systolic function after adult MI. We conclude that the neonatal mammalian heart can regenerate after myocardial infarction through proliferation of preexisting cardiomyocytes and that the miR-15 family contributes to postnatal loss of cardiac regenerative capacity. PMID:23248315

  8. Regulation of proto-oncogene expression in adult and developing lungs.

    PubMed Central

    Molinar-Rode, R; Smeyne, R J; Curran, T; Morgan, J I

    1993-01-01

    Activation of immediate-early gene expression has been associated with mitogenesis, differentiation, nerve cell depolarization, and recently, terminal differentiation processes and programmed cell death. Previous evidence also suggested that immediate-early genes play a role in the physiology of the lungs (J. I. Morgan, D. R. Cohen, J. L. Hempstead, and T. Curran, Science 237:192-197, 1987). Therefore, we analyzed c-fos expression in adult and developing lung tissues. Seizures elicited by chemoconvulsants induced expression of mRNA for c-fos, c-jun, and junB and Fos-like immunoreactivity in lung tissue. The use of pharmacological antagonists and adrenalectomy indicated that this increased expression was neurogenic. Interestingly, by using a fos-lacZ transgenic mouse, it was shown that Fos-LacZ expression in response to seizure occurred preferentially in clusters of epithelial cells at the poles of the bronchioles. This was the same location of Fos-LacZ expression detected during early lung development. These data imply that pharmacological induction of immediate-early gene expression in adult mice recapitulates an embryological program of gene expression. Images PMID:8497249

  9. Impaired prefrontal sleep spindle regulation of hippocampal-dependent learning in older adults.

    PubMed

    Mander, Bryce A; Rao, Vikram; Lu, Brandon; Saletin, Jared M; Ancoli-Israel, Sonia; Jagust, William J; Walker, Matthew P

    2014-12-01

    A hallmark feature of cognitive aging is a decline in the ability to form new memories. Parallel to these cognitive impairments are marked disruptions in sleep physiology. Despite recent evidence in young adults establishing a role for sleep spindles in restoring hippocampal-dependent memory formation, the possibility that disrupted sleep physiology contributes to age-related decline in hippocampal-dependent learning remains unknown. Here, we demonstrate that reduced prefrontal sleep spindles by over 40% in older adults statistically mediates the effects of old age on next day episodic learning, such that the degree of impaired episodic learning is explained by the extent of impoverished prefrontal sleep spindles. In addition, prefrontal spindles significantly predicted the magnitude of impaired next day hippocampal activation, thereby determining the influence of spindles on post-sleep learning capacity. These data support the hypothesis that disrupted sleep physiology contributes to age-related cognitive decline in later life, the consequence of which has significant treatment intervention potential. PMID:23901074

  10. MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

    PubMed Central

    Moretti, Irene; Ciciliot, Stefano; Dyar, Kenneth A.; Abraham, Reimar; Murgia, Marta; Agatea, Lisa; Akimoto, Takayuki; Bicciato, Silvio; Forcato, Mattia; Pierre, Philippe; Uhlenhaut, N. Henriette; Rigby, Peter W. J.; Carvajal, Jaime J.; Blaauw, Bert; Calabria, Elisa; Schiaffino, Stefano

    2016-01-01

    The myogenic regulatory factor MRF4 is highly expressed in adult skeletal muscle but its function is unknown. Here we show that Mrf4 knockdown in adult muscle induces hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and widespread activation of muscle-specific genes, many of which are targets of MEF2 transcription factors. MEF2-dependent genes represent the top-ranking gene set enriched after Mrf4 RNAi and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The Mrf4 RNAi-dependent increase in fibre size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofibre hypertrophy. The nuclear localization of the MEF2 corepressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. These findings open new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia. PMID:27484840

  11. Adult Age Differences in the Effects of Goals on Self-Regulated Sentence Processing

    PubMed Central

    Stine-Morrow, Elizabeth A. L.; Shake, Matthew C.; Miles, Joseph R.; Noh, Soo Rim

    2008-01-01

    We examined age differences in the allocation of effort when reading text for either high levels of recall accuracy or high levels of efficiency. Older and younger adults read a series of sentences, making judgments of learning before recalling the information they had studied. Older adults showed less sensitivity than the young to the accuracy goal in terms of both reading time allocation and memory performance. Memory monitoring (i.e., the correspondence between actual and perceived learning) and differential allocation of effort to unlearned items were age-equivalent, so that age differences in goal adherence were not attributable to these factors. However, comparison with data from a judgment task neutral with respect to memory monitoring showed that learning gains among the old across trial were reduced relative to young by memory monitoring, suggesting that active memory monitoring may be resource-consuming for older learners. Regression analysis was used to show that age differences in the responsiveness to (cognitive/information-acquisition) goals could be accounted for, in part, by independent contributions from working memory and memory self-efficacy. Our data suggest that both processing capacity (“what you have”) and beliefs (“knowing you can do it”) can contribute to individual differences in engaging resources (“what you do”) to effectively learn novel content from text. PMID:17201498

  12. Fibroblast-Derived MMP-14 Regulates Collagen Homeostasis in Adult Skin.

    PubMed

    Zigrino, Paola; Brinckmann, Jürgen; Niehoff, Anja; Lu, Yinhui; Giebeler, Nives; Eckes, Beate; Kadler, Karl E; Mauch, Cornelia

    2016-08-01

    Proteolytic activities in the extracellular matrix by the matrix metalloproteinase (MMP)-14 have been implicated in the remodeling of collagenous proteins during development. To analyze the function of fibroblast-derived MMP-14 in adult skin homeostasis, we generated mice with inducible deletion of MMP-14 in the dermal fibroblast (MMP-14(Sf-/-)). These mice are smaller and display a fibrosis-like phenotype in the skin. The skin of these mice showed increased stiffness and tensile strength but no altered collagen cross-links. In vivo, we measured a significantly increased amount of collagen type I accumulated in the skin of MMP-14(Sf-/-) mice without an increase in collagen fibril diameters. However, bleomycin-induced fibrosis in skin proceeded in a comparable manner in MMP-14(Sf+/+) and MMP-14(Sf-/-) mice, but resolution over time was impaired in MMP-14(Sf-/-) mice. Increased accumulation of collagen type I was detected in MMP-14(Sf-/-) fibroblasts in culture without significant enhancement of collagen de novo synthesis. This points to a degradative but not synthetic phenotype. In support of this, MMP-14(Sf-/-) fibroblasts lost their ability to process fibrillar collagen type I and to activate proMMP-2. Taken together, these data indicate that MMP-14 expression in fibroblasts plays a crucial role in collagen remodeling in adult skin and largely contributes to dermal homeostasis underlying its pathogenic role in fibrotic skin disease. PMID:27066886

  13. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages

    PubMed Central

    Pearson, Bret J.; Alvarado, Alejandro Sánchez

    2010-01-01

    The functions of adult stem cells and tumor suppressor genes are known to intersect. However, when and how tumor suppressors function in the lineages produced by adult stem cells is unknown. With a large population of stem cells that can be manipulated and studied in vivo, the freshwater planarian is an ideal system with which to investigate these questions. Here, we focus on the tumor suppressor p53, homologs of which have no known role in stem cell biology in any invertebrate examined thus far. Planaria have a single p53 family member, Smed-p53, which is predominantly expressed in newly made stem cell progeny. When Smed-p53 is targeted by RNAi, the stem cell population increases at the expense of progeny, resulting in hyper-proliferation. However, ultimately the stem cell population fails to self-renew. Our results suggest that prior to the vertebrates, an ancestral p53-like molecule already had functions in stem cell proliferation control and self-renewal. PMID:20040488

  14. Self-Regulation and Milestones of Adult Development: Intimacy and Generativity

    ERIC Educational Resources Information Center

    Busch, Holger; Hofer, Jan

    2012-01-01

    In 2 separate studies, the idea is tested that the positive association between self-regulatory capacities and well-being is partly explained by the positive effect self-regulation has on the successful resolution of developmental crises in Eriksonian terms. In Study 1, attentional control, intimacy, and subjective well-being are assessed in 177…

  15. Isolating Metamemory Deficits in the Self-Regulated Learning of Adults with ADHD

    ERIC Educational Resources Information Center

    Knouse, Laura E.; Anastopoulos, Arthur D.; Dunlosky, John

    2012-01-01

    ADHD in adulthood is associated with chronic academic impairments and problems with strategic memory encoding on standardized memory assessments, but little is known about self-regulated learning that might guide intervention. Objective: Examine the contribution of metamemory judgment accuracy and use of learning strategies to self-regulated…

  16. Lamina-associated polypeptide (LAP)2α and nucleoplasmic lamins in adult stem cell regulation and disease.

    PubMed

    Gesson, Kevin; Vidak, Sandra; Foisner, Roland

    2014-05-01

    A-type lamins are components of the lamina network at the nuclear envelope, which mediates nuclear stiffness and anchors chromatin to the nuclear periphery. However, A-type lamins are also found in the nuclear interior. Here we review the roles of the chromatin-associated, nucleoplasmic LEM protein, lamina-associated polypeptide 2α (LAP2α) in the regulation of A-type lamins in the nuclear interior. The lamin A/C-LAP2α complex may be involved in the regulation of the retinoblastoma protein-mediated pathway and other signaling pathways balancing proliferation and differentiation, and in the stabilization of higher-order chromatin organization throughout the nucleus. Loss of LAP2α in mice leads to selective depletion of the nucleoplasmic A-type lamin pool, promotes the proliferative stem cell phenotype of tissue progenitor cells, and delays stem cell differentiation. These findings support the hypothesis that LAP2α and nucleoplasmic lamins are regulators of adult stem cell function and tissue homeostasis. Finally, we discuss potential implications of this concept for defining the molecular disease mechanisms of lamin-linked diseases such as muscular dystrophy and premature aging syndromes. PMID:24374133

  17. MicroRNA-124 suppresses the migration and invasion of osteosarcoma cells via targeting ROR2-mediated non-canonical Wnt signaling.

    PubMed

    Zhang, Can; Hu, Yihe; Wan, Jun; He, Hongbo

    2015-10-01

    MicroRNAs (miRs) have been implicated in tumorigenesis through inhibition of the expression of their target genes at post-transcriptional levels. miR-124 has been found to be downregulated in many malignant tumors including osteosarcoma (OS). However, the detailed mechanism of miR-124 in the regulation of OS malignant phenotypes remains largely unclear. Here we aimed to explore the role of miR-124 in mediating OS cell migration and invasion, as well as the underlying regulatory mechanisms. Real-time RT-PCR data showed that miR-124 was frequently downregulated in OS cell lines compared to normal human osteoblast cells. We further conducted bioinformatic analysis and a luciferase reporter assay, and identified receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a novel target of miR-124. Furthermore, we found that ROR2 was significantly upregulated in OS cell lines compared to normal human osteoblast cells, and miR-124 negatively mediated the protein level of ROR2 in U-2OS and Saos-2 cells. Moreover, transfection with miR-124 mimics significantly suppressed migration and invasion in the U-2OS and Saos-2 cells, while overexpression of ROR2 in the miR-124-transfected OS cells reversed the inhibitory effect of miR-124 upregulation on OS cell migration and invasion. In addition, we found that overexpression of miR-124 significantly suppressed the activity of non-canonical Wnt signaling, downstream of ROR2. Based on these findings, we suggest that miR-124 may inhibit OS metastasis, partly at least, via targeting ROR2 and thus suppressing the activity of ROR2-mediated non-canonical Wnt signaling. PMID:26259653

  18. Alterations of microRNA-124 expression in peripheral blood mononuclear cells in pre- and post-treatment patients with major depressive disorder.

    PubMed

    He, Shen; Liu, Xiaohua; Jiang, Kaida; Peng, Daihui; Hong, Wu; Fang, Yiru; Qian, Yiping; Yu, Shunying; Li, Huafang

    2016-07-01

    Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p < 0.001), and that the area under the curve of miR-124 from ROC analysis was 0.762 with a sensitivity of 83.33% and specificity of 66.67% in distinguishing MDD patients from healthy controls. In addition, the expression levels of miR-124 were significantly down-regulated after eight weeks of treatment (p < 0.001). MiRNA target gene prediction and functional annotation analysis indicated that altered miR-124 was involved in affecting some important biological processes and pathways related to MDD. These results provide new information on miR-124 involvement in the biological alterations of MDD and in antidepressant effects. PMID:27078210

  19. Stress and serial adult metamorphosis: multiple roles for the stress axis in socially regulated sex change

    PubMed Central

    Solomon-Lane, Tessa K.; Crespi, Erica J.; Grober, Matthew S.

    2013-01-01

    Socially regulated sex change in teleost fishes is a striking example of social status information regulating biological function in the service of reproductive success. The establishment of social dominance in sex changing species is translated into a cascade of changes in behavior, physiology, neuroendocrine function, and morphology that transforms a female into a male, or vice versa. The hypothalamic-pituitary-interrenal axis (HPI, homologous to HP-adrenal axis in mammals and birds) has been hypothesized to play a mechanistic role linking status to sex change. The HPA/I axis responds to environmental stressors by integrating relevant external and internal cues and coordinating biological responses including changes in behavior, energetics, physiology, and morphology (i.e., metamorphosis). Through actions of both corticotropin-releasing factor and glucocorticoids, the HPA/I axis has been implicated in processes central to sex change, including the regulation of agonistic behavior, social status, energetic investment, and life history transitions. In this paper, we review the hypothesized roles of the HPA/I axis in the regulation of sex change and how those hypotheses have been tested to date. We include original data on sex change in the bluebanded goby (Lythyrpnus dalli), a highly social fish capable of bidirectional sex change. We then propose a model for HPA/I involvement in sex change and discuss how these ideas might be tested in the future. Understanding the regulation of sex change has the potential to elucidate evolutionarily conserved mechanisms responsible for translating pertinent information about the environment into coordinated biological changes along multiple body axes. PMID:24265604

  20. [Mediating role of emotional regulation between impulsive behavior in gambling, Internet and videogame abuse, and dysfunctional symptomatology in young adults and adolescents].

    PubMed

    Estévez Gutiérrez, Ana; Herrero Fernández, David; Sarabia Gonzalvo, Izaskun; Jáuregui Bilbao, Paula

    2014-01-01

    The way emotions are regulated might affect the engagement on risk behaviors in adolescents and young adults. Therefore, studying the relationship between these variables could be of great importance. Some of the less studied risky behaviors are pathological gambling, and Internet and videogame abuse. This research aims to analyze the existing relationship between such risky behaviors, emotion regulation, and dysfunctional psychological symptomatology (depression, anxiety, phobic anxiety, somatization, obsessive-–compulsive behavior, interpersonal sensitivity, hostility, paranoid ideation, and psychoticism). In addition, it also looks to assess whether emotional regulation plays a mediating role between pathological gambling, and Internet and videogame abuse, and psychological symptomatology. The sample was composed of 1312 young adults and adolescents, aged between 12 and 30, recruited from scholar centers, universities and free time groups, and from associations and centers associated with FEJAR (Spanish Federation of Rehabilitated Gamblers). Participants completed measurements of impulsive behavior, emotion regulation, and dysfunctional symptomatology. Results showed that there is generally a positive and significant relation between these variables. Moreover, it has been pointed out that emotion regulation mediates the association between impulsive behavior and dysfunctional symptomatology among those young adults and adolescents who engage in these impulsive behaviors, except for the relation between videogame abuse and depressive symptomatology. Training in emotional regulation skills could be useful in dealing with and treating this type of behaviors in adolescents and young adults. PMID:25577999

  1. Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury

    PubMed Central

    2009-01-01

    Background Neuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period. Results We have performed a microarray analysis of the rat L4/L5 dorsal root ganglia (DRG), 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour. The results show a set of genes, differentially regulated in the adult DRG, that are principally involved in immune system modulation. A functional consequence of this different immune response to injury is that resident macrophages cluster around the large A sensory neuron bodies in the adult DRG seven days post injury, whereas the macrophages in young DRG remain scattered evenly throughout the ganglion, as in controls. Conclusions The results show, for the first time, a major difference in the neuroimmune response to nerve injury in the dorsal root ganglion of young and adult rats. Differential analysis reveals a new set of immune related genes in the ganglia, that are differentially regulated in adult neuropathic pain, and that are consistent with the selective activation of macrophages around adult, but not young large A sensory neurons post injury. These

  2. Leptin signaling in GFAP-expressing adult glia cells regulates hypothalamic neuronal circuits and feeding

    PubMed Central

    Kim1, Jae Geun; Suyama, Shigetomo; Koch, Marco; Jin, Sungho; Argente-Arizon, Pilar; Argente, Jesus; Liu, Zhong-Wu; Zimmer, Marcelo R.; Jeong, Jin Kwon; Szigeti-Buck, Klara; Gao, Yuanqing; Garcia-Caceres, Cristina; Yi, Chun-Xia; Salmaso, Natalina; Vaccarino, Flora M.; Chowen, Julie; Diano, Sabrina; Dietrich, Marcelo O; Tschöp, Matthias H.; Horvath, Tamas L.

    2014-01-01

    We have shown that synaptic re-organization of hypothalamic feeding circuits in response to metabolic shifts involves astrocytes, cells that can directly respond to the metabolic hormone, leptin, in vitro. It is not known whether the role of glia cells in hypothalamic synaptic adaptions is active or passive. Here we show that leptin receptors are expressed in hypothalamic astrocytes and that conditional, adult deletion of leptin receptors in astrocytes leads to altered glial morphology, decreased glial coverage and elevated synaptic inputs onto pro-opiomelanocortin (POMC)- and Agouti-related protein (AgRP)-producing neurons. Leptin-induced suppression of feeding was diminished, while rebound feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data unmask an active role of glial cells in the initiation of hypothalamic synaptic plasticity and neuroendocrine control of feeding by leptin. PMID:24880214

  3. Regulation of behavioral maturation by a primer pheromone produced by adult worker honey bees

    PubMed Central

    Leoncini, Isabelle; Le Conte, Yves; Costagliola, Guy; Plettner, Erika; Toth, Amy L.; Wang, Mianwei; Huang, Zachary; Bécard, Jean-Marc; Crauser, Didier; Slessor, Keith N.; Robinson, Gene E.

    2004-01-01

    Previous research showed that the presence of older workers causes a delayed onset of foraging in younger individuals in honey bee colonies, but a specific worker inhibitory factor had not yet been identified. Here, we report on the identification of a substance produced by adult forager honey bees, ethyl oleate, that acts as a chemical inhibitory factor to delay age at onset of foraging. Ethyl oleate is synthesized de novo and is present in highest concentrations in the bee's crop. These results suggest that worker behavioral maturation is modulated via trophallaxis, a form of food exchange that also serves as a prominent communication channel in insect societies. Our findings provide critical validation for a model of self-organization explaining how bees are able to respond to fragmentary information with actions that are appropriate to the state of the whole colony. PMID:15572455

  4. Immune regulation by mesenchymal stem cells derived from adult spleen and thymus.

    PubMed

    Krampera, Mauro; Sartoris, Silvia; Liotta, Francesco; Pasini, Annalisa; Angeli, Roberta; Cosmi, Lorenzo; Andreini, Angelo; Mosna, Federico; Bonetti, Bruno; Rebellato, Elisabetta; Testi, Maria Grazia; Frosali, Francesca; Pizzolo, Giovanni; Tridente, Giuseppe; Maggi, Enrico; Romagnani, Sergio; Annunziato, Francesco

    2007-10-01

    We show here that human and mouse mesenchymal stem cells (MSCs) can be obtained not only from bone marrow (BM), but also from adult spleen and thymus. In vitro, both human and mouse spleen- and thymus-derived MSCs exhibit immunophenotypic characteristics and differentiation potential completely comparable to BM-MSCs. In addition, they can inhibit immune responses mediated by activated T lymphocytes with efficiency comparable to BM-MSCs. In vivo, mouse MSCs from BM, spleen, and thymus, if injected together with a genetically modified tumor cell vaccine, can equally prevent the onset of an anti-tumor memory immune response, thus leading to tumor growth in normally resistant mice. Our data suggest that not only do spleen and thymus have a stem cell reservoir to build up their stromal architecture, but also contain microenviromental immunoregulatory cells with the same properties of BM-MSCs. PMID:17999601

  5. Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

    PubMed Central

    Bozec, Aline; Hannemann, Nicole

    2016-01-01

    Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes. PMID:27284940

  6. Brain apoptosis signaling pathways are regulated by methylphenidate treatment in young and adult rats.

    PubMed

    Réus, Gislaine Z; Scaini, Giselli; Jeremias, Gabriela C; Furlanetto, Camila B; Morais, Meline O S; Mello-Santos, Lis Maira; Quevedo, João; Streck, Emilio L

    2014-10-01

    Methylphenidate (MPH) is commonly prescribed for children who have been diagnosed with attention deficit hyperactivity disorder (ADHD); however, the action mechanisms of methylphenidate have not been fully elucidated. Studies have shown a relationship between apoptosis signaling pathways and psychiatric disorders, as well as in therapeutic targets for such disorders. So, we investigated if chronic treatment with MPH at doses of 1, 2 and 10mg/kg could alter the levels of pro-apoptotic protein, Bax, anti-apoptotic protein, Bcl-2, caspase-3 and cytochrome c in the brain of young and adult Wistar rats. Our results showed that MPH at all doses increased Bax in the cortex; the Bcl-2 and caspase-3 were increased with MPH (1mg/kg) and were reduced with MPH (2 and 10mg/kg); the cytochrome c was reduced in the cortex after treatment with MPH at all doses; in the cerebellum there was an increase of Bax with MPH at all doses, however, there was a reduction of Bcl-2, caspase-3, and cytochrome c with MPH (2 and 10mg/kg); in the striatum the treatment with MPH (10mg/kg) decreased caspase-3 and cytochrome c; treatment with MPH (2 and 10mg/kg) increased Bax and decreased Bcl-2 in the hippocampus; and the caspase-3 and cytochrome c were reduced in the hippocampus with MPH (10mg/kg). In conclusion, our results suggest that MPH influences plasticity in the brain of young and adult rats; however, the effects were dependent of age and brain area, on the one hand activating the initial cascade of apoptosis, increasing Bax and reducing Bcl-2, but otherwise inhibiting apoptosis by reduction of caspase-3 and cytochrome c. PMID:25128604

  7. FoxP2 regulation during undirected singing in adult songbirds.

    PubMed

    Teramitsu, Ikuko; White, Stephanie A

    2006-07-12

    Learned vocal communication, including human speech, is a socially influenced behavior limited to certain animals. This ability requires auditory feedback during vocalization, which allows for on-line evaluation, to achieve the desired vocal output. To date, FOXP2 (forkhead box P2), a transcriptional repressor, is the only molecule directly linked to human speech. Identified FOXP2 mutations cause orofacial dyspraxia accompanied by abnormalities in corticostriatal circuitry controlling voluntary orofacial movements. These observations implicate FOXP2 in the developmental formation of neural circuits used in speech, but whether FOXP2 additionally plays an active role in mature circuitry was unknown. To address this question, we use a songbird, the zebra finch (Taeniopygia guttata), whose learned song and underlying circuitry are well characterized. We show that, when adult males sing, FoxP2 mRNA is acutely downregulated within area X, the specific region of the songbird striatum dedicated to song. Furthermore, we find downregulation in males that sing by themselves (undirected singers) but not in males that sing to females (directed singers). This FoxP2 downregulation cannot be a simple consequence of the motor act because birds sang in both directed and undirected contexts. Our data suggest that FoxP2 is important not only for the formation but also for the function of vocal control circuitry. Social context-dependent, acute changes in FoxP2 within the basal ganglia of adult songbirds also suggest, by analogy, that the core deficits of affected humans extend beyond development and beyond basic central motor control. PMID:16837586

  8. Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism.

    PubMed

    Andreoli, María Florencia; Stoker, Cora; Rossetti, María Florencia; Alzamendi, Ana; Castrogiovanni, Daniel; Luque, Enrique H; Ramos, Jorge Guillermo

    2015-02-01

    The absence of phytoestrogens in the diet during pregnancy has been reported to result in obesity later in adulthood. We investigated whether phytoestrogen withdrawal in adult life could alter the hypothalamic signals that regulate food intake and affect body weight and glucose homeostasis. Male Wistar rats fed from conception to adulthood with a high phytoestrogen diet were submitted to phytoestrogen withdrawal by feeding a low phytoestrogen diet, or a high phytoestrogen-high fat diet. Withdrawal of dietary phytoestrogens increased body weight, adiposity and energy intake through an orexigenic hypothalamic response characterized by upregulation of AGRP and downregulation of POMC. This was associated with elevated leptin and T4, reduced TSH, testosterone and estradiol, and diminished hypothalamic ERα expression, concomitant with alterations in glucose tolerance. Removing dietary phytoestrogens caused manifestations of obesity and diabetes that were more pronounced than those induced by the high phytoestrogen-high fat diet intake. PMID:25486512

  9. Regulating Availability: How Access to Alcohol Affects Drinking and Problems in Youth and Adults

    PubMed Central

    Gruenewald, Paul J.

    2011-01-01

    Regulations on the availability of alcohol have been used to moderate alcohol problems in communities throughout the world for thousands of years. In the latter half of the 20th century, quantitative studies of the effects of these regulations on drinking and related problems began in earnest as public health practitioners began to recognize the full extent of the harmful consequences related to drinking. This article briefly outlines the history of this work over four areas, focusing on the minimum legal drinking age, the privatization of alcohol control systems, outlet densities, and hours and days of sale. Some historical background is provided to emphasize the theoretical and empirical roots of this work and to highlight the substantial progress that has been made in each area. In general, this assessment suggests that higher minimum legal drinking ages, greater monopoly controls over alcohol sales, lower outlet numbers and reduced outlet densities, and limited hours and days of sale can effectively reduce alcohol sales, use, and problems. There are, however, substantial gaps in the research literature and a near absence of the quantitative theoretical work needed to direct alcohol-control efforts. Local community responses to alcohol policies are complex and heterogeneous, sometimes reinforcing and sometimes mitigating the effects of availability regulations. Quantitative models of policy effects are essential to accelerate progress toward the formulation and testing of optimal control strategies for the reduction of alcohol problems. PMID:22330225

  10. PPARγ mRNA in the adult mouse hypothalamus: distribution and regulation in response to dietary challenges

    PubMed Central

    Liu, Yang; Huang, Ying; Lee, Syann; Bookout, Angie L.; Castorena, Carlos M.; Wu, Hua; Gautron, Laurent

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that was originally identified as a regulator of peroxisome proliferation and adipocyte differentiation. Emerging evidence suggests that functional PPARγ signaling also occurs within the hypothalamus. However, the exact distribution and identities of PPARγ-expressing hypothalamic cells remains under debate. The present study systematically mapped PPARγ mRNA expression in the adult mouse brain using in situ hybridization histochemistry. PPARγ mRNA was found to be expressed at high levels outside the hypothalamus including the neocortex, the olfactory bulb, the organ of the vasculosum of the lamina terminalis (VOLT), and the subfornical organ. Within the hypothalamus, PPARγ was present at moderate levels in the suprachiasmatic nucleus (SCh) and the ependymal of the 3rd ventricle. In all examined feeding-related hypothalamic nuclei, PPARγ was expressed at very low levels that were close to the limit of detection. Using qPCR techniques, we demonstrated that PPARγ mRNA expression was upregulated in the SCh in response to fasting. Double in situ hybridization further demonstrated that PPARγ was primarily expressed in neurons rather than glia. Collectively, our observations provide a comprehensive map of PPARγ distribution in the intact adult mouse hypothalamus. PMID:26388745

  11. A Cyclin D2-Rb Pathway Regulates Cardiac Myocyte Size and RNA Polymerase III After Biomechanical Stress in Adult Myocardium

    PubMed Central

    Angelis, Ekaterini; Garcia, Alejandro; Chan, Shing S.; Schenke-Layland, Katja; Ren, Shuxen; Goodfellow, Sarah J.; Jordan, Maria C.; Roos, Kenneth P.; White, Robert J.; MacLellan, W. Robb

    2008-01-01

    Normally, cell cycle progression is tightly coupled to the accumulation of cell mass; however, the mechanisms whereby proliferation and cell growth are linked are poorly understood. We have identified Cyclin D2 (CycD2), a G1 cyclin implicated in mediating S phase entry, as a potential regulator of hypertrophic growth in adult post mitotic myocardium. To examine the role of CycD2 and its downstream targets, we subjected CycD2-null mice to mechanical stress. Hypertrophic growth in response to transverse aortic constriction (TAC) was attenuated in CycD2 null compared to wildtype mice. Blocking the increase in CycD2 in response to hypertrophic agonists prevented phosphorylation of CycD2-target Rb in vitro and mice deficient for Rb had potentiated hypertrophic growth. Hypertrophic growth requires new protein synthesis and transcription of tRNA genes by RNA pol III, which increases with hypertrophic signals. This load-induced increase in RNA pol III activity is augmented in Rb-deficient hearts. Rb binds and represses Brf-1 and TBP, subunits of RNA pol III-specific transcription factor B, in adult myocardium under basal conditions. However this association is disrupted in response to TAC. RNA pol III activity is unchanged in CycD2-/- myocardium after TAC, and there is no dissociation of TBP from Rb. These investigations identify an essential role for the CycD2-Rb pathway as a governor of cardiac myocyte enlargement in response to biomechanical stress and, more fundamentally, as a regulator of the load-induced activation of RNA pol III. PMID:18420946

  12. Gestational nicotine exposure regulates expression of AMPA and NMDA receptors and their signaling apparatus in developing and adult rat hippocampus

    PubMed Central

    Wang, Hong; Dávila-García, Martha I.; Yarl, Weonpo; Gondré-Lewis, Marjorie C.

    2011-01-01

    Untimely activation of nicotinic acetylcholine receptor (nAChR) by nicotine results in short- and long-term consequences on learning and behavior. In this study, the aim was to determine how prenatal nicotine exposure affects components of glutamatergic signaling in the hippocampus during postnatal development. We investigated regulation of both nAChRs and glutamate receptors for α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA), from postnatal day (P) 1 to P63 after a temporally restricted exposure to saline or nicotine for 14 days in utero. We analyzed postsynaptic density components associated with AMPAR and NMDAR signaling: Calcium/calmodulin-dependent protein kinase II α (CaMKIIα), Calmodulin (CaM), and postsynaptic density-95 (PSD95), as well as presynaptically localized synaptosomal-associated protein 25 (SNAP25). At P1, there was significantly heightened expression of AMPAR subunit GluR1 but not GluR2, and of NMDAR subunits NR1, NR2a and NR2d but not NR2b. NR2c was not detectable. At P1, the postsynaptic proteins CaMKIIα, CaM, and PSD95 were also significantly upregulated, together with presynaptic SNAP25. This enhanced expression of glutamate receptors and signaling proteins was concomitant with elevated levels of [3H] Epibatidine (EB) binding in prenatal nicotine-exposed hippocampus, indicating that α4β2 nAChR may influence glutamatergic function in the hippocampus at P1. By P14, neither [3H]EB binding nor the expression levels of subunits GluR1, GluR2, NR1, NR2a, NR2b, NR2c, or NR2d seemed changed with prenatal nicotine. However, CaMKIIα was significantly upregulated with nicotine treatment while CaM showed downregulation at P14. The effects of nicotine persisted in young adult brains at P63. They exhibited significantly downregulated GluR2, NR1, and NR2c expression levels in hippocampal homogenates and a considerably muted overall distribution of [3H]AMPA binding in areas CA1, CA2, CA3, and the dentate

  13. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration

    PubMed Central

    Shaw, Rachael L.; Kohlmaier, Alexander; Polesello, Cédric; Veelken, Cornelia; Edgar, Bruce A.; Tapon, Nicolas

    2010-01-01

    Intestinal stem cells (ISCs) in the adult Drosophila midgut proliferate to self-renew and to produce differentiating daughter cells that replace those lost as part of normal gut function. Intestinal stress induces the activation of Upd/Jak/Stat signalling, which promotes intestinal regeneration by inducing rapid stem cell proliferation. We have investigated the role of the Hippo (Hpo) pathway in the Drosophila intestine (midgut). Hpo pathway inactivation in either the ISCs or the differentiated enterocytes induces a phenotype similar to that observed under stress situations, including increased stem cell proliferation and expression of Jak/Stat pathway ligands. Hpo pathway targets are induced by stresses such as bacterial infection, suggesting that the Hpo pathway functions as a sensor of cellular stress in the differentiated cells of the midgut. In addition, Yki, the pro-growth transcription factor target of the Hpo pathway, is required in ISCs to drive the proliferative response to stress. Our results suggest that the Hpo pathway is a mediator of the regenerative response in the Drosophila midgut. PMID:21068063

  14. Crossveinless and the TGFbeta pathway regulate fiber number in the Drosophila adult jump muscle.

    PubMed

    Jaramillo, Maryann S; Lovato, Candice V; Baca, Erica M; Cripps, Richard M

    2009-04-01

    Skeletal muscles are readily characterized by their location within the body and by the number and composition of their constituent muscle fibers. Here, we characterize a mutation that causes a severe reduction in the number of fibers comprising the tergal depressor of the trochanter muscle (TDT, or jump muscle), which functions in the escape response of the Drosophila adult. The wild-type TDT comprises over 20 large muscle fibers and four small fibers. In crossveinless (cv) mutants, the number of large fibers is reduced by 50%, and the number of small fibers is also occasionally reduced. This reduction in fiber number arises from a reduction in the number of founder cells contributing to the TDT at the early pupal stage. Given the role of cv in TGFbeta signaling, we determined whether this pathway directly impacts TDT development. Indeed, gain- and loss-of-function manipulations in the TGFbeta pathway resulted in dramatic increases and decreases, respectively, in TDT fiber number. By identifying the origins of the TDT muscle, from founder cells specified in the mesothoracic leg imaginal disc, we also demonstrate that the TGFbeta pathway directly impacts the specification of founder cells for the jump muscle. Our studies define a new role for the TGFbeta pathway in the control of specific skeletal muscle characteristics. PMID:19244280

  15. Spatio-temporal regulations and functions of neuronal alternative RNA splicing in developing and adult brains.

    PubMed

    Iijima, Takatoshi; Hidaka, Chiharu; Iijima, Yoko

    2016-08-01

    Alternative pre-mRNA splicing is a fundamental mechanism that generates molecular diversity from a single gene. In the central nervous system (CNS), key neural developmental steps are thought to be controlled by alternative splicing decisions, including the molecular diversity underlying synaptic wiring, plasticity, and remodeling. Significant progress has been made in understanding the molecular mechanisms and functions of alternative pre-mRNA splicing in neurons through studies in invertebrate systems; however, recent studies have begun to uncover the potential role of neuronal alternative splicing in the mammalian CNS. This article provides an overview of recent findings regarding the regulation and function of neuronal alternative splicing. In particular, we focus on the spatio-temporal regulation of neurexin, a synaptic adhesion molecule, by neuronal cell type-specific factors and neuronal activity, which are thought to be especially important for characterizing neural development and function within the mammalian CNS. Notably, there is increasing evidence that implicates the dysregulation of neuronal splicing events in several neurological disorders. Therefore, understanding the detailed mechanisms of neuronal alternative splicing in the mammalian CNS may provide plausible treatment strategies for these diseases. PMID:26853282

  16. Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain

    PubMed Central

    Trujillo-Paredes, Niurka; Valencia, Concepción; Guerrero-Flores, Gilda; Arzate, Dulce-María; Baizabal, José-Manuel; Guerra-Crespo, Magdalena; Fuentes-Hernández, Ayari; Zea-Armenta, Iván; Covarrubias, Luis

    2016-01-01

    ABSTRACT Notch signalling is a well-established pathway that regulates neurogenesis. However, little is known about the role of Notch signalling in specific neuronal differentiation. Using Dll1 null mice, we found that Notch signalling has no function in the specification of mesencephalic dopaminergic neural precursor cells (NPCs), but plays an important role in regulating their expansion and differentiation into neurons. Premature neuronal differentiation was observed in mesencephalons of Dll1-deficient mice or after treatment with a Notch signalling inhibitor. Coupling between neurogenesis and dopaminergic differentiation was indicated from the coincident emergence of neuronal and dopaminergic markers. Early in differentiation, decreasing Notch signalling caused a reduction in NPCs and an increase in dopaminergic neurons in association with dynamic changes in the proportion of sequentially-linked dopaminergic NPCs (Msx1/2+, Ngn2+, Nurr1+). These effects in differentiation caused a significant reduction in the number of dopaminergic neurons produced. Accordingly, Dll1 haploinsufficient adult mice, in comparison with their wild-type littermates, have a consistent reduction in neuronal density that was particularly evident in the substantia nigra pars compacta. Our results are in agreement with a mathematical model based on a Dll1-mediated regulatory feedback loop between early progenitors and their dividing precursors that controls the emergence and number of dopaminergic neurons. PMID:26912775

  17. STAT3 Regulates Self-Renewal of Adult Muscle Satellite Cells during Injury-Induced Muscle Regeneration.

    PubMed

    Zhu, Han; Xiao, Fang; Wang, Gang; Wei, Xiuqing; Jiang, Lei; Chen, Yan; Zhu, Lin; Wang, Haixia; Diao, Yarui; Wang, Huating; Ip, Nancy Y; Cheung, Tom H; Wu, Zhenguo

    2016-08-23

    Recent studies have shown that STAT3 negatively regulates the proliferation of muscle satellite cells (MuSCs) and injury-induced muscle regeneration. These studies have been largely based on STAT3 inhibitors, which may produce off-target effects and are not cell type-specific in vivo. Here, we examine the role of STAT3 in MuSCs using two different mouse models: a MuSC-specific Stat3 knockout line and a Stat3 (MuSC-specific)/dystrophin (Dmd) double knockout (dKO) line. Stat3(-/-) MuSCs from both mutant lines were defective in proliferation. Moreover, in both mutant strains, the MuSC pool shrank, and regeneration was compromised after injury, with defects more pronounced in dKO mice along with severe muscle inflammation and fibrosis. We analyzed the transcriptomes of MuSCs from dKO and Dmd(-/-) control mice and identified multiple STAT3 target genes, including Pax7. Collectively, our work reveals a critical role of STAT3 in adult MuSCs that regulates their self-renewal during injury-induced muscle regeneration. PMID:27524611

  18. Tumor suppressors Sav/Scrib and oncogene Ras regulate stem cell transformation in adult Drosophila Malpighian Tubules

    PubMed Central

    Zeng, Xiankun; Singh, Shree Ram; Hou, David; Hou, Steven X.

    2012-01-01

    An increasing body of evidence suggests that tumors might originate from a few transformed cells that share many properties with normal stem cells. However, it remains unclear how normal stem cells are transformed into cancer stem cells. Here, we demonstrated that mutations causing the loss of tumor suppressor Sav or Scrib or activation of the oncogene Ras transform normal stem cells into cancer stem cells through a multistep process in the adult Drosophila Malpighian Tubules (MTs). In wild-type MTs, each stem cell generates one self-renewing and one differentiating daughter cell. However, in flies with loss-of-function sav or scrib or gain-of-function Ras mutations, both daughter cells grew and behaved like stem cells, leading to the formation of tumors in MTs. Ras functioned downstream of Sav and Scrib in regulating the stem cell transformation. The Ras-transformed stem cells exhibited many of the hallmarks of cancer, such as increased proliferation, reduced cell death, and failure to differentiate. We further demonstrated that several signal transduction pathways (including MEK/MAPK, RhoA, PKA, and TOR) mediate Rasṕ function in the stem cell transformation. Therefore, we have identified a molecular mechanism that regulates stem cell transformation, and this finding may lead to strategies for preventing tumor formation in certain organs. PMID:20432470

  19. Regional specific regulation of steroid receptor coactivator-1 immunoreactivity by orchidectomy in the brain of adult male mice.

    PubMed

    Bian, Chen; Zhang, Kaiyuan; Zhao, Yangang; Guo, Qiang; Cai, Wenqin; Zhang, Jiqiang

    2014-10-01

    Androgens including testosterone and dihydrotestosterone play important roles on brain structure and function, either directly through androgen receptor or indirectly through estrogen receptors, which need coactivators for their transcription activation. Steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but how it is regulated by androgens in the brain remains unclear. In this study, we explored the effect of orchidectomy (ORX) on the expression of SRC-1 in the adult male mice using nickel-intensified immunohistochemistry. The results showed that ORX induced dramatic decrease of SRC-1 immunoreactivity in the olfactory tubercle, piriform cortex, ventral pallidum, most parts of the septal area, hippocampus, substantia nigra (compact part), pontine nuclei and nucleus of the trapezoid body (p<0.01). Significant decrease of SRC-1 was noticed in the dorsal and lateral septal nucleus, medial preoptical area, dorsomedial and ventromedial hypothalamic nucleus and superior paraolivary nucleus (p<0.05). Whereas in other regions examined, levels of SRC-1 immunoreactivity were not obviously changed by ORX (p>0.05). The above results demonstrated ORX downregulation of SRC-1 in specific regions that have been involved in sense of smell, learning and memory, cognition, neuroendocrine, reproduction and motor control, indicating that SRC-1 play pivotal role in the mediating circulating androgenic regulation on these important brain functions. It also indicates that SRC-1 may serve as a novel target for the central disorders caused by the age-related decrease of circulating androgens. PMID:24945110

  20. Hes3 expression in the adult mouse brain is regulated during demyelination and remyelination.

    PubMed

    Toutouna, Louiza; Nikolakopoulou, Polyxeni; Poser, Steven W; Masjkur, Jimmy; Arps-Forker, Carina; Troullinaki, Maria; Grossklaus, Sylvia; Bosak, Viktoria; Friedrich, Ulrike; Ziemssen, Tjalf; Bornstein, Stefan R; Chavakis, Triantafyllos; Androutsellis-Theotokis, Andreas

    2016-07-01

    Hes3 is a component of the STAT3-Ser/Hes3 Signaling Axis controlling the growth and survival of neural stem cells and other plastic cells. Pharmacological activation of this pathway promotes neuronal rescue and behavioral recovery in models of ischemic stroke and Parkinson's disease. Here we provide initial observations implicating Hes3 in the cuprizone model of demyelination and remyelination. We focus on the subpial motor cortex of mice because we detected high Hes3 expression. This area is of interest as it is impacted both in human demyelinating diseases and in the cuprizone model. We report that Hes3 expression is reduced at peak demyelination and is partially restored within 1 week after cuprizone withdrawal. This raises the possibility of Hes3 involvement in demyelination/remyelination that may warrant additional research. Supporting a possible role of Hes3 in the maintenance of oligodendrocyte markers, a Hes3 null mouse strain shows lower levels of myelin basic protein in undamaged adult mice, compared to wild-type controls. We also present a novel method for culturing the established oligodendrocyte progenitor cell line oli-neu in a manner that maintains Hes3 expression as well as its self-renewal and differentiation potential, offering an experimental tool to study Hes3. Based upon this approach, we identify a Janus kinase inhibitor and dbcAMP as powerful inducers of Hes3 gene expression. We provide a new biomarker and cell culture method that may be of interest in demyelination/remyelination research. PMID:27018293

  1. Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system.

    PubMed

    Lemmens, Kim; Bollaerts, Ilse; Bhumika, Stitipragyan; de Groef, Lies; Van Houcke, Jessie; Darras, Veerle M; Van Hove, Inge; Moons, Lieve

    2016-05-01

    Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp-2 and -13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp-2 and -9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp-14 expression decreased during regeneration. Altogether, a phase-dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron-intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472-1493, 2016. © 2015 Wiley Periodicals, Inc. PMID:26509469

  2. MicroRNAs Regulate Osteogenesis and Chondrogenesis of Mouse Bone Marrow Stromal Cells

    PubMed Central

    Suomi, Salla; Taipaleenmäki, Hanna; Seppänen, Anne; Ripatti, Tommi; Väänänen, Kalervo; Hentunen, Teuvo; Säämänen, Anna-Marja; Laitala-Leinonen, Tiina

    2008-01-01

    MicroRNAs (miRNAs) are non-coding RNAs that bind to target mRNA leading to translational arrest or mRNA degradation. To study miRNA-mediated regulation of osteogenesis and chondrogenesis, we compared the expression of 35 miRNAs in osteoblasts and chondroblasts derived from mouse marrow stromal cells (MSCs). Differentiation of MSCs resulted in up- or downregulation of several miRNAs, with miR-199a expression being over 10-fold higher in chondroblasts than in undifferentiated MSCs. In addition, miR-124a was strongly upregulated during chondrogenesis while the expression of miR-96 was substantially suppressed. A systems biological analysis of the potential miRNA target genes and their interaction networks was combined with promoter analysis. These studies link the differentially expressed miRNAs to collagen synthesis and hypoxia, key pathways related to bone and cartilage physiology. The global regulatory networks described here suggest for the first time how miRNAs and transcription factors are capable of fine-tuning the osteogenic and chondrogenic differentiation of mouse MSCs. PMID:19787082

  3. Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma.

    PubMed

    Jiang, Xingming; Ma, Ning; Wang, Dayong; Li, Fuyuan; He, Rongzhang; Li, Dongliang; Zhao, Ruiqi; Zhou, Qingxin; Wang, Yimin; Zhang, Fumin; Wan, Ming; Kang, Pengcheng; Gao, Xu; Cui, Yunfu

    2015-02-20

    The antidiabetic drug metformin exerts antineoplastic effects in many types of malignancies, however the effect of metformin on cholangiocarcinoma (CCA) still remains unclear. In the present study, we investigated that metformin treatment was closely associated with the clinicopathologic characteristics and improved postoperative survival of CCA patients. Metformin inhibited CCA tumor growth by cell cycle arrest in vitro and in vivo. We explored that the expression of six miRNAs (mir124, 182, 27b, let7b, 221 and 181a), which could directly target cell-cycle-regulatory genes, was altered by metformin in vitro and in vivo. These miRNAs were dysregulated in cholangiocarcinoma and promoted the CCA genesis and metformin exactly modulated these carcinogenic miRNAs expression to arrest the cell cycle and inhibit the proliferation. Meanwhile, these miRNAs expression changes correlated with the tumor volume and postoperative survival of CCA patients and could be used to predict the prognosis. Further we confirmed that metformin upregulated Drosha to modulate these miRNAs expression. Our results elucidated that metformin inhibited CCA tumor growth via the regulation of Drosha-mediated multiple carcinogenic miRNAs expression and comprehensive evaluation of these miRNAs expression could be more efficient to predict the prognosis. Moreover, metformin might be a quite promising strategy for CCA prevention and treatment. PMID:25605008

  4. Chronic Morphine-Induced MicroRNA-124 Promotes Microglial Immunosuppression by Modulating P65 and TRAF6

    PubMed Central

    Qiu, Shuwei; Feng, Yimin; LeSage, Gene; Zhang, Ying; Stuart, Charles; He, Lei; Li, Yi; Caudle, Yi; Peng, Ying; Yin, Deling

    2014-01-01

    Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects including immunosuppression. However, the mechanisms are unclear. Toll-like receptors (TLRs) and acetylcholine (ACh) are widely expressed in the immune and nervous systems and play critical roles in immune responses. Here we show that morphine suppresses the innate immunity in microglia and bone marrow-derived macrophages (BMM) through differential regulation of TLRs and acetylcholinesterase (AChE). Either morphine or inhibition of ACh significantly promoted up-regulation of microRNA-124 (miR-124) in microglia, BMM, and in the mouse brain, where miR-124 mediates morphine inhibition of the innate immunity by directly targeting a subunit of NF-κB p65 and TNF receptor-associated factor 6 (TRAF6). Furthermore, transcription factors AP-1 and CREB inhibited miR-124, while p65 bound directly to promoters of miR-124, thereby enhancing miR-124 transcription. Moreover, acute morphine treatment transiently up-regulated the expression of p65 and phospho-p65 in both nucleus and cytoplasm priming the expression of miR-124, whereas long exposure of morphine maintained miR-124 expression which inhibited p65- and TRAF6-dependent TLR signaling. These data suggest that modulation of miRs is capable of preventing opioid-induced damage to microglia. PMID:25539811

  5. Testosterone regulates androgen receptor immunoreactivity in the copulatory, but not courtship, neuromuscular system in adult male green anoles.

    PubMed

    Holmes, M M; Wade, J

    2005-09-01

    Androgens regulate the expression of male reproductive behaviour in diverse vertebrate species, often acting on androgen receptors (AR) to induce structural or functional changes in the nervous system and periphery. Male green anoles possess two sexually dimorphic neuromuscular systems, one controlling throat fan (dewlap) extension, which occurs during courtship, and the other mediating copulatory organ function. Although androgens are required for behavioural activation in both systems, testosterone has differential effects on the neuromuscular morphology. It increases the size of copulatory muscle fibres during the breeding season, but significant effects on dewlap muscle fibre size and motoneurone soma size in either system have not been detected. Corresponding to the lack of testosterone-induced morphological effects in the courtship system, relatively low levels of AR are expressed in the associated motoneurones. The present experiment had two goals, aiming to determine whether: (i) the other courtship and copulatory neuromuscular tissues express AR and (ii) testosterone and/or seasonal environmental changes regulate AR expression. The percentage of AR+ nuclei was evaluated in both the breeding and nonbreeding seasons in gonadally intact adult males (Experiment 1) and in castrated males treated with either testosterone or vehicle (Experiment 2). AR was extensively expressed in the dewlap and copulatory muscles, and in a high percentage of the copulatory motoneurones, but immunoreactivity did not vary across season. Testosterone increased the percentage of AR+ nuclei in the copulatory muscles of both breeding and nonbreeding males but not in the dewlap muscle or copulatory motoneurones. Finally, the target structures for both systems (cartilages and hemipenes) expressed AR in all animals. Therefore, the effects of testosterone on AR immunoreactivity suggest that up-regulation of the receptors may be important for morphological change. However, because all

  6. Pericentral activity of AFP enhancer E3 and glutamine synthetase upstream enhancer in the adult liver are regulated by β-catenin

    PubMed Central

    Clinkenbeard, Erica L.; Butler, James E.; Spear, Brett T.

    2015-01-01

    We previously showed that mouse alpha-fetoprotein enhancer E3 activity is highly restricted to pericentral hepatocytes in the adult liver. Here, using transgenic mice, we show that the upstream enhancer of the rat glutamine synthetase gene is also active specifically in pericentral regions. Activity of both enhancers is lost in the absence of β-catenin, a key regulator of zonal gene expression in the adult liver. Both enhancers contain a single highly conserved TCF/LEF binding site that is required for responsiveness to β-catenin. We also show that endogenous AFP mRNA levels in the perinatal liver are lower when β-catenin is reduced. These data identify the first distinct zonally-active regulatory regions required for β-catenin responsiveness in the adult liver and suggest that postnatal AFP repression and the establishment of zonal regulation are controlled, at least in part, by the same factors. PMID:22544812

  7. Transitions to Competence: An Investigation of Adult Mediation in Preschoolers' Self-Regulation with a Microcomputer-Based Problem-Solving Task.

    ERIC Educational Resources Information Center

    Samaras, Anastasia P.

    1991-01-01

    The effectiveness of specific dimensions of adult mediation on preschoolers' self-regulation of a model consultation strategy was evaluated using microcomputer puzzle tasks. Findings suggest that children's acquisition of the model consultation can improve over a short period of time with culturally mediated instruction. (Author/GLR)

  8. The Effects of Self-Regulated Strategy Development on the Writing of Expository Essays for Adults with Written Expression Difficulties: Preparing for the GED

    ERIC Educational Resources Information Center

    Berry, Ann Bassett; Mason, Linda H.

    2012-01-01

    A multiple-probe, multiple-baseline, across-subjects design was used to examine the writing performance of four low-achieving adult students with and without disabilities enrolled in general equivalency diploma (GED) preparatory classes. Students' writing was evaluated before instruction and after self-regulated strategy development (SRSD)…

  9. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    PubMed

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. PMID:26844865

  10. Fasting induced kisspeptin signaling suppression is regulated by glutamate mediated cues in adult male rhesus macaque (Macaca mulatta).

    PubMed

    Shamas, Shazia; Khan, Saeed-Ul-Hassan; Khan, Muhammad Yousaf; Shabbir, Nadia; Zubair, Hira; Shafqat, Saira; Wahab, Fazal; Shahab, Muhammad

    2015-08-01

    Kisspeptin signaling is suppressed by short term fasting. It has been reported that hypothalamic Kiss1 and Kiss1r mRNA expression decreased after 48h of fasting in male rhesus monkey. But the mechanism involved in the reduction of kisspeptin signaling after 48h of fasting is unknown. Recent studies have suggested the role of afferent excitatory and inhibitory pathways in the regulation of kisspeptin neurons. Therefore, this study was designed to observe the changes in the glutamate and GABA signaling during fed and 48h fasting states by performing immunofluorescence to examine the interaction of kisspeptin neurons with NR1 subunit of NMDA receptors and by performing SYBR green qRT-PCR to measure and quantify the levels of Kiss1, Kiss1r, NR1 and GAD67 mRNA in the POA and MBH of adult male rhesus macaque (Macaca mulatta) during 48h of fasting (n=2) and fed ad libitum (n=2). Plasma testosterone (p<0.05) and blood glucose levels were significantly (p<0.001) decreased after short term fasting. Our results clearly showed that expression of hypothalamic Kiss1, Kiss1r and NR1 mRNA was significantly (p<0.05) reduced in adult male rhesus monkeys which were fasted for 48h as compared to those which were fed ad libitum. There was no clear difference in the GAD67 mRNA contents between the two groups. Number of kisspeptin neurons and the interactions of kisspeptin neurons with NR1 were significantly (p<0.05) reduced after 48h fasting. These observations suggest that decreased kisspeptin signaling during fasting may occur due to reduction in glutamatergic inputs to kisspeptin neurons. Our results also suggest that fasting induced suppression of kisspeptin signaling is not mediated through GABAergic neurons. PMID:26138506

  11. Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development.

    PubMed

    Walton, Noah M; de Koning, Anoek; Xie, Xiuyuan; Shin, Rick; Chen, Qian; Miyake, Shinichi; Tajinda, Katsunori; Gross, Adam K; Kogan, Jeffrey H; Heusner, Carrie L; Tamura, Kouichi; Matsumoto, Mitsuyuki

    2014-09-01

    In the postnatal hippocampus, newly generated neurons contribute to learning and memory. Disruptions in neurogenesis and neuronal development have been linked to cognitive impairment and are implicated in a broad variety of neurological and psychiatric disorders. To identify putative factors involved in this process, we examined hippocampal gene expression alterations in mice possessing a heterozygous knockout of the calcium/calmodulin-dependent protein kinase II alpha heterozygous knockout gene (CaMK2α-hKO), an established model of cognitive impairment that also displays altered neurogenesis and neuronal development. Using this approach, we identified gastrin-releasing peptide (GRP) as the most dysregulated gene. In wild-type mice, GRP labels NeuN-positive neurons, the lone exception being GRP-positive, NeuN-negative cells in the subgranular zone, suggesting GRP expression may be relevant to neurogenesis and/or neuronal development. Using a model of in vitro hippocampal neurogenesis, we determined that GRP signaling is essential for the continued survival and development of newborn neurons, both of which are blocked by transient knockdown of GRP's cognate receptor (GRPR). Furthermore, GRP appears to negatively regulate neurogenesis-associated proliferation in neural stem cells both in vitro and in vivo. Intracerebroventricular infusion of GRP resulted in a decrease in immature neuronal markers, increased cAMP response element-binding protein (CREB) phosphorylation, and decreased neurogenesis. Despite increased levels of GRP mRNA, CaMK2α-hKO mutant mice expressed reduced levels of GRP peptide. This lack of GRP may contribute to the elevated neurogenesis and impaired neuronal development, which are reversed following exogenous GRP infusion. Based on these findings, we hypothesize that GRP modulates neurogenesis and neuronal development and may contribute to hippocampus-associated cognitive impairment. PMID:24806094

  12. O-GlcNAcylation Negatively Regulates Cardiomyogenic Fate in Adult Mouse Cardiac Mesenchymal Stromal Cells.

    PubMed

    Zafir, Ayesha; Bradley, James A; Long, Bethany W; Muthusamy, Senthilkumar; Li, Qianhong; Hill, Bradford G; Wysoczynski, Marcin; Prabhu, Sumanth D; Bhatnagar, Aruni; Bolli, Roberto; Jones, Steven P

    2015-01-01

    In both preclinical and clinical studies, cell transplantation of several cell types is used to promote repair of damaged organs and tissues. Nevertheless, despite the widespread use of such strategies, there remains little understanding of how the efficacy of cell therapy is regulated. We showed previously that augmentation of a unique, metabolically derived stress signal (i.e., O-GlcNAc) improves survival of cardiac mesenchymal stromal cells; however, it is not known whether enhancing O-GlcNAcylation affects lineage commitment or other aspects of cell competency. In this study, we assessed the role of O-GlcNAc in differentiation of cardiac mesenchymal stromal cells. Exposure of these cells to routine differentiation protocols in culture increased markers of the cardiomyogenic lineage such as Nkx2.5 and connexin 40, and augmented the abundance of transcripts associated with endothelial and fibroblast cell fates. Differentiation significantly decreased the abundance of O-GlcNAcylated proteins. To determine if O-GlcNAc is involved in stromal cell differentiation, O-GlcNAcylation was increased pharmacologically during the differentiation protocol. Although elevated O-GlcNAc levels did not significantly affect fibroblast and endothelial marker expression, acquisition of cardiomyocyte markers was limited. In addition, increasing O-GlcNAcylation further elevated smooth muscle actin expression. In addition to lineage commitment, we also evaluated proliferation and migration, and found that increasing O-GlcNAcylation did not significantly affect either; however, we found that O-GlcNAc transferase--the protein responsible for adding O-GlcNAc to proteins--is at least partially required for maintaining cellular proliferative and migratory capacities. We conclude that O-GlcNAcylation contributes significantly to cardiac mesenchymal stromal cell lineage and function. O-GlcNAcylation and pathological conditions that may affect O-GlcNAc levels (such as diabetes) should be

  13. Duration of prepupal summer dormancy regulates synchronization of adult diapause with winter temperatures in bees of the genus Osmia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Osmia (Osmia) bees are strictly univoltine and winter as diapausing adults. In these species, the timing of adult eclosion with the onset of wintering conditions is critical, because adults exposed to long pre-wintering periods show increased lipid loss and winter mortality. Populations from warm ar...

  14. FFAs are not involved in regulation of gluconeogenesis and glycogenolysis in adults with uncomplicated P. falciparum malaria.

    PubMed

    van Thien, Huynh; Weverling, G J; Ackermans, M T; canh Hung, Nguyen; Endert, E; Kager, P A; Sauerwein, H P

    2004-10-01

    In normal subjects, elevation of plasma free fatty acid (FFA) levels stimulates gluconeogenesis (GNG) and inhibits glycogenolysis (GLY). In adults with uncomplicated Plasmodium falciparum malaria, GNG is increased and GLY decreased. To test the hypothesis that FFAs are regulators of GNG and GLY in uncomplicated falciparum malaria, we investigated the effect of inhibition of lipolysis by acipimox in 12 patients with uncomplicated falciparum malaria. Six of them were given acipimox, and six served as controls. Also as controls, six matched healthy subjects were studied on two occasions with and without acipimox. After 16 h of fasting, glucose production and GNG were significantly higher in the malaria patients compared with the healthy controls (P = 0.003 and < 0.0001, respectively), whereas GLY was significantly lower (P < 0.001), together with elevated plasma concentrations of cortisol and glucagon. During the study, glucose production in patients declined over time (P < 0.0001), without a statistically significant difference between the acipimox-treated and untreated patients. In controls, however, with acipimox the decline was less outspoken compared with nontreated controls (P = 0.005). GNG was unchanged over time in patients as well as in healthy controls, and no influence of acipimox was found. In patients, GLY declined over time (P < 0.001), without a difference between acipimox-treated and untreated patients. In contrast, in controls treated with acipimox, no change over time was found, which was statistically different from the decline in untreated controls (P = 0.002). In conclusion, in falciparum malaria, FFAs are not involved in regulation of glucose production, nor of GNG or GLY. PMID:15165991

  15. Interactions with the young down-regulate adult olfactory neurogenesis and enhance the maturation of olfactory neuroblasts in sheep mothers

    PubMed Central

    Brus, Maïna; Meurisse, Maryse; Keller, Matthieu; Lévy, Frédéric

    2014-01-01

    New neurons are continuously added in the dentate gyrus (DG) and the olfactory bulb of mammalian brain. While numerous environmental factors controlling survival of newborn neurons have been extensively studied, regulation by social interactions is less documented. We addressed this question by investigating the influence of parturition and interactions with the young on neurogenesis in sheep mothers. Using Bromodeoxyuridine, a marker of cell division, in combination with markers of neuronal maturation, the percentage of neuroblasts and new mature neurons in the olfactory bulb and the DG was compared between groups of parturient ewes which could interact or not with their lamb, and virgins. In addition, a morphological analysis was performed by measuring the dendritic arbor of neuroblasts in both structures. We showed that the postpartum period was associated with a decrease in olfactory and hippocampal adult neurogenesis. In the olfactory bulb, the suppressive effect on neuroblasts was dependent on interactions with the young whereas in the DG the decrease in new mature neurons was associated with parturition. In addition, dendritic length and number of nodes of neuroblasts were significantly enhanced by interactions with the lamb in the olfactory bulb but not in the DG. Because interactions with the young involved learning of the olfactory signature of the lamb, we hypothesize that this learning is associated with a down-regulation in olfactory neurogenesis and an enhancement of olfactory neuroblast maturation. Our assumption is that fewer new neurons decrease cell competition in the olfactory bulb and enhance maturation of those new neurons selected to participate in the learning of the young odor. PMID:24600367

  16. Bone Morphogenetic Protein Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells

    PubMed Central

    Cheng, Xiaoxin; Wang, Yaping; He, Qian; Qiu, Mengsheng; Whittemore, Scott R.; Cao, Qilin

    2009-01-01

    Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed bone morphogenetic protein (BMP) type Ia, Ib, and II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders. PMID:17872503

  17. The Drosophila Prosecretory Transcription Factor dimmed Is Dynamically Regulated in Adult Enteroendocrine Cells and Protects Against Gram-Negative Infection.

    PubMed

    Beebe, Katherine; Park, Dongkook; Taghert, Paul H; Micchelli, Craig A

    2015-07-01

    The endocrine system employs peptide hormone signals to translate environmental changes into physiological responses. The diffuse endocrine system embedded in the gastrointestinal barrier epithelium is one of the largest and most diverse endocrine tissues. Furthermore, it is the only endocrine tissue in direct physical contact with the microbial environment of the gut lumen. However, it remains unclear how this sensory epithelium responds to specific pathogenic challenges in a dynamic and regulated manner. We demonstrate that the enteroendocrine cells of the adult Drosophila melanogaster midgut display a transient, sensitive, and systemic induction of the prosecretory factor dimmed (dimm) in response to the Gram-negative pathogen Pseudomonas entomophila (Pe). In enteroendocrine cells, dimm controls the levels of the targets Phm, dcat-4, and the peptide hormone, Allatostatin A. Finally, we identify dimm as a host factor that protects against Pe infection and controls the expression of antimicrobial peptides. We propose that dimm provides "gain" in enteroendocrine output during the adaptive response to episodic pathogen exposure. PMID:25999585

  18. N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo

    PubMed Central

    Nikitczuk, Jessica S.; Patil, Shekhar B.; Matikainen-Ankney, Bridget A.; Scarpa, Joseph; Shapiro, Matthew L.

    2016-01-01

    N-cadherin and β-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, β-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N-cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N-cadherin/β-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function. PMID:24753442

  19. The Drosophila Prosecretory Transcription Factor dimmed Is Dynamically Regulated in Adult Enteroendocrine Cells and Protects Against Gram-Negative Infection

    PubMed Central

    Beebe, Katherine; Park, Dongkook; Taghert, Paul H.; Micchelli, Craig A.

    2015-01-01

    The endocrine system employs peptide hormone signals to translate environmental changes into physiological responses. The diffuse endocrine system embedded in the gastrointestinal barrier epithelium is one of the largest and most diverse endocrine tissues. Furthermore, it is the only endocrine tissue in direct physical contact with the microbial environment of the gut lumen. However, it remains unclear how this sensory epithelium responds to specific pathogenic challenges in a dynamic and regulated manner. We demonstrate that the enteroendocrine cells of the adult Drosophila melanogaster midgut display a transient, sensitive, and systemic induction of the prosecretory factor dimmed (dimm) in response to the Gram-negative pathogen Pseudomonas entomophila (Pe). In enteroendocrine cells, dimm controls the levels of the targets Phm, dcat-4, and the peptide hormone, Allatostatin A. Finally, we identify dimm as a host factor that protects against Pe infection and controls the expression of antimicrobial peptides. We propose that dimm provides “gain” in enteroendocrine output during the adaptive response to episodic pathogen exposure. PMID:25999585

  20. Dual and opposing roles of microRNA-124 in epilepsy are mediated through inflammatory and NRSF-dependent gene networks

    PubMed Central

    Brennan, Gary P.; Dey, Deblina; Chen, Yuncai; Patterson, Katelin P.; Magnetta, Eric J.; Hall, Alicia M.; Dube, Celine M.; Mei, Yu-Tang; Baram, Tallie Z.

    2016-01-01

    Insult-provoked transformation of neuronal networks into epileptic ones involves multiple mechanisms. Intervention studies have identified both dysregulated inflammatory pathways and NRSF-mediated repression of crucial neuronal genes as contributors to epileptogenesis. However, it remains unclear how epilepsy-provoking insults (e.g., prolonged seizures) induce both inflammation and NRSF, and whether common mechanisms exist. We examined miR-124 as a candidate dual regulator of NRSF- and inflammatory-pathways. Status epilepticus (SE) led to reduced miR-124 expression via SIRT1, and in turn MiR-124 repression, via C/EBPα, upregulated NRSF. We tested whether augmenting miR-124 after SE would abort epileptogenesis by preventing inflammation and NRSF upregulation. SE-sustaining animals developed epilepsy but supplementing miR-124 did not modify epileptogenesis. Examining this result further, we found that synthetic miR-124 effectively blocked NRSF upregulation and rescued NRSF target genes, but also augmented microglia activation and inflammatory cytokines. Thus, miR-124 attenuates epileptogenesis via NRSF while promoting epilepsy via inflammation. PMID:26947066

  1. p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC).

    PubMed

    Rieger, Megan E; Zhou, Beiyun; Solomon, Nicola; Sunohara, Mitsuhiro; Li, Changgong; Nguyen, Cu; Liu, Yixin; Pan, Jie-Hong; Minoo, Parviz; Crandall, Edward D; Brody, Steven L; Kahn, Michael; Borok, Zea

    2016-03-18

    Maintenance of stem/progenitor cell-progeny relationships is required for tissue homeostasis during normal turnover and repair. Wnt signaling is implicated in both maintenance and differentiation of adult stem/progenitor cells, yet how this pathway serves these dichotomous roles remains enigmatic. We previously proposed a model suggesting that specific interaction of β-catenin with either of the homologous Kat3 co-activators, p300 or CREB-binding protein, differentially regulates maintenance versus differentiation of embryonic stem cells. Limited knowledge of endogenous mechanisms driving differential β-catenin/co-activator interactions and their role in adult somatic stem/progenitor cell maintenance versus differentiation led us to explore this process in defined models of adult progenitor cell differentiation. We focused primarily on alveolar epithelial type II (AT2) cells, progenitors of distal lung epithelium, and identified a novel axis whereby WNT5a/protein kinase C (PKC) signaling regulates specific β-catenin/co-activator interactions to promote adult progenitor cell differentiation. p300/β-catenin but not CBP/β-catenin interaction increases as AT2 cells differentiate to a type I (AT1) cell-like phenotype. Additionally, p300 transcriptionally activates AT1 cell-specific gene Aqp-5. IQ-1, a specific inhibitor of p300/β-catenin interaction, prevents differentiation of not only primary AT2 cells, but also tracheal epithelial cells, and C2C12 myoblasts. p300 phosphorylation at Ser-89 enhances p300/β-catenin interaction, concurrent with alveolar epithelial cell differentiation. WNT5a, a traditionally non-canonical WNT ligand regulates Ser-89 phosphorylation and p300/β-catenin interactions in a PKC-dependent manner, likely involving PKCζ. These studies identify a novel intersection of canonical and non-canonical Wnt signaling in adult progenitor cell differentiation that has important implications for targeting β-catenin to modulate adult progenitor cell

  2. MicroRNA-mediated regulation of p21 and TASK1 cellular restriction factors enhances HIV-1 infection

    PubMed Central

    Farberov, Luba; Herzig, Eytan; Modai, Shira; Isakov, Ofer; Hizi, Amnon; Shomron, Noam

    2015-01-01

    MicroRNAs (miRNAs) are short non-coding RNAs that play a central role in the regulation of gene expression by binding to target mRNAs. Several studies have revealed alterations in cellular miRNA profiles following HIV-1 infection, mostly for miRNAs involved in inhibiting viral infection. These miRNA expression modifications might also serve to block the innate HIV-1 inhibition mechanism. As a result, it is expected that during HIV-1 infection miRNAs target genes that hinder or prevent the progression of the HIV-1 replication cycle. One of the major sets of genes known to inhibit the progression of HIV-1 infection are cellular restriction factors. In this study, we identified a direct miRNA target gene that modulates viral spread in T-lymphocytes and HeLa-CCR5 cell lines. Following infection, let-7c, miR-34a or miR-124a were upregulated, and they targeted and downregulated p21 and TASK1 (also known as CDKN1A and KCNK3, respectively) cellular proteins. This eventually led to increased virion release and higher copy number of viral genome transcripts in infected cells. Conversely, by downregulating these miRNAs, we could suppress viral replication and spread. Our data suggest that HIV-1 exploits the host miRNA cellular systems in order to block the innate inhibition mechanism, allowing a more efficient infection process. PMID:25717002

  3. Chronic hemodynamic unloading regulates the morphologic development of newborn mouse hearts transplanted into the ear of isogeneic adult mice.

    PubMed Central

    Rossi, M. A.

    1992-01-01

    months after transplantation, the myocytes of heterotopic hearts were smaller in size in comparison to those after 2 or 6 months. The graft cells were separated from each other by fibrous tissue and mononuclear cells and were not aligned in parallel within the tissue; often, they appeared to have lost their connections with adjacent cells. The myofibrils within cells were strikingly disorganized, coursing in different directions. Severely degenerated myocytes were commonly seen. These results, without precluding the possible role of neural and hormonal stimuli, clearly indicate that hemodynamic work load regulates the developmental growth of newborn mouse heart transplanted into the pinna of the ear of isogeneic adult recipient mice. In other words, the mass of cardiac tissue would be adjusted to meet the prevailing hemodynamic demands.(ABSTRACT TRUNCATED AT 400 WORDS) Images Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 PMID:1632462

  4. Differential expression of id genes and their potential regulator znf238 in zebrafish adult neural progenitor cells and neurons suggests distinct functions in adult neurogenesis.

    PubMed

    Diotel, Nicolas; Beil, Tanja; Strähle, Uwe; Rastegar, Sepand

    2015-01-01

    Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas. Interestingly, znf238 was also detected in these regions, its expression overlapping with id2a, id3 and id4 expression. Further detailed characterization of the id-expressing cells demonstrated that (a) id1 is expressed in type 1 and type 2 neural progenitors as previously published, (b) id2a in type 1, 2 and 3 neural progenitors, (c) id3 in type 3 neural progenitors and (d) id4 in postmitotic neurons. Our data provide a detailed map of id and znf238 expression in the brain of adult zebrafish, supplying a framework for studies of id genes function during adult neurogenesis and brain regeneration in the zebrafish. PMID:26107416

  5. Cell swelling impairs dye coupling in adult rat ventricular myocytes. Cell volume as a regulator of cell communication

    PubMed Central

    De Mello, WC

    2013-01-01

    The influence of cell swelling on cell communication was investigated in cardiomyocytes isolated from the ventricle of adult rats. Measurements of dye coupling were performed in cell pairs using intracellular dialysis of Lucifer Yellow CH. The pipette was attached to one cell of the pair and after a gig ohm seal was achieved, the membrane was ruptured by a brief suction allowing the dye to diffuse from the pipette into the cell. Fluorescence of the dye in the injected as well as in non-dialyzed cell of the pair was continuously monitored. The results indicate that in cell pairs exposed to hypotonic solution the cell volume was increased by about 60% within 35 min and the dye coupling was significantly reduced by cell swelling. Calculation of gap junction permeability (P(j)) assuming an the intracellular volume accessible to intracellular diffusion of the dye as 12% of total cell volume, showed an average P(j) value of 0.16 ± 0.04 × 10−4 cm/s (n = 35) in the control and 0.89 ± 1.1 × 10−5 cm (n = 40) for cells exposed to hypotonic solution (P < 0.05). Similar results were found assuming intracellular volumes accessible to the dye of 20 and 30% of total cell volume, respectively. Cell swelling did not change the rate of intracellular diffusion of the dye. The results, which indicate that cell volume is an important regulator of gap junction permeability, have important implications to myocardial ischemia and heart failure as well as to heart pharmacology because changes in cell volume caused by drugs and transmitters can impair cell communication with consequent generation of slow conduction and cardiac arrhythmias. PMID:20512611

  6. Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity.

    PubMed

    Schwaiger, Marion; Grinberg, Marianna; Moser, Dirk; Zang, Johannes C S; Heinrichs, Markus; Hengstler, Jan G; Rahnenführer, Jörg; Cole, Steve; Kumsta, Robert

    2016-09-01

    Exposure to serious or traumatic events early in life can lead to persistent alterations in physiological stress response systems, including enhanced cross talk between the neuroendocrine and immune system. These programming effects may be mechanistically involved in mediating the effects of adverse childhood experience on disease risk in adulthood. We investigated hormonal and genome-wide mRNA expression responses in monocytes to acute stress exposure, in a sample of healthy adults (n=30) with a history of early childhood adversity, and a control group (n=30) without trauma experience. The early adversity group showed altered hypothalamus-pituitary-adrenal axis responses to stress, evidenced by lower ACTH and cortisol responses. Analyses of gene expression patterns showed that stress-responsive transcripts were enriched for genes involved in cytokine activity, cytokine-cytokine receptor interaction, chemokine activity, and G-protein coupled receptor binding. Differences between groups in stress-induced regulation of gene transcription were observed for genes involved in steroid binding, hormone activity, and G-protein coupled receptor binding. Transcription factor binding motif analysis showed an increased activity of pro-inflammatory upstream signaling in the early adversity group. We also identified transcripts that were differentially correlated with stress-induced cortisol increases between the groups, enriched for genes involved in cytokine-cytokine receptor interaction and glutamate receptor signaling. We suggest that childhood adversity leads to persistent alterations in transcriptional control of stress-responsive pathways, which-when chronically or repeatedly activated-might predispose individuals to stress-related psychopathology. PMID:27091381

  7. Effect of a behavioral intervention on dimensions of self-regulation and physical activity among overweight and obese adults with type 2 diabetes: a pilot study.

    PubMed

    Silfee, Valerie; Petosa, Rick; Laurent, Devin; Schaub, Timothy; Focht, Brian

    2016-09-01

    The purpose of this pilot study was to determine the preliminary effect of a behavioral intervention on the use of self-regulation strategies and moderate-to-vigorous physical activity (MVPA) in overweight and obese adults with type 2 diabetes. 23 individuals recruited from ResearchMatc.org and campus advertisements were randomized into an intervention (n = 12) and control (n = 11) group. The intervention group received a behavioral intervention that used goal setting, time management, and self-monitoring to target dimensions of self-regulation and MVPA. The control received information regarding their PA habits. MVPA was measured via BodyMedia Armbands at pre- and post-test. The use of self-regulatory strategies for MVPA was assessed at pretest and posttest using the Self-Regulation for Exercise Scale. Cohen's d effect sizes were calculated to determine the practical impact of the intervention. The intervention had a large effect on all dimensions of self-regulation across time: including total self-regulation (3.15), self-monitoring (4.63), goal setting (3.17), social support (1.29), self-reward (1.98), time management (4.41), and overcoming barriers (2.25). The intervention had no impact on dimensions of MVPA across time. This pilot study demonstrated the ability of a behavioral intervention to improve the use of self-regulation strategies for MVPA in a sample of adults with type 2 diabetes. These findings can further inform the development of health promotion programs to promote self-regulation. Future research should focus on determining ability of improvements in self-regulation to stimulate behavior change. PMID:26785605

  8. Protease-activated receptor-1 negatively regulates proliferation of neural stem/progenitor cells derived from the hippocampal dentate gyrus of the adult mouse.

    PubMed

    Tanaka, Masayuki; Yoneyama, Masanori; Shiba, Tatsuo; Yamaguchi, Taro; Ogita, Kiyokazu

    2016-07-01

    Thrombin-activated protease-activated receptor (PAR)-1 regulates the proliferation of neural cells following brain injury. To elucidate the involvement of PAR-1 in the neurogenesis that occurs in the adult hippocampus, we examined whether PAR-1 regulated the proliferation of neural stem/progenitor cells (NPCs) derived from the murine hippocampal dentate gyrus. NPC cultures expressed PAR-1 protein and mRNA encoding all subtypes of PAR. Direct exposure of the cells to thrombin dramatically attenuated the cell proliferation without causing cell damage. This thrombin-induced attenuation was almost completely abolished by the PAR antagonist RWJ 56110, as well as by dabigatran and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), which are selective and non-selective thrombin inhibitors, respectively. Expectedly, the PAR-1 agonist peptide (AP) SFLLR-NH2 also attenuated the cell proliferation. The cell proliferation was not affected by the PAR-1 negative control peptide RLLFT-NH2, which is an inactive peptide for PAR-1. Independently, we determined the effect of in vivo treatment with AEBSF or AP on hippocampal neurogenesis in the adult mouse. The administration of AEBSF, but not that of AP, significantly increased the number of newly-generated cells in the hippocampal subgranular zone. These data suggest that PAR-1 negatively regulated adult neurogenesis in the hippocampus by inhibiting the proliferative activity of the NPCs. PMID:27426918

  9. Impact of a brief intervention on self-regulation, self-efficacy and physical activity in older adults with type 2 diabetes.

    PubMed

    Olson, Erin A; McAuley, Edward

    2015-12-01

    Despite evidence of the benefits of physical activity, most individuals with type 2 diabetes do not meet physical activity recommendations. The purpose of this study was to test the efficacy of a brief intervention targeting self-efficacy and self-regulation to increase physical activity in older adults with type 2 diabetes. Older adults (Mage = 61.8 ± 6.4) with type 2 diabetes or metabolic syndrome were randomized into a titrated physical activity intervention (n = 58) or an online health education course (n = 58). The intervention included walking exercise and theory-based group workshops. Self-efficacy, self-regulation and physical activity were assessed at baseline, post-intervention, and a follow-up. Results indicated a group by time effect for self-regulation [F(2,88) = 14.021, p < .001, η (2) = .24] and self-efficacy [F(12,77) = 2.322, p < .05, η (2) = .266] with increases in the intervention group. The intervention resulted in short-term increases in physical activity (d = .76, p < .01), which were partially maintained at the 6-month follow-up (d = .35, p < .01). The intervention increased short-term physical activity but was not successful at maintaining increases in physical activity. Similar intervention effects were observed in self-efficacy and self-regulation. Future research warrants adjusting intervention strategies to increase long-term change. PMID:26162648

  10. Toxicity and histopathology of the growth regulator pyriproxyfen to adults and eggs of the cat flea (Siphonaptera:Pulicidae).

    PubMed

    Meola, R; Pullen, S; Meola, S

    1996-07-01

    Adult cat fleas, Ctenocephalides felis (Bouché), exposed continuously to pyriproxyfen died within 8-10 d. Microscopic examination of 7-d-old adults indicated death was caused by histopathological damage to fat body, Malpighian tubules, midgut epithelia, salivary gland cells, and other internal tissues. Fleas were killed by pyriproxyfen regardless of whether they were held as unfed adults on treated filter paper or as feeding adults on treated dog hair. In addition to these toxic effects on adults, pyriproxyfen also induced formation of large autophagic vacuoles in maturing oocytes leading to partial reabsorption of yolk, degeneration of the nucleus, and lysis of the follicular epithelium. Consequently, most of the eggs laid by treated fleas lacked a nucleus, had a poorly formed chorion, and were ruptured during ovulation. These laboratory results suggest that continuous exposure of fleas to pyriproxyfen on a host animal could prevent deposition of viable eggs and eventually kill adults, thereby controlling all stages of flea development. PMID:8699465

  11. The COP1 Ortholog PPS Regulates the Juvenile–Adult and Vegetative–Reproductive Phase Changes in Rice[C][W

    PubMed Central

    Tanaka, Nobuhiro; Itoh, Hironori; Sentoku, Naoki; Kojima, Mikiko; Sakakibara, Hitoshi; Izawa, Takeshi; Itoh, Jun-Ichi; Nagato, Yasuo

    2011-01-01

    Because plant reproductive development occurs only in adult plants, the juvenile-to-adult phase change is an indispensable part of the plant life cycle. We identified two allelic mutants, peter pan syndrome-1 (pps-1) and pps-2, that prolong the juvenile phase in rice (Oryza sativa) and showed that rice PPS is an ortholog of Arabidopsis thaliana CONSTITUTIVE PHOTOMORPHOGENIC1. The pps-1 mutant exhibits delayed expression of miR156 and miR172 and the suppression of GA biosynthetic genes, reducing the GA3 content in this mutant. In spite of its prolonged juvenile phase, the pps-1 mutant flowers early, and this is associated with derepression of RAP1B expression in pps-1 plants independently of the Hd1-Hd3a/RFT1 photoperiodic pathway. PPS is strongly expressed in the fourth and fifth leaves, suggesting that it regulates the onset of the adult phase downstream of MORI1 and upstream of miR156 and miR172. Its ability to regulate the vegetative phase change and the time of flowering suggests that rice PPS acquired novel functions during the evolution of rice/monocots. PMID:21705640

  12. Specification of neural cell fate and regulation of neural stem cell proliferation by microRNAs

    PubMed Central

    Pham, Jacqueline T; Gallicano, G Ian

    2012-01-01

    In the approximately 20 years since microRNAs (miRNAs) were first characterized, they have been shown to play important roles in diverse physiologic functions, particularly those requiring coordinated changes in networks of signaling pathways. The ability of miRNAs to silence expression of multiple gene targets hints at complex connections that research has only begun to elucidate. The nervous system, particularly the brain, and its progenitor cells offer opportunities to examine miRNA function due to the myriad different cell types, numerous functionally distinct regions, and fluidly dynamic connections between them. This review aims to summarize current understanding of miRNA regulation in neurodevelopment, beginning with miRNAs that establish a general neural fate in cells. Particular attention is given to miR-124, the most abundant brain-specific miRNA, along with its key regulators and targets as an example of the potentially far-reaching effects of miRNAs. These modulators and mediators enable miRNAs to subtly calibrate cellular proliferation and differentiation. To better understand their mechanisms of action, miRNA profiles in distinct populations and regions of cells have been examined as well as miRNAs that regulate proliferation of stem cells, a process marked by dramatic morphological shifts in response to temporally subtle and refined shifts in gene expression. To tease out the complex interactions of miRNAs and stem cells more accurately, future studies will require more sensitive methods of assessing miRNA expression and more rigorous models of miRNA pathways. Thorough characterization of similarities and differences in specific miRNAs’ effects in different species is vital to developing better disease models and therapeutics using miRNAs. PMID:23671807

  13. RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro.

    PubMed

    Soldati, Chiara; Caramanica, Pasquale; Burney, Matthew J; Toselli, Camilla; Bithell, Angela; Augusti-Tocco, Gabriella; Stanton, Lawrence W; Biagioni, Stefano; Buckley, Noel J; Cacci, Emanuele

    2015-08-01

    Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate. PMID:25691247

  14. Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries.

    PubMed

    Tian, Ai; Benchabane, Hassina; Wang, Zhenghan; Ahmed, Yashi

    2016-02-01

    Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mechanisms by which Wingless (Wg)/Wnt regulates intestinal homeostasis and development. We provide evidence that the Wg signaling pathway, activation of which peaks at each of the major compartment boundaries of the adult intestine, has essential functions. Wg pathway activation in the intestinal epithelium is required not only to specify cell fate near compartment boundaries during development, but also to control ISC proliferation within compartments during homeostasis. Further, in contrast with the previous focus on Wg pathway activation within ISCs, we demonstrate that the primary mechanism by which Wg signaling regulates ISC proliferation during homeostasis is non-autonomous. Activation of the Wg pathway in absorptive enterocytes is required to suppress JAK-STAT signaling in neighboring ISCs, and thereby their proliferation. We conclude that Wg signaling gradients have essential roles during homeostasis and development of the adult intestine, non-autonomously controlling stem cell proliferation inside compartments, and autonomously specifying cell fate near compartment boundaries. PMID:26845150

  15. Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries

    PubMed Central

    Tian, Ai; Benchabane, Hassina; Wang, Zhenghan; Ahmed, Yashi

    2016-01-01

    Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mechanisms by which Wingless (Wg)/Wnt regulates intestinal homeostasis and development. We provide evidence that the Wg signaling pathway, activation of which peaks at each of the major compartment boundaries of the adult intestine, has essential functions. Wg pathway activation in the intestinal epithelium is required not only to specify cell fate near compartment boundaries during development, but also to control ISC proliferation within compartments during homeostasis. Further, in contrast with the previous focus on Wg pathway activation within ISCs, we demonstrate that the primary mechanism by which Wg signaling regulates ISC proliferation during homeostasis is non-autonomous. Activation of the Wg pathway in absorptive enterocytes is required to suppress JAK-STAT signaling in neighboring ISCs, and thereby their proliferation. We conclude that Wg signaling gradients have essential roles during homeostasis and development of the adult intestine, non-autonomously controlling stem cell proliferation inside compartments, and autonomously specifying cell fate near compartment boundaries. PMID:26845150

  16. Systems Genetics Analysis of a Recombinant Inbred Mouse Cell Culture Panel Reveals Wnt Pathway Member Lrp6 as a Regulator of Adult Hippocampal Precursor Cell Proliferation.

    PubMed

    Kannan, Suresh; Nicola, Zeina; Overall, Rupert W; Ichwan, Muhammad; Ramírez-Rodríguez, Gerardo; N Grzyb, Anna; Patone, Giannino; Saar, Kathrin; Hübner, Norbert; Kempermann, Gerd

    2016-03-01

    In much animal research, genetic variation is rather avoided than used as a powerful tool to identify key regulatory genes in complex phenotypes. Adult hippocampal neurogenesis is one such highly complex polygenic trait, for which the understanding of the molecular basis is fragmented and incomplete, and for which novel genetic approaches are needed. In this study, we aimed at marrying the power of the BXD panel, a mouse genetic reference population, with the flexibility of a cell culture model of adult neural precursor proliferation and differentiation. We established adult-derived hippocampal precursor cell cultures from 20 strains of the BXD panel, including the parental strains C57BL/6J and DBA/2J. The rates of cell proliferation and neuronal differentiation were measured, and transcriptional profiles were obtained from proliferating cultures. Together with the published genotypes of all lines, these data allowed a novel systems genetics analysis combining quantitative trait locus analysis with transcript expression correlation at a cellular level to identify genes linked with the differences in proliferation. In a proof-of-principle analysis, we identified Lrp6, the gene encoding the coreceptor to Frizzled in the Wnt pathway, as a potential negative regulator of precursor proliferation. Overexpression and siRNA silencing confirmed the regulatory role of Lrp6. As well as adding to our knowledge of the pathway surrounding Wnt in adult hippocampal neurogenesis, this finding allows the new appreciation of a negative regulator within this system. In addition, the resource and associated methodology will allow the integration of regulatory mechanisms at a systems level. Stem Cells 2016;34:674-684. PMID:26840599

  17. Flow management and fish density regulate salmonid recruitment and adult size in tailwaters across western North America

    USGS Publications Warehouse

    Dibble, Kimberly L.; Yackulic, Charles B.; Kennedy, Theodore A.; Budy, Phaedra E.

    2015-01-01

    The mean lengths of adult rainbow and brown trout were influenced by similar flow and catch metrics. Length in both species was positively correlated with high annual flow but declined in tailwaters with high daily fluctuations in flow, high catch rates of conspecifics, and when large cohorts recruited to adult size. Whereas brown trout did not respond to the proportion of water allocated between seasons, rainbow trout length increased in rivers that released more water during winter than in spring. Rainbow trout length was primarily related to high catch rates of conspecifics, whereas brown trout length was mainly related to large cohorts recruiting to the adult size class. Species-specific responses to flow management are likely attributable to differences in seasonal timing of key life history events such as spawning, egg hatching, and fry emergence.

  18. Identification of singles bar as a direct transcriptional target of Drosophila Myocyte enhancer factor-2 and a regulator of adult myoblast fusion

    PubMed Central

    Brunetti, Tonya M.; Fremin, Brayon J.; Cripps, Richard M.

    2015-01-01

    In Drosophila, myoblast fusion is a conserved process in which founder cells (FCs) and fusion competent myoblasts (FCMs) fuse to form a syncytial muscle fiber. Mutants for the myogenic regulator Myocyte enhancer factor-2 (MEF2) show a failure of myoblast fusion, indicating that MEF2 regulates the fusion process. Indeed, chromatin immunoprecipitation studies show that several genes involved in myoblast fusion are bound by MEF2 during embryogenesis. Of these, the MARVEL domain gene singles bar (sing), is down-regulated in MEF2 knockdown pupae, and has five consensus MEF2 binding sites within a 9000-bp region. To determine if MEF2 is an essential and direct regulator of sing during pupal muscle development, we identified a 315-bp myoblast enhancer of sing. This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity. We show that lack of sing expression resulted in adult lethality and muscle loss, due to a failure of fusion during the pupal stage. Additionally, we sought to determine if sing was required in either FCs or FCMs to support fusion. Interestingly, knockdown of sing in either population did not significantly affect fusion, however, knockdown in both FCs and FCMs resulted in muscles with significantly reduced nuclei numbers, provisionally indicating that sing function is required in either cell type, but not both. Finally, we found that MEF2 regulated sing expression at the embryonic stage through the same 315-bp enhancer, indicating that sing is a MEF2 target at both critical stages of myoblast fusion. Our studies define for the first time how MEF2 directly controls fusion at multiple stages of the life cycle, and provide further evidence that the mechanisms of fusion characterized in Drosophila embryos is also used in the formation of the more complex adult muscles. PMID:25797154

  19. Migration depths of adult steelhead Oncorhynchus mykiss in relation to dissolved gas supersaturation in a regulated river system

    SciTech Connect

    Johnson, Eric L.; Clabough, Tami S.; Caudill, Christopher C.; keefer, matthew L.; Peery, Christopher A.; Richmond, Marshall C.

    2010-04-01

    Adult steelhead tagged with archival transmitters primarily migrated through a large river corridor at depths > 2 m, interspersed with frequent but short (< 5 min) periods closer to the surface. The recorded swimming depths and behaviours probably provided adequate hydrostatic compensation for the encountered supersaturated dissolved gas conditions and probably limited development of gas bubble disease (GBD). Results parallel those from a concurrent adult Chinook salmon study, except steelhead experienced greater seasonal variability and were more likely to have depth-uncompensated supersaturation exposure in some dam tailraces, perhaps explaining the higher incidence of GBD in this species.

  20. MicroRNA-124 suppresses tumor cell proliferation and invasion by targeting CD164 signaling pathway in non-small cell lung cancer

    PubMed Central

    Lin, Jing; Xu, Kai; Wei, Jun; Heimberger, Amy B; Roth, Jack A.; Ji, Lin

    2016-01-01

    MicroRNAs play critical roles in regulating gene expression and various cellular processes in human cancer malignant progression. Down-regulated expression of miR-124 gene has been shown to be significantly associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC) but its biological function and regulatory roles in lung cancer tumorigenesis are largely unknown. In this study, we aimed to determine effects of ectopic expression of miR-124 on tumor cell proliferation, invasion, and induction of apoptosis by DOTAP:Cholesterol nanoparticle-mediated gene transfer and identify its endogenous targets under physiological conditions in NSCLC cells. Overexpression of miR-124 significantly suppresses tumor cell proliferation, colony formation, migration, and induction of apoptosis in H322 and A549 cells. Two endogenous miR-124 targeting sites in the 3′UTR of CD164 mRNA are identified by a stem-loop-array reverse transcription PCR (SLA-RT-PCR) assay in H1299 cells under physiological condition. Ectopic expression of miR-124 induces CD164 mRNA cleavage and down-regulated its gene and protein expression. Our results suggest that miR-124 function as a tumor suppressor miRNA and suppress tumor proliferation and aggression by directly targeting oncogenic CD164 signaling pathway in NSCLC. PMID:27376157

  1. PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact

    PubMed Central

    Lee, Byung-Chul; Kim, Hyung-Sik; Shin, Tae-Hoon; Kang, Insung; Lee, Jin Young; Kim, Jae-Jun; Kang, Hyun Kyoung; Seo, Yoojin; Lee, Seunghee; Yu, Kyung-Rok; Choi, Soon Won; Kang, Kyung-Sun

    2016-01-01

    Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency. PMID:27230257

  2. PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact.

    PubMed

    Lee, Byung-Chul; Kim, Hyung-Sik; Shin, Tae-Hoon; Kang, Insung; Lee, Jin Young; Kim, Jae-Jun; Kang, Hyun Kyoung; Seo, Yoojin; Lee, Seunghee; Yu, Kyung-Rok; Choi, Soon Won; Kang, Kyung-Sun

    2016-01-01

    Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency. PMID:27230257

  3. The Influence of the Openness of an E-Learning Situation on Adult Students' Self-Regulation

    ERIC Educational Resources Information Center

    Jezegou, Annie

    2013-01-01

    This article presents empirical research conducted with French speaking adults studying for a diploma. Their training took place mainly in e-learning. The goal of this research was to identify and explain the processes of influence existing between two specific dimensions: the degree of openness of the components of the e-learning situation and…

  4. Duration of prepupal summer dormancy regulates synchronization of adult diapause with winter temperatures in bees of the genus Osmia.

    PubMed

    Sgolastra, Fabio; Kemp, William P; Maini, Stefano; Bosch, Jordi

    2012-07-01

    Osmia (Osmia) bees are strictly univoltine and winter as diapausing adults. In these species, the timing of adult eclosion with the onset of wintering conditions is critical, because adults exposed to long pre-wintering periods show increased lipid loss and winter mortality. Populations from warm areas fly in February-March and are exposed to longer growth seasons than populations from colder areas, which fly in April-May. Given their inability to produce an extra generation, early-flying populations should develop more slowly than late-flying populations and thus avoid the negative consequences of long pre-wintering periods. In this study we compare the development under natural and laboratory conditions of phenologically-distinct populations in two Osmia species. Early-flying populations took ∼2 months longer to develop than late-flying populations. Differences between populations in larval and pupal period duration were very small, whereas the prepupal period was much longer in early-flying populations. In contrast to the larval and pupal stages, the prepupal stage showed a non-linear response to temperature, was strongly affected by thermoperiod, and exhibited minimum respiration rates. Coupled with other lines of evidence, these results suggest that the prepupal period in Osmia corresponds to a summer diapause, and its duration may be under local selection to synchronize adult eclosion with the onset of winter temperatures. We discuss the implications of our results relative to current expectations of global warming. PMID:22546562

  5. The Impact of Feedback on Self-Rated Driving Ability and Driving Self-Regulation among Older Adults

    ERIC Educational Resources Information Center

    Ackerman, Michelle L.; Crowe, Michael; Vance, David E.; Wadley, Virginia G.; Owsley, Cynthia; Ball, Karlene K.

    2011-01-01

    In 129 community-dwelling older adults, feedback regarding qualification for an insurance discount (based on a visual speed of processing test; Useful Field of View) was examined as a prospective predictor of change in self-reported driving ability, driving avoidance, and driving exposure over 3 months, along with physical, visual, health, and…

  6. Volunteer Client Adult Attachment, Memory for In-Session Emotion, and Mood Awareness: An Affect Regulation Perspective

    ERIC Educational Resources Information Center

    Woodhouse, Susan S.; Gelso, Charles J.

    2008-01-01

    In this study, the authors examined relations between volunteer client adult attachment and both (a) memory for negative affect occurring within the first session of therapy and (b) mood awareness (mood labeling and mood monitoring). Participants were 80 volunteer clients (students with a personal issue who volunteered to participate in the…

  7. Down-Regulation of Replication Factor C-40 (RFC40) Causes Chromosomal Missegregation in Neonatal and Hypertrophic Adult Rat Cardiac Myocytes

    PubMed Central

    Oka, Masahiko; Ochi, Rikuo; Jong, Chian Ju; Gebb, Sarah; Benjamin, John; Schaffer, Stephen; Hobart, Holly H.; Downey, James; McMurtry, Ivan; Gupte, Rakhee

    2012-01-01

    Background Adult mammalian cardiac myocytes are generally assumed to be terminally differentiated; nonetheless, a small fraction of cardiac myocytes have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36) and DNA polymerase δ (Pol δ) proteins, which are required for DNA synthesis and cell proliferation, in the adult normal and hypertrophied hearts has been rarely studied. Methods We performed qRT-PCR and Western blot analysis to determine the levels of RFC and Pol δ message and proteins in the adult normal cardiac myocytes and cardiac fibroblasts, as well as in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. Immunohistochemical analyses were performed to determine the localization of the re-expressed DNA replication and cell cycle proteins in adult normal (control) and hypertrophied right ventricle. We determined right ventricular cardiac myocyte polyploidy and chromosomal missegregation/aneuploidy using Fluorescent in situ hybridization (FISH) for rat chromosome 12. Results RFC40-mRNA and protein was undetectable, whereas Pol δ message was detectable in the cardiac myocytes isolated from control adult hearts. Although RFC40 and Pol δ message and protein significantly increased in hypertrophied hearts as compared to the control hearts; however, this increase was marginal as compared to the fetal hearts. Immunohistochemical analyses revealed that in addition to RFC40, proliferative and mitotic markers such as cyclin A, phospho-Aurora A/B/C kinase and phospho-histone 3 were also re-expressed/up-regulated simultaneously in the cardiac myocytes. Interestingly, FISH analyses demonstrated cardiac myocytes polyploidy and chromosomal missegregation/aneuploidy in these hearts. Knock-down of endogenous RFC40 caused chromosomal missegregation/aneuploidy and decrease in the rat neonatal cardiac myocyte numbers. Conclusion Our novel findings

  8. MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response.

    PubMed

    Essandoh, Kobina; Li, Yutian; Huo, Jiuzhou; Fan, Guo-Chang

    2016-08-01

    Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive immunity through antigen presentation. Essential to such functions is classical activation (M1) and alternative activation (M2) of macrophages. M1 polarization of macrophages is characterized by production of pro-inflammatory cytokines, antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is linked to immunosuppression, tumorigenesis, wound repair, and elimination of parasites. MiRNAs are small non-coding RNAs with the ability to regulate gene expression and network of cellular processes. A number of studies have determined miRNA expression profiles in M1 and M2 polarized human and murine macrophages using microarray and RT-qPCR arrays techniques. More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Further, M1 and M2 phenotypes play distinctive roles in cell growth and progression of inflammation-related diseases such as sepsis, obesity, cancer, and multiple sclerosis. Hence, miRNAs that modulate macrophage polarization may have therapeutic potential in the treatment of inflammation-related diseases. This review highlights recent findings in miRNA expression profiles in polarized macrophages from murine and human sources, and summarizes how these miRNAs regulate macrophage polarization. Last, therapeutic potential of miRNAs in inflammation-related diseases through modulation of macrophage polarization is also discussed. PMID:26954942

  9. Association of Self-Efficacy and Self-Regulation with Nutrition and Exercise Behaviors in a Community Sample of Adults.

    PubMed

    Shieh, Carol; Weaver, Michael T; Hanna, Kathleen M; Newsome, Kathleen; Mogos, Mulubrhan

    2015-01-01

    This study examined the association of self-efficacy and self-regulation with nutrition and exercise behaviors. The study used a cross-sectional design and included 108 participants (54 men, 54 women). Nutrition behaviors (fruit/vegetable consumption, dinner cooking, and restaurant eating) and exercise were measured using total days in last week a behavior was reported. Instruments measuring self-efficacy and self-regulation demonstrated excellent Cronbach's alphas (.93-.95). Path analysis indicated only fruit/vegetable consumption and exercise were associated with self-efficacy and self-regulation. Self-regulation showed direct association with fruit/vegetable consumption and exercise, but self-efficacy had direct association only with exercise. Self-efficacy and self-regulation should be strategically used to promote health behaviors. PMID:26529105

  10. The Osa-containing SWI/SNF chromatin-remodeling complex regulates stem cell commitment in the adult Drosophila intestine

    PubMed Central

    Zeng, Xiankun; Lin, Xinhua; Hou, Steven X.

    2013-01-01

    The proportion of stem cells versus differentiated progeny is well balanced to maintain tissue homeostasis, which in turn depends on the balance of the different signaling pathways involved in stem cell self-renewal versus lineage-specific differentiation. In a screen for genes that regulate cell lineage determination in the posterior midgut, we identified that the Osa-containing SWI/SNF (Brahma) chromatin-remodeling complex regulates Drosophila midgut homeostasis. Mutations in subunits of the Osa-containing complex result in intestinal stem cell (ISC) expansion as well as enteroendocrine (EE) cell reduction. We further demonstrated that Osa regulates ISC self-renewal and differentiation into enterocytes by elaborating Notch signaling, and ISC commitment to differentiation into EE cells by regulating the expression of Asense, an EE cell fate determinant. Our data uncover a unique mechanism whereby the commitment of stem cells to discrete lineages is coordinately regulated by chromatin-remodeling factors. PMID:23942514

  11. Proteomic identification of non-erythrocytic alpha-spectrin-1 down-regulation in the pre-optic area of neonatally estradiol-17β treated female adult rats.

    PubMed

    Govindaraj, Vijayakumar; Rao, Addicam Jagannadha

    2016-06-01

    It is well established that sexually dimorphic brain regions, which are critical for reproductive physiology and behavior, are organized by steroid hormones during the first 2 weeks after birth in the rodents. In our recent observation, neonatal exposure to estradiol-17β (E2) in the female rat revealed increase in cyclooxygenase 2 (COX-2) level, sexually dimorphic nucleus (SDN)-pre-optic area (POA) size and down-regulation of synaptogenesis related genes in POA in the adult stage. In the present study, using the same animal model, the protein profile of control and neonatally E2-treated POA was compared by 1D-SDS-PAGE, and the protein that shows a change in abundance was identified by LC-MS/MS analysis. Results indicated that there was a single protein band, which was down-regulation in E2-treated POA and it was identified as spectrin alpha chain, non-erythrocytic 1 (SPTAN1). Consistently, the down-regulation of SPTAN1 expression was also confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The SPTAN1 was identified as a cytoskeletal protein that is involved in stabilization of the plasma membrane and organizes intracellular organelles, and it has been implicated in cellular functions including DNA repair and cell cycle regulation. The evidence shows that any mutation in spectrins causes impairment of synaptogenesis and other neurological disorders. Also, protein-protein interaction analysis of SPTAN1 revealed a strong association with proteins such as kirrel, actinin, alpha 4 (ACTN4) and vinculin (VCL) which are implicated in sexual behavior, masculinization and defeminization. Our results indicate that SPTAN1 expression in the developing rat brain is sexually dimorphic, and we suggest that this gene may mediate E2-17β-induced masculinization and defeminization, and disrupted reproductive function in the adult stage. PMID:27166725

  12. Investigation of Van Gogh-like 2 mRNA regulation and localisation in response to nociception in the brain of adult common carp (Cyprinus carpio).

    PubMed

    Reilly, Siobhan C; Kipar, Anja; Hughes, David J; Quinn, John P; Cossins, Andrew R; Sneddon, Lynne U

    2009-11-20

    The Van Gogh-like 2 (vangl2) gene is typically associated with planar cell polarity pathways, which is essential for correct orientation of epithelial cells during development. The encoded protein of this gene is a transmembrane protein and is highly conserved through evolution. Van Gogh-like 2 was selected for further study on the basis of consistent regulation after a nociceptive stimulus in adult common carp and rainbow trout in a microarray study. An in situ hybridisation was conducted in the brain of mature common carp (Cyprinus carpio), 1.5 and 3 h after a nociceptive stimulus comprising of an acetic acid injection to the lips of the fish and compared with a saline-injected control. The vangl2 gene was expressed in all brain regions, and particularly intensely in neurons of the telencephalon and in ependymal cells. In the cerebellum, a greater number (P=0.018) of Purkinje cells expressed vangl2 after nociception (n=7) compared with controls (n=5). This regulation opens the possibility that vangl2 is involved in nociceptive processing in the adult fish brain and may be a novel target for central nociception in vertebrates. PMID:19781599

  13. Single-Stranded DNA-Binding Transcriptional Regulator FUBP1 Is Essential for Fetal and Adult Hematopoietic Stem Cell Self-Renewal.

    PubMed

    Rabenhorst, Uta; Thalheimer, Frederic B; Gerlach, Katharina; Kijonka, Marek; Böhm, Stefanie; Krause, Daniela S; Vauti, Franz; Arnold, Hans-Henning; Schroeder, Timm; Schnütgen, Frank; von Melchner, Harald; Rieger, Michael A; Zörnig, Martin

    2015-06-30

    The ability of hematopoietic stem cells (HSCs) to self-renew is a prerequisite for the establishment of definitive hematopoiesis and life-long blood regeneration. Here, we report the single-stranded DNA-binding transcriptional regulator far upstream element (FUSE)-binding protein 1 (FUBP1) as an essential factor of HSC self-renewal. Functional inactivation of FUBP1 in two different mouse models resulted in embryonic lethal anemia at around E15.5 caused by severely diminished HSCs. Fetal and adult HSCs lacking FUBP1 revealed an HSC-intrinsic defect in their maintenance, expansion, and long-term blood reconstitution, but could differentiate into all hematopoietic lineages. FUBP1-deficient adult HSCs exhibit significant transcriptional changes, including upregulation of the cell-cycle inhibitor p21 and the pro-apoptotic Noxa molecule. These changes caused an increase in generation time and death of HSCs as determined by video-microscopy-based tracking. Our data establish FUBP1 and its recognition of single-stranded genomic DNA as an important element in the transcriptional regulation of HSC self-renewal. PMID:26095368

  14. Translational Control of Myelin Basic Protein Expression by ERK2 MAP Kinase Regulates Timely Remyelination in the Adult Brain

    PubMed Central

    Michel, Kelly; Zhao, Tianna; Karl, Molly; Lewis, Katherine

    2015-01-01

    Successful myelin repair in the adult CNS requires the robust and timely production of myelin proteins to generate new myelin sheaths. The underlying regulatory mechanisms and complex molecular basis of myelin regeneration, however, remain poorly understood. Here, we investigate the role of ERK MAP kinase signaling in this process. Conditional deletion of Erk2 from cells of the oligodendrocyte lineage resulted in delayed remyelination following demyelinating injury to the adult mouse corpus callosum. The delayed repair occurred as a result of a specific deficit in the translation of the major myelin protein, MBP. In the absence of ERK2, activation of the ribosomal protein S6 kinase (p70S6K) and its downstream target, ribosomal protein S6 (S6RP), was impaired at a critical time when premyelinating oligodendrocytes were transitioning to mature cells capable of generating new myelin sheaths. Thus, we have described an important link between the ERK MAP kinase signaling cascade and the translational machinery specifically in remyelinating oligodendrocytes in vivo. These results suggest an important role for ERK2 in the translational control of MBP, a myelin protein that appears critical for ensuring the timely generation of new myelin sheaths following demyelinating injury in the adult CNS. PMID:25995471

  15. Translational control of myelin basic protein expression by ERK2 MAP kinase regulates timely remyelination in the adult brain.

    PubMed

    Michel, Kelly; Zhao, Tianna; Karl, Molly; Lewis, Katherine; Fyffe-Maricich, Sharyl L

    2015-05-20

    Successful myelin repair in the adult CNS requires the robust and timely production of myelin proteins to generate new myelin sheaths. The underlying regulatory mechanisms and complex molecular basis of myelin regeneration, however, remain poorly understood. Here, we investigate the role of ERK MAP kinase signaling in this process. Conditional deletion of Erk2 from cells of the oligodendrocyte lineage resulted in delayed remyelination following demyelinating injury to the adult mouse corpus callosum. The delayed repair occurred as a result of a specific deficit in the translation of the major myelin protein, MBP. In the absence of ERK2, activation of the ribosomal protein S6 kinase (p70S6K) and its downstream target, ribosomal protein S6 (S6RP), was impaired at a critical time when premyelinating oligodendrocytes were transitioning to mature cells capable of generating new myelin sheaths. Thus, we have described an important link between the ERK MAP kinase signaling cascade and the translational machinery specifically in remyelinating oligodendrocytes in vivo. These results suggest an important role for ERK2 in the translational control of MBP, a myelin protein that appears critical for ensuring the timely generation of new myelin sheaths following demyelinating injury in the adult CNS. PMID:25995471

  16. Microglial Kv1.3 Channels and P2Y12 Receptors Differentially Regulate Cytokine and Chemokine Release from Brain Slices of Young Adult and Aged Mice

    PubMed Central

    Eder, Claudia

    2015-01-01

    Brain tissue damage following stroke or traumatic brain injury is accompanied by neuroinflammatory processes, while microglia play a central role in causing and regulating neuroinflammation via production of proinflammatory substances, including cytokines and chemokines. Here, we used brain slices, an established in situ brain injury model, from young adult and aged mice to investigate cytokine and chemokine production with particular focus on the role of microglia. Twenty four hours after slice preparation, higher concentrations of proinflammatory cytokines, i.e. TNF-α and IL-6, and chemokines, i.e. CCL2 and CXCL1, were released from brain slices of aged mice than from slices of young adult mice. However, maximal microglial stimulation with LPS for 24 h did not reveal age-dependent differences in the amounts of released cytokines and chemokines. Mechanisms underlying microglial cytokine and chemokine production appear to be similar in young adult and aged mice. Inhibition of microglial Kv1.3 channels with margatoxin reduced release of IL-6, but not release of CCL2 and CXCL1. In contrast, blockade of microglial P2Y12 receptors with PSB0739 inhibited release of CCL2 and CXCL1, whereas release of IL-6 remained unaffected. Cytokine and chemokine production was not reduced by inhibitors of Kir2.1 K+ channels or adenosine receptors. In summary, our data suggest that brain tissue damage-induced production of cytokines and chemokines is age-dependent, and differentially regulated by microglial Kv1.3 channels and P2Y12 receptors. PMID:26011191

  17. Spatiotemporally Regulated Ablation of Klf4 in Adult Mouse Corneal Epithelial Cells Results in Altered Epithelial Cell Identity and Disrupted Homeostasis

    PubMed Central

    Delp, Emili E.; Swamynathan, Sudha; Kao, Winston W.; Swamynathan, Shivalingappa K.

    2015-01-01

    Purpose. In previous studies, conditional disruption of Klf4 in the developing mouse ocular surface from embryonic day 10 resulted in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells, revealing the importance of Klf4 in ocular surface maturation. Here, we use spatiotemporally regulated ablation of Klf4 to investigate its functions in maintenance of adult corneal epithelial homeostasis. Methods. Expression of Cre was induced in ternary transgenic (Klf4LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre) mouse corneal epithelium by doxycycline administered through intraperitoneal injections and drinking water, to generate corneal epithelium–specific deletion of Klf4 (Klf4Δ/ΔCE). Corneal epithelial barrier function was tested by fluorescein staining. Expression of selected Klf4-target genes was determined by quantitative PCR (QPCR), immunoblotting, and immunofluorescent staining. Results. Klf4 was efficiently ablated within 5 days of doxycycline administration in adult Klf4Δ/ΔCE corneal epithelium. The Klf4Δ/ΔCE corneal epithelial barrier function was disrupted, and the basal cells were swollen and rounded after 15 days of doxycycline treatment. Increased numbers of cell layers and Ki67-positive proliferating cells suggested deregulated Klf4Δ/ΔCE corneal epithelial homeostasis. Expression of tight junction proteins ZO-1 and occludin, desmosomal Dsg and Dsp, basement membrane laminin-332, and corneal epithelial–specific keratin-12 was decreased, while that of matrix metalloproteinase Mmp9 and noncorneal keratin-17 increased, suggesting altered Klf4Δ/ΔCE corneal epithelial cell identity. Conclusions. Ablation of Klf4 in the adult mouse corneas resulted in the absence of characteristic corneal epithelial cell differentiation, disrupted barrier function, and squamous metaplasia, revealing that Klf4 is essential for maintenance of the adult corneal epithelial cell identity and homeostasis. PMID:26047041

  18. Direct Regulation of Aromatase B Expression by 17β-Estradiol and Dopamine D1 Receptor Agonist in Adult Radial Glial Cells

    PubMed Central

    Xing, Lei; Esau, Crystal; Trudeau, Vance L.

    2016-01-01

    Aromatase cytochrome P450arom (cyp19) is the only enzyme that has the ability to convert androgens into estrogens. Estrogens, which are produced locally in the vertebrate brain play many fundamental roles in neuroendocrine functions, reproductive functions, socio-sexual behaviors, and neurogenesis. Radial glial cells (RGCs) are neuronal progenitor cells that are abundant in fish brains and are the exclusive site of aromatase B expression and neuroestrogen synthesis. Using a novel in vitro RGC culture preparation we studied the regulation of aromatase B by 17β-estradiol (E2) and dopamine (DA). We have established that activation of the dopamine D1 receptor (D1R) by SKF 38393 up-regulates aromatase B gene expression most likely through the phosphorylation of cyclic AMP response element binding protein (CREB). This up-regulation can be enhanced by low concentration of E2 (100 nM) through increasing the expression of D1R and the level of p-CREB protein. However, a high concentration of E2 (1 μM) and D1R agonist together failed to up-regulate aromatase B, potentially due to attenuation of esr2b expression and p-CREB levels. Furthermore, we found the up-regulation of aromatase B by E2 and DA both requires the involvement of esr1 and esr2a. The combined effect of E2 and DA agonist indicates that aromatase B in the adult teleost brain is under tight control by both steroids and neurotransmitters to precisely regulate neuroestrogen levels. PMID:26793050

  19. Flow management and fish density regulate salmonid recruitment and adult size in tailwaters across western North America.

    PubMed

    Dibble, Kimberly L; Yackulic, Charles B; Kennedy, Theodore A; Budy, Phaedra

    2015-12-01

    Rainbow and brown trout have been intentionally introduced into tailwaters downriver of dams globally and provide billions of dollars in economic benefits. At the same time, recruitment and maximum length of trout populations in tailwaters often fluctuate erratically, which negatively affects the value of fisheries. Large recruitment events may increase dispersal downriver where other fish species may be a priority (e.g., endangered species). There is an urgent need to understand the drivers of trout population dynamics in tailwaters, in particular the role of flow management. Here, we evaluate how flow, fish density, and other physical factors of the river influence recruitment and mean adult length in tailwaters across western North America, using data from 29 dams spanning 1-19 years. Rainbow trout recruitment was negatively correlated with high annual, summer, and spring flow and dam latitude, and positively correlated with high winter flow, subadult brown trout catch, and reservoir storage capacity. Brown trout recruitment was negatively correlated with high water velocity and daily fluctuations in flow (i.e., hydropeaking) and positively correlated with adult rainbow trout catch. Among these many drivers, rainbow trout recruitment was primarily correlated with high winter flow combined with low spring flow, whereas brown trout recruitment was most related to high water velocity. The mean lengths of adult rainbow and brown trout were influenced by similar flow and catch metrics. Length in both species was positively correlated with high annual flow but declined in tailwaters with high daily fluctuations in flow, high catch rates of conspecifics, and when large cohorts recruited to adult size. Whereas brown trout did not respond to the proportion of water allocated between seasons, rainbow trout length increased in rivers that released more water during winter than in spring. Rainbow trout length was primarily related to high catch rates of conspecifics

  20. Linking an Anxiety-Related Personality Trait to Cardiac Autonomic Regulation in Well-Defined Healthy Adults: Harm Avoidance and Resting Heart Rate Variability

    PubMed Central

    Kao, Lien-Cheng; Liu, Yu-Wen; Tzeng, Nian-Sheng; Kuo, Terry B. J.; Huang, San-Yuan

    2016-01-01

    Objective Anxiety trait, anxiety and depression states have all been reported to increase risks for cardiovascular disease (CVD), possibly through altering cardiac autonomic regulation. Our aim was to investigate whether the relationship between harm avoidance (HA, an anxiety-related personality trait) and cardiac autonomic regulation is independent of anxiety and depression states in healthy adults. Methods We recruited 535 physically and mentally healthy volunteers. Participants completed the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI) and Tri-dimensional Personality Questionnaire. Participants were divided into high or low HA groups as discriminated by the quartile value. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV). We obtained the time and frequency-domain indices of HRV including variance (total HRV), the low-frequency power (LF; 0.05–0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15–0.40 Hz), which reflects cardiac parasympathetic activity, as well as the LF/HF ratio. Results The BDI and HA scores showed associations with HRV parameters. After adjustment for the BDI scores and other control variables, HA is still associated with reduced variance, LF and HF power. Compared with the participants with low HA, those with high HA displayed significant reductions in variance, LF and HF power and a significant increase in their LF/HF ratio. Conclusion This study highlights the independent role of HA in contributing to decreased autonomic cardiac regulation in healthy adults and provides a potential underlying mechanism for anxiety trait to confer increased risk for CVD. PMID:27482240

  1. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice

    PubMed Central

    Zhang, Xiuqi; Garcia, Oscar A.; Wang, Rebecca F.; Stevenson, Mary C.; Threadgill, David W.; Russell, William E.

    2014-01-01

    Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies. PMID:24407590

  2. Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.

    PubMed

    Doucet-Beaupré, Hélène; Gilbert, Catherine; Profes, Marcos Schaan; Chabrat, Audrey; Pacelli, Consiglia; Giguère, Nicolas; Rioux, Véronique; Charest, Julien; Deng, Qiaolin; Laguna, Ariadna; Ericson, Johan; Perlmann, Thomas; Ang, Siew-Lan; Cicchetti, Francesca; Parent, Martin; Trudeau, Louis-Eric; Lévesque, Martin

    2016-07-26

    The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein(+) inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. PMID:27407143

  3. Gap Junctions Contribute to the Regulation of Walking-Like Activity in the Adult Mudpuppy (Necturus Maculatus).

    PubMed

    Lavrov, Igor; Fox, Lyle; Shen, Jun; Han, Yingchun; Cheng, Jianguo

    2016-01-01

    Although gap junctions are widely expressed in the developing central nervous system, the role of electrical coupling of neurons and glial cells via gap junctions in the spinal cord in adults is largely unknown. We investigated whether gap junctions are expressed in the mature spinal cord of the mudpuppy and tested the effects of applying gap junction blocker on the walking-like activity induced by NMDA or glutamate in an in vitro mudpuppy preparation. We found that glial and neural cells in the mudpuppy spinal cord expressed different types of connexins that include connexin 32 (Cx32), connexin 36 (Cx36), connexin 37 (Cx37), and connexin 43 (Cx43). Application of a battery of gap junction blockers from three different structural classes (carbenexolone, flufenamic acid, and long chain alcohols) substantially and consistently altered the locomotor-like activity in a dose-dependent manner. In contrast, these blockers did not significantly change the amplitude of the dorsal root reflex, indicating that gap junction blockers did not inhibit neuronal excitability nonselectively in the spinal cord. Taken together, these results suggest that gap junctions play a significant modulatory role in the spinal neural networks responsible for the generation of walking-like activity in the adult mudpuppy. PMID:27023006

  4. Gap Junctions Contribute to the Regulation of Walking-Like Activity in the Adult Mudpuppy (Necturus Maculatus)

    PubMed Central

    Lavrov, Igor; Fox, Lyle; Shen, Jun; Han, Yingchun; Cheng, Jianguo

    2016-01-01

    Although gap junctions are widely expressed in the developing central nervous system, the role of electrical coupling of neurons and glial cells via gap junctions in the spinal cord in adults is largely unknown. We investigated whether gap junctions are expressed in the mature spinal cord of the mudpuppy and tested the effects of applying gap junction blocker on the walking-like activity induced by NMDA or glutamate in an in vitro mudpuppy preparation. We found that glial and neural cells in the mudpuppy spinal cord expressed different types of connexins that include connexin 32 (Cx32), connexin 36 (Cx36), connexin 37 (Cx37), and connexin 43 (Cx43). Application of a battery of gap junction blockers from three different structural classes (carbenexolone, flufenamic acid, and long chain alcohols) substantially and consistently altered the locomotor-like activity in a dose-dependent manner. In contrast, these blockers did not significantly change the amplitude of the dorsal root reflex, indicating that gap junction blockers did not inhibit neuronal excitability nonselectively in the spinal cord. Taken together, these results suggest that gap junctions play a significant modulatory role in the spinal neural networks responsible for the generation of walking-like activity in the adult mudpuppy. PMID:27023006

  5. Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells

    PubMed Central

    Staber, Philipp B.; Zhang, Pu; Ye, Min; Welner, Robert S.; Nombela-Arrieta, César; Bach, Christian; Kerenyi, Marc; Bartholdy, Boris A.; Zhang, Hong; Alberich-Jordà, Meritxell; Lee, Sanghoon; Yang, Henry; Ng, Felicia; Zhang, Junyan; Leddin, Mathias; Silberstein, Leslie E.; Hoefler, Gerald; Orkin, Stuart H.; Göttgens, Berthold; Rosenbauer, Frank; Huang, Gang; Tenen, Daniel G.

    2013-01-01

    SUMMARY To provide a lifelong supply of blood cells, hematopoietic stem cells (HSCs) need to carefully balance both self-renewing cell divisions and quiescence. Although several regulators that control this mechanism have been identified, we demonstrate that the transcription factor PU.1 acts upstream of these regulators. So far, attempts to uncover PU.1’s role in HSC biology have failed because of the technical limitations of complete loss-of-function models. With the use of hypomorphic mice with decreased PU.1 levels specifically in phenotypic HSCs, we found reduced HSC long-term repopulation potential that could be rescued completely by restoring PU.1 levels. PU.1 prevented excessive HSC division and exhaustion by controlling the transcription of multiple cell-cycle regulators. Levels of PU.1 were sustained through autoregulatory PU.1 binding to an upstream enhancer that formed an active looped chromosome architecture in HSCs. These results establish that PU.1 mediates chromosome looping and functions as a master regulator of HSC proliferation. PMID:23395001

  6. Comparative insights into the regulation of inflammation: Levels and predictors of interleukin 6 and interleukin 10 in young adults in the Philippines

    PubMed Central

    Tallman, Paula S.; Adair, Linda S.; Judith, Borja; Kuzawa, Christopher W.

    2013-01-01

    Inflammation is a central part of innate immunity, but its role in anti-pathogen defenses has been overshadowed by recent interest in the contribution of inflammation to a wide range of chronic degenerative diseases. Current research on chronic inflammation is conducted primarily in affluent populations with low levels of infectious disease; comparative research in different ecological settings is needed to advance understandings of the causes and consequences of variation in the regulation of inflammation. This paper investigates the levels and predictors of interleukin-6 (IL-6) and interleukin-10 (IL-10)–two cytokines important to the regulation of inflammation—in a large, population-based study in the Philippines. Concentrations of IL-6 and IL-10 were determined in N=1569 healthy young adults (20-22 yrs) in Metro Cebu, Philippines. IL-6 and IL-10 concentrations were positively correlated, and body mass index and symptoms of infectious disease were both associated with higher concentrations of IL-6 and IL-10. Median concentrations of IL-6 (1.0 pg/mL) and IL-10 (7.56 pg/mL) were substantially lower and higher, respectively, than levels reported for other populations based on a systematic review of prior research. This study contributes to a growing body of research in human ecological immunology, and suggests that there may be substantial population differences in the regulation of inflammation that has implications for the association between inflammation and disease. PMID:21994014

  7. The Impact of Feedback on Self-rated Driving Ability and Driving Self-regulation Among Older Adults

    PubMed Central

    Ackerman, Michelle L.; Crowe, Michael; Vance, David E.; Wadley, Virginia G.; Owsley, Cynthia; Ball, Karlene K.

    2011-01-01

    In 129 community-dwelling older adults, feedback regarding qualification for an insurance discount (based on a visual speed of processing test; Useful Field of View) was examined as a prospective predictor of change in self-reported driving ability, driving avoidance, and driving exposure over 3 months, along with physical, visual, health, and cognitive variables. Multiple regression models indicated that after controlling for baseline scores on the outcome measures, failure to qualify was a significant predictor of increased avoidance over 3 months (p = .02) but not change in self-rated driving ability or exposure. Female gender (p = .03) was a significant predictor of subsequent lower self-rated driving ability. Overall, the findings of this study provide support for the role of feedback in the self-monitoring of older adults’ driving behavior through avoidance of challenging driving situations but not through driving exposure or self-rated driving ability. PMID:21071621

  8. Prenatal Stress Down-Regulates Reelin Expression by Methylation of Its Promoter and Induces Adult Behavioral Impairments in Rats

    PubMed Central

    Palacios-García, Ismael; Lara-Vásquez, Ariel; Montiel, Juan F.; Díaz-Véliz, Gabriela F.; Sepúlveda, Hugo; Utreras, Elías; Montecino, Martín; González-Billault, Christian; Aboitiz, Francisco

    2015-01-01

    Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new

  9. Cre recombinase-regulated Endothelin1 transgenic mouse lines: novel tools for analysis of embryonic and adult disorders

    PubMed Central

    Tavares, Andre L.P.; Clouthier, David E.

    2015-01-01

    Endothelin-1 (EDN1) influences both craniofacial and cardiovascular development and a number of adult physiological conditions by binding to one or both of the known endothelin receptors, thus initiating multiple signaling cascades. Animal models containing both conventional and conditional loss of the Edn1 gene have been used to dissect EDN1 function in both embryos and adults. However, while transgenic Edn1 over-expression or targeted genomic insertion of Edn1 has been performed to understand how elevated levels of Edn1 result in or exacerbate disease states, an animal model in which Edn1 over-expression can be achieved in a spatiotemporal-specific manner has not been reported. Here we describe the creation of Edn1 conditional over-expression transgenic mouse lines in which the chicken β-actin promoter and an Edn1 cDNA are separated by a strong stop sequence flanked by loxP sites. In the presence of Cre, the stop cassette is removed, leading to Edn1 expression. Using the Wnt1-Cre strain, in which Cre expression is targeted to the Wnt1-expressing domain of the central nervous system (CNS) from which neural crest cells (NCCs) arise, we show that stable CBA-Edn1 transgenic lines with varying EDN1 protein levels develop defects in NCC-derived tissues of the face, though the severity differs between lines. We also show that Edn1 expression can be achieved in other embryonic tissues utilizing other Cre strains, with this expression also resulting in developmental defects. CBA-Edn1 transgenic mice will be useful in investigating diverse aspects of EDN1-mediated-development and disease, including understanding how NCCs achieve and maintain a positional and functional identity and how aberrant EDN1 levels can lead to multiple physiological changes and diseases. PMID:25725491

  10. Chronic MDMA induces neurochemical changes in the hippocampus of adolescent and young adult rats: Down-regulation of apoptotic markers.

    PubMed

    García-Cabrerizo, Rubén; García-Fuster, M Julia

    2015-07-01

    While hippocampus is a brain region particularly susceptible to the effects of MDMA, the cellular and molecular changes induced by MDMA are still to be fully elucidated, being the dosage regimen, the species and the developmental stage under study great variables. This study compared the effects of one and four days of MDMA administration following a binge paradigm (3×5 mg/kg, i.p., every 2 h) on inducing hippocampal neurochemical changes in adolescent (PND 37) and young adult (PND 58) rats. The results showed that chronic MDMA caused hippocampal protein deficits in adolescent and young adult rats at different levels: (1) impaired serotonergic (5-HT2A and 5-HT2C post-synaptic receptors) and GABAergic (GAD2 enzyme) signaling, and (2) decreased structural cytoskeletal neurofilament proteins (NF-H, NF-M and NF-L). Interestingly, these effects were not accompanied by an increase in apoptotic markers. In fact, chronic MDMA inhibited proteins of the apoptotic pathway (i.e., pro-apoptotic FADD, Bax and cytochrome c) leading to an inhibition of cell death markers (i.e., p-JNK1/2, cleavage of PARP-1) and suggesting regulatory mechanisms in response to the neurochemical changes caused by the drug. The data, together with the observed lack of GFAP activation, support the view that chronic MDMA effects, regardless of the rat developmental age, extends beyond neurotransmitter systems to impair other hippocampal structural cell markers. Interestingly, inhibitory changes in proteins from the apoptotic pathway might be taking place to overcome the protein deficits caused by MDMA. PMID:26068050

  11. Pharmacological and Genetic Manipulation of p53 in Brown Fat at Adult But Not Embryonic Stages Regulates Thermogenesis and Body Weight in Male Mice.

    PubMed

    Al-Massadi, Omar; Porteiro, Begoña; Kuhlow, Doreen; Köhler, Markus; Gonzalez-Rellan, María J; Garcia-Lavandeira, Montserrat; Díaz-Rodríguez, Esther; Quiñones, Mar; Senra, Ana; Alvarez, Clara V; López, Miguel; Diéguez, Carlos; Schulz, Tim J; Nogueiras, Rubén

    2016-07-01

    p53 is a well-known tumor suppressor that plays multiple biological roles, including the capacity to modulate metabolism at different levels. However, its metabolic role in brown adipose tissue (BAT) remains largely unknown. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance. To this end, we generated and characterized global p53-null mice and mice lacking p53 specifically in BAT. Additionally we performed gain-and-loss-of-function experiments in the BAT of adult mice using virogenetic and pharmacological approaches. BAT was collected and analyzed by immunohistochemistry, thermography, real-time PCR, and Western blot. p53-deficient mice were resistant to diet-induced obesity due to increased energy expenditure and BAT activity. However, the deletion of p53 in BAT using a Myf5-Cre driven p53 knockout did not show any changes in body weight or the expression of thermogenic markers. The acute inhibition of p53 in the BAT of adult mice slightly increased body weight and inhibited BAT thermogenesis, whereas its overexpression in the BAT of diet-induced obese mice reduced body weight and increased thermogenesis. On the other hand, pharmacological activation of p53 improves body weight gain due to increased BAT thermogenesis by sympathetic nervous system in obese adult wild-type mice but not in p53(-/-) animals. These results reveal that p53 regulates BAT metabolism by coordinating body weight and thermogenesis, but these metabolic actions are tissue specific and also dependent on the developmental stage. PMID:27183316

  12. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

    PubMed Central

    Chambers, Edward S; Viardot, Alexander; Psichas, Arianna; Morrison, Douglas J; Murphy, Kevin G; Zac-Varghese, Sagen E K; MacDougall, Kenneth; Preston, Tom; Tedford, Catriona; Finlayson, Graham S; Blundell, John E; Bell, Jimmy D; Thomas, E Louise; Mt-Isa, Shahrul; Ashby, Deborah; Gibson, Glen R; Kolida, Sofia; Dhillo, Waljit S; Bloom, Stephen R; Morley, Wayne; Clegg, Stuart; Frost, Gary

    2015-01-01

    Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. Trial registration number NCT00750438. PMID:25500202

  13. The α1 isoform of the Na+/K+ ATPase is up-regulated in dedifferentiated progenitor cells that mediate lens and retina regeneration in adult newts*

    PubMed Central

    Vergara, M. Natalia; Smiley, Laura K.; Del Rio-Tsonis, Katia; Tsonis, Panagiotis A.

    2009-01-01

    Adult newts are able to regenerate their retina and lens after injury or complete removal through transdifferentiation of the pigmented epithelial tissues of the eye. This process needs to be tightly controlled, and several different mechanisms are likely to be recruited for this function. The Na+/K+ ATPase is a transmembrane protein that establishes electrochemical gradients through the transport of Na+ and K+ and has been implicated in the modulation of key cellular processes such as cell division, migration and adhesion. Even though it is expressed in all cells, its isoform composition varies with cell type and is tightly controlled during development and regeneration. In the present study we characterize the expression pattern of Na+/K+ ATPase α1 in the adult newt eye and during the process of lens and retina regeneration. We show that this isoform is up-regulated in undifferentiated cells during transdifferentiation. Such change in composition could be one of the mechanisms that newt cells utilize to modulate this process. PMID:18755185

  14. 26S Proteasome regulation of Ankrd1/CARP in adult rat ventricular myocytes and human microvascular endothelial cells

    SciTech Connect

    Samaras, Susan E.; Chen, Billy; Koch, Stephen R.; Sawyer, Douglas B.; Lim, Chee Chew; Davidson, Jeffrey M.

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer The 26S proteasome regulates Ankrd1 levels in cardiomyocytes and endothelial cells. Black-Right-Pointing-Pointer Ankrd1 protein degrades 60-fold faster in endothelial cells than cardiomyocytes. Black-Right-Pointing-Pointer Differential degradation appears related to nuclear vs. sarcolemmal localization. Black-Right-Pointing-Pointer Endothelial cell density shows uncoupling of Ankrd1 mRNA and protein levels. -- Abstract: Ankyrin repeat domain 1 protein (Ankrd1), also known as cardiac ankyrin repeat protein (CARP), increases dramatically after tissue injury, and its overexpression improves aspects of wound healing. Reports that Ankrd1/CARP protein stability may affect cardiovascular organization, together with our findings that the protein is crucial to stability of the cardiomyocyte sarcomere and increased in wound healing, led us to compare the contribution of Ankrd1/CARP stability to its abundance. We found that the 26S proteasome is the dominant regulator of Ankrd1/CARP degradation, and that Ankrd1/CARP half-life is significantly longer in cardiomyocytes (h) than endothelial cells (min). In addition, higher endothelial cell density decreased the abundance of the protein without affecting steady state mRNA levels. Taken together, our data and that of others indicate that Ankrd1/CARP is highly regulated at multiple levels of its expression. The striking difference in protein half-life between a muscle and a non-muscle cell type suggests that post-translational proteolysis is correlated with the predominantly structural versus regulatory role of the protein in the two cell types.

  15. RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription

    NASA Astrophysics Data System (ADS)

    Gerald, Damien; Adini, Irit; Shechter, Sharon; Perruzzi, Carole; Varnau, Joseph; Hopkins, Benjamin; Kazerounian, Shiva; Kurschat, Peter; Blachon, Stephanie; Khedkar, Santosh; Bagchi, Mandrita; Sherris, David; Prendergast, George C.; Klagsbrun, Michael; Stuhlmann, Heidi; Rigby, Alan C.; Nagy, Janice A.; Benjamin, Laura E.

    2013-11-01

    Mechanisms governing the distinct temporal dynamics that characterize post-natal angiogenesis and lymphangiogenesis elicited by cutaneous wounds and inflammation remain unclear. RhoB, a stress-induced small GTPase, modulates cellular responses to growth factors, genotoxic stress and neoplastic transformation. Here we show, using RhoB null mice, that loss of RhoB decreases pathological angiogenesis in the ischaemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge. We link these unique and opposing roles of RhoB in blood versus lymphatic vasculatures to the RhoB-mediated differential regulation of sprouting and proliferation in primary human blood versus lymphatic endothelial cells. We demonstrate that nuclear RhoB-GTP controls expression of distinct gene sets in each endothelial lineage by regulating VEZF1-mediated transcription. Finally, we identify a small-molecule inhibitor of VEZF1-DNA interaction that recapitulates RhoB loss in ischaemic retinopathy. Our findings establish the first intra-endothelial molecular pathway governing the phased response of angiogenesis and lymphangiogenesis following injury.

  16. Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity.

    PubMed

    Chenette, Devon M; Cadwallader, Adam B; Antwine, Tiffany L; Larkin, Lauren C; Wang, Jinhua; Olwin, Bradley B; Schneider, Robert J

    2016-08-01

    Following skeletal muscle injury, muscle stem cells (satellite cells) are activated, proliferate, and differentiate to form myofibers. We show that mRNA-decay protein AUF1 regulates satellite cell function through targeted degradation of specific mRNAs containing 3' AU-rich elements (AREs). auf1(-/-) mice undergo accelerated skeletal muscle wasting with age and impaired skeletal muscle repair following injury. Satellite cell mRNA analysis and regeneration studies demonstrate that auf1(-/-) satellite cell self-renewal is impaired due to increased stability and overexpression of ARE-mRNAs, including cell-autonomous overexpression of matrix metalloprotease MMP9. Secreted MMP9 degrades the skeletal muscle matrix, preventing satellite-cell-mediated regeneration and return to quiescence. Blocking MMP9 activity in auf1(-/-) mice restores skeletal muscle repair and maintenance of the satellite cell population. Control of ARE-mRNA decay by AUF1 represents a mechanism for adult stem cell regulation and is implicated in human skeletal muscle wasting diseases. PMID:27452471

  17. Snoo and Dpp Act as Spatial and Temporal Regulators Respectively of Adult Progenitor Cells in the Drosophila Trachea

    PubMed Central

    Djabrayan, Nareg J.-V.; Casanova, Jordi

    2016-01-01

    Clusters of differentiated cells contributing to organ structures retain the potential to re-enter the cell cycle and replace cells lost during development or upon damage. To do so, they must be designated spatially and respond to proper activation cues. Here we show that in the case of Drosophila differentiated larval tracheal cells, progenitor potential is conferred by the spatially restricted activity of the Snoo transcription cofactor. Furthermore, Dpp signalling regulated by endocrine hormonal cues provides the temporal trigger for their activation. Finally, we elucidate the genetic network elicited by Snoo and Dpp activity. These results illustrate a regulatory mechanism that translates intrinsic potential and extrinsic cues into the facultative stem cell features of differentiated progenitors. PMID:26942411

  18. Snoo and Dpp Act as Spatial and Temporal Regulators Respectively of Adult Progenitor Cells in the Drosophila Trachea.

    PubMed

    Djabrayan, Nareg J-V; Casanova, Jordi

    2016-03-01

    Clusters of differentiated cells contributing to organ structures retain the potential to re-enter the cell cycle and replace cells lost during development or upon damage. To do so, they must be designated spatially and respond to proper activation cues. Here we show that in the case of Drosophila differentiated larval tracheal cells, progenitor potential is conferred by the spatially restricted activity of the Snoo transcription cofactor. Furthermore, Dpp signalling regulated by endocrine hormonal cues provides the temporal trigger for their activation. Finally, we elucidate the genetic network elicited by Snoo and Dpp activity. These results illustrate a regulatory mechanism that translates intrinsic potential and extrinsic cues into the facultative stem cell features of differentiated progenitors. PMID:26942411

  19. Biologically active substances-enriched diet regulates gonadotrope cell activation pathway in liver of adult and old rats.

    PubMed

    Oszkiel, Hanna; Wilczak, Jacek; Jank, Michał

    2014-09-01

    According to the Hippocrates' theorem "Let food be your medicine and medicine be your food", dietary interventions may induce changes in the metabolic and inflammatory state by modulating the expression of important genes involved in the chronic disorders. The aim of the present study was to evaluate the influence of long-term (14 months) use of biologically active substances-enriched diet (BASE-diet) on transcriptomic profile of rats' liver. The experiment was conducted on 36 Sprague-Dawley rats divided into two experimental groups (fed with control or BASE-diet, both n = 18). Control diet was a semi-synthetic diet formulated according to the nutritional requirements for laboratory animals. The BASE-diet was enriched with a mixture of polyphenolic compounds, β-carotene, probiotics, and n-3 and n-6 polyunsaturated fatty acids. In total, n = 3,017 differentially expressed (DE) genes were identified, including n = 218 DE genes between control and BASE groups after 3 months of feeding and n = 1,262 after 14 months. BASE-diet influenced the expression of genes involved particularly in the gonadotrope cell activation pathway and guanylate cyclase pathway, as well as in mast cell activation, gap junction regulation, melanogenesis and apoptosis. Especially genes involved in regulation of GnRH were strongly affected by BASE-diet. This effect was stronger with the age of animals and the length of diet use. It may suggest a link between the diet, reproductive system function and aging. PMID:25156242

  20. Maternal gestational betaine supplementation-mediated suppression of hepatic cyclin D2 and presenilin1 gene in newborn piglets is associated with epigenetic regulation of the STAT3-dependent pathway.

    PubMed

    Cai, Demin; Yuan, Mengjie; Jia, Yimin; Liu, Haoyu; Hu, Yun; Zhao, Ruqian

    2015-12-01

    Betaine, which donates methyl groups through methionine metabolism for DNA and protein methylation, is critical for epigenetic gene regulation, especially during fetal development. Here we fed gestational sows with control or betaine supplemented diets (3 g/kg) throughout the pregnancy to explore the effects of maternal betaine on hepatic cell proliferation in neonatal piglets. Neonatal piglets born to betaine-supplemented sows demonstrated a reduction of cell number and DNA content in the liver, which was associated with significantly down-regulated hepatic expression of cell cycle regulatory genes, cyclin D2 (CCND2) and presenilin1 (PSEN1). Moreover, STAT3 binding to the promoter of CCND2 and PSEN1 was also lower in betaine-exposed piglets, accompanied by strong reduction of STAT3 mRNA and protein expression, along with its phosphorylation at Tyr705 and Ser727 residues. Also, prenatal betaine exposure significantly attenuated upstream kinases of STAT3 signaling pathway (phospho-ERK1/2, phospho-SRC and phospho-JAK2) in the livers of neonates. Furthermore, the repressed STAT3 expression in the liver of betaine-exposed piglets was associated with DNA hypermethylation and more enriched repression histone mark H3K27me3 on its promoter, together with significantly up-regulated expression of H3K27me3 and enhancer of zeste homolog 2 (EZH2) proteins, as well as miR-124a, which targets STAT3. Taken together, our results suggest that maternal dietary betaine supplementation during gestation inhibits hepatic cell proliferation in neonatal piglets, at least partly, through epigenetic regulation of hepatic CCND2 and PSEN1 genes via a STAT3-dependent pathway. These neonatal changes in cell cycle and proliferation regulation may lead to lower liver weight and hepatic DNA content at weaning. PMID:26359029

  1. Thought suppression, impaired regulation of urges, and Addiction-Stroop predict affect-modulated cue-reactivity among alcohol dependent adults.

    PubMed

    Garland, Eric L; Carter, Kristin; Ropes, Katie; Howard, Matthew O

    2012-01-01

    Abstinent alcohol dependent individuals commonly employ thought suppression to cope with stress and intrusive cognitions about alcohol. This strategy may inadvertently bias attention towards alcohol-related stimuli while depleting neurocognitive resources needed to regulate urges, manifested as decreased heart rate variability (HRV) responsivity to alcohol cues. The present study tested the hypothesis that trait and state thought suppression, impaired regulation of urges, and alcohol attentional bias as measured by the Addiction-Stroop would have significant effects on the HRV responsivity of 58 adults in residential treatment for alcohol dependence (mean age=39.6 ± 9.4, 81% female) who participated in an affect-modulated cue-reactivity protocol. Regression analyses controlling for age, level of pre-treatment alcohol consumption, and baseline HRV indicated that higher levels of trait thought suppression, impaired regulation of alcohol urges, and attentional fixation on alcohol cues were associated with lower HRV responsivity during stress-primed alcohol cue-exposure. Moreover, there was a significant state × trait suppression interaction on HRV cue-responsivity, such that alcohol dependent persons reporting high levels of state and trait suppression exhibited less HRV during cue-exposure than persons reporting low levels of state and trait suppression. Results suggest that chronic thought suppression taxes regulatory resources reflected in reduced HRV responsivity, an effect that is particularly evident when high trait suppressors engage in intensive suppression of drinking-related thoughts under conditions of stress. Treatment approaches that offer effective alternatives to the maladaptive strategy of suppressing alcohol urges may be crucial for relapse prevention. PMID:21967855

  2. High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring.

    PubMed

    Kruse, Michael; Keyhani-Nejad, Farnaz; Isken, Frank; Nitz, Barbara; Kretschmer, Anja; Reischl, Eva; de las Heras Gala, Tonia; Osterhoff, Martin A; Grallert, Harald; Pfeiffer, Andreas F H

    2016-03-01

    Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming. PMID:26631738

  3. Sustained lentiviral-mediated overexpression of microRNA124a in the dentate gyrus exacerbates anxiety- and autism-like behaviors associated with neonatal isolation in rats.

    PubMed

    Bahi, Amine

    2016-09-15

    Autism spectrum disorders (ASD) are highly disabling psychiatric disorders. Despite a strong genetic etiology, there are no efficient therapeutic interventions that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of microRNA (miR) machinery may contribute to the underlying molecular mechanisms involved in ASD. Here, we report a stress model demonstrating that neonatal isolation-induced long-lasting hippocampal elevation of miR124a was associated with reduced expression of its target BDNF mRNA. In addition, we investigated the impact of lentiviral-mediated overexpression of miR124a into the dentate gyrus (DG) on social interaction, repetitive- and anxiety-like behaviors in the neonatal isolation (Iso) model of autism. Rats isolated from the dams on PND 1 to PND 11 were assessed for their social interaction, marble burying test (MBT) and repetitive self-grooming behaviors as adults following miR124a overexpression. Also, anxiety-like behavior and locomotion were evaluated in the elevated plus maze (EPM) and open-field (OF) tests. Results show that, consistent with previously published reports, Iso rats displayed decreased social interaction contacts but increased repetitive- and anxiety-like behaviors. Interestingly, across both autism- and anxiety-like behavioral assays, miR124a overexpression in the DG significantly exacerbated repetitive behaviors, social impairments and anxiety with no effect on locomotor activity. Our novel findings attribute neonatal isolation-inducible cognitive impairments to induction of miR124a and consequently suppressed BDNF mRNA, opening venues for intercepting these miR124a-mediated damages. They also highlight the importance of studying microRNAs in the context of ASD and identify miR124a as a novel potential therapeutic target for improving mood disorders. PMID:27211062

  4. MicroRNA-mediated GABA Aα-1 receptor subunit down-regulation in adult spinal cord following neonatal cystitis-induced chronic visceral pain in rats.

    PubMed

    Sengupta, Jyoti N; Pochiraju, Soumya; Pochiraju, Soumiya; Kannampalli, Pradeep; Bruckert, Mitchell; Addya, Sankar; Yadav, Priyanka; Miranda, Adrian; Shaker, Reza; Banerjee, Banani

    2013-01-01

    The nociceptive transmission under pathological chronic pain conditions involves transcriptional and/or translational alteration in spinal neurotransmitters, receptor expressions, and modification of neuronal functions. Studies indicate the involvement of microRNA (miRNA) - mediated transcriptional deregulation in the pathophysiology of acute and chronic pain. In the present study, we tested the hypothesis that long-term cross-organ colonic hypersensitivity in neonatal zymosan-induced cystitis is due to miRNA-mediated posttranscriptional suppression of the developing spinal GABAergic system. Cystitis was produced by intravesicular injection of zymosan (1% in saline) into the bladder during postnatal (P) days P14 through P16 and spinal dorsal horns (L6-S1) were collected either on P60 (unchallenged groups) or on P30 after a zymosan re-challenge on P29 (re-challenged groups). miRNA arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significant, but differential, up-regulation of mature miR-181a in the L6-S1 spinal dorsal horns from zymosan-treated rats compared with saline-treated controls in both the unchallenged and re-challenged groups. The target gene analysis demonstrated multiple complementary binding sites in miR-181a for GABA(A) receptor subunit GABA(Aα-1) gene with a miRSVR score of -1.83. An increase in miR-181a concomitantly resulted in significant down-regulation of GABA(Aα-1) receptor subunit gene and protein expression in adult spinal cords from rats with neonatal cystitis. Intrathecal administration of the GABA(A) receptor agonist muscimol failed to attenuate the viscero-motor response (VMR) to colon distension in rats with neonatal cystitis, whereas in adult zymosan-treated rats the drug produced significant decrease in VMR. These results support an integral role for miRNA-mediated transcriptional deregulation of the GABAergic system in neonatal cystitis-induced chronic pelvic pain. PMID:23273104

  5. TGF-β1, released by myofibroblasts, differentially regulates transcription and function of sodium and potassium channels in adult rat ventricular myocytes.

    PubMed

    Kaur, Kuljeet; Zarzoso, Manuel; Ponce-Balbuena, Daniela; Guerrero-Serna, Guadalupe; Hou, Luqia; Musa, Hassan; Jalife, José

    2013-01-01

    Cardiac injury promotes fibroblasts activation and differentiation into myofibroblasts, which are hypersecretory of multiple cytokines. It is unknown whether any of such cytokines are involved in the electrophysiological remodeling of adult cardiomyocytes. We cultured adult cardiomyocytes for 3 days in cardiac fibroblast conditioned medium (FCM) from adult rats. In whole-cell voltage-clamp experiments, FCM-treated myocytes had 41% more peak inward sodium current (I(Na)) density at -40 mV than myocytes in control medium (p<0.01). In contrast, peak transient outward current (I(to)) was decreased by ∼55% at 60 mV (p<0.001). Protein analysis of FCM demonstrated that the concentration of TGF-β1 was >3 fold greater in FCM than control, which suggested that FCM effects could be mediated by TGF-β1. This was confirmed by pre-treatment with TGF-β1 neutralizing antibody, which abolished the FCM-induced changes in both I(Na) and I(to). In current-clamp experiments TGF-β1 (10 ng/ml) prolonged the action potential duration at 30, 50, and 90 repolarization (p<0.05); at 50 ng/ml it gave rise to early afterdepolarizations. In voltage-clamp experiments, TGF-β1 increased I(Na) density in a dose-dependent manner without affecting voltage dependence of activation or inactivation. I(Na) density was -36.25±2.8 pA/pF in control, -59.17±6.2 pA/pF at 0.1 ng/ml (p<0.01), and -58.22±6.6 pA/pF at 1 ng/ml (p<0.01). In sharp contrast, I(to) density decreased from 22.2±1.2 pA/pF to 12.7±0.98 pA/pF (p<0.001) at 10 ng/ml. At 1 ng/ml TGF-β1 significantly increased SCN5A (Na(V)1.5) (+73%; p<0.01), while reducing KCNIP2 (Kchip2; -77%; p<0.01) and KCND2 (K(V)4.2; -50% p<0.05) mRNA levels. Further, the TGF-β1-induced increase in I(Na) was mediated through activation of the PI3K-AKT pathway via phosphorylation of FOXO1 (a negative regulator of SCN5A). TGF-β1 released by myofibroblasts differentially regulates transcription and function of the main cardiac sodium channel and of the channel

  6. A self-limiting switch based on translational control regulates the transition from proliferation to differentiation in an adult stem cell lineage

    PubMed Central

    Insco, Megan L.; Bailey, Alexis S.; Kim, Jongmin; Olivares, Gonzalo H.; Wapinski, Orly L.; Tam, Cheuk Ho; Fuller, Margaret T.

    2012-01-01

    Summary In adult stem cell lineages, progenitor cells commonly undergo mitotic transit amplifying (TA) divisions before terminal differentiation, allowing production of many differentiated progeny per stem cell division. Mechanisms that limit TA divisions and trigger the switch to differentiation may protect against cancer by preventing accumulation of oncogenic mutations in the proliferating population. Here we show that the switch from TA proliferation to differentiation in the Drosophila male germline stem cell lineage is mediated by translational control. The TRIM-NHL tumor suppressor homolog Mei-P26 facilitates accumulation of the differentiation regulator Bam in TA cells. In turn, Bam and its partner Bgcn bind the mei-P26 3′UTR and repress translation of mei-P26 in late TA cells. Thus, germ cells progress through distinct, sequential regulatory states, from Mei-P26 on/Bam off to Bam on/Mei-P26 off. TRIM-NHL homologs across species facilitate the switch from proliferation to differentiation, suggesting a novel and conserved developmentally-programmed tumor suppressor mechanism. PMID:23122292

  7. Spontaneous Cannabinoid Receptor 2 (CB2) Expression in the Cochlea of Adult Albino Rat and Its Up-Regulation after Cisplatin Treatment

    PubMed Central

    Trinidad, Almudena; Ramil, Elvira; Sánchez-López, Antonio J.; Coronado, Maria José; Martínez-Martínez, Esther; García, José Miguel; García-Berrocal, José Ramón; Ramírez-Camacho, Rafael

    2016-01-01

    We provide evidence for the presence of cannabinoid CB2 receptors in some cellular types of the cochlea of the adult albino rat. Cannabinoids and their receptors are increasingly being studied because of their high potential for clinical use. As a hyperspecialized portion of the peripheral nervous system, study of the expression and function of cannabinoid receptors in the hearing organ is of high interest. Stria vascularis and inner hair cells express CB2 receptor, as well as neurites and cell bodies of the spiral ganglion. Cellular types such as supporting cells and outer hair cells, in which the expression of other types of functional receptors has been reported, do not significantly express CB2 receptors in this study. An up-regulation of CB2 gene expression was detected after an ototoxic event such as cisplatin treatment, probably due to pro-inflammatory events triggered by the drug. That fact suggests promising potential of CB2 receptor as a therapeutic target for new treatments to palliate cisplatin-induced hearing loss and other ototoxic events which triggers inflammatory pathways. PMID:27564061

  8. Spontaneous Cannabinoid Receptor 2 (CB2) Expression in the Cochlea of Adult Albino Rat and Its Up-Regulation after Cisplatin Treatment.

    PubMed

    Martín-Saldaña, Sergio; Trinidad, Almudena; Ramil, Elvira; Sánchez-López, Antonio J; Coronado, Maria José; Martínez-Martínez, Esther; García, José Miguel; García-Berrocal, José Ramón; Ramírez-Camacho, Rafael

    2016-01-01

    We provide evidence for the presence of cannabinoid CB2 receptors in some cellular types of the cochlea of the adult albino rat. Cannabinoids and their receptors are increasingly being studied because of their high potential for clinical use. As a hyperspecialized portion of the peripheral nervous system, study of the expression and function of cannabinoid receptors in the hearing organ is of high interest. Stria vascularis and inner hair cells express CB2 receptor, as well as neurites and cell bodies of the spiral ganglion. Cellular types such as supporting cells and outer hair cells, in which the expression of other types of functional receptors has been reported, do not significantly express CB2 receptors in this study. An up-regulation of CB2 gene expression was detected after an ototoxic event such as cisplatin treatment, probably due to pro-inflammatory events triggered by the drug. That fact suggests promising potential of CB2 receptor as a therapeutic target for new treatments to palliate cisplatin-induced hearing loss and other ototoxic events which triggers inflammatory pathways. PMID:27564061

  9. Muscle-Derived Extracellular Signal-Regulated Kinases 1 and 2 Are Required for the Maintenance of Adult Myofibers and Their Neuromuscular Junctions

    PubMed Central

    Seaberg, Bonnie; Henslee, Gabrielle; Wang, Shuo; Paez-Colasante, Ximena; Landreth, Gary E.

    2015-01-01

    The Ras–extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway appears to be important for the development, maintenance, aging, and pathology of mammalian skeletal muscle. Yet no gene targeting of Erk1/2 in muscle fibers in vivo has been reported to date. We combined a germ line Erk1 mutation with Cre-loxP Erk2 inactivation in skeletal muscle to produce, for the first time, mice lacking ERK1/2 selectively in skeletal myofibers. Animals lacking muscle ERK1/2 displayed stunted postnatal growth, muscle weakness, and a shorter life span. Their muscles examined in this study, sternomastoid and tibialis anterior, displayed fragmented neuromuscular synapses and a mixture of modest fiber atrophy and loss but failed to show major changes in fiber type composition or absence of cell surface dystrophin. Whereas the lack of only ERK1 had no effects on the phenotypes studied, the lack of myofiber ERK2 explained synaptic fragmentation in the sternomastoid but not the tibialis anterior and a decrease in the expression of the acetylcholine receptor (AChR) epsilon subunit gene mRNA in both muscles. A reduction in AChR protein was documented in line with the above mRNA results. Evidence of partial denervation was found in the sternomastoid but not the tibialis anterior. Thus, myofiber ERK1/2 are differentially required for the maintenance of myofibers and neuromuscular synapses in adult mice. PMID:25605336

  10. Identifying microRNAs regulating B7-H3 in breast cancer: the clinical impact of microRNA-29c

    PubMed Central

    Nygren, M K; Tekle, C; Ingebrigtsen, V A; Mäkelä, R; Krohn, M; Aure, M R; Nunes-Xavier, C E; Perälä, M; Tramm, T; Alsner, J; Overgaard, J; Nesland, J M; Borgen, E; Børresen-Dale, A-L; Fodstad, Ø; Sahlberg, K K; Leivonen, S-K

    2014-01-01

    Background: B7-H3, an immunoregulatory protein, is overexpressed in several cancers and is often associated with metastasis and poor prognosis. Here, our aim was to identify microRNAs (miRNAs) regulating B7-H3 and assess their potential prognostic implications in breast cancer. Methods: MicroRNAs targeting B7-H3 were identified by transfecting two breast cancer cell lines with a library of 810 miRNA mimics and quantifying changes of B7-H3 protein levels using protein lysate microarrays. For validations we used western immunoblotting and 3′-UTR luciferase assays. Clinical significance of the miRNAs was assayed by analysing whether their expression levels correlated with outcome in two cohorts of breast cancer patients (142 and 81 patients). Results: We identified nearly 50 miRNAs that downregulated B7-H3 protein levels. Western immunoblotting validated the impact of the 20 most effective miRNAs. Thirteen miRNAs (miR-214, miR-363*, miR-326, miR-940, miR-29c, miR-665, miR-34b*, miR-708, miR-601, miR-124a, miR-380-5p, miR-885-3p, and miR-593) targeted B7-H3 directly by binding to its 3′-UTR region. Finally, high expression of miR-29c was associated with a significant reduced risk of dying from breast cancer in both cohorts. Conclusions: We identified miRNAs efficiently downregulating B7-H3 expression. The expression of miR-29c correlated with survival in breast cancer patients, suggesting a tumour suppressive role for this miRNA. PMID:24577056

  11. Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats.

    PubMed

    Sun, Yan-Yan; Cai, Wei; Yu, Jie; Liu, Shu-Su; Zhuo, Min; Li, Bao-Ming; Zhang, Xue-Han

    2016-01-01

    The number and subtype composition of N-methyl-d-aspartate receptor (NMDAR) at synapses determines their functional properties and role in learning and memory. Genetically increased or decreased amount of GluN2B affects hippocampus-dependent memory in the adult brain. But in some experimental conditions (e.g., memory elicited by a single conditioning trial (1 CS-US)), GluN2B is not a necessary factor, which indicates that the precise role of GluN2B in memory formation requires further exploration. Here, we examined the role of GluN2B in the consolidation of fear memory using two training paradigms. We found that GluN2B was only required for the consolidation of memory elicited by five conditioning trials (5 CS-US), not by 1 CS-US. Strikingly, the expression of membrane GluN2B in CA1was training-strength-dependently increased after conditioning, and that the amount of membrane GluN2B determined its involvement in memory consolidation. Additionally, we demonstrated the increases in the activities of cAMP, ERK, and CREB in the CA1 after conditioning, as well as the enhanced intrinsic excitability and synaptic efficacy in CA1 neurons. Up-regulation of membrane GluN2B contributed to these enhancements. These studies uncover a novel mechanism for the involvement of GluN2B in memory consolidation by its accumulation at the cell surface in response to behavioral training. PMID:27487820

  12. Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats

    PubMed Central

    Sun, Yan-Yan; Cai, Wei; Yu, Jie; Liu, Shu-Su; Zhuo, Min; Li, Bao-Ming; Zhang, Xue-Han

    2016-01-01

    The number and subtype composition of N-methyl-d-aspartate receptor (NMDAR) at synapses determines their functional properties and role in learning and memory. Genetically increased or decreased amount of GluN2B affects hippocampus-dependent memory in the adult brain. But in some experimental conditions (e.g., memory elicited by a single conditioning trial (1 CS-US)), GluN2B is not a necessary factor, which indicates that the precise role of GluN2B in memory formation requires further exploration. Here, we examined the role of GluN2B in the consolidation of fear memory using two training paradigms. We found that GluN2B was only required for the consolidation of memory elicited by five conditioning trials (5 CS-US), not by 1 CS-US. Strikingly, the expression of membrane GluN2B in CA1was training-strength-dependently increased after conditioning, and that the amount of membrane GluN2B determined its involvement in memory consolidation. Additionally, we demonstrated the increases in the activities of cAMP, ERK, and CREB in the CA1 after conditioning, as well as the enhanced intrinsic excitability and synaptic efficacy in CA1 neurons. Up-regulation of membrane GluN2B contributed to these enhancements. These studies uncover a novel mechanism for the involvement of GluN2B in memory consolidation by its accumulation at the cell surface in response to behavioral training. PMID:27487820

  13. Policy Review on Adult Learning: The Adult Non-Formal Education Policy of Mali, West Africa

    ERIC Educational Resources Information Center

    Gadio, Moussa

    2011-01-01

    This article focuses on the issue of policy development for adult learning in Mali, West Africa. On January 2007, the Malian government adopted the "Adult Non-formal Education Policy Document," which was intended to regulate the adult learning sector and federate the actions of policy makers, adult education providers, and adult learners. The…

  14. Functional Studies of microRNAs in Neural Stem Cells: Problems and Perspectives

    PubMed Central

    Åkerblom, Malin; Sachdeva, Rohit; Jakobsson, Johan

    2012-01-01

    In adult mammals, neural stem cells (NSCs) are found in two niches of the brain; the subventricular zone by the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Neurogenesis is a complex process that is tightly controlled on a molecular level. Recently, microRNAs (miRNAs) have been implicated to play a central role in the regulation of NCSs. miRNAs are small, endogenously expressed RNAs that regulate gene expression at the post-transcriptional level. However, functional studies of miRNAs are complicated due to current technical limitations. In this review we describe recent findings about miRNAs in NSCs looking closely at miR-124, miR-9, and let-7. In addition, we highlight technical strategies used to investigate miRNA function, accentuating limitations, and potentials. PMID:22347160

  15. The receptor protein tyrosine phosphatase HmLAR1 is up-regulated in the CNS of the adult medicinal leech following injury and is required for neuronal sprouting and regeneration.

    PubMed

    Sethi, Jasmine; Zhao, Bailey; Cuvillier-Hot, Virginie; Boidin-Wichlacz, Céline; Salzet, Michel; Macagno, Eduardo R; Baker, Michael W

    2010-12-01

    LAR-like receptor protein tyrosine phosphatases (RPTPs), which are abundantly expressed in the nervous systems of most if not all bilaterian animals thus far examined, have been implicated in regulating a variety of critical neuronal processes. These include neuronal pathfinding, adhesion and synaptogenesis during development and, in adult mammals, neuronal regeneration. Here we explored a possible role of a LAR-like RPTP (HmLAR1) in response to mechanical trauma in the adult nervous system of the medicinal leech. In situ hybridization and QPCR analyses of HmLAR1 expression in individual segmental ganglia revealed a significant up-regulation in receptor expression following CNS injury, both in situ and following a period in vitro. Furthermore, we observed up-regulation in the expression of the leech homologue of the Abelson tyrosine kinase, a putative signaling partner to LAR receptors, but not among other tyrosine kinases. The effects on neuronal regeneration were assayed by comparing growth across a nerve crush by projections of individual dorsal P neurons (P(D)) following single-cell injection of interfering RNAs against the receptor or control RNAs. Receptor RNAi led to a significant reduction in HmLAR1 expression by the injected cells and resulted in a significant decrease in sprouting and regenerative growth at the crush site relative to controls. These studies extend the role of the HmLARs from leech neuronal development to adult neuronal regeneration and provide a platform to investigate neuronal regeneration and gene regulation at the single cell level. PMID:20708686

  16. Impact of the UV-B filter 4-(Methylbenzylidene)-camphor (4-MBC) during prenatal development in the neuroendocrine regulation of gonadal axis in male and female adult rats.

    PubMed

    Carou, M E; Deguiz, M L; Reynoso, R; Szwarcfarb, B; Carbone, S; Moguilevsky, J A; Scacchi, P; Ponzo, O J

    2009-05-01

    4-(Methylbenzylidene)-camphor (4-MBC), a UV-B ray filter, is an endocrine disruptors (ED). Our goal was to study the effect of 4-MBC on the neuroendocrine parameters that regulate reproduction in adult female and male rats that received this disrupter during prenatal development. The 4-MBC was administered (sc) to female rats (FO) since pregnancy onset, in doses of 100mg/kg every other day. The litters (F1) were sacrificed at 70 days to determine gonadotrophin serum levels and also GnRH and the amino acids glutamate, aspartate and GABA release from the hypothalamus. The male litter rats (F1) present at adult age a decrease in serum LH and FSH concentration and so also GnRH, excitatory amino acids and GABA hypothalamic secretion. The female litters (F1) rats present at adult age an increase in serum LH and FSH concentration, whereas hypothalamic GnRH release was not modified. In these animals a significant increase of hypothalamic aspartate release as well as GABA secretion decrease were observed. Glutamate secretion was not modified. All these changes were accompanied by an advance (3 days) on the vaginal opening in 4-MBC rats group. In conclusion, prenatal administration of 4-MBC disrupts the gonadal axis in a sexual dimorphic mode that could be connected with the physiological sexual differences in the development of gonadotrophin secretion hypothalamic control mechanisms. PMID:21783972

  17. A FEEDBACK MODEL FOR TESTICULAR-PITUITARY AXIS HORMONE KINETICS AND THEIR EFFECTS ON THE REGULATION OF THE PROSTATE IN ADULT MALE RATS

    EPA Science Inventory

    The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. A model describing the kinetics and dynamics of testosterone (T), dihydrotestosterone (DHT) and luteinizing hormone (LH) was developed based on a model by Barton and Anderson (1997). The mode...

  18. Ethanol Exposure Induces Neonatal Neurodegeneration by Enhancing CB1R Exon1 Histone H4K8 Acetylation and Up-regulating CB1R Function causing Neurobehavioral Abnormalities in Adult Mice

    PubMed Central

    Subbanna, Shivakumar; Nagre, Nagaraja N.; Umapathy, Nagavedi S.; Pace, Betty S.

    2015-01-01

    Background: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. Methods: In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. Results: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanol-induced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Conclusions: Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice. PMID:25609594

  19. Dose-dependent regulation of steroid receptor coactivator-1 and steroid receptors by testosterone propionate in the hippocampus of adult male mice.

    PubMed

    Qiu, Linli; Zhao, Yangang; Guo, Qiang; Zhang, Yuanyuan; He, Li; Li, Wei; Zhang, Jiqiang

    2016-02-01

    Androgens have been proposed to play important roles in the regulation of hippocampus function either directly, through the androgen receptor (AR), or indirectly, through estrogen receptors (ERs), after aromatization into estradiol. Steroid receptor coactivator-1 (SRC-1) is present in the hippocampus of several species, and its expression is regulated by development and aging, as well as by orchidectomy and aromatase inhibitor letrozole administration, while ovariectomy only transiently downregulated hippocampal SRC-1. However, whether the expression of hippocampal SRC-1 can be directly regulated by testosterone, the principal male sex hormone, remains unclear. In the present study, we investigated the expression of hippocampal SRC-1 after orchidectomy and testosterone treatment using immunohistochemistry and Western blot analysis. We found that while hippocampal SRC-1 was significantly downregulated by orchidectomy (ORX), its expression was rescued by treatment with testosterone in a dose-dependent manner. Furthermore, we noticed that the decreased expression of hippocampal AR, ERs and the synaptic proteins GluR-1 and PSD-95 induced by ORX was also rescued by testosterone treatment in a dose-dependent manner. However, we found that hippocampal membrane estrogen receptor GPR30 and dendritic spine marker spinophilin were not altered by ORX or testosterone treatment. Together, the above results provided the first direct evidence for the androgenic regulation on hippocampal SRC-1, indicating that SRC-1 may be a direct target of androgenic regulation on the hippocampus. Furthermore, because AR and ERs can be differentially regulated by testosterone, and the transcriptional activity requires the involvement of local SRC-1, and considering the complicated regulatory pathway of each individual receptor, the converged hub regulator SRC-1 of these nuclear receptor networks is worthy of further investigation. PMID:26607693

  20. Cocaine exposure prior to pregnancy alters the psychomotor response to cocaine and transcriptional regulation of the dopamine D1 receptor in adult male offspring.

    PubMed

    Sasaki, Aya; Constantinof, Andrea; Pan, Pauline; Kupferschmidt, Dave A; McGowan, Patrick O; Erb, Suzanne

    2014-05-15

    There is evidence that maternal experience prior to pregnancy can play an important role in behavioral, physiological, and genetic programming of offspring. Likewise, exposure to cocaine in utero can result in marked changes in central nervous system function of offspring. In this study, we examined whether exposure of rat dams to cocaine prior to pregnancy subsequently alters indices of behavior, physiology, and gene expression in offspring. Multiple outcome measures were examined in adult male offspring: (1) behavioral expression of cocaine-induced psychomotor activation; (2) levels of corticosterone in response to immobilization stress; and (3) expression of multiple genes, including dopamine receptor D1 (DRD1) and D2 (DRD2), glucocorticoid receptor (GR), and corticotropin-releasing factor (CRF), in functionally relevant brain regions. Adult Sprague-Dawley females were exposed to cocaine (15-30 mg/kg, i.p.) or saline for 10 days, and were then mated to drug naïve males of the same strain. Separate groups of adult male offspring were tested for their acute psychomotor response to cocaine (0, 15, 30 mg/kg, i.p.), corticosterone responsivity to 20 min of immobilization stress, and expression of multiple genes using quantitative PCR. Offspring of dams exposed to cocaine prior to conception exhibited increased psychomotor sensitivity to cocaine, and upregulated gene expression of DRD1 in the medial prefrontal cortex (mPFC). Neither stress-induced corticosterone levels nor gene expression of GR or CRF genes were altered. These data suggest that cocaine exposure before pregnancy can serve to enhance psychomotor sensitivity to cocaine in offspring, possibly via alterations in dopamine function that include upregulation of the DRD1. PMID:24583058

  1. Adult Compacts.

    ERIC Educational Resources Information Center

    Further Education Unit, London (England).

    This bulletin focuses on adult compacts, three-way agreements among employers, potential employees, and trainers to provide the right kind of quality training to meet the employers' requirements. Part 1 is an executive summary of a report of the Adult Compacts Project, which studied three adult compacts in Birmingham and Loughborough, England, and…

  2. Vibrio parahaemolyticus ToxRS regulator is required for stress tolerance and colonization in a novel orogastric streptomycin-induced adult murine model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vibrio parahaemolyticus, a marine bacterium, is the causative agent of gastroenteritis associated with the consumption of seafood. It contains a homologue of the toxRS operon that in V. cholerae is the key regulator of virulence gene expression. We examined a non-polar mutation in toxRS to determi...

  3. Effect of cocoa and green tea on biomarkers of glucose regulation, oxidative stress, inflammation and hemostasis in obese adults at risk for insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Flavanols may provide protection against insulin resistance, but little is known about the amounts and types of flavanols that may be efficacious. This study was designed to determine whether cocoa flavanols, over a range of intakes, improve biomarkers of glucose regulation, inflammation and hemost...

  4. Regulating Pornography: A Public Dilemma.

    ERIC Educational Resources Information Center

    Thompson, Margaret E.; And Others

    1990-01-01

    Examines attitudes toward sex and pornography by means of a telephone survey of Dane County, Wisconsin, adults. Describes survey questions about sexual attitudes, perceived effects of pornography, and pornography regulation. Concludes that adults who feel more strongly that pornography has negative effects are more opposed to its regulation. (SG)

  5. Scorpion venom heat-resistant peptide (SVHRP) enhances neurogenesis and neurite outgrowth of immature neurons in adult mice by up-regulating brain-derived neurotrophic factor (BDNF).

    PubMed

    Wang, Tao; Wang, Shi-Wei; Zhang, Yue; Wu, Xue-Fei; Peng, Yan; Cao, Zhen; Ge, Bi-Ying; Wang, Xi; Wu, Qiong; Lin, Jin-Tao; Zhang, Wan-Qin; Li, Shao; Zhao, Jie

    2014-01-01

    Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2'-dexoxyuridine (BrdU)-positive cells, BrdU-positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP

  6. Scorpion Venom Heat-Resistant Peptide (SVHRP) Enhances Neurogenesis and Neurite Outgrowth of Immature Neurons in Adult Mice by Up-Regulating Brain-Derived Neurotrophic Factor (BDNF)

    PubMed Central

    Zhang, Yue; Wu, Xue-Fei; Peng, Yan; Cao, Zhen; Ge, Bi-Ying; Wang, Xi; Wu, Qiong; Lin, Jin-Tao; Zhang, Wan-Qin; Li, Shao; Zhao, Jie

    2014-01-01

    Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2’-dexoxyuridine (BrdU)-positive cells, BrdU- positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of

  7. Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury.

    PubMed

    Brumovsky, P; Watanabe, M; Hökfelt, T

    2007-06-29

    The expression of two vesicular glutamate transporters (VGLUTs), VGLUT1 and VGLUT2, was studied with immunohistochemistry in lumbar dorsal root ganglia (DRGs), the lumbar spinal cord and the skin of the adult mouse. About 12% and 65% of the total number of DRG neuron profiles (NPs) expressed VGLUT1 and VGLUT2, respectively. VGLUT1-immunoreactive (IR) NPs were usually medium- to large-sized, in contrast to a majority of small- or medium-sized VGLUT2-IR NPs. Most VGLUT1-IR NPs did not coexpress calcitonin gene-related peptide (CGRP) or bound isolectin B4 (IB4). In contrast, approximately 31% and approximately 42% of the VGLUT2-IR DRG NPs were also CGRP-IR or bound IB4, respectively. Conversely, virtually all CGRP-IR and IB4-binding NPs coexpressed VGLUT2. Moderate colocalization between VGLUT1 and VGLUT2 was also observed. Sciatic nerve transection induced a decrease in the overall number of VGLUT1- and VGLUT2-IR NPs (both ipsi- and contralaterally) and, in addition, a parallel, unilateral increase of VGLUT2-like immunoreactivity (LI) in a subpopulation of mostly small NPs. In the dorsal horn of the spinal cord, strong VGLUT1-LI was detected, particularly in deep dorsal horn layers and in the ventral horns. VGLUT2-LI was abundant throughout the gray spinal matter, 'radiating' into/from the white matter. A unilateral dorsal rhizotomy reduced VGLUT1-LI, while apparently leaving unaffected the VGLUT2-LI. Transport through axons for both VGLUTs was confirmed by their accumulation after compression of the sciatic nerve or dorsal roots. In the hind paw skin, abundant VGLUT2-IR nerve fibers were observed, sometimes associated with Merkel cells. Lower numbers of VGLUT1-IR fibers were also detected in the skin. Some VGLUT1-IR and VGLUT2-IR fibers were associated with hair follicles. Based on these data and those by Morris et al. [Morris JL, Konig P, Shimizu T, Jobling P, Gibbins IL (2005) Most peptide-containing sensory neurons lack proteins for exocytotic release and

  8. Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network.

    PubMed

    Dabrowski, Ania; Umemori, Hisashi

    2016-01-01

    Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis. PMID:27605441

  9. Low-Resolution Electromagnetic Tomography (LORETA) of changed Brain Function Provoked by Pro-Dopamine Regulator (KB220z) in one Adult ADHD case

    PubMed Central

    Steinberg, Bruce; Blum, Kenneth; McLaughlin, Thomas; Lubar, Joel; Febo, Marcelo; Braverman, Eric R.; Badgaiyan, Rajendra D

    2016-01-01

    Attention Deficit-Hyperactivity Disorder (ADHD) often continues into adulthood. Recent neuroimaging studies found lowered baseline dopamine tone in the brains of affected individuals that may place them at risk for Substance Use Disorder (SUD). This is an observational case study of the potential for novel management of Adult ADHD with a non-addictive glutaminergic-dopaminergic optimization complex KB200z. Low-resolution electromagnetic tomography (LORETA) was used to evaluate the effects of KB220z on a 72-year-old male with ADHD, at baseline and one hour following administration. The resultant z-scores, averaged across Eyes Closed, Eyes Open and Working Memory conditions, increased for each frequency band, in the anterior, dorsal and posterior cingulate regions, as well as the right dorsolateral prefrontal cortex during Working Memory, with KB220z. These scores are consistent with other human and animal neuroimaging studies that demonstrated increased connectivity volumes in reward circuitry and may offer a new approach to ADHD treatment. However, larger randomized trials to confirm these results are required. PMID:27610420

  10. Sense and antisense transcripts of the developmentally regulated murine hsp70.2 gene are expressed in distinct and only partially overlapping areas in the adult brain

    NASA Technical Reports Server (NTRS)

    Murashov, A. K.; Wolgemuth, D. J.

    1996-01-01

    We have examined the spatial pattern of expression of a member of the hsp70 gene family, hsp70.2, in the mouse central nervous system. Surprisingly, RNA blot analysis and in situ hybridization revealed abundant expression of an 'antisense' hsp70.2 transcript in several areas of adult mouse brain. Two different transcripts recognized by sense and antisense riboprobes for the hsp70.2 gene were expressed in distinct and only partially overlapping neuronal populations. RNA blot analysis revealed low levels of the 2.7 kb transcript of hsp70.2 in several areas of the brain, with highest signal in the hippocampus. Abundant expression of a slightly larger (approximately 2.8 kb) 'antisense' transcript was detected in several brain regions, notably in the brainstem, cerebellum, mesencephalic tectum, thalamus, cortex, and hippocampus. In situ hybridization revealed that the sense and antisense transcripts were both predominantly neuronal and localized to the same cell types in the granular layer of the cerebellum, trapezoid nucleus of the superior olivary complex, locus coeruleus and hippocampus. The hsp70.2 antisense transcripts were particularly abundant in the frontal cortex, dentate gyrus, subthalamic nucleus, zona incerta, superior and inferior colliculi, central gray, brainstem, and cerebellar Purkinje cells. Our findings have revealed a distinct cellular and spatial localization of both sense and antisense transcripts, demonstrating a new level of complexity in the function of the heat shock genes.

  11. DNA-methylation dependent regulation of embryo-specific 5S ribosomal DNA cluster transcription in adult tissues of sea urchin Paracentrotus lividus.

    PubMed

    Bellavia, Daniele; Dimarco, Eufrosina; Naselli, Flores; Caradonna, Fabio

    2013-10-01

    We have previously reported a molecular and cytogenetic characterization of three different 5S rDNA clusters in the sea urchin Paracentrotus lividus and recently, demonstrated the presence of high heterogeneity in functional 5S rRNA. In this paper, we show some important distinctive data on 5S rRNA transcription for this organism. Using single strand conformation polymorphism (SSCP) analysis, we demonstrate the existence of two classes of 5S rRNA, one which is embryo-specific and encoded by the smallest (700 bp) cluster and the other which is expressed at every stage and encoded by longer clusters (900 and 950 bp). We also demonstrate that the embryo-specific class of 5S rRNA is expressed in oocytes and embryonic stages and is silenced in adult tissue and that this phenomenon appears to be due exclusively to DNA methylation, as indicated by sensitivity to 5-azacytidine, unlike Xenopus where this mechanism is necessary but not sufficient to maintain the silenced status. PMID:23933480

  12. Urinary tract infection - adults

    MedlinePlus

    Bladder infection - adults; UTI - adults; Cystitis - bacterial - adults; Pyelonephritis - adults; Kidney infection - adults ... to the hospital if you: Are an older adult Have kidney stones or changes in the anatomy ...

  13. ADAM8 is selectively up-regulated in endothelial cells and is associated with angiogenesis after spinal cord injury in adult mice.

    PubMed

    Mahoney, Edward T; Benton, Richard L; Maddie, Melissa A; Whittemore, Scott R; Hagg, Theo

    2009-01-10

    Endothelial cell (EC) loss and subsequent angiogenesis occur over the first week after spinal cord injury (SCI). To identify molecular mechanisms that could be targeted with intravenous (i.v.) treatments, we determined whether transmembrane "a disintegrin and metalloprotease" (ADAM) proteins are expressed in ECs of the injured spinal cord. ADAMs bind to integrins, which are important for EC survival and angiogenesis. Female adult C57Bl/6 mice with a spinal cord contusion had progressively more ADAM8 (CD156) immunostaining in blood vessels and individual ECs between 1 and 28 days following injury. Uninjured spinal cords had little ADAM8 staining. The increase in ADAM8 mRNA and protein was confirmed in spinal cord lysates, and ADAM8 mRNA was present in FACS-enriched ECs. ADAM8 colocalized extensively and exclusively with the EC marker PECAM and also with i.v.-injected lectins. Intravenous isolectin B4 (IB4) labels a subpopulation of blood vessels at and within the injury epicenter 3-7 days after injury, coincident with angiogenesis. Both ADAM8 and the proliferation marker Ki-67 were present in IB4-positive microvessels. ADAM8-positive proliferating cells were seen at the leading end of IB4-positive blood vessels. Angiogenesis was confirmed by BrdU incorporation, binding of i.v.-injected nucleolin antibodies, and MT1-MMP immunostaining in a subset of blood vessels. These data suggest that ADAM8 is vascular selective and plays a role in proliferation and/or migration of ECs during angiogenesis following SCI. PMID:19003792

  14. Genome-Wide Tissue-Specific Gene Expression, Co-expression and Regulation of Co-expressed Genes in Adult Nematode Ascaris suum

    PubMed Central

    Rosa, Bruce A.; Jasmer, Douglas P.; Mitreva, Makedonka

    2014-01-01

    Background Caenorhabditis elegans has traditionally been used as a model for studying nematode biology, but its small size limits the ability for researchers to perform some experiments such as high-throughput tissue-specific gene expression studies. However, the dissection of individual tissues is possible in the parasitic nematode Ascaris suum due to its relatively large size. Here, we take advantage of the recent genome sequencing of Ascaris suum and the ability to physically dissect its separate tissues to produce a wide-scale tissue-specific nematode RNA-seq datasets, including data on three non-reproductive tissues (head, pharynx, and intestine) in both male and female worms, as well as four reproductive tissues (testis, seminal vesicle, ovary, and uterus). We obtained fundamental information about the biology of diverse cell types and potential interactions among tissues within this multicellular organism. Methodology/Principal Findings Overexpression and functional enrichment analyses identified many putative biological functions enriched in each tissue studied, including functions which have not been previously studied in detail in nematodes. Putative tissue-specific transcriptional factors and corresponding binding motifs that regulate expression in each tissue were identified, including the intestine-enriched ELT-2 motif/transcription factor previously described in nematode intestines. Constitutively expressed and novel genes were also characterized, with the largest number of novel genes found to be overexpressed in the testis. Finally, a putative acetylcholine-mediated transcriptional network connecting biological activity in the head to the male reproductive system is described using co-expression networks, along with a similar ecdysone-mediated system in the female. Conclusions/Significance The expression profiles, co-expression networks and co-expression regulation of the 10 tissues studied and the tissue-specific analysis presented here are a

  15. Nucleus accumbens lentiviral-mediated gain of function of the oxytocin receptor regulates anxiety- and ethanol-related behaviors in adult mice.

    PubMed

    Bahi, Amine; Al Mansouri, Shamma; Al Maamari, Elyazia

    2016-10-01

    Anxiety is believed to influence ethanol use human in alcoholics. Studies using laboratory animals suggested an interaction between oxytocin and the behavioral effects of ethanol. Our previous study implicated a potential role for the oxytocin receptor (OxtR) in regulating ethanol-conditioned place preference. Here, we examined anxiety and the behavioral responses to ethanol in C57BL/6 mice stereotaxically injected in the nucleus accumbens (NAcc) with lentiviral vectors expressing an empty vector (Mock) or the OxtR cDNA. For anxiety we used the elevated-plus maze, the open-field and the marble-burying tests and for ethanol we used the two-bottle choice paradigm, the wire-hanging and ethanol-induced loss-of-righting-reflex tests. We found that, compared to Mock, OxtR overexpression led to anxiolytic-like behavior without altering spontaneous locomotor activity. Most importantly, we found that, relative to Mock controls, increased expression of the OxtR in the NAcc led to decreased ethanol consumption and preference in the two-bottle choice protocol and increased resistance to ethanol-induced sedation. We also compared the consequence of OxtR modulation on the consumption and preference of saccharin and quinine and found that the two experimental groups did not differ for any tastant. These results provide further evidence that the oxytocin system contributes to the regulation of ethanol drinking and sensitivity and position OxtR as a central molecular mediator of ethanol's effects within the mesolimbic system. Taken together, the current findings suggest that OxtR manipulation may be a relevant strategy to address ethanol use disorders. PMID:27306084

  16. Upper gastrointestinal sensitivity to meal-related signals in adult humans - relevance to appetite regulation and gut symptoms in health, obesity and functional dyspepsia.

    PubMed

    Feinle-Bisset, Christine

    2016-08-01

    Both the stomach and small intestine play important roles in sensing the arrival of a meal, and its physico-chemical characteristics, in the gastrointestinal lumen. The presence of a meal in the stomach provides a distension stimulus, and, as the meal empties into the small intestine, nutrients interact with small intestinal receptors, initiating the release of gut hormones, associated with feedback regulation of gastrointestinal functions, including gut motility, and signaling to the central nervous system, modulating eating behaviours, including energy intake. Lipid appears to have particularly potent effects, also in close interaction with, and modulating the effects of, gastric distension, and involving the action of gut hormones, particularly cholecystokinin (CCK). These findings have not only provided important, and novel, insights into how gastrointestinal signals interact to modulate subjective appetite perceptions, including fullness, but also laid the foundation for an increasing appreciation of the role of altered gastrointestinal sensitivities, e.g. as a consequence of excess dietary intake in obesity, or underlying the induction of gastrointestinal symptoms in functional dyspepsia (a condition characterized by symptoms, including bloating, nausea and early fullness, amongst others, after meals, particularly those high in fat, in the absence of any structural or functional abnormalities in the gastrointestinal tract). This paper will review the effects of dietary nutrients, particularly lipid, on gastrointestinal function, and associated effects on appetite perceptions and energy intake, effects of interactions of gastrointestinal stimuli, as well as the role of altered gastrointestinal sensitivities (exaggerated, or reduced) in eating-related disorders, particularly obesity and functional dyspepsia. PMID:27013098

  17. Developmental regulation of ecdysone receptor (EcR) and EcR-controlled gene expression during pharate-adult development of honeybees (Apis mellifera)

    PubMed Central

    Mello, Tathyana R. P.; Aleixo, Aline C.; Pinheiro, Daniel G.; Nunes, Francis M. F.; Bitondi, Márcia M. G.; Hartfelder, Klaus; Barchuk, Angel R.; Simões, Zilá L. P.

    2014-01-01

    Major developmental transitions in multicellular organisms are driven by steroid hormones. In insects, these, together with juvenile hormone (JH), control development, metamorphosis, reproduction and aging, and are also suggested to play an important role in caste differentiation of social insects. Here, we aimed to determine how EcR transcription and ecdysteroid titers are related during honeybee postembryonic development and what may actually be the role of EcR in caste development of this social insect. In addition, we expected that knocking-down EcR gene expression would give us information on the participation of the respective protein in regulating downstream targets of EcR. We found that in Apis mellifera females, EcR-A is the predominantly expressed variant in postembryonic development, while EcR-B transcript levels are higher in embryos, indicating an early developmental switch in EcR function. During larval and pupal stages, EcR-B expression levels are very low, while EcR-A transcripts are more variable and abundant in workers compared to queens. Strikingly, these transcript levels are opposite to the ecdysteroid titer profile. 20-hydroxyecdysone (20E) application experiments revealed that low 20E levels induce EcR expression during development, whereas high ecdysteroid titers seem to be repressive. By means of RNAi-mediated knockdown (KD) of both EcR transcript variants we detected the differential expression of 234 poly-A+ transcripts encoding genes such as CYPs, MRJPs and certain hormone response genes (Kr-h1 and ftz-f1). EcR-KD also promoted the differential expression of 70 miRNAs, including highly conserved ones (e.g., miR-133 and miR-375), as well honeybee-specific ones (e.g., miR-3745 and miR-3761). Our results put in evidence a broad spectrum of EcR-controlled gene expression during postembryonic development of honeybees, revealing new facets of EcR biology in this social insect. PMID:25566327

  18. Developmental regulation of ecdysone receptor (EcR) and EcR-controlled gene expression during pharate-adult development of honeybees (Apis mellifera).

    PubMed

    Mello, Tathyana R P; Aleixo, Aline C; Pinheiro, Daniel G; Nunes, Francis M F; Bitondi, Márcia M G; Hartfelder, Klaus; Barchuk, Angel R; Simões, Zilá L P

    2014-01-01

    Major developmental transitions in multicellular organisms are driven by steroid hormones. In insects, these, together with juvenile hormone (JH), control development, metamorphosis, reproduction and aging, and are also suggested to play an important role in caste differentiation of social insects. Here, we aimed to determine how EcR transcription and ecdysteroid titers are related during honeybee postembryonic development and what may actually be the role of EcR in caste development of this social insect. In addition, we expected that knocking-down EcR gene expression would give us information on the participation of the respective protein in regulating downstream targets of EcR. We found that in Apis mellifera females, EcR-A is the predominantly expressed variant in postembryonic development, while EcR-B transcript levels are higher in embryos, indicating an early developmental switch in EcR function. During larval and pupal stages, EcR-B expression levels are very low, while EcR-A transcripts are more variable and abundant in workers compared to queens. Strikingly, these transcript levels are opposite to the ecdysteroid titer profile. 20-hydroxyecdysone (20E) application experiments revealed that low 20E levels induce EcR expression during development, whereas high ecdysteroid titers seem to be repressive. By means of RNAi-mediated knockdown (KD) of both EcR transcript variants we detected the differential expression of 234 poly-A(+) transcripts encoding genes such as CYPs, MRJPs and certain hormone response genes (Kr-h1 and ftz-f1). EcR-KD also promoted the differential expression of 70 miRNAs, including highly conserved ones (e.g., miR-133 and miR-375), as well honeybee-specific ones (e.g., miR-3745 and miR-3761). Our results put in evidence a broad spectrum of EcR-controlled gene expression during postembryonic development of honeybees, revealing new facets of EcR biology in this social insect. PMID:25566327

  19. Adult Strabismus

    MedlinePlus

    ... will likely improve the double vision and depth perception. Also, strabismus affects adults in emotional, social, and ... muscle surgery is usually not severe. Headache, pulling sensation with eye movement and foreign body sensation in ...

  20. Obstructive sleep apnea - adults

    MedlinePlus

    Sleep apnea - obstructive - adults; Apnea - obstructive sleep apnea syndrome - adults; Sleep-disordered breathing - adults; OSA - adults ... the upper airway for obstructive sleep apnea in adults. Sleep . 2010;33:1408-1413. PMID: 21061864 www. ...

  1. Inverse association between microRNA-124a and ABCC4 in HepG2 cells treated with antiretroviral drugs.

    PubMed

    Nagiah, Savania; Phulukdaree, Alisa; Chuturgoon, Anil

    2016-09-01

    The ATP-binding cassette (ABC) super-family of drug transporters regulates efflux of xenobiotic compounds. The subfamily, multi-drug resistance proteins (MRPs) transports cyclic nucleotides and xenobiotics. Epigenetic modulation of drug transporters is scarcely described. The regulatory role of microRNA (miR)-124a on drug transporter gene ABCC4 was only recently reported. Our study investigated the differential regulation of miR-124a by nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine (AZT), Stavudine (d4T) and Tenofovir (TFV); at 24 h and 120 h treatments in HepG2 cells. ABCC4 mRNA (qPCR) and ABCC4 protein (western blot) were quantified. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) levels. All NRTIs elevated miR-124a levels at 24 h, with a concomitant decline in ABCC4 mRNA levels (p<0.05). At 120 h, d4T and TFV elevated miR-124a and depleted ABCC4 mRNA levels (p<0.0001), while the inverse was observed with AZT (p<0.005). ABCC4 protein was increased by d4T and TFV at 24h. A significant reduction in protein levels was observed at 120 h in all three treatments (p<0.005). The disjoint in mRNA and protein levels is likely due to ABCC4 being a membrane bound protein. Following prolonged exposure, membrane integrity was compromised as evidenced by increased LDH leakage (p<0.005). We conclude antiretroviral drugs have varying effects on miR-124a and ABCC4. PMID:26643107

  2. Adult Personality Development: Dynamics and Processes

    PubMed Central

    Diehl, Manfred; Hooker, Karen

    2013-01-01

    The focus of this special issue of Research in Human Development is on adult personality and how personality may contribute to and be involved in adult development. Specifically, the contributions in this issue focus on the links between personality structures (e.g., traits) and personality processes (e.g., goal pursuit, self--regulation) and emphasize the contributions that intensive repeated measurement approaches can make to the understanding of personality and development across the adult life span. PMID:24068889

  3. Adult Play.

    ERIC Educational Resources Information Center

    Charles, John M.

    In its broadest context, play can be interpreted as any pleasurable use of discretionary time. Playfulness is an intrinsic feature of being human, and should be viewed in the light of a total lifestyle, not as an occurrence in an isolated time of life. Adult play appears to be an indefinable and controversial concept. A holistic approach should be…

  4. CPR: Adult

    MedlinePlus Videos and Cool Tools

    Refresher Center Home FIRST AID, CPR and AED LIFEGUARDING Refresher Putting It All Together: CPR—Adult (2:03) Refresher videos only utilize this player QUICK LINKS Home RedCross.org Purchase Course Materials Shop Our Store ...

  5. Handbook for Volunteers: Adult Education Program.

    ERIC Educational Resources Information Center

    Koehler, C. Russell

    Designed for volunteers in Olympic College's Adult Education Volunteer Classroom Assistant Project, this handbook discusses volunteer tutors' roles, characteristics of Adult Basic Education (ABE) and English as a Second Language (ESL) students, suggested teaching techniques, tips for working with instructors, and college policies and regulations.…

  6. ADULT EDUCATION OF MIGRANT ADULTS.

    ERIC Educational Resources Information Center

    BEAL, CATHERINE; AND OTHERS

    UNITS ON MIGRANT ADULT EDUCATION, AND A UNIT ON ORGANIZING INFORMAL GROUPS OF MIGRANT WOMEN TO DISCUSS MAINTAINING AND IMPROVING THEIR TEMPORARY HOMES, ARE PRESENTED. THE GOALS OF THE UNIT ON EDUCATION FOR MIGRANT MEN ARE ECONOMIC INDEPENDENCE, BETTER HEALTH AND WELL-BEING, AND BETTER HANDLING OF RESPONSIBILITIES. THE MAIN DIVISIONS OF THE…

  7. [Adult twins].

    PubMed

    Charlemaine, Christiane

    2006-12-31

    This paper explores the deep roots of closeness that twins share in their youngest age and their effect on their destiny at the adult age. Psychologists believe the bond between twins begins in utero and develops throughout the twins' lives. The four patterns of twinship described show that the twin bond is determined by the quality of parenting that twins receive in their infancy and early childhood. Common problems of adult twins bring about difficulties to adapt in a non-twin world. The nature versus nurture controversy has taken on new life focusing on inter-twin differences and the importance of parent-child interaction as fundamental to the growth and development of personality. PMID:17352324

  8. Obstructive sleep apnea - adults

    MedlinePlus

    Sleep apnea - obstructive - adults; Apnea - obstructive sleep apnea syndrome - adults; Sleep-disordered breathing - adults; OSA - adults ... When you sleep, all of the muscles in your body become more relaxed. This includes the muscles that help keep your ...

  9. Adult Development and Learning of Older Adults

    ERIC Educational Resources Information Center

    Roberson, Donald N., Jr.

    2005-01-01

    This summary of adult development covers a wide range of authors. Adult development is one way of understanding how the internal and external changes in our lives have an impact on learning. Of particular importance in this work are the developmental issues of older adults. I present various theories of adult development such as linear and…

  10. Genetics and Epigenetics in Adult Neurogenesis.

    PubMed

    Hsieh, Jenny; Zhao, Xinyu

    2016-01-01

    The cellular basis of adult neurogenesis is neural stem cells residing in restricted areas of the adult brain. These cells self-renew and are multipotent. The maintenance of "stemness" and commitment to differentiation are tightly controlled by intricate molecular networks. Epigenetic mechanisms, including chromatin remodeling, DNA methylation, and noncoding RNAs (ncRNAs), have profound regulatory roles in mammalian gene expression. Significant advances have been made regarding the dynamic roles of epigenetic modulation and function. It has become evident that epigenetic regulators are key players in neural-stem-cell self-renewal, fate specification, and final maturation of new neurons, therefore, adult neurogenesis. Altered epigenetic regulation can result in a number of neurological and neurodevelopmental disorders. Here, we review recent discoveries that advance our knowledge in epigenetic regulation of mammalian neural stem cells and neurogenesis. Insights from studies of epigenetic gene regulation in neurogenesis may lead to new therapies for the treatment of neurodevelopmental disorders. PMID:27143699

  11. Adults Need Vaccines, Too!

    MedlinePlus

    ... turn JavaScript on. Feature: Adult Vaccinations Adults Need Vaccines, Too! Past Issues / Summer 2015 Table of Contents ... of the millions of adults not receiving the vaccines you need? What vaccines do you need? All ...

  12. Adult Still's disease

    MedlinePlus

    Still's disease - adult; AOSD ... than 1 out of 100,000 people develop adult-onset Still's disease each year. It affects women more often than men. The cause of adult Still's disease is unknown. No risk factors for ...

  13. Brain tumor - primary - adults

    MedlinePlus

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  14. 34 CFR 491.1 - What is the Adult Education for the Homeless Program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What is the Adult Education for the Homeless Program? 491.1 Section 491.1 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION ADULT EDUCATION FOR THE HOMELESS PROGRAM General § 491.1 What is the Adult...

  15. Panic Disorder among Adults

    MedlinePlus

    ... Hyperactivity Disorder Among Children Autism Spectrum Disorder (ASD) Eating Disorders Among Adults - Anorexia Nervosa Eating Disorders Among Adults - Binge Eating Disorder Eating Disorders Among ...

  16. Bipolar Disorder Among Adults

    MedlinePlus

    ... Hyperactivity Disorder Among Children Autism Spectrum Disorder (ASD) Eating Disorders Among Adults - Anorexia Nervosa Eating Disorders Among Adults - Binge Eating Disorder Eating Disorders Among ...

  17. Major Depression Among Adults

    MedlinePlus

    ... Hyperactivity Disorder Among Children Autism Spectrum Disorder (ASD) Eating Disorders Among Adults - Anorexia Nervosa Eating Disorders Among Adults - Binge Eating Disorder Eating Disorders Among ...

  18. Adult neural stem cells stake their ground

    PubMed Central

    Lim, Daniel A.; Alvarez-Buylla, Arturo

    2014-01-01

    The birth of new neurons in the walls of the adult brain lateral ventricles has captured the attention of many neuroscientists for over two decades, yielding key insights into the identity and regulation of neural stem cells (NSCs). In the adult ventricular-subventricular zone (V-SVZ), NSCs are a specialized form of astrocyte that generates several types of neurons for the olfactory bulb. Here we discuss recent findings regarding the unique organization of the V-SVZ NSCs niche, the multiple regulatory controls of neuronal production, the distinct regional identities of adult NSCs, and the epigenetic mechanisms that maintain adult neurogenesis. Understanding how V-SVZ NSCs establish and maintain lifelong neurogenesis continues to provide surprising insights into the cellular and molecular regulation of neural development. PMID:25223700

  19. Capturing microRNA targets using an RNA-induced silencing complex (RISC)-trap approach

    PubMed Central

    Cambronne, Xiaolu A.; Shen, Rongkun; Auer, Paul L.; Goodman, Richard H.

    2012-01-01

    Identifying targets is critical for understanding the biological effects of microRNA (miRNA) expression. The challenge lies in characterizing the cohort of targets for a specific miRNA, especially when targets are being actively down-regulated in miRNA– RNA-induced silencing complex (RISC)–messengerRNA (mRNA) complexes. We have developed a robust and versatile strategy called RISCtrap to stabilize and purify targets from this transient interaction. Its utility was demonstrated by determining specific high-confidence target datasets for miR-124, miR-132, and miR-181 that contained known and previously unknown transcripts. Two previously unknown miR-132 targets identified with RISCtrap, adaptor protein CT10 regulator of kinase 1 (CRK1) and tight junction-associated protein 1 (TJAP1), were shown to be endogenously regulated by miR-132 in adult mouse forebrain. The datasets, moreover, differed in the number of targets and in the types and frequency of microRNA recognition element (MRE) motifs, thus revealing a previously underappreciated level of specificity in the target sets regulated by individual miRNAs. PMID:23184980

  20. Endocrine regulation of HOX genes.

    PubMed

    Daftary, Gaurang S; Taylor, Hugh S

    2006-06-01

    Hox genes have a well-characterized role in embryonic development, where they determine identity along the anteroposterior body axis. Hox genes are expressed not only during embryogenesis but also in the adult, where they are necessary for functional differentiation. Despite the known function of these genes as transcription factors, few regulatory mechanisms that drive Hox expression are known. Recently, several hormones and their cognate receptors have been shown to regulate Hox gene expression and thereby mediate development in the embryo as well as functional differentiation in the adult organism. Estradiol, progesterone, testosterone, retinoic acid, and vitamin D have been shown to regulate Hox gene expression. In the embryo, the endocrine system directs axial Hox gene expression; aberrant Hox gene expression due to exposure to endocrine disruptors contributes to the teratogenicity of these compounds. In the adult, endocrine regulation of Hox genes is necessary to enable such diverse functions as hematopoiesis and reproduction; endocrinopathies can result in dysregulated HOX gene expression affecting physiology. By regulating HOX genes, hormonal signals utilize a conserved mechanism that allows generation of structural and functional diversity in both developing and adult tissues. This review discusses endocrine Hox regulation and its impact on physiology and human pathology. PMID:16632680

  1. Testing Solutions for Adult Film Performers.

    PubMed

    Bergman, Zachary R

    2014-01-01

    The majority of the nation's adult films are produced in California, and within California, most production occurs in Los Angeles. In order to regulate that content, the County of Los Angeles passed the Safer Sex in the Adult Film Industry Act (Measure B) by way of referendum in November 2012. Measure B requires that adult film producers wishing to film in Los Angeles County obtain permits from the Los Angeles County Department of Public Health, and it also mandates that adult film performers use condoms while filming and "engaging in anal or vaginal sexual intercourse." Nevertheless, between August 2013 and January 2014, several adult film performers in California tested positive for HIV, and the threat of infection remains. Although Measure B is not the best way forward for Los Angeles County, elements of the ordinance should be incorporated into future legislative efforts. Given the economic ramifications of industry flight due to more localized regulations, this Note concludes that California should pass statewide comprehensive reform. Any such new legislation must treat "independent contractors," the classification generally used for adult film performs, as if they were regular employees. Legislation should also couple mandatory testing mechanisms with provisions granting performers the right to choose whether they use condoms. Finally, legislation must include mechanisms that ensure performers' preferences are not improperly tainted by outside forces and pressures. While there will always be risks associated with the production of adult content, if undertaken, these reforms could significantly mitigate those hazards. PMID:26809162

  2. Arizona Adult Education Standards

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2006

    2006-01-01

    Adult education standards are the cornerstone for quality teaching, quality learning, and quality lives. The Arizona Adult Education Standards Initiative (Standards Initiative) represents a proactive effort by Arizona's adult education community to ensure rigor and consistency in program content and student outcomes for adult learners throughout…

  3. Adult Cancers in Adolescents and Young Adults.

    PubMed

    Laurence, Valérie; Marples, Maria; Stark, Daniel P

    2016-01-01

    The pattern of cancer seen in young people changes with increasing age, transitioning from childhood- to adult-type cancer in adolescence and the third decade. The risk factors, presentation and biology of cancer in young adults differ from those in the older adult population. Factors of particular significance in adolescents and young adults (AYAs) include genetic predisposition to adult-type cancer, diagnostic uncertainty, long-term morbidity and considerations of fertility. New systemic therapies are being introduced that can prolong life and even increase the chance of cure, but the impact on AYAs is uncertain, as these patients are often under-represented in clinical trials. Here, we discuss the management of AYAs with 3 of the most common cancers affecting adults, when they emerge in the AYA populations, and therefore are currently met by medical oncologists - breast cancer, colorectal cancer and melanoma. PMID:27595357

  4. Detrimental role of prolonged sleep deprivation on adult neurogenesis

    PubMed Central

    Fernandes, Carina; Rocha, Nuno Barbosa F.; Rocha, Susana; Herrera-Solís, Andrea; Salas-Pacheco, José; García-García, Fabio; Murillo-Rodríguez, Eric; Yuan, Ti-Fei; Machado, Sergio; Arias-Carrión, Oscar

    2015-01-01

    Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis. PMID:25926773

  5. Detrimental role of prolonged sleep deprivation on adult neurogenesis.

    PubMed

    Fernandes, Carina; Rocha, Nuno Barbosa F; Rocha, Susana; Herrera-Solís, Andrea; Salas-Pacheco, José; García-García, Fabio; Murillo-Rodríguez, Eric; Yuan, Ti-Fei; Machado, Sergio; Arias-Carrión, Oscar

    2015-01-01

    Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis. PMID:25926773

  6. VOLTAGE REGULATOR

    DOEpatents

    Von Eschen, R.L.; Scheele, P.F.

    1962-04-24

    A transistorized voltage regulator which provides very close voitage regulation up to about 180 deg F is described. A diode in the positive line provides a constant voltage drop from the input to a regulating transistor emitter. An amplifier is coupled to the positive line through a resistor and is connected between a difference circuit and the regulating transistor base which is negative due to the difference in voltage drop across thc diode and the resistor so that a change in the regulator output causes the amplifier to increase or decrease the base voltage and current and incrcase or decrease the transistor impedance to return the regulator output to normal. (AEC)

  7. 34 CFR 461.4 - What regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) The regulations in 34 CFR part 460. (Authority: 20 U.S.C. 1201 et seq.) ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION ADULT EDUCATION STATE-ADMINISTERED BASIC GRANT PROGRAM General § 461.4...

  8. 34 CFR 461.4 - What regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) The regulations in 34 CFR part 460. (Authority: 20 U.S.C. 1201 et seq.) ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION ADULT EDUCATION STATE-ADMINISTERED BASIC GRANT PROGRAM General § 461.4...

  9. 34 CFR 461.4 - What regulations apply?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) The regulations in 34 CFR part 460. (Authority: 20 U.S.C. 1201 et seq.) ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION ADULT EDUCATION STATE-ADMINISTERED BASIC GRANT PROGRAM General § 461.4...

  10. 34 CFR 427.4 - What regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION BILINGUAL VOCATIONAL TRAINING PROGRAM General § 427.4 What regulations apply? The following regulations apply to the Bilingual Vocational Training Program: (a) The regulations in 34 CFR...

  11. 34 CFR 411.4 - What regulations apply?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION VOCATIONAL EDUCATION RESEARCH PROGRAM General § 411.4 What regulations apply? The following regulations apply to the Vocational Education Research Program: (a) The regulations in this...

  12. 34 CFR 401.4 - What regulations apply?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION INDIAN VOCATIONAL EDUCATION PROGRAM General § 401.4 What regulations apply? The following regulations apply to the Indian Vocational Education Program: (a) The regulations in 34 CFR...

  13. 34 CFR 411.4 - What regulations apply?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION VOCATIONAL EDUCATION RESEARCH PROGRAM General § 411.4 What regulations apply? The following regulations apply to the Vocational Education Research Program: (a) The regulations in this...

  14. 34 CFR 401.4 - What regulations apply?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION INDIAN VOCATIONAL EDUCATION PROGRAM General § 401.4 What regulations apply? The following regulations apply to the Indian Vocational Education Program: (a) The regulations in 34 CFR...

  15. 34 CFR 411.4 - What regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION VOCATIONAL EDUCATION RESEARCH PROGRAM General § 411.4 What regulations apply? The following regulations apply to the Vocational Education Research Program: (a) The regulations in this...

  16. 34 CFR 411.4 - What regulations apply?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION VOCATIONAL EDUCATION RESEARCH PROGRAM General § 411.4 What regulations apply? The following regulations apply to the Vocational Education Research Program: (a) The regulations in this...

  17. 34 CFR 401.4 - What regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION INDIAN VOCATIONAL EDUCATION PROGRAM General § 401.4 What regulations apply? The following regulations apply to the Indian Vocational Education Program: (a) The regulations in 34 CFR...

  18. 34 CFR 411.4 - What regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION VOCATIONAL EDUCATION RESEARCH PROGRAM General § 411.4 What regulations apply? The following regulations apply to the Vocational Education Research Program: (a) The regulations in this...

  19. 34 CFR 401.4 - What regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION INDIAN VOCATIONAL EDUCATION PROGRAM General § 401.4 What regulations apply? The following regulations apply to the Indian Vocational Education Program: (a) The regulations in 34 CFR...

  20. 34 CFR 401.4 - What regulations apply?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION INDIAN VOCATIONAL EDUCATION PROGRAM General § 401.4 What regulations apply? The following regulations apply to the Indian Vocational Education Program: (a) The regulations in 34 CFR...

  1. Effect of Opioid on Adult Hippocampal Neurogenesis

    PubMed Central

    Zhang, Yue; Loh, Horace H.; Law, Ping-Yee

    2016-01-01

    During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal's opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse. PMID:27127799

  2. Dilemma of Democracy and Adult Education in Poland.

    ERIC Educational Resources Information Center

    Ratman-Liwerska, Izabela

    1993-01-01

    Political changes in Poland are affecting the educational sector. There is a need for regulation in adult education, and the polycentric model is shifting government responsibility for education from financial support to political and moral oversight. (SK)

  3. Isolation of diapause-regulated transcripts by differential display from the Colorado potato beetle, and their expression in prediapausing and nondiapausing adults. GenBank. Accessions: FG591137-FG591192

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Using differential display, 56 putatively diapause regulated transcripts were isolated from the Colorado potato beetle, Leptinotarsa decemlineata. The clones insert sizes range from 114 to 795 bp with mean length of 392 ± SD of 191 bp. Fourteen of the transcripts were confirmed by northern blot anal...

  4. Year Book of Adult Education, 1969-70.

    ERIC Educational Resources Information Center

    National Inst. of Adult Education, London (England).

    The directory of the National Institute of Adult Education (NIAE) reviews major events in British adult education during 1968-69, followed by principles and functions of the NIAE, abstracts of legislation and regulations, listings of addresses and principal staff members for organizations throughout Great Britain, and overseas contacts through…

  5. Interleukin-17 inhibits Adult Hippocampal Neurogenesis

    PubMed Central

    Liu, Qiang; Xin, Wei; He, Ping; Turner, Dharshaun; Yin, Junxiang; Gan, Yan; Shi, Fu-Dong; Wu, Jie

    2014-01-01

    Interleukin 17(A) (IL-17) is a potent pro-inflammatory cytokine that acts as a central regulator of inflammatory response within the brain, but its physiological roles under non-inflammatory conditions remain elusive. Here we report that endogenous IL-17 ablates neurogenesis in the adult dentate gyrus (DG) of hippocampus. Genetic deletion of IL-17 increased the number of adult-born neurons in the DG. Further, we found that IL-17 deletion altered cytokine network, facilitated basal excitatory synaptic transmission, enhanced intrinsic neuronal excitability, and increased expression of proneuronal genes in neuronal progenitor cells (NPCs). Our findings suggest a profound role of IL-17 in the negative regulation of adult hippocampal neurogenesis under physiology conditions. PMID:25523081

  6. Patient Eye Examinations - Adults

    MedlinePlus

    ... Examinations, Adults Patient Eye Examinations, Children Refractive Errors Scientists in the Laboratory Visual Acuity Testing Patient Eye Examinations, Adults × Warning message Automatic fallback to the cURL connection method kicked in to handle the request. Result code ...

  7. Immunization Schedules for Adults

    MedlinePlus

    ... ACIP Vaccination Recommendations Why Immunize? Vaccines: The Basics Immunization Schedules for Adults in Easy-to-read Formats ... previous immunizations. View or Print a Schedule Recommended Immunizations for Adults (19 Years and Older) by Age ...

  8. Adult Congenital Heart Association

    MedlinePlus

    ... survivable, manageable, yet in the routine years between infancy and adulthood, sometimes forgettable. The Adult Congenital Heart ... understand the continuum of the disease from its infancy. The Adult Congential Heart Association brings together valuable ...

  9. Adult Congenital Heart Association

    MedlinePlus

    ... to ACHA Search The futures of adults with congenital heart disease made brighter by their pasts Get Involved 2016 ... conference theme is "The Changing Landscape of Adult Congenital Heart Disease." Join Us Help us improve the quality of ...

  10. Depression in Older Adults

    ERIC Educational Resources Information Center

    Stickle, Fred; Onedera, Jill D.

    2006-01-01

    The purpose of this article is to address selected aspects of depression in older adults. Specifically, symptoms, risk factors, diagnosis, and interventions for depression in older adults are reviewed.

  11. Adult myelination: wrapping up neuronal plasticity

    PubMed Central

    O’Rourke, Megan; Gasperini, Robert; Young, Kaylene M.

    2014-01-01

    In this review, we outline the major neural plasticity mechanisms that have been identified in the adult central nervous system (CNS), and offer a perspective on how they regulate CNS function. In particular we examine how myelin plasticity can operate alongside neurogenesis and synaptic plasticity to influence information processing and transfer in the mature CNS. PMID:25221576

  12. Assessment of adult neurogenesis in mice.

    PubMed

    Pan, Yung-Wei; Wang, Wenbin; Xia, Zhengui

    2013-05-01

    Adult neurogenesis is a lifelong developmental process that occurs in two discrete regions in the adult mammalian brain: the subgranular zone of the dentate gyrus (DG) and the subventricular zone (SVZ) along the lateral ventricles. Despite immense interest in the therapeutic potential of adult neural stem cells (aNSCs) residing along these two neurogenic regions, molecular and cellular mechanisms regulating this process are not fully defined. Defining the regulatory mechanisms responsible for the genesis of new neurons in the adult brain is integral to understanding the basic biology of aNSCs. The techniques described here provide a basic blueprint to isolate, culture, and perform experiments using aNSCs in vitro as well as providing methods to perform immunohistochemistry on brain sections. Curr. Protoc. Toxicol. 56:12.20.1-12.20.16. © 2013 by John Wiley & Sons, Inc. PMID:23670864

  13. TAM receptor deficiency affects adult hippocampal neurogenesis

    PubMed Central

    Ji, Rui; Meng, Lingbin; Li, Qiutang; Lu, Qingxian

    2014-01-01

    The Tyro3, Axl and Mertk (TAM) subfamily of receptor protein tyrosine kinases functions in cell growth, differentiation, survival, and most recently found, in the regulation of immune responses and phagocytosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS). TAM receptors play pivotal roles in adult hippocampal neurogenesis. Loss of these receptors causes a comprised neurogenesis in the dentate gyrus of adult hippocampus. TAM receptors have a negative regulatory effect on microglia and peripheral antigen-presenting cells, and play a critical role in preventing overproduction of pro-inflammatory cytokines detrimental to the proliferation, differentiation, and survival of adult neuronal stem cells (NSCs). Besides, these receptors also play an intrinsic trophic function in supporting NSC survival, proliferation, and differentiation into immature neurons. All these events collectively ensure a sustained neurogenesis in adult hippocampus. PMID:25487541

  14. TAM receptor deficiency affects adult hippocampal neurogenesis.

    PubMed

    Ji, Rui; Meng, Lingbin; Li, Qiutang; Lu, Qingxian

    2015-06-01

    The Tyro3, Axl and Mertk (TAM) subfamily of receptor protein tyrosine kinases functions in cell growth, differentiation, survival, and most recently found, in the regulation of immune responses and phagocytosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS). TAM receptors play pivotal roles in adult hippocampal neurogenesis. Loss of these receptors causes a comprised neurogenesis in the dentate gyrus of adult hippocampus. TAM receptors have a negative regulatory effect on microglia and peripheral antigen-presenting cells, and play a critical role in preventing overproduction of pro-inflammatory cytokines detrimental to the proliferation, differentiation, and survival of adult neuronal stem cells (NSCs). Besides, these receptors also play an intrinsic trophic function in supporting NSC survival, proliferation, and differentiation into immature neurons. All these events collectively ensure a sustained neurogenesis in adult hippocampus. PMID:25487541

  15. The Social Environment and Neurogenesis in the Adult Mammalian Brain

    PubMed Central

    Lieberwirth, Claudia; Wang, Zuoxin

    2012-01-01

    Adult neurogenesis – the formation of new neurons in adulthood – has been shown to be modulated by a variety of endogenous (e.g., trophic factors, neurotransmitters, and hormones) as well as exogenous (e.g., physical activity and environmental complexity) factors. Research on exogenous regulators of adult neurogenesis has focused primarily on the non-social environment. More recently, however, evidence has emerged suggesting that the social environment can also affect adult neurogenesis. The present review details the effects of adult–adult (e.g., mating and chemosensory interactions) and adult–offspring (e.g., gestation, parenthood, and exposure to offspring) interactions on adult neurogenesis. In addition, the effects of a stressful social environment (e.g., lack of social support and dominant–subordinate interactions) on adult neurogenesis are reviewed. The underlying hormonal mechanisms and potential functional significance of adult-generated neurons in mediating social behaviors are also discussed. PMID:22586385

  16. 7 CFR 240.4 - Cash in lieu of donated foods for nonresidential child and adult care institutions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... and adult care institutions. 240.4 Section 240.4 Agriculture Regulations of the Department of... LIEU OF DONATED FOODS § 240.4 Cash in lieu of donated foods for nonresidential child and adult care... or adult care institutions participating in the Child and Adult Care Food Program. FNS shall pay...

  17. 7 CFR 240.4 - Cash in lieu of donated foods for nonresidential child and adult care institutions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... and adult care institutions. 240.4 Section 240.4 Agriculture Regulations of the Department of... LIEU OF DONATED FOODS § 240.4 Cash in lieu of donated foods for nonresidential child and adult care... or adult care institutions participating in the Child and Adult Care Food Program. FNS shall pay...

  18. 7 CFR 240.4 - Cash in lieu of donated foods for nonresidential child and adult care institutions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... and adult care institutions. 240.4 Section 240.4 Agriculture Regulations of the Department of... LIEU OF DONATED FOODS § 240.4 Cash in lieu of donated foods for nonresidential child and adult care... or adult care institutions participating in the Child and Adult Care Food Program. FNS shall pay...

  19. 7 CFR 240.4 - Cash in lieu of donated foods for nonresidential child and adult care institutions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... and adult care institutions. 240.4 Section 240.4 Agriculture Regulations of the Department of... LIEU OF DONATED FOODS § 240.4 Cash in lieu of donated foods for nonresidential child and adult care... or adult care institutions participating in the Child and Adult Care Food Program. FNS shall pay...

  20. 34 CFR 472.33 - How must projects that serve adults with limited English proficiency provide for the needs of...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... English proficiency provide for the needs of those adults? 472.33 Section 472.33 Education Regulations of....33 How must projects that serve adults with limited English proficiency provide for the needs of those adults? (a) Projects serving adults with limited English proficiency or no English...

  1. 34 CFR 472.33 - How must projects that serve adults with limited English proficiency provide for the needs of...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... English proficiency provide for the needs of those adults? 472.33 Section 472.33 Education Regulations of....33 How must projects that serve adults with limited English proficiency provide for the needs of those adults? (a) Projects serving adults with limited English proficiency or no English...

  2. 34 CFR 472.33 - How must projects that serve adults with limited English proficiency provide for the needs of...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... English proficiency provide for the needs of those adults? 472.33 Section 472.33 Education Regulations of....33 How must projects that serve adults with limited English proficiency provide for the needs of those adults? (a) Projects serving adults with limited English proficiency or no English...

  3. 34 CFR 472.33 - How must projects that serve adults with limited English proficiency provide for the needs of...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... English proficiency provide for the needs of those adults? 472.33 Section 472.33 Education Regulations of....33 How must projects that serve adults with limited English proficiency provide for the needs of those adults? (a) Projects serving adults with limited English proficiency or no English...

  4. 34 CFR 472.33 - How must projects that serve adults with limited English proficiency provide for the needs of...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... English proficiency provide for the needs of those adults? 472.33 Section 472.33 Education Regulations of....33 How must projects that serve adults with limited English proficiency provide for the needs of those adults? (a) Projects serving adults with limited English proficiency or no English...

  5. Adult Learning: A Reader.

    ERIC Educational Resources Information Center

    Sutherland, Peter, Ed.

    This book on adult learning is divided into six sections. Section 1, Cognitive Processes, includes the following chapters: "Cognitive Processes: Contemporary Paradigms of Learning" (Jack Mezirow); "Information Processing, Memory, Age and Adult Learning" (Gillian Boulton-Lewis); "Adult Learners' Metacognitive Behaviour in Higher Education" (Barry…

  6. Aspects of Adult Education.

    ERIC Educational Resources Information Center

    Chandrasekhar, Rajkumari

    This book presents an overview of and prescription for adult education in India. Following an introduction to the problem of illiteracy in India, the book's 14 chapters cover a broad spectrum of adult education issues. Topics discussed include adult education and national development; roles of voluntary organizations, universities, colleges, and…

  7. Dimensions of Adult Learning

    ERIC Educational Resources Information Center

    Foley, Griff, Ed.

    2004-01-01

    This broad introduction to adult and postcompulsory education offers an overview of the field for students, adult educators and workplace trainers. The book establishes an analytical framework to emphasize the nature of learning and agency of learners; examines the core knowledge and skills that adult educators need; discusses policy, research and…

  8. Kids Who Outwit Adults.

    ERIC Educational Resources Information Center

    Seita, John R.; Brendtro, Larry K.

    Kids who distrust adults are highly skilled at hiding their real nature and resisting change. Most adults shun such youths or get mired in conflict with them. Punitive get tough practices as well as traditional flaw-fixing treatment are reactive strategies that often drive these youths further from adult bonds and reinforce oppositional and…

  9. Adult Learners in Universities.

    ERIC Educational Resources Information Center

    Baker, Janette, Ed.

    1981-01-01

    Theories on adult development and learning and some of the Ontario universities' programs and services for the adult learner are examined, and Athabasca University, Alberta's answer to the British Open University, is described. Peter O'Donnell discusses adult learners' needs and explains how Athabasca University serves this specific type of…

  10. Adult Competency Education Resources.

    ERIC Educational Resources Information Center

    Bureau of Occupational and Adult Education (DHEW/OE), Washington, DC. Div. of Adult Education.

    A compilation of brief descriptions of 20 current resources for Adult Performance Level (APL) and Adult Competency Education (ACE) programs, this guide was developed for adult and secondary education administrators, teachers, and program developers who are beginning or are already involved with APL/ACE programs. Each citation contains information…

  11. Adult Competency Education Profile.

    ERIC Educational Resources Information Center

    Bureau of Occupational and Adult Education (DHEW/OE), Washington, DC. Div. of Adult Education.

    A compilation of abstracts of 120 current Adult Performance Level (APL) and Adult Competency Education (ACE) federally supported projects being conducted in 34 States and the District of Columbia, this project profile was developed for adult and secondary education administrators, teachers, and program developers who are beginning or are currently…

  12. Adult Education in Turkey

    ERIC Educational Resources Information Center

    Miser, Rifat; Ural, Ozana; Ünlühisarýklý, Özlem

    2013-01-01

    This study investigates the situation and practices of adult education in Turkey in terms of (a) participants, (b) providers, and (c) program areas. The data were derived from published statistical data and one-to-one interaction with adult education providers when such data are unavailable. Turkey has a long tradition of adult education with…

  13. Navajo Adult Basic Education.

    ERIC Educational Resources Information Center

    Navajo Community Coll., Tsaile, AZ.

    The objectives of this Special Experimental Demonstration Project in Adult Basic Education for the Navajo were: (1) to raise the educational and social level of Navajo adult students who are unable to read, write, and speak English; (2) to assist the Navajo adult students to take advantage of occupational and vocational training programs; (3) to…

  14. The Adult Experience.

    ERIC Educational Resources Information Center

    Belsky, Janet

    The 14 chapters of this textbook chronicle adult development from youth through old age, emphasizing both research and interviews with adults at various stages in their lives. Topics covered include the following: (1) the academic field of adult development; (2) theories and research methods; (3) aging and disease prevention; (4) sexuality and…

  15. Adult Numeracy Core Curriculum.

    ERIC Educational Resources Information Center

    Steeds, Andrew, Ed.

    Designed primarily for adult literacy teachers and tutors, this curriculum describes the content of what should be taught in numeracy programs in order to meet the individual needs of adults through the selection and teaching of skills appropriate to those adults' needs. An introduction describes national standards and qualifications, learners,…

  16. Adults and GNVQs.

    ERIC Educational Resources Information Center

    Pettitt, Aidan

    1996-01-01

    This document is intended for further education colleges in the United Kingdom wishing to extend their General National Vocational Qualification (GNVQ) provision to adults, extend their adult students' options for accreditation, or review the suitability of different qualification routes for adults. It presents information about the development of…

  17. Canadian Adult Basic Education.

    ERIC Educational Resources Information Center

    Brooke, W. Michael, Comp.

    "Trends," a publication of the Canadian Association for Adult Education, is a collection of abstracts on selected subjects affecting adult education; this issue is on adult basic education (ABE). It covers teachers and teacher training, psychological factors relating to the ABE teacher and students, manuals for teachers, instructional materials,…

  18. Adult Survival Skills Assessment.

    ERIC Educational Resources Information Center

    Walsko, Gregory M.

    The purpose of this instrument is to supplement data from the Adult Basic Learning Examination in assessing the functional level of adults in daily situations. It may also be used as a teaching tool for adults requesting tutoring in specific concepts and skills presented in the instrument. This instrument is an informal assessment instrument and…

  19. Adults Role in Bullying

    ERIC Educational Resources Information Center

    Notar, Charles E.; Padgett, Sharon

    2013-01-01

    Do adults play a role in bullying? Do parents, teachers, school staff, and community adult leaders influence bullying behavior in children and teenagers? This article will focus on research regarding all adults who have almost daily contact with children and teens and their part in how bullying is identified, addressed, and prevented. This article…

  20. Adult Learning Assumptions

    ERIC Educational Resources Information Center

    Baskas, Richard S.

    2011-01-01

    The purpose of this study is to examine Knowles' theory of andragogy and his six assumptions of how adults learn while providing evidence to support two of his assumptions based on the theory of andragogy. As no single theory explains how adults learn, it can best be assumed that adults learn through the accumulation of formal and informal…

  1. Adult Education in Greece

    ERIC Educational Resources Information Center

    Kokkos, Alexios

    2008-01-01

    The central aim of this article is to analyse the current situation of adult education in Greece. The article focuses on the following points: (a) the degree of participation in programmes of continuing professional training and general adult education courses, (b) the quality and the outcomes of the adult education provision in Greece, and (c)…

  2. An Adult ESL Curriculum.

    ERIC Educational Resources Information Center

    South Carolina Literacy Resource Center, Columbia.

    This curriculum framework for adult literacy was written by 21 South Carolina adult English-as-a-Second-Language (ESL) instructors, as submitted to the South Carolina Literacy Resource Center. It is based on current theories in the fields of adult education and second language acquisition and is designed to be flexible so that it may be adapted to…

  3. Distinct cognitive effects and underlying transcriptome changes upon inhibition of individual miRNAs in hippocampal neurons

    PubMed Central

    Malmevik, Josephine; Petri, Rebecca; Knauff, Pina; Brattås, Per Ludvik; Åkerblom, Malin; Jakobsson, Johan

    2016-01-01

    MicroRNAs (miRNA) are small, non-coding RNAs mediating post-transcriptional regulation of gene expression. miRNAs have recently been implicated in hippocampus-dependent functions such as learning and memory, although the roles of individual miRNAs in these processes remain largely unknown. Here, we achieved stable inhibition using AAV-delivered miRNA sponges of individual, highly expressed and brain-enriched miRNAs; miR-124, miR-9 and miR-34, in hippocampal neurons. Molecular and cognitive studies revealed a role for miR-124 in learning and memory. Inhibition of miR-124 resulted in an enhanced spatial learning and working memory capacity, potentially through altered levels of genes linked to synaptic plasticity and neuronal transmission. In contrast, inhibition of miR-9 or miR-34 led to a decreased capacity of spatial learning and of reference memory, respectively. On a molecular level, miR-9 inhibition resulted in altered expression of genes related to cell adhesion, endocytosis and cell death, while miR-34 inhibition caused transcriptome changes linked to neuroactive ligand-receptor transduction and cell communication. In summary, this study establishes distinct roles for individual miRNAs in hippocampal function. PMID:26813637

  4. Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer

    PubMed Central

    Seviour, E G; Sehgal, V; Lu, Y; Luo, Z; Moss, T; Zhang, F; Hill, S M; Liu, W; Maiti, S N; Cooper, L; Azencot, R; Lopez-Berestein, G; Rodriguez-Aguayo, C; Roopaimoole, R; Pecot, C; Sood, A K; Mukherjee, S; Gray, J W; Mills, G B; Ram, P T

    2016-01-01

    The myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attempts at therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biological processes, including the cell cycle, and as such is associated with cell proliferation and tumor progression. We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated with poor patient survival in breast and ovarian cancers. Screening of a miRNA library by functional proteomics in multiple cell lines and integration of data from patient tumors revealed a panel of five microRNAs (miRNAs) (miR-124, miR-365, miR-34b*, miR-18a and miR-506) as potential tumor suppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studies revealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels by binding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest. Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated delivery of miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application of miRNAs as therapeutics to target the functional effect of myc on tumor growth. PMID:25639871

  5. Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer.

    PubMed

    Seviour, E G; Sehgal, V; Lu, Y; Luo, Z; Moss, T; Zhang, F; Hill, S M; Liu, W; Maiti, S N; Cooper, L; Azencot, R; Lopez-Berestein, G; Rodriguez-Aguayo, C; Roopaimoole, R; Pecot, C; Sood, A K; Mukherjee, S; Gray, J W; Mills, G B; Ram, P T

    2016-02-11

    The myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attempts at therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biological processes, including the cell cycle, and as such is associated with cell proliferation and tumor progression. We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated with poor patient survival in breast and ovarian cancers. Screening of a miRNA library by functional proteomics in multiple cell lines and integration of data from patient tumors revealed a panel of five microRNAs (miRNAs) (miR-124, miR-365, miR-34b*, miR-18a and miR-506) as potential tumor suppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studies revealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels by binding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest. Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated delivery of miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application of miRNAs as therapeutics to target the functional effect of myc on tumor growth. PMID:25639871

  6. Adult Neurogenesis and Psychiatric Disorders.

    PubMed

    Kang, Eunchai; Wen, Zhexing; Song, Hongjun; Christian, Kimberly M; Ming, Guo-Li

    2016-01-01

    Psychiatric disorders continue to be among the most challenging disorders to diagnose and treat because there is no single genetic or anatomical locus that is causative for the disease. Current treatments are often blunt tools used to ameliorate the most severe symptoms, at the risk of disrupting functional neural systems. There is a critical need to develop new therapeutic strategies that can target circumscribed functional or anatomical domains of pathology. Adult hippocampal neurogenesis may be one such domain. Here, we review the evidence suggesting that adult hippocampal neurogenesis plays a role in emotional regulation and forms of learning and memory that include temporal and spatial memory encoding and context discrimination, and that its dysregulation is associated with psychiatric disorders, such as affective disorders, schizophrenia, and drug addiction. Further, adult neurogenesis has proven to be an effective model to investigate basic processes of neuronal development and converging evidence suggests that aberrant neural development may be an etiological factor, even in late-onset diseases. Constitutive neurogenesis in the hippocampus of the mature brain reflects large-scale plasticity unique to this region and could be a potential hub for modulation of a subset of cognitive and affective behaviors that are affected by multiple psychiatric disorders. PMID:26801682

  7. Why Do Adults Learn? Developing a Motivational Typology across 12 European Countries

    ERIC Educational Resources Information Center

    Boeren, Ellen; Holford, John; Nicaise, Ides; Baert, Herman

    2012-01-01

    Participation in adult education is today generally considered an individual responsibility. However, participation is the result of a complex bounded agency between individuals, educational institutions and regulating governments. This paper explores the motives of 12,000 European adult learners in formal adult education in 12 European countries.…

  8. G-Protein-Coupled Receptors in Adult Neurogenesis

    PubMed Central

    Doze, Van A.

    2012-01-01

    The importance of adult neurogenesis has only recently been accepted, resulting in a completely new field of investigation within stem cell biology. The regulation and functional significance of adult neurogenesis is currently an area of highly active research. G-protein-coupled receptors (GPCRs) have emerged as potential modulators of adult neurogenesis. GPCRs represent a class of proteins with significant clinical importance, because approximately 30% of all modern therapeutic treatments target these receptors. GPCRs bind to a large class of neurotransmitters and neuromodulators such as norepinephrine, dopamine, and serotonin. Besides their typical role in cellular communication, GPCRs are expressed on adult neural stem cells and their progenitors that relay specific signals to regulate the neurogenic process. This review summarizes the field of adult neurogenesis and its methods and specifies the roles of various GPCRs and their signal transduction pathways that are involved in the regulation of adult neural stem cells and their progenitors. Current evidence supporting adult neurogenesis as a model for self-repair in neuropathologic conditions, adult neural stem cell therapeutic strategies, and potential avenues for GPCR-based therapeutics are also discussed. PMID:22611178

  9. Neurodevelopmental origin and adult neurogenesis of the neuroendocrine hypothalamus

    PubMed Central

    Maggi, Roberto; Zasso, Jacopo; Conti, Luciano

    2015-01-01

    The adult hypothalamus regulates many physiological functions and homeostatic loops, including growth, feeding and reproduction. In mammals, the hypothalamus derives from the ventral diencephalon where two distinct ventricular proliferative zones have been described. Although a set of transcription factors regulating the hypothalamic development has been identified, the exact molecular mechanisms that drive the differentiation of hypothalamic neural precursor cells (NPCs) toward specific neuroendocrine neuronal subtypes is yet not fully disclosed. Neurogenesis has been also reported in the adult hypothalamus at the level of specific niches located in the ventrolateral region of ventricle wall, where NPCs have been identified as radial glia-like tanycytes. Here we review the molecular and cellular systems proposed to support the neurogenic potential of developing and adult hypothalamic NPCs. We also report new insights on the mechanisms by which adult hypothalamic neurogenesis modulates key functions of this brain region. Finally, we discuss how environmental factors may modulate the adult hypothalamic neurogenic cascade. PMID:25610370

  10. Preschool Regulations.

    ERIC Educational Resources Information Center

    Nebraska State Dept. of Health and Human Services, Lincoln.

    Published by the Department of Health and Human Services, as required by Nebraska law, this guide details regulations for the physical well-being, safety, and protection of children and defines the minimum levels of acceptable services to be provided in Nebraska preschools. The first section of the guide lists specific preschool regulations,…

  11. Safeguarding vulnerable adults.

    PubMed

    Griffith, Richard

    Nurses have a professional duty to safeguard vulnerable adults from abuse under the provisions of the Nursing and Midwifery Council's (NMC) revised Code (2015). With adult abuse continuing to increase, all members of the nursing team are well placed to identify and take action to safeguard the vulnerable. This article sets out how the Care Act 2014 seeks to improve the safeguarding of vulnerable adults and the role of nurses in that process. PMID:26153813

  12. 34 CFR 460.1 - What is the purpose of the Adult Education Act?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What is the purpose of the Adult Education Act? 460.1 Section 460.1 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION ADULT EDUCATION-GENERAL PROVISIONS § 460.1 What is the purpose of the Adult Education...

  13. 34 CFR 402.4 - What regulations apply?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIVE HAWAIIAN VOCATIONAL EDUCATION PROGRAM General § 402.4 What regulations apply? The following regulations apply to the Native Hawaiian Vocational Education Program: (a)...

  14. 34 CFR 402.4 - What regulations apply?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIVE HAWAIIAN VOCATIONAL EDUCATION PROGRAM General § 402.4 What regulations apply? The following regulations apply to the Native Hawaiian Vocational Education Program: (a)...

  15. 34 CFR 402.4 - What regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIVE HAWAIIAN VOCATIONAL EDUCATION PROGRAM General § 402.4 What regulations apply? The following regulations apply to the Native Hawaiian Vocational Education Program: (a)...

  16. 34 CFR 402.4 - What regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIVE HAWAIIAN VOCATIONAL EDUCATION PROGRAM General § 402.4 What regulations apply? The following regulations apply to the Native Hawaiian Vocational Education Program: (a)...

  17. 34 CFR 402.4 - What regulations apply?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION NATIVE HAWAIIAN VOCATIONAL EDUCATION PROGRAM General § 402.4 What regulations apply? The following regulations apply to the Native Hawaiian Vocational Education Program: (a)...

  18. 34 CFR 429.3 - What regulations apply to this program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... the Bilingual Vocational Materials, Methods, and Techniques Program: (a) The regulations in 34 CFR... VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION BILINGUAL VOCATIONAL MATERIALS, METHODS,...

  19. Alternative Programming for Adults.

    ERIC Educational Resources Information Center

    Flint, Thomas A.; Frey, Ruth

    2003-01-01

    The Council for Adult and Experiential Learning is currently cataloguing alternative programming features that are most effective with adult students in a best practices inventory organized around a framework of high-level descriptive principles of effectiveness. This chapter identifies a few interesting features from a quick survey of this…

  20. Adult Education in Germany.

    ERIC Educational Resources Information Center

    Huddleston, John

    This study is limited essentially to adult education in West Germany, although the historical sections include references to earlier experiences and experiments in areas now Russian-occupied. The terms "adult edcuation" and "workers' education" are clarified. Both are presented as separate movements. Brief reference is made to political, social,…

  1. Adult Learning Matters

    ERIC Educational Resources Information Center

    Thomson, Rachel

    2009-01-01

    Adult Learners' Week--which is supported by the Department for Innovation, Universities and Skills and the European Social Fund, amongst a raft of other organisations--is all about raising demand for learning. At its core, the campaign is about encouraging under-represented groups--including low-skilled, unemployed and low-paid adults and those…

  2. Teachers of Adults Will...

    ERIC Educational Resources Information Center

    Pankowski, Mary L.

    1975-01-01

    The article lists the 12 competencies of adult education teachers that are considered essential to assist adults in achieving instructional goals and objectives. Following the listing a brief justification and examples of ways to evaluate teacher competencies are discussed. (Author/BP)

  3. Recruiting Adult Education Students.

    ERIC Educational Resources Information Center

    Learning Resources Network, Manhattan, KS.

    This document is the first nationwide compilation of successful recruiting techniques for students in adult basic education, literacy, General Educational Development classes, and adult high school degree programs. Information for the publication was gathered from a literature search and other sources, especially "Reaching the Least Educated," a…

  4. Counseling Adult Adoptees

    ERIC Educational Resources Information Center

    Corder, Kate

    2012-01-01

    This review presents various resources about working with adult adoptees in order to inform counselors in their practice. Topics covered include basics of adoption, including types of adoption and adoption statistics; possible issues adult adoptees may face; and suggestions and implications for counselors. The article addresses some of the serious…

  5. Adult Education and Development.

    ERIC Educational Resources Information Center

    Hinzen, Heribert, Ed.

    2002-01-01

    This document contains 19 papers on adult education and development worldwide. The following papers are included: "Editorial" (Heribert Hinzen); "Lifelong Learning in Europe: Moving towards EFA (Dakar Framework for Action on Education for All) Goals and the CONFINTEA V Agenda" (Sofia Conference on Adult Education); "Poverty and Schooling in the…

  6. Adult Day Services

    MedlinePlus

    A Smart Choice Adult Day Services Comparison At-a-Glance 1 Adult Day Services Assisted Living Home Care Nursing Homes Live at home with family ... supervision Nursing care available as needed during the day Flexibility to receive care only on days when ...

  7. Today's Adult Students

    ERIC Educational Resources Information Center

    Reese, Susan

    2012-01-01

    Who are the adult students in career and technical education (CTE) today? There is not one simple answer to that question. Some are young with little life experience, while others are returning to the workforce and learning new skills to reinvent themselves. Whatever the case, educating adult students is an integral part of ACTE's mission, and the…

  8. Adult Learning and Education

    ERIC Educational Resources Information Center

    Rubenson, Kjell, Ed.

    2011-01-01

    As individuals and societies try to respond to fundamental economic and social transformation, the field of adult learning and education is rapidly getting increased attention and new topics for research on adult learning have emerged. This collection of articles from the International Encyclopedia of Education 3e offers practitioners and…

  9. Dialogue and Adult Learning.

    ERIC Educational Resources Information Center

    Tarule, Jill Mattuck

    1992-01-01

    Discussion of the role of language and dialogue in adult learning looks at dialogue as epistemology and at talk as learning. It is proposed that the challenge in teaching and retaining adult learners is to create dialogue-rich classrooms, including many external speech opportunities, small-group discussion, and group projects. (MSE)

  10. Libraries and Adult Learners.

    ERIC Educational Resources Information Center

    Josey, E. J., Ed.

    1982-01-01

    Of the 13 essays presented in this special issue on libraries and adult education, 8 focus on programs and services from the public library for adult learners. These essays provide information on: (1) an Education Information Centers Program (EIC) designed to complement employment skills training provided under the Comprehensive Employment and…

  11. Adult Education in Finland

    ERIC Educational Resources Information Center

    Szekely, Radu

    2006-01-01

    Ever since the first ideas of national independence appeared in Finland, adult education has played an essential role in shaping the destiny of the Finns. With a history of almost 130 years, during which it has continuously increased in quality and quantity, the Finnish adult education system has ensured that Finland stays among the most…

  12. Adult Education Regional Planning

    ERIC Educational Resources Information Center

    California Community Colleges, Chancellor's Office, 2015

    2015-01-01

    For more than one hundred and fifty years, until 2008, California was an undisputed national leader in its commitment to adult education. The state's investment in adult learners topped $750 million, a sum greater than the combined total of every other state in the nation. However, for the past several years recession and fiscal crisis have left…

  13. Adult Education in Cohesion.

    ERIC Educational Resources Information Center

    Rubenson, Kjell

    2003-01-01

    International Adult Literacy Survey data show the average adult education participation in Nordic countries is 14% higher than in other industrialized nations. Public support for participation of the disadvantaged, an active labor market policy, and popular education are key characteristics. (Contains 37 references.) (Author/JOW)

  14. Young Adult Literature.

    ERIC Educational Resources Information Center

    Sewell, Ernestine P., Ed.

    1981-01-01

    The major articles in this journal issue deal with various aspects of young adult literature. Specific topics covered in the articles are (1) questions worth asking students about young adult novels, (2) the five major functions of adolescent literature in high school literature programs, (3) Southwestern literature for adolescents, (4) teaching…

  15. Adult Vocational Training.

    ERIC Educational Resources Information Center

    Ministry of Labour, Copenhagen (Denmark).

    Danish adult vocational training activities take the form of specifically targeted initial and continued training for employed and unemployed adults. Planning, development, and adaptation of vocational training programs (AMU programs) are characterized by tripartite cooperation among public authorities and organizations of employers and employees.…

  16. Adult Counseling Project.

    ERIC Educational Resources Information Center

    Perrone, Phil; Davis, Sandy A.

    In order to determine the specific counseling needs of the adult learner, staff of the Adult Counseling Project began by conducting a literature search pertaining to the problems of returning students and those considering a return to school. The review revealed that little is known about the educational and vocational needs of the returning…

  17. Toward Transpersonal Adult Development

    ERIC Educational Resources Information Center

    Boucouvalas, Marcie

    2016-01-01

    As a foundation for discussing transpersonal adult development, the author traces her trajectory, involvement in, and contribution to the modern transpersonal movement and her introduction of it to the adult learning literature, beginning during the early 1980s. Highlighted are the transpersonal domain and a differentiation between transpersonal…

  18. Adult Vocational Teacher Competencies.

    ERIC Educational Resources Information Center

    Hole, F. Marvin

    As part of a larger study to investigate the backgrounds and professional inservice needs of part-time adult vocational teachers in Pennsylvania, research was conducted to identify and assess adult vocational teacher competencies. Following a literature review, a survey instrument was devised which listed thirty-four competencies (basically…

  19. Adult Tech Prep.

    ERIC Educational Resources Information Center

    Schaad, Donna

    For over 2 years, Blak Hawk College (Illinois) has provided high school equivalency (GED) candidates and recipients, older returning students, and underprepared high school graduates with a Tech Prep curriculum to give them the skills to make the transition from adult basic education to college or work. The Adult Tech Prep (ATP) core curriculum…

  20. Financing of Adult Education

    ERIC Educational Resources Information Center

    Archer, David

    2007-01-01

    The 2008 EFA Global Monitoring Report recognises adult literacy as the most neglected of the EFA goals. It is neglected most obviously in respect of the financial allocations made by governments and donors. This shortage of financing creates a dangerous situation in which adult educators seek to convince politicians to invest, based on false…

  1. Authenticity in Adult Learning

    ERIC Educational Resources Information Center

    Ashton, Sam

    2010-01-01

    This paper is concerned with the relationship between authenticity and adult learning and prompted by some studies in which adult "authentic learning" is a central concept. The implication revealed by them is that real-worldness of learning contexts, learning content and learning tasks is perceived as conferring authenticity on learning. Here,…

  2. Gender Dysphoria in Adults.

    PubMed

    Zucker, Kenneth J; Lawrence, Anne A; Kreukels, Baudewijntje P C

    2016-03-28

    Gender dysphoria (GD), a term that denotes persistent discomfort with one's biologic sex or assigned gender, replaced the diagnosis of gender identity disorder in the Diagnostic and Statistical Manual of Mental Disorders in 2013. Subtypes of GD in adults, defined by sexual orientation and age of onset, have been described; these display different developmental trajectories and prognoses. Prevalence studies conclude that fewer than 1 in 10,000 adult natal males and 1 in 30,000 adult natal females experience GD, but such estimates vary widely. GD in adults is associated with an elevated prevalence of comorbid psychopathology, especially mood disorders, anxiety disorders, and suicidality. Causal mechanisms in GD are incompletely understood, but genetic, neurodevelopmental, and psychosocial factors probably all contribute. Treatment of GD in adults, although largely standardized, is likely to evolve in response to the increasing diversity of persons seeking treatment, demands for greater client autonomy, and improved understanding of the benefits and limitations of current treatment modalities. PMID:26788901

  3. Macrophages modulate adult zebrafish tail fin regeneration.

    PubMed

    Petrie, Timothy A; Strand, Nicholas S; Yang, Chao-Tsung; Tsung-Yang, Chao; Rabinowitz, Jeremy S; Moon, Randall T

    2014-07-01

    Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Although recent evidence suggests that similar cells exist in zebrafish and also migrate to sites of injury in larvae, whether these cells are functionally important for wound healing or regeneration in adult zebrafish is unknown. To begin to address these questions, we first tracked neutrophils (lyzC(+), mpo(+)) and macrophages (mpeg1(+)) in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype. These results provide a cellular and molecular link between components of the inflammation response and regeneration in adult zebrafish. PMID:24961798

  4. Adult Education in the Seventies.

    ERIC Educational Resources Information Center

    Indian Adult Education Association, New Delhi.

    The proceedings of the 24th All India Adult Education Conference highlight two symposia, "Adult Education and Urban Development" and "Adult Education and Green Revolution." Commission Reports on the two symposia are given. (DB)

  5. Voltage regulator

    SciTech Connect

    Rossetti, N.

    1986-12-09

    This patent describes a prior art integrated circuit voltage regulator having an unregulated voltage input terminal and a regulated voltage output terminal, and further comprising: a first transistor having an emitter, a collector and a base, the first transistor having a first base-emitter voltage characteristic, the collector of the first transistor being connected through a first resistor to a current source. The current source is derived from the unregulated voltage, the emitter of the first transistor being connected through a second resistor to a reference voltage; and a second transistor having an emitter, a collector and a base, the second transistor having a second base-emitter voltage characteristic, the base of the second transistor being connected to the collector of the first transistor. The collector of the second transistor is connected to the current source, the emitter of the second transistor being connected to the reference voltage. The regulated output of the voltage regulator is provided at the collector of the second transistor and the regulated voltage output is a function of the first base-emitter voltage characteristic of the first transistor plus the quantity comprising the difference between the first base-emitter voltage characteristic of the first transistor and the second base-emitter voltage characteristic of the second transistor, times the ratio of the value of resistance of the first resistor and the value of resistance of the second resistor. The improvement described here comprises: a third transistor having a collector, an emitter and a base.

  6. NORM regulations

    SciTech Connect

    Gray, P.

    1997-02-01

    The author reviews the question of regulation for naturally occuring radioactive material (NORM), and the factors that have made this a more prominent concern today. Past practices have been very relaxed, and have often involved very poor records, the involvment of contractors, and the disposition of contaminated equipment back into commercial service. The rationale behind the establishment of regulations is to provide worker protection, to exempt low risk materials, to aid in scrap recycling, to provide direction for remediation and to examine disposal options. The author reviews existing regulations at federal and state levels, impending legislation, and touches on the issue of site remediation and potential liabilities affecting the release of sites contaminated by NORM.

  7. Young Adult Smoking Behavior

    PubMed Central

    Ling, Pamela M.; Neilands, Torsten B.; Glantz, Stanton A.

    2009-01-01

    Background Young adults have the highest smoking rate of any age group in the U.S., and new strategies to decrease young adult smoking are needed. The objective of the current study was to identify psychographic and demographic factors associated with current smoking and quitting behaviors among young adults. Methods Attitudes, social groups, and self-descriptors, including supporting action against the tobacco industry, advertising receptivity, depression, alcohol use, and other factors associated with smoking were tested for associations with smoking behaviors in a 2005 cross-sectional survey of 1528 young adults (aged 18–25 years) from a web-enabled panel. Analyses were conducted in 2007. Results Being older was associated with current smoking, whereas having some higher education and being African American or Hispanic were negatively associated with smoking. Supporting action against the tobacco industry was negatively associated with smoking (AOR=0.34 [95% CI=0.22, 0.52]). Perceived usefulness of smoking, exposure to smokers, increased perceived smoking prevalence, receptivity to tobacco advertising, binge drinking, and exposure to tobacco advertising in bars and clubs were associated with smoking. Supporting action against the tobacco industry was associated with intentions to quit smoking (AOR= 4.43 [95% CI=2.18, 8.60]). Conclusions Young adults are vulnerable to tobacco-industry advertising. Media campaigns that denormalize the tobacco industry and appeal to young adults appear to be a powerful intervention to decrease young adult smoking. PMID:19269128

  8. Depression in Older Adults

    PubMed Central

    Fiske, Amy; Wetherell, Julie Loebach; Gatz, Margaret

    2010-01-01

    Depression is less prevalent among older adults than among younger adults but can have serious consequences. Over half of cases represent a first onset in later life. Although suicide rates in the elderly are declining, they are still higher than in younger adults and more closely associated with depression. Depressed older adults are less likely to endorse affective symptoms and more likely to display cognitive changes, somatic symptoms, and loss of interest than are younger adults. Risk factors leading to the development of late life depression likely comprise complex interactions among genetic vulnerabilities, cognitive diathesis, age-associated neurobiological changes, and stressful events. Insomnia is an often overlooked risk factor for late life depression. We suggest that a common pathway to depression in older adults, regardless of which predisposing risks are most prominent, may be curtailment of daily activities. Accompanying self-critical thinking may exacerbate and maintain a depressed state. Offsetting the increasing prevalence of certain risk factors in late life are age-related increases in psychological resilience. Other protective factors include higher education and socioeconomic status, engagement in valued activities, and religious or spiritual involvement. Treatments including behavioral therapy, cognitive behavioral therapy, cognitive bibliotherapy, problem-solving therapy, brief psychodynamic therapy, and life review/reminiscence therapy are effective but too infrequently used with older adults. Preventive interventions including education for individuals with chronic illness, behavioral activation, cognitive restructuring, problem-solving skills training, group support, and life review have also received support. PMID:19327033

  9. Obsessive Compulsive Disorder among Adults

    MedlinePlus

    ... Hyperactivity Disorder Among Children Autism Spectrum Disorder (ASD) Eating Disorders Among Adults - Anorexia Nervosa Eating Disorders Among Adults - Binge Eating Disorder Eating Disorders Among ...

  10. Brainstem Glioma in Adults

    PubMed Central

    Hu, Jethro; Western, Stephen; Kesari, Santosh

    2016-01-01

    Brainstem gliomas are not nearly as common in adults as they are in children. They are likely the final common consequence not of a single disease process but of several. They can be difficult to diagnose, and are challenging to treat. Clinical studies of this diagnosis are few and generally small. Because of these factors, our understanding of the biology of adult brainstem glioma is incomplete. However, the knowledge base is growing and progress is being made. In this article, we review the current state of knowledge for brainstem glioma in adults and identify key areas for which additional information is required. PMID:27556016

  11. Emotion Regulation in Sexually Abused Preschoolers.

    PubMed

    Langevin, Rachel; Cossette, Louise; Hébert, Martine

    2016-02-01

    Emotion regulation is closely related to mental health in children and adults. Low emotion regulation competencies have been found in school-aged sexually abused girls. The aim of the present study was to investigate emotion regulation competencies in sexually abused preschool girls and boys using a multi-informant approach. Emotion regulation was assessed in 62 sexually abused and 65 non-abused preschoolers using the Emotion Regulation Checklist and the MacArthur Story Stem Battery. Both parents and educators reported lower emotion regulation competencies in sexually abused preschoolers, especially boys, than in non-abused children. The narrative task completed by the children also revealed lower emotion regulation competencies in sexually abused boys. These findings could have an important impact on intervention programs offered to these at-risk children. PMID:25724803

  12. Pubertal development and regulation.

    PubMed

    Abreu, Ana Paula; Kaiser, Ursula B

    2016-03-01

    Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors. This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood, and its reactivation culminates in puberty initiation. The mechanisms underlying this reactivation are not completely known. The age of puberty onset varies between individuals and the timing of puberty initiation is associated with several health outcomes in adult life. In this Series paper, we discuss pubertal markers, epidemiological trends of puberty initiation over time, and the mechanisms whereby genetic, metabolic, and other factors control secretion of gonadotropin-releasing hormone to determine initiation of puberty. PMID:26852256

  13. Self-Regulated Learning in Doctor of Physical Therapy Students

    ERIC Educational Resources Information Center

    Heath, Amy E.

    2013-01-01

    There is a paucity of adult professional education literature, yet there are multiple theories and models from which to extrapolate information regarding learning in this population, including self-regulated learning theory and adult learning models. The first aim of this study was to explore these bodies of literature and provide a compelling…

  14. Older Adults and Drinking

    MedlinePlus

    ... this page please turn JavaScript on. Feature: Rethinking Drinking Older Adults and Drinking Past Issues / Spring 2014 Table of Contents Generally, ... liver problems, osteoporosis, memory problems, and mood disorders. Drinking and Medications Many medications, such as the ones ...

  15. The Colonial Adult Educator

    ERIC Educational Resources Information Center

    Long, Huey B.

    1975-01-01

    The adult evening schools of colonial America served a mixed clientele and provided instruction in a variety of subjects. Although most historians have described evening schoolmasters as incompetent frauds, research indicates that such descriptions are generally unjust and unfounded. (NHM)

  16. Motivation and Adult Education.

    ERIC Educational Resources Information Center

    Taylor, J. Rodney

    1982-01-01

    The author reviews theories of human motivation: Lewin's force field analysis, Skinner's operant reinforcement theory, and Maslow's hierarchy of needs. He then extracts the implications of these theories for adult learning. SK)

  17. CPR - adult - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100219.htm CPR - adult - series To use the sharing features on ... A.M. Editorial team. Related MedlinePlus Health Topics CPR A.D.A.M., Inc. is accredited by ...

  18. Mosquito, adult (image)

    MedlinePlus

    This illustration shows an adult southern house mosquito. This mosquito feeds on blood and is the carrier of many diseases, such as encephalitis, West Nile, dengue fever, yellow fever, and others. ( ...

  19. About BMI for Adults

    MedlinePlus

    ... Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs About Adult BMI Language: ... Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs Language: English Español (Spanish) ...

  20. Pneumonia - adults - discharge

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000017.htm Pneumonia in adults - discharge To use the sharing features on this page, please enable JavaScript. You have pneumonia, which is an infection in your lungs. In ...