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Sample records for d1 receptor-dependent 3hgaba

  1. Single exposure to cocaine impairs aspartate uptake in the pre-frontal cortex via dopamine D1-receptor dependent mechanisms.

    PubMed

    Sathler, Matheus Figueiredo; Stutz, Bernardo; Martins, Robertta Silva; Dos Santos Pereira, Maurício; Pecinalli, Ney Roner; Santos, Luis E; Taveira-da-Silva, Rosilane; Lowe, Jennifer; de Freitas, Isis Grigorio; de Melo Reis, Ricardo Augusto; Manhães, Alex C; Kubrusly, Regina C C

    2016-08-04

    Dopamine and glutamate play critical roles in the reinforcing effects of cocaine. We demonstrated that a single intraperitoneal administration of cocaine induces a significant decrease in [(3)H]-d-aspartate uptake in the pre-frontal cortex (PFC). This decrease is associated with elevated dopamine levels, and requires dopamine D1-receptor signaling (D1R) and adenylyl cyclase activation. The effect was observed within 10min of cocaine administration and lasted for up to 30min. This rapid response is related to D1R-mediated cAMP-mediated activation of PKA and phosphorylation of the excitatory amino acid transporters EAAT1, EAAT2 and EAAT3. We also demonstrated that cocaine exposure increases extracellular d-aspartate, l-glutamate and d-serine in the PFC. Our data suggest that cocaine activates dopamine D1 receptor signaling and PKA pathway to regulate EAATs function and extracellular EAA level in the PFC.

  2. Adolescent nicotine-induced dendrite remodeling in the nucleus accumbens is rapid, persistent, and D1-dopamine receptor dependent.

    PubMed

    Ehlinger, D G; Bergstrom, H C; Burke, J C; Fernandez, G M; McDonald, C G; Smith, R F

    2016-01-01

    Chronic nicotine exposure during adolescence induces dendritic remodeling of medium spiny neurons (MSNs) in the nucleus accumbens (NAcc) shell. While nicotine-induced dendritic remodeling has frequently been described as persistent, the trajectory of dendrite remodeling is unknown. Specifically, no study to date has characterized the structural plasticity of dendrites in the NAcc immediately following chronic nicotine, leaving open the possibility that dendrite remodeling emerges gradually over time. Further, the neuropharmacological mechanisms through which nicotine induces dendrite remodeling are not well understood. To address these questions, rats were co-administered chronic nicotine (0.5 mg/kg) and the D1-dopamine receptor (D1DR) antagonist SCH-23390 (0.05 mg/kg) subcutaneously every other day during adolescence. Brains were then processed for Golgi-Cox staining either 1 day or 21 days following drug exposure and dendrites from MSNs in the NAcc shell digitally reconstructed in 3D. Spine density was also measured at both time points. Our morphometric results show (1) the formation of new dendritic branches and spines 1 day following nicotine exposure, (2) new dendritic branches, but not spine density, remains relatively stable for at least 21 days, (3) the co-administration of SCH-23390 completely blocked nicotine-induced dendritic remodeling of MSNs at both early and late time points, suggesting the formation of new dendritic branches in response to nicotine is D1DR-dependent, and (4) SCH-23390 failed to block nicotine-induced increases in spine density. Overall this study provides new insight into how nicotine influences the normal trajectory of adolescent brain development and demonstrates a persistent form of nicotine-induced neuroplasticity in the NAcc shell that develops rapidly and is D1DR dependent.

  3. Methamphetamine induces Shati/Nat8L expression in the mouse nucleus accumbens via CREB- and dopamine D1 receptor-dependent mechanism

    PubMed Central

    Uno, Kyosuke; Miyazaki, Toh; Sodeyama, Kengo; Miyamoto, Yoshiaki

    2017-01-01

    Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated N-acetylaspartylglutamate following N-acetylaspartate increase due to the overexpression. These findings suggest that Shati/Nat8L suppresses METH-induced responses. However, the mechanism by which METH increases the Shati/Nat8L mRNA expression in NAc is unclear. To investigate the regulatory mechanism of Shati/Nat8L mRNA expression, we performed a mouse Shati/Nat8L luciferase assay using PC12 cells. Next, we investigated the response of METH to Shati/Nat8L expression and CREB activity using mouse brain slices of NAc, METH administration to mice, and western blotting for CREB activity of specific dopamine receptor signals in vivo and ex vivo. We found that METH activates CREB binding to the Shati/Nat8L promoter to induce the Shati/Nat8L mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of Shati/Nat8L and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the Shati/Nat8L mRNA expression in mouse NAc. These results showed that the Shati/Nat8L mRNA was increased by METH-induced CREB pathway via dopamine D1 receptor signaling in mouse NAc. These findings may contribute to development of a clinical tool for METH addiction. PMID:28319198

  4. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning.

    PubMed

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  5. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning

    PubMed Central

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  6. Spacelab D-1 mission

    NASA Technical Reports Server (NTRS)

    Dunbar, Bonnie J.

    1990-01-01

    The Spacelab D-1 (Deutchland Eins) Mission is discussed from the points of view of safety, materials handling, and toxic materials; the laboratory and equipment used; and some of the different philosophies utilized on this flight. How to enhance scientific return at the same time as being safe was examined.

  7. D1 Mission Project Implementation

    NASA Astrophysics Data System (ADS)

    Brandt, Gunther

    1982-02-01

    The mission D1 is the first complete SL mission in the framework of the German Manned Space Program. This Mission will be under the mission management responsibility of the German Space Agency DFVLR. Its primary objective is to support basic and applied research in the following fields: materials processing, fluid physics, medicine, biology, botany. A further mission objective is to test: instrument reflyability (reuse of FSLP equipment, efficiency of crew operations in space and economies possible in crew operations. An important spin-off will be establishment of the management capability to implement and control complex manned space programs. This paper describes how the D1 project is implemented under German mission management responsibility. The major project tasks as they will be performed using German facilities, in particular all D1 unique aspects, will be addressed.

  8. Topological strings in d < 1

    NASA Astrophysics Data System (ADS)

    Dijkgraaf, Robbert; Verlinde, Herman; Verlinde, Erik

    1991-03-01

    We calculate correlation functions in minimal topological field theories. These twisted versions of N = 2 minimal models have recently been proposed to describe d < 1 matrix models, once coupled to topological gravity. In our calculation we make use of the Landau-Ginzburg formulation of the N = 2 models, and we find a direct relation between the Landau-Ginzburg superpotential and the KdV differential operator. Using this correspondence we show that the minimal topological models are in perfect agreement with the matrix models as solved in terms of the KdV hierarchy. This proves the equivalence at tree-level of topological and ordinary string thoery in d < 1.

  9. A calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression.

    PubMed

    Jurado, Sandra; Biou, Virginie; Malenka, Robert C

    2010-09-01

    AKAP79/150 is a protein scaffold that is thought to position specific kinases (protein kinase A and C) and phosphatases (calcineurin) in appropriate synaptic domains so that their activities can regulate excitatory synaptic strength. Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin.

  10. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  11. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

    PubMed Central

    2011-01-01

    Background Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments. Results We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7. Conclusions These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. PMID:22182308

  12. IL-10 mediates sigma 1 receptor-dependent suppression of antitumor immunity.

    PubMed

    Zhu, Li X; Sharma, Sherven; Gardner, Brian; Escuadro, Brian; Atianzar, Kimberly; Tashkin, Donald P; Dubinett, Steven M

    2003-04-01

    Sigma receptors are unique endoplasmic reticulum proteins that mediate signaling for a variety of drugs. We determined the effect of sigma(1) receptor agonists on immune responses in a syngeneic lung cancer model. Sigma(1) receptor agonists, including cocaine, up-regulated splenocyte IL-10 mRNA and protein production in vitro in a sigma receptor-dependent, pertussis toxin-sensitive manner. In vivo, sigma(1) receptor agonists promoted tumor growth and induced IL-10 at the tumor site. Increased tumor growth was prevented by administration of specific Abs to IL-10 or by administration of specific sigma(1) receptor antagonists. We report that sigma(1) receptor ligands, including cocaine, augment tumor growth through an IL-10 dependent mechanism.

  13. Cyclin D1 expression in prostate carcinoma.

    PubMed

    Pereira, R A; Ravinal, R C; Costa, R S; Lima, M S; Tucci, S; Muglia, V F; Reis, R B dos; Silva, G E B

    2014-06-01

    The purpose of this study was to investigate the relationship between cyclin D1 expression and clinicopathological parameters in patients with prostate carcinoma. We assessed cyclin D1 expression by conventional immunohistochemistry in 85 patients who underwent radical prostatectomy for prostate carcinoma and 10 normal prostate tissue samples retrieved from autopsies. We measured nuclear immunostaining in the entire tumor area and based the results on the percentage of positive tumor cells. The preoperative prostate-specific antigen (PSA) level was 8.68±5.16 ng/mL (mean±SD). Cyclin D1 staining was positive (cyclin D1 expression in >5% of tumor cells) in 64 cases (75.4%) and negative (cyclin D1 expression in ≤5% of tumor cells) in 21 cases (including 15 cases with no immunostaining). Normal prostate tissues were negative for cyclin D1. Among patients with a high-grade Gleason score (≥7), 86% of patients demonstrated cyclin D1 immunostaining of >5% (P<0.05). In the crude analysis of cyclin D1 expression, the high-grade Gleason score group showed a mean expression of 39.6%, compared to 26.9% in the low-grade Gleason score group (P<0.05). Perineural invasion tended to be associated with cyclin D1 expression (P=0.07), whereas cyclin D1 expression was not associated with PSA levels or other parameters. Our results suggest that high cyclin D1 expression could be a potential marker for tumor aggressiveness.

  14. 7 CFR 15d.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Purpose. 15d.1 Section 15d.1 Agriculture Office of the Secretary of Agriculture NONDISCRIMINATION IN PROGRAMS OR ACTIVITIES CONDUCTED BY THE UNITED STATES... policy of the United States Department of Agriculture in programs or activities conducted by...

  15. 7 CFR 15d.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Purpose. 15d.1 Section 15d.1 Agriculture Office of the Secretary of Agriculture NONDISCRIMINATION IN PROGRAMS OR ACTIVITIES CONDUCTED BY THE UNITED STATES... policy of the United States Department of Agriculture in programs or activities conducted by...

  16. HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression

    PubMed Central

    Revollo, Javier R.; Oakley, Robert H.; Lu, Nick Z.; Kadmiel, Mahita; Gandhavadi, Maheer; Cidlowski, John A.

    2014-01-01

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the genome. We now establish a genome wide molecular link between HES1 and glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This glucocorticoid-dependent repression of HES1 was necessary for the glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper glucocorticoid signaling. PMID:24300895

  17. Phagocytosis of aggregated lipoprotein by macrophages: Low density lipoprotein receptor-dependent foam-cell formation

    SciTech Connect

    Suits, A.G.; Chait, A.; Aviram, M.; Heinecke, J.W. )

    1989-04-01

    Low density lipoprotein (LDL) modified by incubation with phospholipase C (PLC-LDL) aggregates in solution and is rapidly taken up and degraded by human and mouse macrophages, producing foam cells in vitro. Human, mouse, and rabbit macrophages degraded {sup 125}I-labeled PLC-LDL ({sup 125}I-PLC-LDL) more rapidly than native {sup 125}I-labeled LDL ({sup 125}I-LDL), while nonphagocytic cells such as human fibroblasts and bovine aortic endothelial cells degraded {sup 125}I-PLC-LDL more slowly than {sup 125}I-LDL. This suggested the mechanism for internalization of PLC-LDL was phagocytosis. When examined by electron microscopy, mouse peritoneal macrophages appeared to be phagocytosing PLC-LDL. The uptake and degradation of {sup 125}I-PLC-LDL by human macrophages was inhibited >80% by the monoclonal antibody C7 (IgG2b) produced by hybridoma C7, which blocks the ligand binding domain of the LDL receptor. Similarly, methylation of {sup 125}I-LDL ({sup 125}I-MeLDL) prior to treatment with phospholipase C decreased its subsequent uptake and degradation by human macrophages by >90%. The uptake and degradation of phospholipase C-modified {sup 125}I-MeLDL by macrophages could be restored by incubation of the methylated lipoprotein with apoprotein E, a ligand recognized by the LDL receptor. These results indicate that macrophages internalize PLC-LDL by LDL receptor-dependent phagocytosis.

  18. The receptor-dependent LQTA-QSAR: application to a set of trypanothione reductase inhibitors

    NASA Astrophysics Data System (ADS)

    Barbosa, Euzébio G.; Pasqualoto, Kerly Fernanda M.; Ferreira, Márcia M. C.

    2012-09-01

    A new Receptor- Dependent LQTA- QSAR approach, RD- LQTA- QSAR, is proposed as a new 4D-QSAR method. It is an evolution of receptor independent LQTA-QSAR. This approach uses the free GROMACS package to carry out molecular dynamics simulations and generates a conformational ensemble profile for each compound. Such an ensemble is used to build molecular interaction field-based QSAR models, as in CoMFA. To show the potential of this methodology, a set of 38 phenothiazine derivatives that are specific competitive T. cruzi trypanothione reductase inhibitors, was chosen. Using a combination of molecular docking and molecular dynamics simulations, the binding mode of the phenotiazine derivatives was evaluated in a simulated induced fit approach. The ligands alignments were performed using both ligand and binding site atoms, enabling unbiased alignment. The models obtained were extensively validated by leave- N-out cross-validation and y-randomization techniques to test for their robustness and absence of chance correlation. The final model presented Q 2 LOO of 0.87 and R² of 0.92 and a suitable external prediction of Q_{ext}2 = 0.78. The adapted binding site obtained is useful to perform virtual screening and ligand structure-based design and the descriptors in the final model can aid in the design new inhibitors.

  19. β-caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

    PubMed Central

    Horváth, Béla; Mukhopadhyay, Partha; Kechrid, Malek; Patel, Vivek; Tanashian, Galin; Wink, David A.; Gertsch, Jürg; Pacher, Pál

    2012-01-01

    (E)-β-caryophyllene (BCP) is a natural sequiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB2) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2, NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB2 knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB2 receptor dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in multitude of diseases associated with inflammation and oxidative stress. PMID:22326488

  20. β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner.

    PubMed

    Horváth, Béla; Mukhopadhyay, Partha; Kechrid, Malek; Patel, Vivek; Tanchian, Galin; Wink, David A; Gertsch, Jürg; Pacher, Pál

    2012-04-15

    (E)-β-caryophyllene (BCP) is a natural sesquiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB(2)) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2 and NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB(2) knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB(2) receptor-dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in a multitude of diseases associated with inflammation and oxidative stress.

  1. Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism.

    PubMed

    Hayakawa, Kazuhide; Mishima, Kenichi; Hazekawa, Mai; Sano, Kazunori; Irie, Keiichi; Orito, Kensuke; Egawa, Takashi; Kitamura, Yoshihisa; Uchida, Naoki; Nishimura, Ryoji; Egashira, Nobuaki; Iwasaki, Katsunori; Fujiwara, Michihiro

    2008-01-10

    Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). However, such interactions have not sufficiently been clear and may have important implications for understanding the pharmacological effects of marijuana. In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Delta(9)-THC on locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory in the eight-arm radial maze task in mice. In addition, we measured expression level of cannabinoid CB(1) receptor at striatum, cortex, hippocampus and hypothalamus. Delta(9)-THC (1, 3, 6 and 10 mg/kg) induced hypoactivity, catalepsy-like immobilisation and hypothermia in a dose-dependent manner. In addition, Delta(9)-THC (1, 3 and 6 mg/kg) dose-dependently impaired spatial memory in eight-arm radial maze. On the other hand, cannabidiol (1, 3, 10, 25 and 50 mg/kg) did not affect locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory on its own. However, higher dose of cannabidiol (10 or 50 mg/kg) exacerbated pharmacological effects of lower dose of Delta(9)-THC, such as hypoactivity, hypothermia and impairment of spatial memory. Moreover, cannabidiol (50 mg/kg) with Delta(9)-THC (1 mg/kg) enhanced the expression level of CB(1) receptor expression in hippocampus and hypothalamus. Cannabidiol potentiated pharmacological effects of Delta(9)-THC via CB(1) receptor-dependent mechanism. These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.

  2. Blueberry-enriched diet ameliorates age-related declines in NMDA receptor-dependent LTP

    PubMed Central

    Bickford, Paula C.; Browning, Michael D.

    2008-01-01

    NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus is widely accepted as a cellular substrate for memory formation. Age-related declines in the expression of both NMDAR-dependent LTP and NMDAR subunit proteins in the CA1 region of the hippocampus have been well characterized and likely underlie age-related memory impairment. In the current study, we examined NMDAR-dependent LTP in young Fischer 344 rats (4 months old) and aged rats (24 months old) given either a control diet or a diet supplemented with blueberry extract for 6–8 weeks. NMDAR-dependent LTP was evoked by high-frequency stimulation (HFS) in the presence of nifedipine, to eliminate voltage-gated calcium channel LTP. Field excitatory postsynaptic potentials (fEPSPs) were increased by 57% 1 h after HFS in young animals, but this potentiation was reduced to 31% in aged animals. Supplementation of the diet with blueberry extract elevated LTP (63%) in aged animals to levels seen in young. The normalization of LTP may be due to the blueberry diet preventing a decline in synaptic strength, as measured by the slope of the fEPSP for a given fiber potential. The blueberry diet did not prevent age-related declines in NMDAR protein expression. However, phosphorylation of a key tyrosine residue on the NR2B subunit, important for increasing NMDAR function, was enhanced by the diet, suggesting that an increase in NMDAR function might overcome the loss in protein. This report provides evidence that dietary alterations later in life may prevent or postpone the cognitive declines associated with aging. PMID:19424850

  3. 42 CFR 52d.1 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.1 Applicability. The regulations in this part apply to grants under the Clinical Cancer Education Program authorized by section 404(a)(4) of the Public Health Service Act,...

  4. 42 CFR 52d.1 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.1 Applicability. The regulations in this part apply to grants under the Clinical Cancer Education Program authorized by section 404(a)(4) of the Public Health Service Act,...

  5. 42 CFR 52d.1 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.1 Applicability. The regulations in this part apply to grants under the Clinical Cancer Education Program authorized by section 404(a)(4) of the Public Health Service Act,...

  6. 42 CFR 52d.1 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.1 Applicability. The regulations in this part apply to grants under the Clinical Cancer Education Program authorized by section 404(a)(4) of the Public Health Service Act,...

  7. 42 CFR 52d.1 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.1 Applicability. The regulations in this part apply to grants under the Clinical Cancer Education Program authorized by section 404(a)(4) of the Public Health Service Act,...

  8. Stereocontrolled total synthesis of neuroprotectin D1 / protectin D1 and its aspirin-triggered stereoisomer

    PubMed Central

    Petasis, Nicos A.; Yang, Rong; Winkler, Jeremy W.; Zhu, Min; Uddin, Jasim; Bazan, Nicolas G.; Serhan, Charles N.

    2012-01-01

    Neuroprotectin D1 / protectin D1, a potent anti-inflammatory, proresolving, and neuroprotective lipid mediator derived biosynthetically from docosahexaenoic acid, was prepared in enantiomerically pure form via total organic synthesis. The synthetic strategy is highly stereocontrolled and convergent, featuring epoxide opening of glycidol starting materials for the introduction of the 10(R) and 17(S) hydroxyl groups. The desired alkene Z geometry was secured via the cis-reduction of alkyne precursors, while the conjugated E,E,Z triene was introduced at the end, in order to minimize Z/E isomerization. The same strategy, was also employed for the total synthesis of aspirin-triggered neuroprotectin D1 / protectin D1 having the 17(R)-stereochemistry. Synthetic compounds obtained with the reported method were matched with endogenously derived materials, and helped establish their complete stereochemistry. PMID:22690022

  9. Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory

    PubMed Central

    Martel, Guillaume; Uchida, Shusaku; Hevi, Charles; Chévere-Torres, Itzamarie; Fuentes, Ileana; Park, Young Jin; Hafeez, Hannah; Yamagata, Hirotaka; Watanabe, Yoshifumi

    2016-01-01

    Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG. SIGNIFICANCE STATEMENT In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an

  10. 75 FR 27411 - Airworthiness Directives; Turbomeca Arriel 1B, 1D, 1D1, and 1S1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    ... (that incorporate Turbomeca Modification (mod) TU 148), Arriel 1D, 1D1, and 1S1 turboshaft engines that do not incorporate mod TU 347. That AD also requires initial and repetitive replacements of 2nd stage... incorporate mod TU 148), 1D, 1D1, and 1S1 turboshaft engines that do not incorporate mod TU 347. We...

  11. Cocaine withdrawal impairs metabotropic glutamate receptor-dependent long-term depression in the nucleus accumbens.

    PubMed

    Huang, Chiung-Chun; Yeh, Che-Ming; Wu, Mei-Ying; Chang, Alice Y W; Chan, Julie Y H; Chan, Samuel H H; Hsu, Kuei-Sen

    2011-03-16

    Neuroadaptation in the nucleus accumbens (NAc), a central component of the mesolimbic dopamine (DA) system, has been implicated in the development of cocaine-induced psychomotor sensitization and relapse to cocaine seeking. However, little is known about the cellular and synaptic mechanisms underlying such adaptation. Using a mouse model of behavioral sensitization, we show that animals withdrawn from repeated cocaine exposure have a selective deficit in the ability to elicit metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in the shell of the NAc in response to bath application of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Experiments conducted in the presence of the selective mGluR1 antagonists 7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid, or the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine, demonstrated that the impaired DHPG-LTD is likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcriptase-PCR and Western blot analysis revealed significant downregulation of mGluR5, but not mGluR1, mRNA and protein levels in the NAc shell. The inhibitory effect of repeated cocaine exposure on DHPG-LTD was selectively prevented when cocaine was coadministered with the selective D(1)-like DA receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Furthermore, the levels of brain-derived neurotrophic factor (BDNF) protein in the NAc shell increased progressively after cocaine withdrawal, and the impairment of DHPG-LTD in the NAc shell was not found in slices from BDNF-knock-out mice after cocaine withdrawal. These results suggest that withdrawal from repeated cocaine exposure may result in increased BDNF levels in the NAc shell, which leads to a selective downregulation of mGluR5 and thereby impairs the induction of mGluR-dependent LTD.

  12. The Phospholipase D1 Pathway Modulates Macroautophagy

    PubMed Central

    Dall’Armi, Claudia; Hurtado-Lorenzo, Andres; Tian, Huasong; Morel, Etienne; Nezu, Akiko; Chan, Robin B.; Yu, W. Haung; Robinson, Kimberly S.; Yeku, Oladapo; Small, Scott A.; Duff, Karen; Frohman, Michael A.; Wenk, Markus R.; Yamamoto, Akitsugu; Di Paolo, Gilbert

    2012-01-01

    While macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. Here we show that phospholipase D1 (PLD1), which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation. The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in the mouse decrease the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of tau and p62 aggregates in organotypic brain slices. Our in vitro and in vivo findings establish a novel role for PLD1 in autophagy. PMID:21266992

  13. Medial prefrontal D1 dopamine neurons control food intake

    PubMed Central

    Land, Benjamin B; Narayanan, Nandakumar S; Liu, Rong-Jian; Gianessi, Carol A; Brayton, Catherine E; Grimaldi, David; Sarhan, Maysa; Guarnieri, Douglas J; Deisseroth, Karl; Aghajanian, George K; Dileone, Ralph J

    2014-01-01

    Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake. PMID:24441680

  14. Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans.

    PubMed

    Hoiland, Ryan L; Bain, Anthony R; Tymko, Michael M; Rieger, Mathew G; Howe, Connor A; Willie, Christopher K; Hansen, Alex B; Flück, Daniela; Wildfong, Kevin W; Stembridge, Mike; Subedi, Prajan; Anholm, James; Ainslie, Philip N

    2017-04-01

    Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end-tidal gases were comparable (P > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the

  15. D1-protein dynamics in photosystem II: the lingering enigma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The D1/D2 heterodimer core dominates the photosystem II reaction center. A characteristic feature of this heterodimer is the differentially rapid, light-dependent degradation of the D1 protein. The D1 protein is possibly the most researched photosynthetic polypeptide, with aspects of structure–funct...

  16. AT-RvD1 Modulates CCL-2 and CXCL-8 Production and NF-κB, STAT-6, SOCS1, and SOCS3 Expression on Bronchial Epithelial Cells Stimulated with IL-4

    PubMed Central

    de Oliveira, Jhony Robison; Favarin, Daniely Cornélio; Tanaka, Sarah Cristina Sato Vaz; Balarin, Marly Aparecida Spadotto; Silva Teixeira, David Nascimento; Rogério, Alexandre de Paula

    2015-01-01

    Bronchial epithelial cells represent the first line of defense against microorganisms and allergens in the airways and play an important role in chronic inflammatory processes such as asthma. In an experimental model, both RvD1 and AT-RvD1, lipid mediators of inflammation resolution, ameliorated some of the most important phenotypes of experimental asthma. Here, we extend these results and demonstrate the effect of AT-RvD1 on bronchial epithelial cells (BEAS-2B) stimulated with IL-4. AT-RvD1 (100 nM) decreased both CCL2 and CXCL-8 production, in part by decreasing STAT6 and NF-κB pathways. Furthermore, the effects of AT-RvD1 were ALX/FRP2 receptor dependent, as the antagonist of this receptor (BOC1) reversed the inhibition of these chemokines by AT-RvD1. In addition, AT-RvD1 decreased SOCS1 and increased SOCS3 expression, which play important roles in Th1 and Th17 modulation, respectively. In conclusion, AT-RvD1 demonstrated significant effects on the IL-4-induced activation of bronchial epithelial cells and consequently the potential to modulate neutrophilic and eosinophilic airway inflammation in asthma. Taken together, these findings identify AT-RvD1 as a potential proresolving therapeutic agent for allergic responses in the airways. PMID:26075216

  17. Nucleic acid sequences encoding D1 and D1/D2 domains of human coxsackievirus and adenovirus receptor (CAR)

    DOEpatents

    Freimuth, Paul I.

    2010-04-06

    The invention provides recombinant human CAR (coxsackievirus and adenovirus receptor) polypeptides which bind adenovirus. Specifically, polypeptides corresponding to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2 are provided. In another aspect, the invention provides nucleic acid sequences encoding these domains and expression vectors for producing the domains and bacterial cells containing such vectors. The invention also includes an isolated fusion protein comprised of the D1 polypeptide fused to a polypeptide which facilitates folding of D1 when expressed in bacteria. The functional D1 domain finds application in a therapeutic method for treating a patient infected with a CAR D1-binding virus, and also in a method for identifying an antiviral compound which interferes with viral attachment. The invention also provides a method for specifically targeting a cell for infection by a virus which binds to D1.

  18. Epidermal growth factor receptor-dependent stimulation of amphiregulin expression in androgen-stimulated human prostate cancer cells.

    PubMed Central

    Sehgal, I; Bailey, J; Hitzemann, K; Pittelkow, M R; Maihle, N J

    1994-01-01

    Amphiregulin is a heparin-binding epidermal growth factor (EGF)-related peptide that binds to the EGF receptor (EGF-R) with high affinity. In this study, we report a role for amphiregulin in androgen-stimulated regulation of prostate cancer cell growth. Androgen is known to enhance EGF-R expression in the androgen-sensitive LNCaP human prostate carcinoma cell line, and it has been suggested that androgenic stimuli may regulate proliferation, in part, through autocrine mechanisms involving the EGF-R. In this study, we demonstrate that LNCaP cells express amphiregulin mRNA and peptide and that this expression is elevated by androgenic stimulation. We also show that ligand-dependent EGF-R stimulation induces amphiregulin expression and that androgenic effects on amphiregulin synthesis are mediated through this EGF-R pathway. Parallel studies using the estrogen-responsive breast carcinoma cell line, MCF-7, suggest that regulation of amphiregulin by estrogen may also be mediated via an EGF-R pathway. In addition, heparin treatment of LNCaP cells inhibits androgen-stimulated cell growth further suggesting that amphiregulin can mediate androgen-stimulated LNCaP proliferation. Together, these results implicate an androgen-regulated autocrine loop composed of amphiregulin and its receptor in prostate cancer cell growth and suggest that the mechanism of steroid hormone regulation of amphiregulin synthesis may occur through androgen upregulation of the EGF-R and subsequent receptor-dependent pathways. Images PMID:8049525

  19. NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis

    PubMed Central

    Glangetas, Christelle; Massi, Léma; Fois, Giulia R.; Jalabert, Marion; Girard, Delphine; Diana, Marco; Yonehara, Keisuke; Roska, Botond; Xu, Chun; Lüthi, Andreas; Caille, Stéphanie; Georges, François

    2017-01-01

    Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST). We find that an NMDA-receptor-dependent homosynaptic long-term potentiation is instrumental for anxiolysis. These findings suggest that the vSUB/CA1-driven LTP in the amBNST is involved in eliciting an appropriate response to anxiogenic context and dysfunction of this compensatory mechanism may underlie pathologic anxiety states. PMID:28218243

  20. Cyclin D1 regulates hepatic estrogen and androgen metabolism.

    PubMed

    Mullany, Lisa K; Hanse, Eric A; Romano, Andrea; Blomquist, Charles H; Mason, J Ian; Delvoux, Bert; Anttila, Chelsea; Albrecht, Jeffrey H

    2010-06-01

    Cyclin D1 is a cell cycle control protein that plays an important role in regenerating liver and many types of cancer. Previous reports have shown that cyclin D1 can directly enhance estrogen receptor activity and inhibit androgen receptor activity in a ligand-independent manner and thus may play an important role in hormone-responsive malignancies. In this study, we examine a distinct mechanism by which cyclin D1 regulates sex steroid signaling, via altered metabolism of these hormones at the tissue and cellular level. In male mouse liver, ectopic expression of cyclin D1 regulated genes involved in the synthesis and degradation of sex steroid hormones in a pattern that would predict increased estrogen and decreased androgen levels. Indeed, hepatic expression of cyclin D1 led to increased serum estradiol levels, increased estrogen-responsive gene expression, and decreased androgen-responsive gene expression. Cyclin D1 also regulated the activity of several key enzymatic reactions in the liver, including increased oxidation of testosterone to androstenedione and decreased conversion of estradiol to estrone. Similar findings were seen in the setting of physiological cyclin D1 expression in regenerating liver. Knockdown of cyclin D1 in HuH7 cells produced reciprocal changes in steroid metabolism genes compared with cyclin D1 overexpression in mouse liver. In conclusion, these studies establish a novel link between the cell cycle machinery and sex steroid metabolism and provide a distinct mechanism by which cyclin D1 may regulate hormone signaling. Furthermore, these results suggest that increased cyclin D1 expression, which occurs in liver regeneration and liver diseases, may contribute to the feminization seen in these settings.

  1. Fermions in d = 1 + 2 dimensions from first principles

    SciTech Connect

    Carrillo-Ruiz, Ma. Georgina; Napsuciale, Mauro

    2006-09-25

    In this work we construct states describing planar electrons ('spin' (1/2) particles with well defined parity) in d = 1 + 2 from first principles and show that they satisfy Dirac equation, which turns out to be the covariant form of the eigenvalue equation for spatial inversion (parity) just like in d = 1 + 3.

  2. 26 CFR 25.2523(d)-1 - Joint interests.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Joint interests. 25.2523(d)-1 Section 25.2523(d... TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2523(d)-1 Joint interests. Section 2523(d) provides that if a property interest is transferred to the donee spouse as sole joint...

  3. 26 CFR 25.2523(d)-1 - Joint interests.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Joint interests. 25.2523(d)-1 Section 25.2523(d... TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2523(d)-1 Joint interests. Section 2523(d) provides that if a property interest is transferred to the donee spouse as sole joint...

  4. 26 CFR 25.2523(d)-1 - Joint interests.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Joint interests. 25.2523(d)-1 Section 25.2523(d... TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2523(d)-1 Joint interests. Section 2523(d) provides that if a property interest is transferred to the donee spouse as sole joint...

  5. 26 CFR 25.2523(d)-1 - Joint interests.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Joint interests. 25.2523(d)-1 Section 25.2523(d... TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2523(d)-1 Joint interests. Section 2523(d) provides that if a property interest is transferred to the donee spouse as sole joint...

  6. 26 CFR 25.2523(d)-1 - Joint interests.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Joint interests. 25.2523(d)-1 Section 25.2523(d... TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2523(d)-1 Joint interests. Section 2523(d) provides that if a property interest is transferred to the donee spouse as sole joint...

  7. Opioid Receptor-Dependent Sex Differences in Synaptic Plasticity in the Hippocampal Mossy Fiber Pathway of the Adult Rat

    PubMed Central

    Harte-Hargrove, Lauren C.; Varga-Wesson, Ada; Duffy, Aine M.; Milner, Teresa A.

    2015-01-01

    The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17β-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 μm) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17β-estradiol levels are elevated. The μ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 μm) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 μm) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 μm) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17β-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus. PMID:25632146

  8. Interaction of environmental contaminants with zebrafish organic anion transporting polypeptide, Oatp1d1 (Slco1d1)

    SciTech Connect

    Popovic, Marta; Zaja, Roko; Fent, Karl; Smital, Tvrtko

    2014-10-01

    Polyspecific transporters from the organic anion transporting polypeptide (OATP/Oatp) superfamily mediate the uptake of a wide range of compounds. In zebrafish, Oatp1d1 transports conjugated steroid hormones and cortisol. It is predominantly expressed in the liver, brain and testes. In this study we have characterized the transport of xenobiotics by the zebrafish Oatp1d1 transporter. We developed a novel assay for assessing Oatp1d1 interactors using the fluorescent probe Lucifer yellow and transient transfection in HEK293 cells. Our data showed that numerous environmental contaminants interact with zebrafish Oatp1d1. Oatp1d1 mediated the transport of diclofenac with very high affinity, followed by high affinity towards perfluorooctanesulfonic acid (PFOS), nonylphenol, gemfibrozil and 17α-ethinylestradiol; moderate affinity towards carbaryl, diazinon and caffeine; and low affinity towards metolachlor. Importantly, many environmental chemicals acted as strong inhibitors of Oatp1d1. A strong inhibition of Oatp1d1 transport activity was found by perfluorooctanoic acid (PFOA), chlorpyrifos-methyl, estrone (E1) and 17β-estradiol (E2), followed by moderate to low inhibition by diethyl phthalate, bisphenol A, 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4 tetrahydronapthalene and clofibrate. In this study we identified Oatp1d1 as a first Solute Carrier (SLC) transporter involved in the transport of a wide range of xenobiotics in fish. Considering that Oatps in zebrafish have not been characterized before, our work on zebrafish Oatp1d1 offers important new insights on the understanding of uptake processes of environmental contaminants, and contributes to the better characterization of zebrafish as a model species. - Highlights: • We optimized a novel assay for determination of Oatp1d1 interactors • Oatp1d1 is the first SLC characterized fish xenobiotic transporter • PFOS, nonylphenol, diclofenac, EE2, caffeine are high affinity Oatp1d1substrates • PFOA, chlorpyrifos

  9. Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

    PubMed

    Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

    2015-12-01

    Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

  10. D1/D5 dopamine receptors modulate spatial memory formation.

    PubMed

    da Silva, Weber C N; Köhler, Cristiano C; Radiske, Andressa; Cammarota, Martín

    2012-02-01

    We investigated the effect of the intra-CA1 administration of the D1/D5 receptor antagonist SCH23390 and the D1/D5 receptor agonist SKF38393 on spatial memory in the water maze. When given immediately, but not 3h after training, SCH23390 hindered long-term spatial memory formation without affecting non-spatial memory or the normal functionality of the hippocampus. On the contrary, post-training infusion of SKF38393 enhanced retention and facilitated the spontaneous recovery of the original spatial preference after reversal learning. Our findings demonstrate that hippocampal D1/D5 receptors play an essential role in spatial memory processing.

  11. D1 dopamine receptors of NS20Y neuroblastoma cells are functionally similar to rat striatal D1 receptors.

    PubMed

    Lovenberg, T W; Roth, R H; Nichols, D E; Mailman, R B

    1991-11-01

    Dopamine or agonists with D1 receptor potency stimulated cyclic AMP (cAMP) accumulation in whole cell preparations of NS20Y neuroblastoma cells. The accumulation of cAMP after D1 stimulation was rapid and linear for 3 min. Both dopamine and the novel D1 receptor agonist dihydrexidine stimulated cAMP accumulation two- to three-fold over baseline. The pseudo-Km for dopamine was approximately 2 microM, whereas for dihydrexidine it was approximately 30 nM. The effects of both drugs were blocked by either the D1-selective antagonist SCH23390 (Ki, 0.3 nM) or the nonselective antagonist (+)-butaclamol (Ki, 5 nM). Both (-)-butaclamol and the D2-selective antagonist (-)-sulpiride were ineffective (Ki greater than 3 microM). Forskolin (10 microM), prostaglandin E1 (1 microM), and adenosine (10 microM) also stimulated cAMP accumulation, but none were antagonized by SCH23390 (1 microM). Finally, muscarinic receptor stimulation (100 microM carbachol) inhibited both D1- and forskolin-stimulated increases in cAMP accumulation by 80%. The present results indicate that NS20Y neuroblastoma cells have D1 receptors that are coupled to adenylate cyclase, and that these receptors have a pharmacological profile similar to that of the D1 receptor(s) found in rat striatum.

  12. D2-D1 phase transition of columnar liquid crystals

    NASA Astrophysics Data System (ADS)

    Sun, Y. F.; Swift, J.

    1986-04-01

    The D2-D1 phase transition in columnar liquid crystals of the HAT series [e.g., HAT11 (triphenelene hexa-n-dodecanoate)] is discussed within the framework of Landau theory. The order parameters which describe the transition are abstracted from a tensor density function, and are associated with two irreducible representations of the symmetry group of the high-temperature D2 phase. A mechanism for a first-order transition is then suggested in accordance with both theoretical considerations and the experimental result for the D2-D1 transition. Two possible arrangements of the herringbone structure of the D1 phase are obtained, each of which gives six orientational states in the low-temperature D1 phase.

  13. Dopamine D1 signaling organizes network dynamics underlying working memory

    PubMed Central

    Roffman, Joshua L.; Tanner, Alexandra S.; Eryilmaz, Hamdi; Rodriguez-Thompson, Anais; Silverstein, Noah J.; Ho, New Fei; Nitenson, Adam Z.; Chonde, Daniel B.; Greve, Douglas N.; Abi-Dargham, Anissa; Buckner, Randy L.; Manoach, Dara S.; Rosen, Bruce R.; Hooker, Jacob M.; Catana, Ciprian

    2016-01-01

    Local prefrontal dopamine signaling supports working memory by tuning pyramidal neurons to task-relevant stimuli. Enabled by simultaneous positron emission tomography–magnetic resonance imaging (PET-MRI), we determined whether neuromodulatory effects of dopamine scale to the level of cortical networks and coordinate their interplay during working memory. Among network territories, mean cortical D1 receptor densities differed substantially but were strongly interrelated, suggesting cross-network regulation. Indeed, mean cortical D1 density predicted working memory–emergent decoupling of the frontoparietal and default networks, which respectively manage task-related and internal stimuli. In contrast, striatal D1 predicted opposing effects within these two networks but no between-network effects. These findings specifically link cortical dopamine signaling to network crosstalk that redirects cognitive resources to working memory, echoing neuromodulatory effects of D1 signaling on the level of cortical microcircuits. PMID:27386561

  14. Underground storage tank 291-D1U1: Closure plan

    SciTech Connect

    Mancieri, S.; Giuntoli, N.

    1993-09-01

    The 291-D1U1 tank system was installed in 1983 on the north side of Building 291. It supplies diesel fuel to the Building 291 emergency generator and air compressor. The emergency generator and air compressor are located southwest and southeast, respectively, of the tank (see Appendix B, Figure 2). The tank system consists of a single-walled, 2,000- gallon, fiberglass tank and a fuel pump system, fill pipe, vent pipe, electrical conduit, and fuel supply and return piping. The area to be excavated is paved with asphalt and concrete. It is not known whether a concrete anchor pad is associated with this tank. Additionally, this closure plan assumes that the diesel tank is below the fill pad. The emergency generator and air compressor for Building 291 and its associated UST, 291-D1U1, are currently in use. The generator and air compressor will be supplied by a temporary above-ground fuel tank prior to the removal of 291-D1U1. An above-ground fuel tank will be installed as a permanent replacement for 291-D1U1. The system was registered with the State Water Resources Control Board on June 27, 1984, as 291-41D and has subsequently been renamed 291-D1U1. Figure 1 (see Appendix B) shows the location of the 291-D1U1 tank system in relation to the Lawrence Livermore National Laboratory (LLNL). Figure 2 (see Appendix B) shows the 291-D1U1 tank system in relation to Building 291. Figure 3 (see Appendix B) shows a plan view of the 291-D1U1 tank system.

  15. Dopamine D1 receptor involvement in latent inhibition and overshadowing.

    PubMed

    Nelson, Andrew J D; Thur, Karen E; Cassaday, Helen J

    2012-11-01

    Latent inhibition (LI) manifests as poorer conditioning to a stimulus that has previously been experienced without consequence. There is good evidence of dopaminergic modulation of LI, as the effect is reliably disrupted by the indirect dopamine (DA) agonist amphetamine. The disruptive effects of amphetamine on LI are reversed by both typical and atypical antipsychotics, which on their own are able to facilitate LI. However, the contribution of different DA receptors to these effects is poorly understood. Amphetamine effects on another stimulus selection procedure, overshadowing, have been suggested to be D1-mediated. Thus, in the current experiments, we systematically investigated the role of D1 receptors in LI. First, we tested the ability of the full D1 agonist SKF 81297 to abolish LI and compared the effects of this drug on LI and overshadowing. Subsequently, we examined whether the D1 antagonist SCH 23390 can lead to the emergence of LI under conditions that do not produce the effect in normal animals (weak pre-exposure). Finally, we tested the ability of SCH 23390 to block amphetamine-induced disruption of LI. We found little evidence that direct stimulation of D1 receptors abolishes LI (although there was some attenuation of LI at 0.4 mg/kg SKF 81297). Similarly, SCH 23390 failed to enhance LI. However, SCH 23390 did block amphetamine-induced disruption of LI. These data indicate that, while LI may be unaffected by selective manipulation of activity at D1 receptors, the effects of amphetamine on LI are to some extent dependent on actions at D1 receptors.

  16. Study of Light Scalar Meson Structure in D1 Decay

    NASA Astrophysics Data System (ADS)

    Hoshino, H.; Harada, M.; Ma, Y. L.

    2013-03-01

    We study the quark structure of the sigma meson through the decay of D1(2430) meson by constructing an effective Lagrangian for charmed mesons interacting with light mesons based on the chiral symmetry and heavy quark symmetry. Within the linear realization of the chiral symmetry, we include the P-wave charmed mesons (D1(2430), D0(2400)) as the chiral partners of (D., D), and the light scalar mesons as the chiral partner of the pseudoscalar mesons. In the light meson sector, both the qbar {q} and qqbar {q}bar {q} states are incorporated respecting their different U(1)A transformation properties. We predict the D1 → Dππ decay width with two pions in the I = 0, l = 0 channel, which can be tested in the future experiment. We find that the width increases with the percentage of the qbar {q} content in the sigma meson.

  17. Geoscience for Alaska's D-1 Lands: A preliminary report

    USGS Publications Warehouse

    Schmidt, Jeanine M.; Gamble, B.M.; Labay, K.A.

    2007-01-01

    Purpose of This Report This interim report follows from the June 2006 recommendations to Congress by the BLM concerning disposition of the d-1 lands. That report recommended lifting of a significant number of d-1 PLOs, through the ongoing land management process within the BLM (e.g. resource management planning areas), or through Congressional action. The strategic actions outlined in this document refer only to Federal lands under US Bureau of Land Management (BLM) jurisdiction that 1) are affected by temporary withdrawals from mineral entry and mineral leasing by PLOs made pursuant to the Section 17(d)(1) of the ANCSA; 2) have been identified by the BLM as candidates for possible lifting of these PLOs and restrictions (U.S. Bureau of Land Management, 2006); and 3) lie outside of current Federal parks, preserves, monuments, refuges, reserves, wilderness areas and military installations that are closed to mineral entry, because within those areas the potential lifting of the d-1 restrictions has no practical effect. The resulting lands discussed here comprise approximately 121,000 km2 (29.9 million acres) of Alaska (Table 1) that, pending final resolution of Native and State land claims, will or may remain under Federal (BLM) control, and could be opened to mineral entry. For the purposes of this report, only these 29.9 million acres will hereafter be referred to as 'd-1' lands. This report gives a brief overview of the spatial distribution and physiographic setting, mineral occurrences, and mineral resource potential of the d-1lands. It outlines further geoscience information which could be compiled, collected, and evaluated in order to make a more accurate and comprehensive examination of the potential for undiscovered, locatable mineral resources on these Federal lands. This information is intended to provide guidance to USGS program managers and Federal land managers on matters of future exploration, access needs, and consequences of land status changes.

  18. Inflammation compromises renal dopamine D1 receptor function in rats

    PubMed Central

    Chugh, Gaurav; Lokhandwala, Mustafa F.

    2009-01-01

    We tested the effects of inflammation on renal dopamine D1 receptor signaling cascade, a key pathway that maintains sodium homeostasis and blood pressure during increased salt intake. Inflammation was produced by administering lipopolysaccharide (LPS; 4 mg/kg ip) to rats provided without (normal salt) and with 1% NaCl in drinking water for 2 wk (high salt). Control rats had saline injection and received tap water. We found that LPS increased the levels of inflammatory cytokines, interleukin-6, and tumor necrosis factor-α in the rats given either normal- or high-salt intake. Also, these rats had higher levels of oxidative stress markers, malondialdehyde and nitrotyrosine, and lower levels of antioxidant enzyme superoxide dismutase in the renal proximal tubules (RPTs). The nuclear levels of transcription factors NF-κB increased and Nrf2 decreased in the RPTs in response to LPS in rats given normal and high salt. Furthermore, D1 receptor numbers, D1 receptor proteins, and D1 receptor agonist (SKF38393)-mediated 35S-GTPγS binding decreased in the RPTs in these rats. The basal activities of Na-K-ATPase in the RPTs were similar in control and LPS-treated rats given normal and high salt. SKF38393 caused inhibition of Na-K-ATPase activity in the primary cultures of RPTs treated with vehicle but not in the cultures treated with LPS. Furthermore, LPS caused an increase in blood pressure in the rats given high salt but not in the rats given normal salt. These results suggest that LPS differentially regulates NF-κB and Nrf2, produces inflammation, decreases antioxidant enzyme, increases oxidative stress, and causes D1 receptor dysfunction in the RPTs. The LPS-induced dysfunction of renal D1 receptors alters salt handling and causes hypertension in rats during salt overload. PMID:19794106

  19. Aberrant expression of cyclin D1 in cancer

    PubMed Central

    Inoue, Kazushi; Fry, Elizabeth A.

    2016-01-01

    Cyclin D1 binds and activates cyclin-dependent kinases 4/6 (Cdk4/6) to phosphorylate the retinoblastoma (RB) family proteins, relieving E2F/DPs from the negative restraint of RB proteins and histone deacetylases. The cyclin D-Cdk4/6 complexes activate cyclin E/Cdk2 through titration of the Cdk inhibitors p21Cip1/p27Kip1. Cyclin E/Cdk2 further phosphorylates RBs, thereby activating E2F/DPs, and cells enter the S phase of the cell cycle. Cyclin D-Cdk4/6 also phosphorylates MEP50 subunit of the protein arginine methyltransferase 5 (PRMT5), which cooperates with cyclin D1 to drive lymphomagenesis in vivo. Activated PRMPT5 causes arginine methylation of p53 to suppress expression of pro-apoptotic and anti-proliferative target genes, explaining the molecular mechanism for tumorigenesis. Cyclin D1 physically interacts with transcription factors such as estrogen receptor, androgen receptor, and Myb family proteins to regulate gene expression in Cdk-independent fashion. Dmp1 is a Myb-like protein that quenches the oncogenic signals from activated Ras or HER2 by inducing Arf/p53-dependent cell cycle arrest. Cyclin D1 binds to Dmp1α to activate both Arf and Ink4a promoters to induce cell cycle arrest or apoptosis in non-transformed cells to prevent them from neoplastic transformation. Dmp1-deficiency significantly accelerates mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Cyclin D1 interferes with ligand activation of PPARγ involved in cellular differentiation; it also physically interacts with histone deacetylases (HDACs) and p300 to repress gene expression. It has also been shown that cyclin D1 accelerates tumorigenesis through transcriptional activation of miR-17/20 and Dicer1 which, in turn, represses cyclin D1 expression. Identification of cyclin D1-binding proteins/promoters will be essential for further clarification of its biological activities. PMID:28090171

  20. In adult female hamsters hypothyroidism stimulates D1 receptor-mediated breathing without altering D1 receptor expression.

    PubMed

    Schlenker, Evelyn H; Del Rio, Rodrigo; Schultz, Harold D

    2015-11-01

    Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.

  1. The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.

    PubMed

    Yohn, Samantha E; Santerre, Jessica L; Nunes, Eric J; Kozak, Rouba; Podurgiel, Samantha J; Correa, Mercè; Salamone, John D

    2015-08-01

    Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.

  2. Underground storage tank 511-D1U1 closure plan

    SciTech Connect

    Mancieri, S.; Giuntoli, N.

    1993-09-01

    This document contains the closure plan for diesel fuel underground storage tank 511-D1U1 and appendices containing supplemental information such as staff training certification and task summaries. Precision tank test data, a site health and safety plan, and material safety data sheets are also included.

  3. 26 CFR 31.3231(d)-1 - Service.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Railroad Retirement Tax Act (Chapter 22, Internal Revenue Code of 1954) General Provisions § 31.3231(d)-1 Service....

  4. 17 CFR 270.35d-1 - Investment company names.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Investment company names. 270... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.35d-1 Investment company names. (a... registered investment company and any series of the investment company. (2) Assets means net assets, plus...

  5. 17 CFR 270.35d-1 - Investment company names.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Investment company names. 270... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.35d-1 Investment company names. (a... registered investment company and any series of the investment company. (2) Assets means net assets, plus...

  6. 17 CFR 270.35d-1 - Investment company names.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Investment company names. 270... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.35d-1 Investment company names. (a... registered investment company and any series of the investment company. (2) Assets means net assets, plus...

  7. 17 CFR 270.35d-1 - Investment company names.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Investment company names. 270... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.35d-1 Investment company names. (a... registered investment company and any series of the investment company. (2) Assets means net assets, plus...

  8. 17 CFR 270.35d-1 - Investment company names.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Investment company names. 270... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.35d-1 Investment company names. (a... registered investment company and any series of the investment company. (2) Assets means net assets, plus...

  9. Evolution of Dopamine Receptor Genes of the D1 Class in Vertebrates

    PubMed Central

    Yamamoto, Kei; Mirabeau, Olivier; Bureau, Charlotte; Blin, Maryline; Michon-Coudouel, Sophie; Demarque, Michaël; Vernier, Philippe

    2013-01-01

    The receptors of the dopamine neurotransmitter belong to two unrelated classes named D1 and D2. For the D1 receptor class, only two subtypes are found in mammals, the D1A and D1B, receptors, whereas additional subtypes, named D1C, D1D, and D1X, have been found in other vertebrate species. Here, we analyzed molecular phylogeny, gene synteny, and gene expression pattern of the D1 receptor subtypes in a large range of vertebrate species, which leads us to propose a new view of the evolution of D1 dopamine receptor genes. First, we show that D1C and D1D receptor sequences are encoded by orthologous genes. Second, the previously identified Cypriniform D1X sequence is a teleost-specific paralog of the D1B sequences found in all groups of jawed vertebrates. Third, zebrafish and several sauropsid species possess an additional D1-like gene, which is likely to form another orthology group of vertebrate ancestral genes, which we propose to name D1E. Ancestral jawed vertebrates are thus likely to have possessed four classes of D1 receptor genes—D1A, D1B(X), D1C(D), and D1E—which arose from large-scale gene duplications. The D1C receptor gene would have been secondarily lost in the mammalian lineage, whereas the D1E receptor gene would have been lost independently in several lineages of modern vertebrates. The D1A receptors are well conserved throughout jawed vertebrates, whereas sauropsid D1C receptors have rapidly diverged, to the point that they were misidentified as D1D. The functional significance of the D1C receptor loss is not known. It is possible that the function may have been substituted with D1A or D1B receptors in mammals, following the disappearance of D1C receptors in these species. PMID:23197594

  10. Evolution of dopamine receptor genes of the D1 class in vertebrates.

    PubMed

    Yamamoto, Kei; Mirabeau, Olivier; Bureau, Charlotte; Blin, Maryline; Michon-Coudouel, Sophie; Demarque, Michaël; Vernier, Philippe

    2013-04-01

    The receptors of the dopamine neurotransmitter belong to two unrelated classes named D1 and D2. For the D1 receptor class, only two subtypes are found in mammals, the D1A and D1B, receptors, whereas additional subtypes, named D1C, D1D, and D1X, have been found in other vertebrate species. Here, we analyzed molecular phylogeny, gene synteny, and gene expression pattern of the D1 receptor subtypes in a large range of vertebrate species, which leads us to propose a new view of the evolution of D1 dopamine receptor genes. First, we show that D1C and D1D receptor sequences are encoded by orthologous genes. Second, the previously identified Cypriniform D1X sequence is a teleost-specific paralog of the D1B sequences found in all groups of jawed vertebrates. Third, zebrafish and several sauropsid species possess an additional D1-like gene, which is likely to form another orthology group of vertebrate ancestral genes, which we propose to name D1E. Ancestral jawed vertebrates are thus likely to have possessed four classes of D1 receptor genes-D1A, D1B(X), D1C(D), and D1E-which arose from large-scale gene duplications. The D1C receptor gene would have been secondarily lost in the mammalian lineage, whereas the D1E receptor gene would have been lost independently in several lineages of modern vertebrates. The D1A receptors are well conserved throughout jawed vertebrates, whereas sauropsid D1C receptors have rapidly diverged, to the point that they were misidentified as D1D. The functional significance of the D1C receptor loss is not known. It is possible that the function may have been substituted with D1A or D1B receptors in mammals, following the disappearance of D1C receptors in these species.

  11. Prenatal ethanol exposure persistently impairs N-methyl-D-aspartate receptor-dependent activation of extracellular signal-regulated kinase in the mouse dentate gyrus

    PubMed Central

    Samudio-Ruiz, Sabrina L.; Allan, Andrea M.; Valenzuela, C. Fernando; Perrone-Bizzozero, Nora I.; Caldwell, Kevin K.

    2009-01-01

    The dentate gyrus (DG) is the central input region to the hippocampus and is known to play an important role in learning and memory. Previous studies have shown that prenatal alcohol is associated with hippocampal-dependent learning deficits and a decreased ability to elicit long term potentiation (LTP) in the DG in adult animals. Given that activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade by N-methyl-D-aspartate (NMDA) receptors is required for various forms of learning and memory, as well as LTP, in hippocampal regions, including the DG, we hypothesized that fetal alcohol-exposed (FAE) adult animals would have deficits in hippocampal NMDA receptor-dependent ERK1/2 activation. We used immunoblotting and immunohistochemistry techniques to detect NMDA-stimulated ERK1/2 activation in acute hippocampal slices prepared from adult FAE mice. We present the first evidence linking prenatal alcohol exposure to deficits in NMDA receptor-dependent ERK1/2 activation specifically in the DG of adult offspring. This deficit may account for the LTP deficits previously observed in the DG, as well as the life-long cognitive deficits, associated with prenatal alcohol exposure. PMID:19317851

  12. Centaur D-1A nose fairing jettison test

    NASA Technical Reports Server (NTRS)

    Prati, W. M.

    1976-01-01

    An experimental investigation was conducted to verify the functional and structural capability of the Centaur D-1A nose fairing. A full-scale flight-type nose fairing was jettisoned at the Lewis Research Center Space Power Chamber at simulated altitude. Two complete jettisons of the nose fairing were performed, one without aft helper springs and one with aft helper springs. A ''static'' rotation test was also performed to verify capability of the helper springs and to allow clearance measurements between the nose fairing and spacecraft envelope mock-up at certain discrete nose fairing rotation angles. Nose fairing trajectories, structural deflections, clearances, and hinge forces during jettison are presented. Data from subsequent Centaur D-1A flights, relative to nose fairing jettisons, are compared with the experimental results.

  13. Underground storage tank 431-D1U1, Closure Plan

    SciTech Connect

    Mancieri, S.

    1993-09-01

    This document contains information about the decommissioning of Tank 431-D1U1. This tank was installed in 1965 for diesel fuel storage. This tank will remain in active usage until closure procedures begin. Soils and ground water around the tank will be sampled to check for leakage. Appendices include; proof of proper training for workers, health and safety briefing record, task hazard analysis summary, and emergency plans.

  14. Redesign of Glenn Research Center D1 Flywheel Module

    NASA Technical Reports Server (NTRS)

    Jansen, Ralph H.; Wagner, Robert C.; Duffy, Kirsten P.; Hervol, David S.; Storozuk, Ronald J.; Dever, Timothy P.; Anzalone, Salvatore M.; Trudell, Jeffrey J.; Konno, Kevin E.; Kenny, Andrew

    2002-01-01

    Glenn Research Center has completed the redesign of the D1 flywheel module. The redesign includes a new rotor with a composite rim, motor/generator, touchdown bearings, sensors, and a magnetic actuator. The purpose of the relatively low cost module upgrade is to enable it to continuously operate throughout its speed range of 0 to 60,000 RPM. The module will be used as part of a combined attitude control and bus regulation experiment.

  15. Resolvin D1 Reduces Emphysema and Chronic Inflammation

    PubMed Central

    Hsiao, Hsi-Min; Thatcher, Thomas H.; Colas, Romain A.; Serhan, Charles N.; Phipps, Richard P.; Sime, Patricia J.

    2016-01-01

    Chronic obstructive pulmonary disease is characterized, in part, by chronic inflammation that persists even after smoking cessation, suggesting that a failure to resolve inflammation plays an important role in the pathogenesis of the disease. It is widely recognized that the resolution of inflammation is an active process, governed by specialized proresolving lipid mediators, including lipoxins, resolvins, maresins, and protectins. Here, we report that proresolving signaling and metabolic pathways are disrupted in lung tissue from patients with chronic obstructive pulmonary disease, suggesting that supplementation with proresolving lipid mediators might reduce the development of emphysema by controlling chronic inflammation. Groups of mice were exposed long-term to cigarette smoke and treated with the proresolving mediator resolvin D1. Resolvin D1 was associated with a reduced development of cigarette smoke–induced emphysema and airspace enlargement, with concurrent reductions in inflammation, oxidative stress, and cell death. Interestingly, resolvin D1 did not promote the differentiation of M2 macrophages and did not promote tissue fibrosis. Taken together, our results suggest that cigarette smoking disrupts endogenous proresolving pathways and that supplementation with specialized proresolving lipid mediators is an important therapeutic strategy in chronic lung disease, especially if endogenous specialized proresolving lipid mediator signaling is impaired. PMID:26468975

  16. Ontogeny of dopamine D1 receptors in rat striatum

    SciTech Connect

    Zeng, W.; Hyttel, J.; Murrin, L.C.

    1986-03-01

    In recent years direct analysis of dopamine D1 receptors has been made possible by the development of ligands with high affinity and specificity for these receptors. The authors examined the development of dopamine D1 receptors in postnatal rat striatum using standard membrane binding techniques. Rat pups 0 to 35 days of age were decapitated and striata dissected. Membranes were prepared by homogenization and centrifugation. The ligand used was /sup 3/H-piflutixol (1.5 nM). Dopamine D2 and serotonin S2 receptors were blocked by 50 nM spiperone. Blanks were generated by 1 ..mu..M cis-flupenthixol. Assays were carried out at 37/sup 0/C for 15 min and terminated by vacuum filtration (GF/B). Receptor number increased 9-fold from birth to 26 days of age, when adult levels were reached. Equilibrium was reached within 4 min. half-time of dissociation was approx. 1.5 min. Pharmacologically the receptors were identified as D1 type by the IC/sub 50/'s of numerous compounds: cis-flupenthixol (30nM), SCH 23390 (25 nM), fluphenazine (200 nM), chlorpromazine (300 nM), haloperidol (4 ..mu..M). Sulpiride, domperidone, atropine and naloxone had IC/sub 50/'s greater than 10 ..mu..M. Initial saturation studies indicate a Km of 0.6 nM with increasing Bmax with increasing age.

  17. Resolvin D1 drives establishment of Leishmania amazonensis infection

    PubMed Central

    Malta-Santos, Hayna; Andrade, Bruno B.; Zanette, Dalila L.; Costa, Jackson M.; Bozza, Patrícia T.; Bandeira-Melo, Christianne; Barral, Aldina; França-Costa, Jaqueline; Borges, Valéria M.

    2017-01-01

    Previous studies have indicated that the balance between different eicosanoids reflect the intensity of the inflammatory profile in patients with tegumentary leishmaniasis. More recently, pro-resolution lipid mediators have been shown to play critical roles in dampening pathological inflammatory processes to reestablish homeostasis in a diverse range of experimental settings. Among these lipid mediator, resolvins from D series have been described as potent anti-inflammatory and immunomodulatory mediators, and its activities include inhibition of leukocyte chemotaxis and blockage production of proinflammatory cytokines, while increasing the expression of regulatory mediators. Whether resolvins play significant roles in establishment and persistence of Leishmania infection is currently unknown. We addressed this question in the current study by assessing circulating levels of D-series resolvins in tegumentary leishmaniasis patients presenting with localized or diffuse disease. We found heightened expression of resolvin D1 in diffuse cutaneous leishmaniasis which was correlated with expression profile of biomarkers associated with disease pathogenesis. Additional in vitro experiments using primary human macrophages indicated that resolvin D1 may promote intracellular Leishmania amazonensis replication through a mechanism associated with induction of heme oxygenase-1. These results suggest that targeting resolvin D1 could serve as potential strategy for host directed therapy in diffuse cutaneous leishmaniasis. PMID:28393908

  18. Evaluation of D-1 tape and cassette characteristics: Moisture content of Sony and Ampex D-1 tapes when delivered

    NASA Astrophysics Data System (ADS)

    Ashton, Gary

    Commercial D-1 cassette tapes and their associated recorders were designed to operate in broadcast studios and record in accordance with the International Radio Consultative Committee (CCIR) 607 digital video standards. The D-1 recorder resulted in the Society of Motion Picture and Television Engineers (SMPTE) standards 224 to 228 and is the first digital video recorder to be standardized for the broadcast industry. The D-1 cassette and associated media are currently marketed for broadcast use. The recorder was redesigned for data applications and is in the early stages of being evaluated. The digital data formats used are specified in MIL-STD-2179 and the American National Standards Institute (ANSI) X3.175-190 standard. In early 1990, the National Media Laboratory (NML) was asked to study the effects of time, temperature, and relative humidity on commercial D-1 cassettes. The environmental range to be studied was the one selected for the Advanced Tactical Air Reconnaissance System (ATARS) program. Several discussions between NML personnel, ATARS representatives, recorder contractors, and other interested parties were held to decide upon the experimental plan to be implemented. Review meetings were held periodically during the course of the experiment. The experiments were designed to determine the dimensional stability of the media and cassette since this is one of the major limiting factors of helical recorders when the media or recorders are subjected to non-broadcasting environments. Measurements were also made to characterize each sample of cassettes to give preliminary information on which purchase specifications could be developed. The actual tests performed on the cassettes and media before and after aging fall into the general categories listed.

  19. Antagonism by d,1-propranolol of imipramine effects in mice.

    PubMed

    Souto, M; Francès, H; Lecrubier, Y; Puech, A J; Simon, P

    1979-11-23

    Three agents with known or suspected antidepressant activity, imipramine, salbutamol and dexamphetamine, were active in animal tests predictive of an antidepressant effect in man: antagonism of the hypothermia induced by reserpine, by oxotremorine or by a high dose of apomorphine, and the potentiation of the yohimbine-induced toxicity. These effects were antagonized by d,1-propranolol, suggesting that the stimulation of beta-adrenergic receptors could be a common mechanism underlying their effects. These results agree with the noradrenergic hypothesis of the pathophysiology of affective disorders.

  20. Titan 3E/Centaur D-1T Systems Summary

    NASA Technical Reports Server (NTRS)

    1973-01-01

    A systems and operational summary of the Titan 3E/Centaur D-1T program is presented which describes vehicle assembly facilities, launch facilities, and management responsibilities, and also provides detailed information on the following separate systems: (1) mechanical systems, including structural components, insulation, propulsion units, reaction control, thrust vector control, hydraulic systems, and pneumatic equipment; (2) astrionics systems, such as instrumentation and telemetry, navigation and guidance, C-Band tracking system, and range safety command system; (3) digital computer unit software; (4) flight control systems; (5) electrical/electronic systems; and (6) ground support equipment, including checkout equipment.

  1. Pimarane diterpenes from the Arctic fungus Eutypella sp. D-1.

    PubMed

    Lu, Xiao-Ling; Liu, Jing-Tang; Liu, Xiao-Yu; Gao, Yun; Zhang, Jianpeng; Jiao, Bing-Hua; Zheng, Heng

    2014-02-01

    Two new diterpenes, libertellenone G(1) and libertellenone H(2) were isolated from the fungus Eutypella sp. D-1 isolated from the soil of high latitude of Arctic, together with two known pimarane diterpenes (3-4). The structures of 1 and 2 were elucidated from spectroscopic data (nuclear magnetic resonance, mass spectrometry and infrared). These compounds were evaluated for cytotoxic activity against seven human tumor cell lines. Compound 2 showed a range of cytotoxicity between 3.31 and 44.1 μM. Compound 1 exhibited antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus.

  2. Silencing of the constitutive activity of the dopamine D1B receptor. Reciprocal mutations between D1 receptor subtypes delineate residues underlying activation properties.

    PubMed

    Charpentier, S; Jarvie, K R; Severynse, D M; Caron, M G; Tiberi, M

    1996-11-08

    Recently, we have shown that the dopamine D1B/D5 receptor displays binding and coupling properties that are reminiscent of those of the constitutively activated G protein-coupled receptors when compared with the related D1A/D1 receptor subtype (Tiberi, M., and Caron, M. G. (1994) J. Biol. Chem. 269, 27925-27931). The carboxyl-terminal region of the third cytoplasmic loop of several G protein-coupled receptors has been demonstrated to be important for the regulation of the equilibrium between inactive and active receptor conformations. In this cytoplasmic region, the primary structure of dopamine D1A and D1B receptors differs by only two residues: Phe264/Arg266 are present in D1A receptor compared with Ile288/Lys290 in the D1B receptor. To investigate whether these structural differences could account for the distinct binding and coupling properties of these dopamine receptor subtypes, we swapped the variant residues located in the carboxyl-terminal region by site-directed mutagenesis. The exchange of the D1A receptor residue Phe264 by the D1B receptor counterpart isoleucine led to a D1A receptor mutant exhibiting D1B-like constitutive properties. In contrast, substitution of D1B receptor Ile288 by the D1A receptor counterpart phenylalanine resulted in a loss of constitutive activation of the D1B receptor with binding and coupling properties similar to the D1A receptor. The Arg/Lys substitution had no effect on the function of either receptor. These results demonstrate that the carboxyl-terminal region, and in particular residue Ile288, is a major determinant of the constitutive activity of the dopamine D1B receptor. Moreover, these results establish that not only can agonist-independent activity of a receptor be induced, but when given the appropriate mutation, it can be reversed or silenced.

  3. Pesticide tolerance of Paenibacillus sp. D1 and its chitinase.

    PubMed

    Singh, Anil Kumar; Ghodke, Indrajeet; Chhatpar, H S

    2009-01-01

    Excessive use of pesticides in agriculture has led to several problems pertaining to loss of soil fertility and environmental degradation. Biological control agents offer the best alternative to reduce use of toxic pesticides. Paenibacillus sp. D1 isolated from the effluent treatment plant of a seafood processing industry exhibited broad spectrum tolerance towards a number of pesticides at concentrations higher than recommended for field applications. The isolate showed enhanced growth and chitinase production in the presence of some protectant fungicides. None of the tested demethylase inhibitor (DMI) fungicides inhibited growth and chitinase production except triadimefon. The isolate was also tolerant to most commonly used insecticides belonging to the organophosphate, carbamate and cyclodiene organochloride classes. Chitinase of Paenibacillus sp. D1 was found to be more tolerant than the organism itself and was highly stable in the presence of pesticides at the temperature under field conditions in Gujarat, India, i.e. 40 degrees C. This was suggestive of its potential in integrated pest management (IPM) to significantly reduce the use of harmful chemicals. To our knowledge this is the first extensive study on pesticide tolerance of the Paenibacillus species and its chitinase.

  4. ECRH launching scenario in FFHR-d1

    NASA Astrophysics Data System (ADS)

    Yanagihara, Kota; Kubo, Shin; Shimozuma, Takashi; Yoshimura, Yasuo; Igami, Hiroe; Takahashi, Hiromi; Tsujimura, Tohru; Makino, Ryohhei

    2016-10-01

    ECRH is promising as a principal heating system in a prototype helical reactor FFHR-d1 where the heating power of 80 MW is required to bring the plasma parameter to break even condition. To generate the plasma and bring it to ignition condition in FFHR-d1, it is effective to heat the under/over-dense plasma with normal ECRH or Electron Bernstein Wave (EBW). Normal ECRH is well established but heating via EBW need sophisticated injection control. EBW can be excited via the O(ordinary)-X(extraordinary)-B(EBW) mode conversion process by launching the ordinary wave from the low field side to plasma cut-off layer with optimum injection angle, and the range of injection angle to get high OXB mode conversion rate is called OXB mode conversion window. Since the window position can change as the plasma parameter, it is necessary to optimize the injection angle so as to aim the window in response to the plasma parameters. Candidates of antenna positions are determined by optimum injection points on the plasma facing wall calculated by the injection angle. Given such picked up area, detailed analysis using ray-tracing calculations and engineering antenna design will be performed.

  5. Haplotype variation of Glu-D1 locus and the origin of Glu-D1d allele conferring superior end-use qualities in common wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In common wheat (Triticum aestivum, AABBDD), the Glu-D1 locus possesses multiple alleles, with Glu-D1a (coding for 1Dx2 and 1Dy12 subunits) and Glu-D1d (encoding 1Dx5 and 1Dy10 subunits) being intensively used in the genetic improvement of end-use qualities. Here, we studied the molecular variatio...

  6. Casimir interaction between spheres in ( D + 1)-dimensional Minkowski spacetime

    NASA Astrophysics Data System (ADS)

    Teo, L. P.

    2014-05-01

    We consider the Casimir interaction between two spheres in ( D + 1)-dimensional Minkowski spacetime due to the vacuum fluctuations of scalar fields. We consider combinations of Dirichlet and Neumann boundary conditions. The TGTG formula of the Casimir interaction energy is derived. The computations of the T matrices of the two spheres are straightforward. To compute the two G matrices, known as translation matrices, which relate the hyper-spherical waves in two spherical coordinate frames differ by a translation, we generalize the operator approach employed in [39]. The result is expressed in terms of an integral over Gegenbauer polynomials. In contrast to the D=3 case, we do not re-express the integral in terms of 3 j-symbols and hyper-spherical waves, which in principle, can be done but does not simplify the formula. Using our expression for the Casimir interaction energy, we derive the large separation and small separation asymptotic expansions of the Casimir interaction energy. In the large separation regime, we find that the Casimir interaction energy is of order L -2 D+3, L -2 D+1 and L -2 D-1 respectively for Dirichlet-Dirichlet, Dirichlet-Neumann and Neumann-Neumann boundary conditions, where L is the center-to-center distance of the two spheres. In the small separation regime, we confirm that the leading term of the Casimir interaction agrees with the proximity force approximation, which is of order , where d is the distance between the two spheres. Another main result of this work is the analytic computations of the next-to-leading order term in the small separation asymptotic expansion. This term is computed using careful order analysis as well as perturbation method. In the case the radius of one of the sphere goes to infinity, we find that the results agree with the one we derive for sphere-plate configuration. When D=3, we also recover previously known results. We find that when D is large, the ratio of the next-to-leading order term to the leading

  7. Transcriptome-based identification of the Sinorhizobium meliloti NodD1 regulon.

    PubMed

    Capela, Delphine; Carrere, Sébastien; Batut, Jacques

    2005-08-01

    The NodD1 regulon of Sinorhizobium meliloti was determined through the analysis of the S. meliloti transcriptome in response to the plant flavone luteolin and the overexpression of nodD1. Nine new genes regulated by both NodD1 and luteolin were identified, demonstrating that NodD1 controls few functions behind nodulation in S. meliloti.

  8. Caffeine stimulates locomotor activity in the mammalian spinal cord via adenosine A1 receptor-dopamine D1 receptor interaction and PKA-dependent mechanisms.

    PubMed

    Acevedo, JeanMarie; Santana-Almansa, Alexandra; Matos-Vergara, Nikol; Marrero-Cordero, Luis René; Cabezas-Bou, Ernesto; Díaz-Ríos, Manuel

    2016-02-01

    Caffeine is a potent psychostimulant that can have significant and widely variable effects on the activity of multiple neuronal pathways. The most pronounced caffeine-induced behavioral effect seen in rodents is to increase locomotor activity which has been linked to a dose-dependent inhibition of A1 and A(2A) receptors. The effects of caffeine at the level of the lumbar spinal central pattern generator (CPG) network for hindlimb locomotion are lacking. We assessed the effects of caffeine to the locomotor function of the spinal CPG network via extracellular ventral root recordings using the isolated neonatal mouse spinal cord preparation. Addition of caffeine and of an A1 receptor antagonist significantly decreased the cycle period accelerating the ongoing locomotor rhythm, while decreasing burst duration reversibly in most preparations suggesting the role of A1 receptors as the primary target of caffeine. Caffeine and an A1 receptor antagonist failed to stimulate ongoing locomotor activity in the absence of dopamine or in the presence of a D1 receptor antagonist supporting A1/D1 receptor-dependent mechanism of action. The use of caffeine or an A1 receptor blocker failed to stimulate an ongoing locomotor rhythm in the presence of a blocker of the cAMP-dependent protein kinase (PKA) supporting the need of this intracellular pathway for the modulatory effects of caffeine to occur. These results support a stimulant effect of caffeine on the lumbar spinal network controlling hindlimb locomotion through the inhibition of A1 receptors and subsequent activation of D1 receptors via a PKA-dependent intracellular mechanism.

  9. Centaur D-1A guidance/software system

    NASA Technical Reports Server (NTRS)

    Gordan, A. L.

    1983-01-01

    The main body of this paper describes the evolution of the Centaur D-1A Guidance and Software System. Specifically, the performance of the explicit guidance equations, using a linear tangent steering law. Inherent flexibility exists in the equations in that they have multimission capability. They can accommodate both Earth-orbital and Earth-escape missions with either one or two Centaur burns. They can also guide for multi-burn orbital missions. The Centaur performance is indicated in terms of optimality (propellant usage), accuracy, flexibility and computer requirements. In the course of the Centaur Guidance development substantial changes and improvements have been made and more improvements are on the way for the Shuttle/Centaur Guidance. It is the intent of this paper to describe, provide insight into, and identify certain unique aspects of the individual Centaur flight profiles. Mission profile(s) are described narratively with some numerical data given in cases where it may be useful.

  10. Sphere-plate Casimir interaction in (D + 1)-dimensional spacetime

    SciTech Connect

    Teo, L. P.

    2014-04-15

    In this paper, we derive the formula for the Casimir interaction energy between a sphere and a plate in (D + 1)-dimensional Minkowski spacetime. It is assumed that the scalar field satisfies the Dirichlet or Neumann boundary conditions on the sphere and the plate. As in the D = 3 case, the formula is of TGTG type. One of our main contributions is deriving the translation matrices which express the change of bases between plane waves and spherical waves for general D. Using orthogonality of Gegenbauer polynomials, it turns out that the final TGTG formula for the Casimir interaction energy can be simplified to one that is similar to the D = 3 case. To illustrate the application of the formula, both large separation and small separation asymptotic behaviors of the Casimir interaction energy are computed. The large separation leading term is proportional to L{sup −D+1} if the sphere is imposed with Dirichlet boundary condition, and to L{sup −D−1} if the sphere is imposed with Neumann boundary condition, where L is distance from the center of the sphere to the plane. For the small separation asymptotic behavior, it is shown that the leading term is equal to the one obtained using proximity force approximation. The next-to-leading order term is also computed using perturbation method. It is shown that when the space dimension D is larger than 5, the next-to-leading order has sign opposite to the leading order term. Moreover, the ratio of the next-to-leading order term to the leading order term is linear in D, indicating a larger correction at higher dimensions.

  11. The microgravity environment of the D1 mission

    NASA Technical Reports Server (NTRS)

    Hamacher, H.; Merbold, U.; Jilg, R.

    1990-01-01

    Some characteristic features and results of D1 microgravity measurements are discussed as performed in the Material Science Double Rack (MSDR) and the Materials Science Double Rack for Experiment Modules and Apparatus (MEDEA). Starting with a brief review of the main potential disturbances, the payload aspects of interest to the analysis and the accelerometer measuring systems are described. The microgravity data are analyzed with respect to selected mission events such as thruster firings for attitude control, operations of Spacelab experiment facilities, vestibular experiments and crew activities. The origins are divided into orbit, vehicle, and experiment induced perturbations. It has been found that the microgravity-environment is dictated mainly by payload-induced perturbations. To reduce the microgravity-level, the design of some experiment facilities has to be improved by minimizing the number of moving parts, decoupling of disturbing units from experiment facilities, by taking damping measures, etc. In addition, strongly disturbing experiments and very sensitive investigations should be performed in separate mission phases.

  12. Glucocorticoid receptor activation lowers the threshold for NMDA-receptor-dependent homosynaptic long-term depression in the hippocampus through activation of voltage-dependent calcium channels.

    PubMed

    Coussens, C M; Kerr, D S; Abraham, W C

    1997-07-01

    The effects of the glucocorticoid receptor agonist RU-28362 on homosynaptic long-term depression (LTD) were examined in hippocampal slices obtained from adrenal-intact adult male rats. Field excitatory postsynaptic potentials were evoked by stimulation of the Schaffer collateral/commissural pathway and recorded in stratum radiatum of area CA1. Low-frequency stimulation (LFS) was delivered at LTD threshold (2 bouts of 600 pulses, 1 Hz, at baseline stimulation intensity). LFS of the Schaffer collaterals did not produce significant homosynaptic LTD in control slices. However, identical conditioning in the presence of the glucocorticoid receptor agonist RU-28362 (10 microM) produced a robust LTD, which was blocked by the selective glucocorticoid antagonist RU-38486. The LTD induced by glucocorticoid receptor activation was dependent on N-methyl-D-aspartate (NMDA) receptor activity, because the specific NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) blocked the facilitation. However, the facilitation of LTD was not due to a potentiation of the isolated NMDA receptor potential by RU-28362. The facilitation of LTD by RU-28362 was also blocked by coincubation of the L-type voltage-dependent calcium channel (VDCC) antagonist nimodipine. Selective activation of the L-type VDCCs by the agonist Bay K 8644 also facilitated LTD induction. Both nimodipine and D-AP5 were effective in blocking the facilitation of LTD by Bay K 8644. These results indicate that L-type VDCCs can contribute to NMDA-receptor-dependent LTD induction.

  13. AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors.

    PubMed Central

    Henttu, P M; Kalkhoven, E; Parker, M G

    1997-01-01

    Hormone-dependent transcriptional activation by nuclear receptors depends on the presence of a conserved C-terminal amphipathic alpha-helix (helix 12) in the ligand-binding domain. Here we show that a lysine residue, which is conserved in most nuclear receptors in the predicted helix 3, is also required for estrogen-dependent transactivation. The replacement of lysine 366 with alanine appreciably reduced activation function 2 (AF-2) activity without affecting steroid- or DNA-binding activity in the mouse estrogen receptor. The mutation dramatically reduced the ability of the receptor to bind steroid receptor coactivator 1 (SRC-1) but had no effect on receptor-interacting protein 140 (RIP-140) binding, indicating that while their sites of interaction overlap, they are not entirely consistent and in keeping with the proposal that the recruitment of coactivators, such as SRC-1, is required for AF-2 activity. Although the function of RIP-140 remains to be established, RIP-140 appears to be capable of recruiting the basal transcription machinery, since overexpression of the protein markedly increased the transcriptional activity of the mutant receptor. Since the lysine residue is conserved, we propose that it is required, together with residues in helix 12, to form the surface by which members of the nuclear receptor family interact with coactivators. PMID:9121431

  14. Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases.

    PubMed

    Gallelli, Luca; Pelaia, Girolamo; D'Agostino, Bruno; Cuda, Giovanni; Vatrella, Alessandro; Fratto, Donatella; Gioffrè, Vincenza; Galderisi, Umberto; De Nardo, Marilisa; Mastruzzo, Claudio; Salinaro, Elisa Trovato; Maniscalco, Mauro; Sofia, Matteo; Crimi, Nunzio; Rossi, Francesco; Caputi, Mario; Costanzo, Francesco S; Maselli, Rosario; Marsico, Serafino A; Vancheri, Carlo

    2005-11-01

    Endothelin-1 (ET-1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET-1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET-1 in the presence or absence of an overnight pre-treatment with either ET(A) or ET(B) selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen-activated protein kinases (MAPK). ET-1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL-6/IL-11 release into cell culture supernatants. All these effects were inhibited by the selective ET(A) antagonist BQ-123, but not by the specific ET(B) antagonist BQ-788. The stimulatory influence of ET-1 on IL-11, but not on IL-6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET-1 exerts a profibrogenic action via an ET(A) receptor-dependent, MAPK-mediated induction of IL-11 release and cell proliferation.

  15. EGF receptor-dependent mechanism may be involved in the Tamm-Horsfall glycoprotein-enhanced PMN phagocytosis via activating Rho family and MAPK signaling pathway.

    PubMed

    Li, Ko-Jen; Siao, Sue-Cien; Wu, Cheng-Han; Shen, Chieh-Yu; Wu, Tsai-Hung; Tsai, Chang-Youh; Hsieh, Song-Chou; Yu, Chia-Li

    2014-01-21

    Our previous studies showed that urinary Tamm-Horsfall glycoprotein (THP) potently enhanced polymorphonuclear neutrophil (PMN) phagocytosis. However, the domain structure(s), signaling pathway and the intracellular events responsible for THP-enhanced PMN phagocytosis remain to be elucidated. THP was purified from normal human urine. The human promyelocytic leukemia cell line HL-60 was induced to differentiate into PMNs by all-trans retinoid acid. Pretreatment with different MAPK and PI3K inhibitors was used to delineate signaling pathways in THP-enhanced PMN phagocytosis. Phosphorylation of molecules responsible for PMN phagocytosis induced by bacterial lipopolysaccharide (LPS), THP, or human recombinant epidermal growth factor (EGF) was evaluated by western blot. A p38 MAPK inhibitor, SB203580, effectively inhibited both spontaneous and LPS- and THP-induced PMN phagocytosis. Both THP and LPS enhanced the expression of the Rho family proteins Cdc42 and Rac that may lead to F-actin re-arrangement. Further studies suggested that THP and EGF enhance PMN and differentiated HL-60 cell phagocytosis in a similar pattern. Furthermore, the EGF receptor inhibitor GW2974 significantly suppressed THP- and EGF-enhanced PMN phagocytosis and p38 and ERK1/2 phosphorylation in differentiated HL-60 cells. We conclude that EGF receptor-dependent signaling may be involved in THP-enhanced PMN phagocytosis by activating Rho family and MAP kinase.

  16. Comparison of the T1 and D1 diagnostics for electronic structure theory: a new definition for the open-shell D1 diagnostic

    NASA Astrophysics Data System (ADS)

    Lee, Timothy J.

    2003-04-01

    It is shown that the coupled-cluster T1 operator used in a previous study to define the open-shell D1 diagnostic is ill defined, and leads to an arbitrary definition of the open-shell D1 diagnostic. A new definition is proposed that eliminates this ambiguity and approximately restores the mathematical relationship previously noted between the closed-shell D1 and T1 diagnostics. Statistical comparison of the T1 and D1 diagnostics shows a very high degree of correlation between them for the molecular systems studied thus far, although it is argued that both diagnostics used together can provide more information than either can separately.

  17. Consequence of the tumor-associated conversion to cyclin D1b

    PubMed Central

    Augello, Michael A; Berman-Booty, Lisa D; Carr, Richard; Yoshida, Akihiro; Dean, Jeffry L; Schiewer, Matthew J; Feng, Felix Y; Tomlins, Scott A; Gao, Erhe; Koch, Walter J; Benovic, Jeffrey L; Diehl, John Alan; Knudsen, Karen E

    2015-01-01

    Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre-clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant. PMID:25787974

  18. 16 CFR Appendix D1 to Part 305 - Water Heaters-Gas

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME APPLIANCES AND OTHER PRODUCTS REQUIRED UNDER THE ENERGY POLICY AND CONSERVATION ACT (âAPPLIANCE LABELING RULEâ) Pt. 305, App. D1 Appendix D1...

  19. 17 CFR 270.12d1-2 - Exemptions for investment companies relying on section 12(d)(1)(G) of the Act.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-12(d)(1)(G)(i)(II)), a registered open-end investment company or a registered unit investment trust... by an investment company); and (3) Securities issued by a money market fund, when the acquisition is in reliance on § 270.12d1-1. (b) Definitions. For purposes of this section, money market fund has...

  20. 17 CFR 270.12d1-2 - Exemptions for investment companies relying on section 12(d)(1)(G) of the Act.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...-12(d)(1)(G)(i)(II)), a registered open-end investment company or a registered unit investment trust... by an investment company); and (3) Securities issued by a money market fund, when the acquisition is in reliance on § 270.12d1-1. (b) Definitions. For purposes of this section, money market fund has...

  1. 17 CFR 270.12d1-2 - Exemptions for investment companies relying on section 12(d)(1)(G) of the Act.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...-12(d)(1)(G)(i)(II)), a registered open-end investment company or a registered unit investment trust... by an investment company); and (3) Securities issued by a money market fund, when the acquisition is in reliance on § 270.12d1-1. (b) Definitions. For purposes of this section, money market fund has...

  2. 26 CFR 1.1033(d)-1 - Destruction or disposition of livestock because of disease.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... of disease. 1.1033(d)-1 Section 1.1033(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... § 1.1033(d)-1 Destruction or disposition of livestock because of disease. (a) The destruction... account of, disease, or the sale or exchange, in such a year, of livestock because of disease, shall...

  3. 26 CFR 1.1033(d)-1 - Destruction or disposition of livestock because of disease.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... of disease. 1.1033(d)-1 Section 1.1033(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... § 1.1033(d)-1 Destruction or disposition of livestock because of disease. (a) The destruction... account of, disease, or the sale or exchange, in such a year, of livestock because of disease, shall...

  4. 26 CFR 1.1033(d)-1 - Destruction or disposition of livestock because of disease.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... of disease. 1.1033(d)-1 Section 1.1033(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... § 1.1033(d)-1 Destruction or disposition of livestock because of disease. (a) The destruction... account of, disease, or the sale or exchange, in such a year, of livestock because of disease, shall...

  5. 26 CFR 1.1033(d)-1 - Destruction or disposition of livestock because of disease.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of disease. 1.1033(d)-1 Section 1.1033(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... § 1.1033(d)-1 Destruction or disposition of livestock because of disease. (a) The destruction... account of, disease, or the sale or exchange, in such a year, of livestock because of disease, shall...

  6. 12 CFR Appendix D-1 to Part 208 - Interagency Guidelines Establishing Standards for Safety and Soundness

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... for Safety and Soundness D Appendix D-1 to Part 208 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM MEMBERSHIP OF STATE BANKING INSTITUTIONS IN THE FEDERAL RESERVE SYSTEM (REGULATION H) Pt. 208, App. D-1 Appendix D-1 to Part 208—Interagency Guidelines...

  7. ATM is required for rapid degradation of cyclin D1 in response to {gamma}-irradiation

    SciTech Connect

    Choo, Dong Wan; Baek, Hye Jung; Motoyama, Noboru; Cho, Kwan Ho; Kim, Hye Sun; Kim, Sang Soo

    2009-01-23

    The cellular response to DNA damage induced by {gamma}-irradiation activates cell-cycle arrest to permit DNA repair and to prevent replication. Cyclin D1 is the key molecule for transition between the G1 and S phases of the cell-cycle, and amplification or overexpression of cyclin D1 plays pivotal roles in the development of several human cancers. To study the regulation of cyclin D1 in the DNA-damaged condition, we analyzed the proteolytic regulation of cyclin D1 expression upon {gamma}-irradiation. Upon {gamma}-irradiation, a rapid reduction in cyclin D1 levels was observed prior to p53 stabilization, indicating that the stability of cyclin D1 is controlled in a p53-independent manner. Further analysis revealed that irradiation facilitated ubiquitination of cyclin D1 and that a proteasome inhibitor blocked cyclin D1 degradation under the same conditions. Interestingly, after mutation of threonine residue 286 of cyclin D1, which is reported to be the GSK-3{beta} phosphorylation site, the mutant protein showed resistance to irradiation-induced proteolysis although inhibitors of GSK-3{beta} failed to prevent cyclin D1 degradation. Rather, ATM inhibition markedly prevented cyclin D1 degradation induced by {gamma}-irradiation. Our data indicate that communication between ATM and cyclin D1 may be required for maintenance of genomic integrity achieved by rapid arrest of the cell-cycle, and that disruption of this crosstalk may increase susceptibility to cancer.

  8. 26 CFR 301.6227(d)-1 - Administrative adjustment request filed on behalf of a partner.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... mailed such notice); (2) Identify the partner and the partnership by name, address, and taxpayer... behalf of a partner. 301.6227(d)-1 Section 301.6227(d)-1 Internal Revenue INTERNAL REVENUE SERVICE... In General § 301.6227(d)-1 Administrative adjustment request filed on behalf of a partner. (a)...

  9. 26 CFR 301.6227(d)-1 - Administrative adjustment request filed on behalf of a partner.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... mailed such notice); (2) Identify the partner and the partnership by name, address, and taxpayer... behalf of a partner. 301.6227(d)-1 Section 301.6227(d)-1 Internal Revenue INTERNAL REVENUE SERVICE... In General § 301.6227(d)-1 Administrative adjustment request filed on behalf of a partner. (a)...

  10. 12 CFR Appendix D-1 to Part 208 - Interagency Guidelines Establishing Standards for Safety and Soundness

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... for Safety and Soundness D Appendix D-1 to Part 208 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF... SYSTEM (REGULATION H) Pt. 208, App. D-1 Appendix D-1 to Part 208—Interagency Guidelines Establishing... systems. B. Internal audit system. C. Loan documentation. D. Credit underwriting. E. Interest...

  11. 26 CFR 1.45D-1 - New markets tax credit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 1 2011-04-01 2009-04-01 true New markets tax credit. 1.45D-1 Section 1.45D-1... Computing Credit for Investment in Certain Depreciable Property § 1.45D-1 New markets tax credit. (a) Table... of new markets tax credit (B) Recapture event (ii) CDE reporting requirements to Secretary...

  12. 26 CFR 1.45D-1 - New markets tax credit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true New markets tax credit. 1.45D-1 Section 1.45D-1... Computing Credit for Investment in Certain Depreciable Property § 1.45D-1 New markets tax credit. (a) Table... of new markets tax credit (B) Recapture event (ii) CDE reporting requirements to Secretary...

  13. 17 CFR 240.12d1-1 - Registration effective as to class or series.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... class or series. 240.12d1-1 Section 240.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Registration § 240.12d1-1 Registration effective as to class or series. (a) An application filed pursuant to... of additional shares or amounts. (d) If a class of security is issuable in two or more series...

  14. 17 CFR 240.12d1-1 - Registration effective as to class or series.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... class or series. 240.12d1-1 Section 240.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Registration § 240.12d1-1 Registration effective as to class or series. (a) An application filed pursuant to... of additional shares or amounts. (d) If a class of security is issuable in two or more series...

  15. 17 CFR 240.12d1-1 - Registration effective as to class or series.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... class or series. 240.12d1-1 Section 240.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Registration § 240.12d1-1 Registration effective as to class or series. (a) An application filed pursuant to... of additional shares or amounts. (d) If a class of security is issuable in two or more series...

  16. 17 CFR 240.12d1-1 - Registration effective as to class or series.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... class or series. 240.12d1-1 Section 240.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Registration § 240.12d1-1 Registration effective as to class or series. (a) An application filed pursuant to... of additional shares or amounts. (d) If a class of security is issuable in two or more series...

  17. 17 CFR 240.12d1-1 - Registration effective as to class or series.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... class or series. 240.12d1-1 Section 240.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Registration § 240.12d1-1 Registration effective as to class or series. (a) An application filed pursuant to... of additional shares or amounts. (d) If a class of security is issuable in two or more series...

  18. 26 CFR 1.167(d)-1 - Agreement as to useful life and rates of depreciation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... depreciation. 1.167(d)-1 Section 1.167(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... and Corporations § 1.167(d)-1 Agreement as to useful life and rates of depreciation. After August 16... respect to the estimated useful life, method and rate of depreciation and treatment of salvage of...

  19. 26 CFR 1.6050D-1 - Information returns relating to energy grants and financing.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Information returns relating to energy grants and financing. 1.6050D-1 Section 1.6050D-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Information Returns § 1.6050D-1 Information returns relating to energy grants...

  20. Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus.

    PubMed

    Mango, D; Braksator, E; Battaglia, G; Marcelli, S; Mercuri, N B; Feligioni, M; Nicoletti, F; Bashir, Z I; Nisticò, R

    2017-01-27

    Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na(+) channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a is highly permeable to Ca(2+) and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.

  1. Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome.

    PubMed

    Pignatelli, Marco; Piccinin, Sonia; Molinaro, Gemma; Di Menna, Luisa; Riozzi, Barbara; Cannella, Milena; Motolese, Marta; Vetere, Gisella; Catania, Maria Vincenza; Battaglia, Giuseppe; Nicoletti, Ferdinando; Nisticò, Robert; Bruno, Valeria

    2014-03-26

    Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.

  2. Latent inhibition of cued fear conditioning: an NMDA receptor-dependent process that can be established in the presence of anisomycin.

    PubMed

    Lewis, Michael C; Gould, Thomas J

    2004-08-01

    Much of the research examining the biological basis for long-term memories has focused on mechanisms that support the formation of conditioned associations. Less information is available on biological mechanisms which underlie processes that modify the strength of conditioned associations. Latent inhibition is a phenomenon by which pre-exposure to a to-be-conditioned stimulus (CS) weakens subsequent conditioning of that CS to an unconditioned stimulus (US). Here we report that latent inhibition of cued fear conditioning is dependent on NMDA receptor activation. MK-801 (1 mg/kg), an NMDA receptor antagonist, abolished latent inhibition of cued fear conditioning. This dose of MK-801 administered before training did not disrupt cued fear conditioning. Conversely, anisomycin (150 mg/kg), a protein synthesis inhibitor, had no effect on latent inhibition of cued fear conditioning when administered 20 min before, immediately after, or 2, 4, 6, or 8 h after CS pre-exposure. Furthermore, continuous anisomycin administration (50 mg/kg, administered every 2 h for 6 h starting 20 min prior to pre-exposure) did not disrupt latent inhibition of cued fear conditioning. In addition, anisomycin had no effect on a long-lasting version of latent inhibition of cued fear conditioning that was maintained over a 7-day interval. Anisomycin administered before training, however, disrupted learning of the CS-US association. These findings suggest that latent inhibition of cued fear conditioning is a long-lasting NMDA receptor-dependent process that can develop during the inhibition of protein synthesis.

  3. Electroacupuncture pretreatment attenuates spinal cord ischemia-reperfusion injury via inhibition of high-mobility group box 1 production in a LXA4 receptor-dependent manner.

    PubMed

    Zhu, Xiao-Ling; Chen, Xin; Wang, Wei; Li, Xu; Huo, Jia; Wang, Yu; Min, Yu-Yuan; Su, Bin-Xiao; Pei, Jian-Ming

    2017-03-15

    Paraplegia caused by spinal cord ischemia is a severe complication following surgeries in the thoracic aneurysm. HMGB1 has been recognized as a key mediator in spinal inflammatory response after spinal cord injury. Electroacupuncture (EA) pretreatment could provide neuroprotection against cerebral ischemic injury through inhibition of HMGB1 release. Therefore, the present study aims to test the hypothesis that EA pretreatment protects against spinal cord ischemia-reperfusion (I/R) injury via inhibition of HMGB1 release. Animals were pre-treated with EA stimulations 30min daily for 4 successive days, followed by 20-min spinal cord ischemia induced by using a balloon catheter placed into the aorta. We found that spinal I/R significantly increased mRNA and cytosolic protein levels of HMGB1 after reperfusion in the spinal cord. The EA-pretreated animals displayed better motor performance after reperfusion along with the decrease of apoptosis, HMGB1, TNF-α and IL-1β expressions in the spinal cord, whereas these effects by EA pretreatment was reversed by rHMGB1 administration. Furthermore, EA pretreatment attenuated the down-regulation of LXA4 receptor (ALX) expression induced by I/R injury, while the decrease of HMGB1 release in EA-pretreated rats was reversed by the combined BOC-2 (an inhibitor of LXA4 receptor) treatment. In conclusion, EA pretreatment may promote spinal I/R injury through the inhibition of HMGB1 release in a LXA4 receptor-dependent manner. Our data may represent a new therapeutic technique for treating spinal cord ischemia-reperfusion injury.

  4. Chronic intermittent alcohol disrupts the GluN2B-associated proteome and specifically regulates group I mGlu receptor-dependent long-term depression.

    PubMed

    Wills, Tiffany A; Baucum, Anthony J; Holleran, Katherine M; Chen, Yaoyi; Pasek, Johanna G; Delpire, Eric; Tabb, David L; Colbran, Roger J; Winder, Danny G

    2017-03-01

    N-Methyl-d-aspartate receptors (NMDARs) are major targets of both acute and chronic alcohol, as well as regulators of plasticity in a number of brain regions. Aberrant plasticity may contribute to the treatment resistance and high relapse rates observed in alcoholics. Recent work suggests that chronic alcohol treatment preferentially modulates both the expression and subcellular localization of NMDARs containing the GluN2B subunit. Signaling through synaptic and extrasynaptic GluN2B-NMDARs has already been implicated in the pathophysiology of various other neurological disorders. NMDARs interact with a large number of proteins at the glutamate synapse, and a better understanding of how alcohol modulates this proteome is needed. We employed a discovery-based proteomic approach in subcellular fractions of hippocampal tissue from chronic intermittent alcohol (CIE)-exposed C57Bl/6J mice to gain insight into alcohol-induced changes in GluN2B signaling complexes. Protein enrichment analyses revealed changes in the association of post-synaptic proteins, including scaffolding, glutamate receptor and PDZ-domain binding proteins with GluN2B. In particular, GluN2B interaction with metabotropic glutamate (mGlu)1/5 receptor-dependent long-term depression (LTD)-associated proteins such as Arc and Homer 1 was increased, while GluA2 was decreased. Accordingly, we found a lack of mGlu1/5 -induced LTD while α1 -adrenergic receptor-induced LTD remained intact in hippocampal CA1 following CIE. These data suggest that CIE specifically disrupts mGlu1/5 -LTD, representing a possible connection between NMDAR and mGlu receptor signaling. These studies not only demonstrate a new way in which alcohol can modulate plasticity in the hippocampus but also emphasize the utility of this discovery-based proteomic approach to generate new hypotheses regarding alcohol-related mechanisms.

  5. Delimitation of the Earliness per se D1 (Eps-D1) flowering gene to a subtelomeric chromosomal deletion in bread wheat (Triticum aestivum).

    PubMed

    Zikhali, Meluleki; Wingen, Luzie U; Griffiths, Simon

    2016-01-01

    Earliness per se (Eps) genes account for the variation in flowering time when vernalization and photoperiod requirements are satisfied. Genomics and bioinformatics approaches were used to describe allelic variation for 40 Triticum aestivum genes predicted, by synteny with Brachypodium distachyon, to be in the 1DL Eps region. Re-sequencing 1DL genes revealed that varieties carrying early heading alleles at this locus, Spark and Cadenza, carry a subtelomeric deletion including several genes. The equivalent region in Rialto and Avalon is intact. A bimodal distribution in the segregating Spark X Rialto single seed descent (SSD) populations enabled the 1DL QTL to be defined as a discrete Mendelian factor, which we named Eps-D1. Near isogenic lines (NILs) and NIL derived key recombinants between markers flanking Eps-D1 suggest that the 1DL deletion contains the gene(s) underlying Eps-D1. The deletion spans the equivalent of the Triticum monoccocum Eps-A (m) 1 locus, and hence includes MODIFIER OF TRANSCRIPTION 1 (MOT1) and FTSH PROTEASE 4 (FTSH4), the candidates for Eps-A (m) 1. The deletion also contains T. aestivum EARLY FLOWERING 3-D1 (TaELF3-D1) a homologue of the Arabidopsis thaliana circadian clock gene EARLY FLOWERING 3. Eps-D1 is possibly a homologue of Eps-B1 on chromosome 1BL. NILs carrying the Eps-D1 deletion have significantly reduced total TaELF3 expression and altered TaGIGANTEA (TaGI) expression compared with wild type. Altered TaGI expression is consistent with an ELF3 mutant, hence we propose TaELF3-D1 as the more likely candidate for Eps-D1. This is the first direct fine mapping of Eps effect in bread wheat.

  6. Delimitation of the Earliness per se D1 (Eps-D1) flowering gene to a subtelomeric chromosomal deletion in bread wheat (Triticum aestivum)

    PubMed Central

    Zikhali, Meluleki; Wingen, Luzie U.; Griffiths, Simon

    2016-01-01

    Earliness per se (Eps) genes account for the variation in flowering time when vernalization and photoperiod requirements are satisfied. Genomics and bioinformatics approaches were used to describe allelic variation for 40 Triticum aestivum genes predicted, by synteny with Brachypodium distachyon, to be in the 1DL Eps region. Re-sequencing 1DL genes revealed that varieties carrying early heading alleles at this locus, Spark and Cadenza, carry a subtelomeric deletion including several genes. The equivalent region in Rialto and Avalon is intact. A bimodal distribution in the segregating Spark X Rialto single seed descent (SSD) populations enabled the 1DL QTL to be defined as a discrete Mendelian factor, which we named Eps-D1. Near isogenic lines (NILs) and NIL derived key recombinants between markers flanking Eps-D1 suggest that the 1DL deletion contains the gene(s) underlying Eps-D1. The deletion spans the equivalent of the Triticum monoccocum Eps-A m 1 locus, and hence includes MODIFIER OF TRANSCRIPTION 1 (MOT1) and FTSH PROTEASE 4 (FTSH4), the candidates for Eps-A m 1. The deletion also contains T. aestivum EARLY FLOWERING 3-D1 (TaELF3-D1) a homologue of the Arabidopsis thaliana circadian clock gene EARLY FLOWERING 3. Eps-D1 is possibly a homologue of Eps-B1 on chromosome 1BL. NILs carrying the Eps-D1 deletion have significantly reduced total TaELF3 expression and altered TaGIGANTEA (TaGI) expression compared with wild type. Altered TaGI expression is consistent with an ELF3 mutant, hence we propose TaELF3-D1 as the more likely candidate for Eps-D1. This is the first direct fine mapping of Eps effect in bread wheat. PMID:26476691

  7. Regulation of Exit from Quiescence by p27 and Cyclin D1-CDK4

    PubMed Central

    Ladha, Mohamed H.; Lee, Kwang Y.; Upton, Todd M.; Reed, Michael F.; Ewen, Mark E.

    1998-01-01

    The synthesis of cyclin D1 and its assembly with cyclin-dependent kinase 4 (CDK4) to form an active complex is a rate-limiting step in progression through the G1 phase of the cell cycle. Using an activated allele of mitogen-activated protein kinase kinase 1 (MEK1), we show that this kinase plays a significant role in positively regulating the expression of cyclin D1. This was found both in quiescent serum-starved cells and in cells expressing dominant-negative Ras. Despite the observation that cyclin D1 is a target of MEK1, in cycling cells, activated MEK1, but not cyclin D1, is capable of overcoming a G1 arrest induced by Ras inactivation. Either wild-type or catalytically inactive CDK4 cooperates with cyclin D1 in reversing the G1 arrest induced by inhibition of Ras activity. In quiescent NIH 3T3 cells expressing either ectopic cyclin D1 or activated MEK1, cyclin D1 is able to efficiently associate with CDK4; however, the complex is inactive. A significant percentage of the cyclin D1-CDK4 complexes are associated with p27 in serum-starved activated MEK1 or cyclin D1 cell lines. Reduction of p27 levels by expression of antisense p27 allows for S-phase entry from quiescence in NIH 3T3 cells expressing ectopic cyclin D1, but not in parental cells. PMID:9774675

  8. Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation

    PubMed Central

    Hanse, Eric A.; Mashek, Douglas G.; Mashek, Mara T.; Hendrickson, Anna M.; Mullany, Lisa K.; Albrecht, Jeffrey H.

    2016-01-01

    Cyclin D1 is a cell cycle protein that promotes proliferation by mediating progression through key checkpoints in G1 phase. It is also a proto-oncogene that is commonly overexpressed in human cancers. In addition to its canonical role in controlling cell cycle progression, cyclin D1 affects other aspects of cell physiology, in part through transcriptional regulation. In this study, we find that cyclin D1 inhibits the activity of a key metabolic transcription factor, peroxisome proliferator-activated receptor α (PPARα), a member of nuclear receptor family that induces fatty acid oxidation and may play an anti-neoplastic role. In primary hepatocytes, cyclin D1 inhibits PPARα transcriptional activity and target gene expression in a cdk4-independent manner. In liver and breast cancer cells, knockdown of cyclin D1 leads to increased PPARα transcriptional activity, expression of PPARα target genes, and fatty acid oxidation. Similarly, cyclin D1 depletion enhances binding of PPARα to target sequences by chromatin immunoprecipitation. In proliferating hepatocytes and regenerating liver in vivo, induction of endogenous cyclin D1 is associated with diminished PPARα activity. Cyclin D1 expression is both necessary and sufficient for growth factor-mediated repression of fatty acid oxidation in proliferating hepatocytes. These studies indicate that in addition to playing a pivotal role in cell cycle progression, cyclin D1 represses PPARα activity and inhibits fatty acid oxidation. Our findings establish a new link between cyclin D1 and metabolism in both tumor cells and physiologic hepatocyte proliferation. PMID:27351284

  9. Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation.

    PubMed

    Kamarajugadda, Sushama; Becker, Jennifer R; Hanse, Eric A; Mashek, Douglas G; Mashek, Mara T; Hendrickson, Anna M; Mullany, Lisa K; Albrecht, Jeffrey H

    2016-07-26

    Cyclin D1 is a cell cycle protein that promotes proliferation by mediating progression through key checkpoints in G1 phase. It is also a proto-oncogene that is commonly overexpressed in human cancers. In addition to its canonical role in controlling cell cycle progression, cyclin D1 affects other aspects of cell physiology, in part through transcriptional regulation. In this study, we find that cyclin D1 inhibits the activity of a key metabolic transcription factor, peroxisome proliferator-activated receptor α (PPARα), a member of nuclear receptor family that induces fatty acid oxidation and may play an anti-neoplastic role. In primary hepatocytes, cyclin D1 inhibits PPARα transcriptional activity and target gene expression in a cdk4-independent manner. In liver and breast cancer cells, knockdown of cyclin D1 leads to increased PPARα transcriptional activity, expression of PPARα target genes, and fatty acid oxidation. Similarly, cyclin D1 depletion enhances binding of PPARα to target sequences by chromatin immunoprecipitation. In proliferating hepatocytes and regenerating liver in vivo, induction of endogenous cyclin D1 is associated with diminished PPARα activity. Cyclin D1 expression is both necessary and sufficient for growth factor-mediated repression of fatty acid oxidation in proliferating hepatocytes. These studies indicate that in addition to playing a pivotal role in cell cycle progression, cyclin D1 represses PPARα activity and inhibits fatty acid oxidation. Our findings establish a new link between cyclin D1 and metabolism in both tumor cells and physiologic hepatocyte proliferation.

  10. Differential expression of D1 and D5 dopamine receptors in the fetal primate cerebral wall.

    PubMed

    Wang, F; Bergson, C; Howard, R L; Lidow, M S

    1997-12-01

    Previous film autoradiographic studies demonstrated that, during corticogenesis, dopamine receptors of the D1 class are abundant in the embryonic primate cerebral wall. In the present study, we expand these findings by identifying the cellular elements of the fetal occipital cerebral wall expressing D1 and D5 subtypes of the D1 dopamine receptor class. We have examined tissue from monkey fetuses collected at 70, 90 and 120 days of gestation using antibodies directed against C-termini of the D1 and D5 dopamine receptors. At all three embryonic ages studied, we found D1 and D5 receptors expressed by multiple cell types of the embryonic cerebral wall. Both D1 and D5 receptor proteins are produced by pyramidal neurons of the cortical plate and by a variety of interstitial neurons of the subplate and intermediate zones. D1 and D5 receptors are also present in cells of the proliferative ventricular and subventricular zones, some of which were identified as dividing cells. In addition, D1 and D5 receptors are detectable in the protoplasmic astroglial and ependymal cells distinguishable in monkey fetuses collected at 120 days of gestation. Some cellular elements of the embryonic monkey cerebral wall express only one subtype of the D1 dopamine receptor class. For example, embryonic Cajal-Retzius neurons in the marginal zone and migrating neurons in the intermediate zone are immunoreactive only to D5 antisera. In contrast, radial glia can be labeled only with D1 receptor-specific antisera. Finally, only D1 receptors are detectable in the blood vessels penetrating the embryonic monkey cerebral wall. Based on these observations, we propose that dopamine receptors of the D1 class play an important role in regulating cerebral cortical formation and that D1 and D5 receptor subtypes may participate in regulation of different aspects of this process.

  11. An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

    PubMed Central

    Heinz, Beverly A.; Schaus, John M.; Beck, James P.; Hao, Junliang; Krushinski, Joseph H.; Reinhard, Matthew R.; Cohen, Michael P.; Hellman, Sarah L.; Getman, Brian G.; Wang, Xushan; Menezes, Michelle M.; Maren, Deanna L.; Falcone, Julie F.; Anderson, Wesley H.; Wright, Rebecca A.; Morin, S. Michelle; Knopp, Kelly L.; Adams, Benjamin L.; Rogovoy, Borys; Okun, Ilya; Suter, Todd M.; Statnick, Michael A.; Gehlert, Donald R.; Nelson, David L.; Lucaites, Virginia L.; Emkey, Renee; DeLapp, Neil W.; Wiernicki, Todd R.; Cramer, Jeffrey W.; Yang, Charles R.; Bruns, Robert F.

    2017-01-01

    Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3–20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30–240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists. PMID:27811173

  12. Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects.

    PubMed

    Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Hoffmann, Hanne M; Fuentes, Silvia; Rosell-Vilar, Santi; Gasperini, Paola; Rodríguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carme; Ferré, Sergi; Ortiz, Jordi; Canela, Enric; McCormick, Peter J

    2014-03-05

    The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.

  13. Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an estrogen receptor-dependent pathway.

    PubMed

    Kim, Joo-Young; Yi, Bo-Rim; Go, Ryeo-Eun; Hwang, Kyung-A; Nam, Ki-Hoan; Choi, Kyung-Chul

    2014-05-01

    Methoxychlor and triclosan are emergent or suspected endocrine-disrupting chemicals (EDCs). Methoxychlor [MXC; 1,1,1-trichlor-2,2-bis (4-methoxyphenyl) ethane] is an organochlorine pesticide that has been primarily used since dichlorodiphenyltrichloroethane (DDT) was banned. In addition, triclosan (TCS) is used as a common component of soaps, deodorants, toothpastes, and other hygiene products at concentrations up to 0.3%. In the present study, the potential impact of MXC and TCS on ovarian cancer cell growth and underlying mechanism(s) was examined following their treatments in BG-1 ovarian cancer cells. As results, MXC and TCS induced BG-1 cell growth via regulating cyclin D1, p21 and Bax genes related with cell cycle and apoptosis. A methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay confirmed that the proliferation of BG-1 ovarian cancer cells was stimulated by MXC (10(-6), 10(-7), 10(-8), and 10(-9)M) or TCS (10(-6), 10(-7), 10(-8), and 10(-9)M). Treatment of BG-1 cells with MXC or TCS resulted in the upregulation of cyclin D1 and downregulation of p21 and Bax transcriptions. In addition, the protein level of cyclin D1 was increased by MXC or TCS while p21 and Bax protein levels appeared to be reduced in these cells. Furthermore, MXC- or TCS-induced alterations of these genes were reversed in the presence of ICI 182,780 (10(-7)M), suggesting that the changes in these gene expressions may be regulated by an ER-dependent signaling pathway. In conclusion, the results of our investigation indicate that two potential EDCs, MXC and TCS, may stimulate ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an ER-dependent pathway.

  14. Striatal dopamine D1 receptor suppression impairs reward-associative learning.

    PubMed

    Higa, Kerin K; Young, Jared W; Ji, Baohu; Nichols, David E; Geyer, Mark A; Zhou, Xianjin

    2017-04-14

    Dopamine (DA) is required for reinforcement learning. Hence, disruptions in DA signaling may contribute to the learning deficits associated with psychiatric disorders. The DA D1 receptor (D1R) has been linked to learning and is a target for cognitive/motivational enhancement in patients with schizophrenia. Separating the striatal D1R contribution to learning vs. motivation, however, has been challenging. We suppressed striatal D1R expression in mice using a D1R-targeting short hairpin RNA (shRNA), delivered locally to the striatum via an adeno-associated virus (AAV). We then assessed reward- and punishment-associative learning using a probabilistic learning task and motivation using a progressive-ratio breakpoint procedure. We confirmed suppression of striatal D1Rs immunohistochemically and by testing locomotor activity after the administration of (+)-doxanthrine, a full D1R agonist, in control mice and those treated with the D1RshRNA. D1RshRNA-treated mice exhibited impaired reward-associative learning, while punishment-associative learning was spared. This deficit was unrelated to general learning impairments or amotivation, because the D1shRNA-treated mice exhibited normal Barnes maze learning and normal motivation in the progressive-ratio breakpoint procedure. Suppression of striatal D1Rs selectively impaired reward-associative learning whereas punishment-associative learning, aversion-motivated learning, and appetitive motivation were spared. Because patients with schizophrenia exhibit similar reward-associative learning deficits, D1R-targeted treatments should be investigated to improve reward learning in these patients.

  15. Transcriptional role of cyclin D1 in development revealed by a “genetic-proteomic” screen

    PubMed Central

    Bienvenu, Frédéric; Jirawatnotai, Siwanon; Elias, Joshua E.; Meyer, Clifford A.; Mizeracka, Karolina; Marson, Alexander; Frampton, Garrett M.; Cole, Megan F.; Odom, Duncan T.; Odajima, Junko; Geng, Yan; Zagozdzon, Agnieszka; Jecrois, Marie; Young, Richard A.; Liu, X. Shirley; Cepko, Constance L.; Gygi, Steven P.; Sicinski, Piotr

    2010-01-01

    Cyclin D1 belongs to the core cell cycle machinery, and it is frequently overexpressed in human cancers1,2. The full repertoire of cyclin D1 functions in normal development and in oncogenesis is currently unclear. Here we developed FLAG- and HA-tagged cyclin D1 knock-in mouse strains that allowed high-throughput mass spectrometry approach to search for cyclin D1-binding proteins in different mouse organs. In addition to cell cycle partners, we observed several proteins involved in transcription. Genome-wide location (ChIP-chip) analyses revealed that during mouse development cyclin D1 occupies promoters of abundantly expressed genes. In particular, we found that in developing mouse retinas – an organ that critically requires cyclin D1 function3,4 – cyclin D1 binds the upstream regulatory region of the Notch1 gene where it serves to recruit CBP histone acetyltransferase. Genetic ablation of cyclin D1 resulted in decreased CBP recruitment, decreased histone acetylation of the Notch1 promoter region, and led to decreased levels of the Notch transcript and protein in cyclin D1-null retinas. Transduction of an activated allele of Notch1 into cyclin D1−/− retinas increased proliferation of retinal progenitor cells, indicating that upregulating Notch1 signaling alleviates the phenotype of cyclin D1-deficiency. These studies reveal that in addition to its well-established cell cycle roles, cyclin D1 plays an in vivo transcriptional function in mouse development. Our approach, which we term “genetic-proteomic” can be used to study the in vivo function of essentially any protein. PMID:20090754

  16. The Role of Cyclin D1 in Altering Stromal-Epithelial Interactions in Prostate Carcinogenesis

    DTIC Science & Technology

    2008-03-01

    adenocarcinomas. One study of cyclin D1 expression in esophageal carcinomas indicated that cyclin D1 is strongly expressed in stromal fibroblasts. In this study...proliferate faster than controls in vivo in our tissue recombination model. Although cyclin D1 can increase BPH-1 cell motility and promote cell...Alarid ET, Turner T, Donjacour AA, Boutin EL, Foster BA. Normal and abnormal development of the male urogenital tract: role of androgens, mesenchymal

  17. 26 CFR 1.45D-1 - New markets tax credit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 1 2013-04-01 2013-04-01 false New markets tax credit. 1.45D-1 Section 1.45D-1... Computing Credit for Investment in Certain Depreciable Property § 1.45D-1 New markets tax credit. (a... markets tax credit under section 45D(a). (b) Allowance of credit—(1) In general. A taxpayer holding...

  18. 26 CFR 1.45D-1 - New markets tax credit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 1 2012-04-01 2012-04-01 false New markets tax credit. 1.45D-1 Section 1.45D-1... Computing Credit for Investment in Certain Depreciable Property § 1.45D-1 New markets tax credit. (a... markets tax credit under section 45D(a). (b) Allowance of credit—(1) In general. A taxpayer holding...

  19. 26 CFR 1.45D-1 - New markets tax credit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 1 2014-04-01 2013-04-01 true New markets tax credit. 1.45D-1 Section 1.45D-1... Computing Credit for Investment in Certain Depreciable Property § 1.45D-1 New markets tax credit. (a... markets tax credit under section 45D(a). (b) Allowance of credit—(1) In general. A taxpayer holding...

  20. Dopamine D1 Receptor Signaling: Does GαQ–Phospholipase C Actually Play a Role?

    PubMed Central

    Lee, Sang-Min; Yang, Yang

    2014-01-01

    Despite numerous studies showing therapeutic potential, no central dopamine D1 receptor ligand has ever been approved, because of potential limitations, such as hypotension, seizures, and tolerance. Functional selectivity has been widely recognized as providing a potential mechanism to develop novel therapeutics from existing targets, and a highly biased, functionally selective D1 ligand might overcome some of the past limitations. SKF-83959 [6-chloro-3-methyl-1-(m-tolyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diol] is reported to be a highly biased D1 ligand, having full agonism at D1-mediated activation of phospholipase C (PLC) signaling (via GαQ) and antagonism at D1-mediated adenylate cyclase signaling (via GαOLF/S). For this reason, numerous studies have used this compound to elucidate the physiologic role of D1-PLC signaling, including a novel molecular mechanism (GαQ-PLC activation via D1-D2 heterodimers). There is, however, contradictory literature that suggests that SKF-83959 is actually a partial agonist at both D1-mediated adenylate cyclase and β-arrestin recruitment. Moreover, the D1-mediated PLC stimulation has also been questioned. This Minireview examines 30 years of relevant literature and proposes that the data strongly favor alternate hypotheses: first, that SKF-83959 is a typical D1 partial agonist; and second, that the reported activation of PLC by SKF-83959 and related benzazepines likely is due to off-target effects, not actions at D1 receptors. If these hypotheses are supported by future studies, it would suggest that caution should be used regarding the role of PLC and downstream pathways in D1 signaling. PMID:25052835

  1. Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

    PubMed Central

    Drago, J; Gerfen, C R; Lachowicz, J E; Steiner, H; Hollon, T R; Love, P E; Ooi, G T; Grinberg, A; Lee, E J; Huang, S P

    1994-01-01

    Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway. Images Fig. 2 Fig. 4 PMID:7809078

  2. Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis

    PubMed Central

    Norling, Lucy V.; Headland, Sarah E.; Arnardottir, Hildur H.; Haworth, Oliver; Jones, Hefin R.; Serhan, Charles N.

    2016-01-01

    Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which — once applied to human neutrophils — attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor–deficient mice termed ALX/fpr2/3–/–. These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA. PMID:27158677

  3. Amphioxus expresses both vertebrate-type and invertebrate-type dopamine D(1) receptors.

    PubMed

    Burman, Chloe; Evans, Peter D

    2010-12-01

    The cephalochordate amphioxus (Branchiostoma floridae) has recently been placed as the most basal of all the chordates, which makes it an ideal organism for studying the molecular basis of the evolutionary transition from invertebrates to vertebrates. The biogenic amine, dopamine regulates many aspects of motor control in both vertebrates and invertebrates, and in both cases, its receptors can be divided into two main groups (D1 and D2) based on sequence similarity, ligand affinity and effector coupling. A bioinformatic study shows that amphioxus has at least three dopamine D1-like receptor sequences. We have recently characterized one of these receptors, AmphiD1/β, which was found to have high levels of sequence similarity to both vertebrate D1 receptors and to β-adrenergic receptors, but functionally appeared to be a vertebrate-type dopamine D(1) receptor. Here, we report on the cloning of two further dopamine D(1) receptors (AmphiAmR1 and AmphiAmR2) from adult amphioxus cDNA libraries and their pharmacological characterisation subsequent to their expression in cell lines. AmphiAmR1 shows closer structural similarities to vertebrate D(1)-like receptors but shows some pharmacological similarities to invertebrate "DOP1" dopamine D(1)-like receptors. In contrast, AmphiAmR2 shows closer structural and pharmacological similarities to invertebrate "INDR"-like dopamine D(1)-like receptors.

  4. New therapeutic strategies targeting D1-type dopamine receptors for neuropsychiatric disease

    PubMed Central

    Kim, Young-Cho; Alberico, Stephanie L.; Emmons, Eric; Narayanan, Nandakumar S.

    2017-01-01

    The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson’s disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders. PMID:28280503

  5. Observation of the 1S0 to 3D1 clock transition in 175Lu+

    NASA Astrophysics Data System (ADS)

    Arnold, K. J.; Kaewuam, R.; Roy, A.; Paez, E.; Wang, S.; Barrett, M. D.

    2016-11-01

    We report direct laser spectroscopy of the 1S0 to 3D1 highly-forbidden M1 clock transition in 175Lu+ . Clock operation is demonstrated on three pairs of Zeeman transitions, one pair from each hyperfine manifold of the 3D1 term. We measure the hyperfine intervals of the 3D1 to 10 ppb uncertainty and infer the optical frequency averaged over the three hyperfine transitions to be 353.639 915 952 2 (6 ) THz. The lifetime of the 3D1 state is inferred to be 174-32+23 hours from the M1 coupling strength.

  6. Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

    PubMed Central

    Voulalas, Pamela J.; Ji, Yadong; Jiang, Li; Asgar, Jamila; Ro, Jin Y.; Masri, Radi

    2016-01-01

    Neuropathic pain resulting from spinal cord injury is often accompanied by maladaptive plasticity of the central nervous system, including the opioid receptor-rich periaqueductal gray (PAG). Evidence suggests that sensory signaling via the PAG is robustly modulated by dopamine D1- and D2-like receptors, but the effect of damage to the spinal cord on D1 and D2 receptor protein expression and function in the PAG has not been examined. Here we show that 21 days after a T10 or C6 spinothalamic tract lesion, both mice and rats display a remarkable decline in the expression of D1 receptors in the PAG, revealed by western blot analysis. These changes were associated with a significant reduction in hindpaw withdrawal thresholds in lesioned animals compared to sham-operated controls. We investigated the consequences of diminished D1 receptor levels by quantifying D1-like receptor-mediated phosphorylation of ERK1,2 and CREB, events that have been observed in numerous brain structures. In naïve animals, western blot analysis revealed that ERK1,2, but not CREB phosphorylation was significantly increased in the PAG by the D1-like agonist SKF 81297. Using immunohistochemistry, we found that SKF 81297 increased ERK1,2 phosphorylation in the PAG of sham animals. However, in lesioned animals, basal pERK1,2 levels were elevated and did not significantly increase after exposure to SKF 81297. Our findings provide support for the hypothesis that molecular adaptions resulting in a decrease in D1 receptor expression and signaling in the PAG are a consequence of SCL. PMID:27932310

  7. Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer

    SciTech Connect

    Jiang, W.; Zhang, Y.J.; Kahn, S.M.; Santella, R.M.; Weinstein, I.B. ); Hollstein, M.C.; Montesano, R. ); Harris, C.C. ); Lu, S.H. )

    1993-10-01

    The authors have examined DNA from four human esophageal carcinoma cell lines and 50 primary esophageal carcinomas obtained from China, Italy, and France for amplification of the cyclin D1 gene. They also examined 36 of these 50 carcinomas for expressions of the cyclin D1 and retinoblastoma (RB) proteins by immunohistochemistry. They found a 3- to 10-fold amplification of the cyclin D1 gene in 16 of the 50 (32%) tumors and in two of the four cell lines. Cyclin D1 protein was overexpressed in 12 of 13 tumors and the two cell lines that showed gene amplification when compared to normal controls. Studies on RB protein expression indicated that 6 of the 36 (17%) tumor samples examined and one cell line did not show detectable expression of this protein. The tumors and cell lines that had cyclin D1 gene amplification and overexpression exhibited normal levels of expression of RB protein. By contrast, the tumors and cell line that did not appear to express the RB protein did not show amplification of the cyclin D1 gene and expressed only low levels of the cyclin D1 protein (P = 0.03). These results suggest that the inhibitory effect of RB on cell cycle progression can be abrogated during tumor development either by loss of expression of the RB gene or by increased expression of the cyclin D1 gene. 46 refs., 5 figs., 2 tabs.

  8. 26 CFR 1.1033(d)-1 - Destruction or disposition of livestock because of disease.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... of disease. 1.1033(d)-1 Section 1.1033(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... Destruction or disposition of livestock because of disease. (a) The destruction occurring in a taxable year to which the Internal Revenue Code of 1954 applies, of livestock by, or on account of, disease, or the...

  9. 17 CFR 270.12d1-1 - Exemptions for investments in money market funds.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... money market funds. 270.12d1-1 Section 270.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Exemptions for investments in money market funds. (a) Exemptions for acquisition of money market fund shares... issued by a money market fund; and (2) A money market fund, any principal underwriter thereof, and...

  10. 17 CFR 270.12d1-1 - Exemptions for investments in money market funds.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... money market funds. 270.12d1-1 Section 270.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Exemptions for investments in money market funds. (a) Exemptions for acquisition of money market fund shares... issued by a money market fund; and (2) A money market fund, any principal underwriter thereof, and...

  11. Translokin (Cep57) interacts with cyclin D1 and prevents its nuclear accumulation in quiescent fibroblasts.

    PubMed

    Ruiz-Miró, Maria; Colomina, Neus; Fernández, Rita M H; Garí, Eloi; Gallego, Carme; Aldea, Martí

    2011-05-01

    Nuclear accumulation of cyclin D1 because of altered trafficking or degradation is thought to contribute directly to neoplastic transformation and growth. Mechanisms of cyclin D1 localization in S phase have been studied in detail, but its control during exit from the cell cycle and quiescence is poorly understood. Here we report that translokin (Tlk), a microtubule-associated protein also termed Cep57, interacts with cyclin D1 and controls its nucleocytoplasmic distribution in quiescent cells. Tlk binds to regions of cyclin D1 also involved in binding to cyclin-dependent kinase 4 (Cdk4), and a fraction of cyclin D1 associates to the juxtanuclear Tlk network in the cell. Downregulation of Tlk levels results in undue nuclear accumulation of cyclin D1 and increased Cdk4-dependent phosphorylation of pRB under quiescence conditions. In turn, overexpression of Tlk prevents proper cyclin D1 accumulation in the nucleus of proliferating cells in an interaction-dependent manner, inhibits Cdk4-dependent phosphorylation of pRB and hinders cell cycle progression to S phase. We propose that the Tlk acts as a key negative regulator in the pathway that drives nuclear import of cyclin D1, thus contributing to prevent pRB inactivation and to maintain cellular quiescence.

  12. 16 CFR Appendix D1 to Part 305 - Water Heaters-Gas

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Water Heaters-Gas D1 Appendix D1 to Part 305 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS RULE CONCERNING DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME APPLIANCES AND OTHER PRODUCTS REQUIRED UNDER THE ENERGY POLICY...

  13. 17 CFR 270.12d1-1 - Exemptions for investments in money market funds.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... money market funds. 270.12d1-1 Section 270.12d1-1 Commodity and Securities Exchanges SECURITIES AND... Exemptions for investments in money market funds. (a) Exemptions for acquisition of money market fund shares... issued by a money market fund; and (2) A money market fund, any principal underwriter thereof, and...

  14. 26 CFR 1.669(d)-1A - Total taxes deemed distributed.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Total taxes deemed distributed. 1.669(d)-1A...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.669(d)-1A Total taxes deemed distributed. (a) If...

  15. Discovery, evaluation and distribution of haplotypes of the wheat Ppd-D1 gene.

    PubMed

    Guo, Zhiai; Song, Yanxia; Zhou, Ronghua; Ren, Zhenglong; Jia, Jizeng

    2010-02-01

    Ppd-D1 is one of the most potent genes affecting the photoperiod response of wheat (Triticum aestivum). Only two alleles, insensitive Ppd-D1a and sensitive Ppd-D1b, were known previously, and these did not adequately explain the broad adaptation of wheat to photoperiod variation. In this study, five diagnostic molecular markers were employed to identify Ppd-D1 haplotypes in 492 wheat varieties from diverse geographic locations and 55 accessions of Aegilops tauschii, the D genome donor species of wheat. Six Ppd-D1 haplotypes, designated I-VI, were identified. Types II, V and VI were considered to be more ancient and types I, III and IV were considered to be derived from type II. The transcript abundances of the Ppd-D1 haplotypes showed continuous variation, being highest for haplotype I, lowest for haplotype III, and correlating negatively with varietal differences in heading time. These haplotypes also significantly affected other agronomic traits. The distribution frequency of Ppd-D1 haplotypes showed partial correlations with both latitudes and altitudes of wheat cultivation regions. The evolution, expression and distribution of Ppd-D1 haplotypes were consistent evidentially with each other. What was regarded as a pair of alleles in the past can now be considered a series of alleles leading to continuous variation.

  16. 26 CFR 1.642(d)-1 - Net operating loss deduction.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Net operating loss deduction. 1.642(d)-1 Section... TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(d)-1 Net operating loss deduction. The net operating loss deduction allowed by section 172 is available to estates...

  17. 26 CFR 1.642(d)-1 - Net operating loss deduction.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Net operating loss deduction. 1.642(d)-1 Section... TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(d)-1 Net operating loss deduction. The net operating loss deduction allowed by section 172 is available to estates...

  18. 26 CFR 1.642(d)-1 - Net operating loss deduction.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Net operating loss deduction. 1.642(d)-1 Section... TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.642(d)-1 Net operating loss deduction. The net operating loss deduction allowed by section 172 is available to estates and...

  19. 26 CFR 1.642(d)-1 - Net operating loss deduction.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Net operating loss deduction. 1.642(d)-1 Section... TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(d)-1 Net operating loss deduction. The net operating loss deduction allowed by section 172 is available to estates...

  20. 26 CFR 1.642(d)-1 - Net operating loss deduction.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Net operating loss deduction. 1.642(d)-1 Section... TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(d)-1 Net operating loss deduction. The net operating loss deduction allowed by section 172 is available to estates...

  1. Dissociable hippocampal and amygdalar D1-like receptor contribution to discriminated Pavlovian conditioned approach learning.

    PubMed

    Andrzejewski, Matthew E; Ryals, Curtis

    2016-02-15

    Pavlovian conditioning is an elementary form of reward-related behavioral adaptation. The mesolimbic dopamine system is widely considered to mediate critical aspects of reward-related learning. For example, initial acquisition of positively-reinforced operant behavior requires dopamine (DA) D1 receptor (D1R) activation in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and the ventral subiculum (vSUB). However, the role of D1R activation in these areas on appetitive, non-drug-related, Pavlovian learning is not currently known. In separate experiments, microinfusions of the D1-like receptor antagonist SCH-23390 (3.0 nmol/0.5 μL per side) into the amygdala and subiculum preceded discriminated Pavlovian conditioned approach (dPCA) training sessions. D1-like antagonism in all three structures impaired the acquisition of discriminated approach, but had no effect on performance after conditioning was asymptotic. Moreover, dissociable effects of D1-like antagonism in the three structures on components of discriminated responding were obtained. Lastly, the lack of latent inhibition in drug-treated groups may elucidate the role of D1-like in reward-related Pavlovian conditioning. The present data suggest a role for the D1 receptors in the amygdala and hippocampus in learning the significance of conditional stimuli, but not in the expression of conditional responses.

  2. 17 CFR 240.17d-1 - Examination for compliance with applicable financial responsibility rules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Examination for compliance with applicable financial responsibility rules. 240.17d-1 Section 240.17d-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES...

  3. Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors *

    PubMed Central

    Ryman-Rasmussen, Jessica P.; Griffith, Adam; Oloff, Scott; Vaidehi, Nagarajan; Brown, Justin T.; Goddard, William A.; Mailman, Richard B.

    2007-01-01

    Recently, we demonstrated that D1 agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D1 receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D1 receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D1 receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1 h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D1 receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D1 receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D1 receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D1 receptor that are distal from the ligand binding domain. PMID:17067639

  4. 26 CFR 1.381(d)-1 - Operations loss carryovers of life insurance companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... companies. 1.381(d)-1 Section 1.381(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... loss carryovers of life insurance companies. For the application of part V, subchapter C, chapter 1 of the Code to operations loss carryovers of life insurance companies, see section 812(f) and §...

  5. 26 CFR 1.430(d)-1 - Determination of target normal cost and funding target.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Determination of target normal cost and funding target. 1.430(d)-1 Section 1.430(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... of target normal cost and funding target. (a) In general—(1) Overview. This section sets forth...

  6. 26 CFR 1.430(d)-1 - Determination of target normal cost and funding target.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Determination of target normal cost and funding target. 1.430(d)-1 Section 1.430(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Determination of target normal cost and funding target. (a) In general—(1) Overview. This section sets...

  7. 26 CFR 1.430(d)-1 - Determination of target normal cost and funding target.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Determination of target normal cost and funding target. 1.430(d)-1 Section 1.430(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Determination of target normal cost and funding target. (a) In general—(1) Overview. This section sets...

  8. 26 CFR 1.430(d)-1 - Determination of target normal cost and funding target.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Determination of target normal cost and funding target. 1.430(d)-1 Section 1.430(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Determination of target normal cost and funding target. (a) In general—(1) Overview. This section sets...

  9. 26 CFR 1.430(d)-1 - Determination of target normal cost and funding target.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Determination of target normal cost and funding target. 1.430(d)-1 Section 1.430(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Determination of target normal cost and funding target. (a) In general—(1) Overview. This section sets...

  10. Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32.

    PubMed

    Schmid, Mattia; Gemperle, Claudio; Rimann, Nicole; Hersberger, Martin

    2016-04-15

    Resolvin D1 (RvD1) was shown to be a potent anti-inflammatory and proresolution lipid mediator in several animal models of inflammation, but its mechanism of action in humans is not clear. We show that the RvD1 receptor GPR32 is present on resting, proinflammatory M(LPS) and alternatively activated primary human M(IL-4) macrophages, whereas TGF-β and IL-6 reduce its membrane expression. Accordingly, stimulation of resting primary human macrophages with 10 nM RvD1 for 48 h maximally reduced the secretion of the proinflammatory cytokines IL-1β and IL-8; abolished chemotaxis to several chemoattractants like chemerin, fMLF, and MCP-1; and doubled the phagocytic activity of these macrophages toward microbial particles. In contrast, these functional changes were not accompanied by surface expression of markers specific for alternatively activated M(IL-4) macrophages. Similar proresolution effects of RvD1 were observed when proinflammatory M(LPS) macrophages were treated with RvD1. In addition, we show that these RvD1-mediated effects are GPR32 dependent because reduction of GPR32 expression by small interfering RNA, TGF-β, and IL-6 treatment ablated these proresolution effects in primary human macrophages. Taken together, our results indicate that in humans RvD1 triggers GPR32 to polarize and repolarize macrophages toward a proresolution phenotype, supporting the role of this mediator in the resolution of inflammation in humans.

  11. New cis-regulatory elements in the Rht-D1b locus region of wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fifteen gene-containing BACs with accumulated length of 1.82-Mb from the Rht-D1b locus region weresequenced and compared in detail with the orthologous regions of rice, sorghum, and maize. Our results show that Rht-D1b represents a conserved genomic region as implied by high gene sequence identity...

  12. 26 CFR 1.665(d)-1 - Taxes imposed on the trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Taxes imposed on the trust. 1.665(d)-1 Section 1... (CONTINUED) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.665(d)-1 Taxes imposed on the trust. (a) For the purpose of subpart D...

  13. 26 CFR 1.666(d)-1A - Information required from trusts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Information required from trusts. 1.666(d)-1A...) INCOME TAX (CONTINUED) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(d)-1A Information required from trusts. (a)...

  14. 26 CFR 48.4216(d)-1 - Sales of installment accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Sales of installment accounts. 48.4216(d)-1... Manufacturers Taxes § 48.4216(d)-1 Sales of installment accounts. (a) In general. Except as provided in paragraph (d) of this section, in case of a sale or other disposition by a manufacturer, producer,...

  15. 16 CFR Appendix D1 to Part 305 - Water Heaters-Gas

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Water Heaters-Gas D1 Appendix D1 to Part 305... DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME APPLIANCES AND OTHER PRODUCTS REQUIRED... Part 305—Water Heaters—Gas Range Information CAPACITY FIRST HOUR RATING Range of Estimated...

  16. 16 CFR Appendix D1 to Part 305 - Water Heaters-Gas

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Water Heaters-Gas D1 Appendix D1 to Part 305... DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME APPLIANCES AND OTHER PRODUCTS REQUIRED... Part 305—Water Heaters—Gas Range Information CAPACITY FIRST HOUR RATING Range of Estimated...

  17. Observation of 2p3d(1Po)→1s3d(1De) radiative transition in He-like Si, S, and Cl ions.

    PubMed

    Kasthurirangan, S; Saha, J K; Agnihotri, A N; Bhattacharyya, S; Misra, D; Kumar, A; Mukherjee, P K; Santos, J P; Costa, A M; Indelicato, P; Mukherjee, T K; Tribedi, L C

    2013-12-13

    We present an experimental determination of the 2p3d(1Po)→1s3d(1De) x-ray line emitted from He-like Si, S, and Cl projectile ions, excited in collisions with thin carbon foils, using a high-resolution bent-crystal spectrometer. A good agreement between the observation and state-of-the-art relativistic calculations using the multiconfiguration Dirac-Fock formalism including the Breit interaction and QED effects implies the dominance of fluorescent decay over the autoionization process for the 2p3d(^{1}P^{o}) state of He-like heavy ions. This is the first observation of the fluorescence-active doubly excited states in He-like Si, S, and Cl ions.

  18. The organic anion transport polypeptide 1d1 (Oatp1d1) mediates hepatocellular uptake of phalloidin and microcystin into skate liver

    SciTech Connect

    Meier-Abt, F.; Hammann-Haenni, A.; Stieger, B.; Ballatori, N.; Boyer, J.L. . E-mail: james.boyer@yale.edu

    2007-02-01

    Organic anion transporting polypeptides (rodent Oatp; human OATP) mediate cellular uptake of numerous organic compounds including xenobiotic toxins into mammalian hepatocytes. In the little skate Leucoraja erinacea a liver-specific Oatp (Oatp1d1, also called sOatp) has been identified and suggested to represent an evolutionarily ancient precursor of the mammalian liver OATP1B1 (human), Oatp1b2 (rat), and OATP1B3 (human). The present study tested whether Oatp1d1 shares functional transport activity of the xenobiotic oligopeptide toxins phalloidin and microcystin with the mammalian liver Oatps/OATPs. The phalloidin analogue [{sup 3}H]-demethylphalloin was taken up into skate hepatocytes with high affinity (Km {approx} 0.4 {mu}M), and uptake could be inhibited by phalloidin and a variety of typical Oatp/OATP substrates such as bromosulfophthalein, bile salts, estrone-3-sulfate, cyclosporine A and high concentrations of microcystin-LR (Ki {approx} 150 {mu}M). When expressed in Xenopus laevis oocytes Oatp1d1 increased uptake of demethylphalloin (Km {approx} 2.2 {mu}M) and microcystin-LR (Km {approx} 27 {mu}M) 2- to 3-fold over water-injected oocytes, whereas the alternative skate liver organic anion transporter, the dimeric Ost{alpha}/{beta}, exhibited no phalloidin and only minor microcystin-LR transport. Also, the closest mammalian Oatp1d1 orthologue, the human brain and testis OATP1C1, did not show any phalloidin transport activity. These results demonstrate that the evolutionarily ancient Oatp1d1 is able to mediate uptake of cyclic oligopeptide toxins into skate liver. The findings support the notion that Oatp1d1 is a precursor of the liver-specific mammalian Oatps/OATPs and that its transport properties are closely associated with certain forms of toxic liver injury such as for example protein phosphatase inhibition by the water-borne toxin microcystin.

  19. The role of MyoD1 and histone modifications in the activation of muscle enhancers.

    PubMed

    Blum, Roy; Dynlacht, Brian D

    2013-08-01

    MyoD1 is a key regulator that orchestrates skeletal muscle differentiation through the regulation of gene expression. Although many studies have focused on its role in transcriptional control at gene promoters, less is known regarding the role of MyoD1 in the assembly of active enhancers. Here, we discuss novel data that point to the ability of MyoD1 to mediate the assembly of active enhancers that augment the transcription of genes essential for muscle development and lineage specification. Based on genome-wide studies of epigenetic marks that typify active enhancers, we recently identified the compendium of distal regulatory elements that dictate transcriptional programs during myogenesis. Superimposition of MyoD1 binding sites upon the locations of muscle enhancers revealed its unequivocal binding to a core region of nearly a third of condition-specific muscle enhancers. Further studies exploring deposition of enhancer-related epigenetic marks in myoblasts lacking MyoD1 demonstrate the dependence of muscle enhancer assembly on the presence of MyoD1. We propose a model wherein MyoD1 mediates recruitment of Set7, H3K4me1, H3K27ac, p300, and RNAP II to MyoD1-bound enhancers to establish condition-specific activation of muscle genes. Moreover, muscle enhancers are modulated through coordinated binding of transcription factors, including c-Jun, Jdp2, Meis, and Runx1, which are recruited to muscle enhancers in a MyoD1-dependent manner. Thus, MyoD1 and enhancer-associated transcription factors function coordinately to assemble and regulate enhancers, thereby augmenting expression of muscle-related genes.

  20. NeuroD1 promotes neuroblastoma cell growth by inducing the expression of ALK.

    PubMed

    Lu, Fangjin; Kishida, Satoshi; Mu, Ping; Huang, Peng; Cao, Dongliang; Tsubota, Shoma; Kadomatsu, Kenji

    2015-04-01

    Neuroblastoma is derived from the sympathetic neuronal lineage of neural crest cells, and is the most frequently observed of the extracranial pediatric solid tumors. The neuronal differentiation factor, NeuroD1, has previously been shown to promote cell motility in neuroblastoma by suppressing the expression of Slit2. Here we report that NeuroD1 is also involved in the proliferation of neuroblastoma cells, including human cell lines and primary tumorspheres cultured from the tumor tissues of model mice. Interestingly, the growth inhibition of neuroblastoma cells induced by knockdown of NeuroD1 was accompanied by a reduction of ALK expression. ALK is known to be one of the important predisposition genes for neuroblastoma. The phenotype resulting from knockdown of NeuroD1 was suppressed by forced expression of ALK and, therefore, NeuroD1 appears to act mainly through ALK to promote the proliferation of neuroblastoma cells. Furthermore, we showed that NeuroD1 directly bound to the promoter region of ALK gene. In addition, the particular E-box in the promoter was responsible for NeuroD1-mediated ALK expression. These results indicate that ALK should be a direct target gene of NeuroD1. Finally, the expressions of NeuroD1 and ALK in the early tumor lesions of neuroblastoma model mice coincided in vivo. We conclude that the novel mechanism would regulate the expression of ALK in neuroblastoma and that NeuroD1 should be significantly involved in neuroblastoma tumorigenesis.

  1. Cyclin D1 in the Liver: Role of Noncanonical Signaling in Liver Steatosis and Hormone Regulation

    PubMed Central

    Núñez, Kelley G.; Gonzalez-Rosario, Janet; Thevenot, Paul T.; Cohen, Ari J.

    2017-01-01

    Background: Cyclin D1 is an important protein for cell cycle progression; however, functions independent of the cell cycle have been described in the liver. Cyclin D1 is also involved in DNA repair, is overexpressed in many cancers, and functions as a proto-oncogene. The lesser-known roles of Cyclin D1, specifically in hepatocytes, impact liver steatosis and hormone regulation in the liver. Methods: A comprehensive search of PubMed was conducted using the keywords Cyclin D1, steatosis, lipogenesis, and liver transplantation. In this article, we review the results from this literature search, with a focus on the role of Cyclin D1 in hepatic lipogenesis and gluconeogenesis, as well as the impact and function of this protein in hepatic steatosis. Results: Cyclin D1 represses carbohydrate response element binding protein (ChREBP) and results in a decrease in transcription of fatty acid synthase (FAS) and acetyl-coenzyme A carboxylase (ACC). Cyclin D1 also inhibits peroxisome proliferator-activated receptor gamma (PPARγ) which is involved in hepatic lipogenesis. Cyclin D1 inhibits both hepatocyte nuclear factor 4 alpha (HNF4α) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) and represses transcription of lipogenic genes FAS and liver-type pyruvate kinase (Pklr), along with the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Conclusion: Cyclin D1 represses multiple proteins involved in both lipogenesis and gluconeogenesis in the liver. Targeting Cyclin D1 to decrease hepatic steatosis in patients with nonalcoholic fatty liver disease or alcoholic fatty liver disease may help improve patient health and the quality of the donor liver pool. PMID:28331449

  2. Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells

    SciTech Connect

    Sumrejkanchanakij, Piyamas; Eto, Kazuhiro; Ikeda, Masa-Aki . E-mail: mikeda.emb@tmd.ac.jp

    2006-02-03

    The regulation of D-type cyclin-dependent kinase activity is critical for neuronal differentiation and apoptosis. We recently showed that cyclin D1 is sequestered in the cytoplasm and that its nuclear localization induces apoptosis in postmitotic primary neurons. Here, we further investigated the role of the subcellular localization of cyclin D1 in cell cycle withdrawal during the differentiation of N1E-115 neuroblastoma cells. We show that cyclin D1 became predominantly cytoplasmic after differentiation. Targeting cyclin D1 expression to the nucleus induced phosphorylation of Rb and cdk2 kinase activity. Furthermore, cyclin D1 nuclear localization promoted differentiated N1E-115 cells to reenter the cell cycle, a process that was inhibited by p16{sup INK4a}, a specific inhibitor of D-type cyclin activity. These results indicate that cytoplasmic sequestration of cyclin D1 plays a role in neuronal cell cycle withdrawal, and suggests that the abrogation of machinery involved in monitoring aberrant nuclear cyclin D1 activity contributes to neuronal tumorigenesis.

  3. D1 dopamine receptor stimulation impairs striatal proteasome activity in Parkinsonism through 26S proteasome disassembly.

    PubMed

    Barroso-Chinea, Pedro; Thiolat, Marie-Laure; Bido, Simone; Martinez, Audrey; Doudnikoff, Evelyne; Baufreton, Jérôme; Bourdenx, Mathieu; Bloch, Bertrand; Bezard, Erwan; Martin-Negrier, Marie-Laure

    2015-06-01

    Among the mechanisms underlying the development of L-dopa-induced dyskinesia (LID) in Parkinson's disease, complex alterations in dopamine signaling in D1 receptor (D1R)-expressing medium spiny striatal neurons have been unraveled such as, but not limited to, dysregulation of D1R expression, lateral diffusion, intraneuronal trafficking, subcellular localization and desensitization, leading to a pathological anchorage of D1R at the plasma membrane. Such anchorage is partly due to a decreased proteasomal activity that is specific of the L-dopa-exposed dopamine-depleted striatum, results from D1R activation and feeds-back the D1R exaggerated cell surface abundance. The precise mechanisms by which L-dopa affects striatal proteasome activity remained however unknown. We here show, in a series of in vitro ex vivo and in vivo models, that such rapid modulation of striatal proteasome activity intervenes through D1R-mediated disassembly of the 26S proteasome rather than change in transcription or translation of proteasome or proteasome subunits intraneuronal relocalization.

  4. Berberine Suppresses Cyclin D1 Expression through Proteasomal Degradation in Human Hepatoma Cells

    PubMed Central

    Wang, Ning; Wang, Xuanbin; Tan, Hor-Yue; Li, Sha; Tsang, Chi Man; Tsao, Sai-Wah; Feng, Yibin

    2016-01-01

    The aim of this study is to explore the underlying mechanism on berberine-induced Cyclin D1 degradation in human hepatic carcinoma. We observed that berberine could suppress both in vitro and in vivo expression of Cyclin D1 in hepatoma cells. Berberine exhibits dose- and time-dependent inhibition on Cyclin D1 expression in human hepatoma cell HepG2. Berberine increases the phosphorylation of Cyclin D1 at Thr286 site and potentiates Cyclin D1 nuclear export to cytoplasm for proteasomal degradation. In addition, berberine recruits the Skp, Cullin, F-box containing complex-β-Transducin Repeat Containing Protein (SCFβ-TrCP) complex to facilitate Cyclin D1 ubiquitin-proteasome dependent proteolysis. Knockdown of β-TrCP blocks Cyclin D1 turnover induced by berberine; blocking the protein degradation induced by berberine in HepG2 cells increases tumor cell resistance to berberine. Our results shed light on berberine′s potential as an anti-tumor agent for clinical cancer therapy. PMID:27854312

  5. Receptor crosstalk protein, calcyon, regulates affinity state of dopamine D1 receptors.

    PubMed

    Lidow, M S; Roberts, A; Zhang, L; Koh, P O; Lezcano, N; Bergson, C

    2001-09-21

    The recently cloned protein, calcyon, potentiates crosstalk between G(s)-coupled dopamine D1 receptors and heterologous G(q/11)-coupled receptors allowing dopamine D1 receptors to stimulate intracellular Ca(2+) release, in addition to cAMP production. This crosstalk also requires the participating G(q/11)-coupled receptors to be primed by their agonists. We examined the ability of calcyon and priming to regulate the affinity of dopamine D1 receptors for its ligands. Receptor binding assays were performed on HEK293 cell membrane preparations expressing dopamine D1 receptors either alone or in combination with calcyon. Co-expression of dopamine D1 receptor and calcyon affected neither the affinity of this receptor for antagonists nor the affinity of agonist binding to this receptor high and low-affinity states. However, the presence of calcyon dramatically decreased the proportion of the high-affinity dopamine D1 receptor agonist binding sites. This decrease was reversed by carbachol, which primes the receptor crosstalk by stimulating endogenous G(q/11)-coupled muscarinic receptors. Our findings suggest that calcyon regulates the ability of dopamine D1 receptors to achieve the high-affinity state for agonists, in a manner that depends on priming of receptor crosstalk.

  6. Monoclonal antibodies identify a possible regulatory domain of MyoD1.

    PubMed

    Cole, F; Timo, K S; Kohtz, D S

    1992-10-01

    A panel of monoclonal antibodies (mAbs) to murine MyoD1 was generated. One set of mAbs is shown to react with epitope(s) in the cysteine/histidine-rich (C/H) region while another set is shown to react with epitope(s) in the C-terminal portion of MyoD1. One of the mAbs reactive with a C-terminal epitope sensitively detected MyoD1 in whole cell extracts by Western blotting. Time course studies of total protein accumulation during C2C12 myoblast differentiation revealed only subtle changes in the phosphorylation and quantity of MyoD1 protein present in C2C12 cells from induction to 120 hr after induction. These results suggest that modulation of MyoD1 protein or total phosphorylation levels is not tightly associated with the transition of undifferentiated myoblasts to differentiated myocytes. Monoclonal antibodies to the C-terminal epitope produced supershifted bands in gel retardation assays, indicating that these mAbs had no effect on DNA binding. Although the C/H region of MyoD1 does not participate in DNA binding, mAbs reactive with the C/H region neutralized this activity in gel retardation assays. These data suggest that the conserved C/H domain may serve to modulate MyoD1 DNA-binding activity by interacting with another regulator.

  7. Functional significance of central D1 receptors in cognition: beyond working memory.

    PubMed

    Takahashi, Hidehiko; Yamada, Makiko; Suhara, Tetsuya

    2012-07-01

    The role of dopamine D1 receptors in prefrontal cortex function, including working memory, is well acknowledged. However, relatively little is known about their role in other cognitive or emotional functions. We measured both D1 and D2 receptors in the brain using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in cognitive and emotional functions beyond working memory. We found an inverted U-shaped relation between prefrontal D1 receptor availability and Wisconsin Card Sorting Test performance, indicating that too little or too much D1 receptor stimulation impairs working memory or set shifting. In addition, variability of D1 receptor availability in the amygdala and striatum was related to individual differences in emotional responses and decision-making processes, respectively. These observations suggest that the variability of available D1 receptors might be associated with individual differences in brain functions that require phasic dopamine release. An interdisciplinary approach combining molecular imaging of dopamine neurotransmission with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders such as schizophrenia, addiction and Parkinson's disease, as well as novel therapeutics for cognitive impairments observed in them.

  8. Dimerization of Plant Defensin NaD1 Enhances Its Antifungal Activity*

    PubMed Central

    Lay, Fung T.; Mills, Grant D.; Poon, Ivan K. H.; Cowieson, Nathan P.; Kirby, Nigel; Baxter, Amy A.; van der Weerden, Nicole L.; Dogovski, Con; Perugini, Matthew A.; Anderson, Marilyn A.; Kvansakul, Marc; Hulett, Mark D.

    2012-01-01

    The plant defensin, NaD1, from the flowers of Nicotiana alata, is a member of a family of cationic peptides that displays growth inhibitory activity against several filamentous fungi, including Fusarium oxysporum. The antifungal activity of NaD1 has been attributed to its ability to permeabilize membranes; however, the molecular basis of this function remains poorly defined. In this study, we have solved the structure of NaD1 from two crystal forms to high resolution (1.4 and 1.58 Å, respectively), both of which contain NaD1 in a dimeric configuration. Using protein cross-linking experiments as well as small angle x-ray scattering analysis and analytical ultracentrifugation, we show that NaD1 forms dimers in solution. The structural studies identified Lys4 as critical in formation of the NaD1 dimer. This was confirmed by site-directed mutagenesis of Lys4 that resulted in substantially reduced dimer formation. Significantly, the reduced ability of the Lys4 mutant to dimerize correlated with diminished antifungal activity. These data demonstrate the importance of dimerization in NaD1 function and have implications for the use of defensins in agribiotechnology applications such as enhancing plant crop protection against fungal pathogens. PMID:22511788

  9. Structure and Catalytic Mechanism of Human Steroid 5-Reductase (AKR1D1)

    SciTech Connect

    Costanzo, L.; Drury, J; Christianson, D; Penning, T

    2009-01-01

    Human steroid 5{beta}-reductase (aldo-keto reductase (AKR) 1D1) catalyzes reduction of {Delta}{sup 4}-ene double bonds in steroid hormones and bile acid precursors. We have reported the structures of an AKR1D1-NADP{sup +} binary complex, and AKR1D1-NADP{sup +}-cortisone, AKR1D1-NADP{sup +}-progesterone and AKR1D1-NADP{sup +}-testosterone ternary complexes at high resolutions. Recently, structures of AKR1D1-NADP{sup +}-5{beta}-dihydroprogesterone complexes showed that the product is bound unproductively. Two quite different mechanisms of steroid double bond reduction have since been proposed. However, site-directed mutagenesis supports only one mechanism. In this mechanism, the 4-pro-R hydride is transferred from the re-face of the nicotinamide ring to C5 of the steroid substrate. E120, a unique substitution in the AKR catalytic tetrad, permits a deeper penetration of the steroid substrate into the active site to promote optimal reactant positioning. It participates with Y58 to create a 'superacidic' oxyanion hole for polarization of the C3 ketone. A role for K87 in the proton relay proposed using the AKR1D1-NADP{sup +}-5{beta}-dihydroprogesterone structure is not supported.

  10. Induction of excitatory and inhibitory presynaptic differentiation by GluD1.

    PubMed

    Ryu, Kyounghee; Yokoyama, Marie; Yamashita, Manami; Hirano, Tomoo

    2012-01-06

    The δ subfamily of ionotropic glutamate receptor subunits consists of GluD1 and GluD2. GluD2, which is selectively expressed in cerebellar Purkinje neurons, has been shown to contribute to the formation of synapses between granule neurons and Purkinje neurons through interaction with Cbln1 (cerebellin precursor protein1) and presynaptic Neurexin. On the other hand, the synaptogenic activity of GluD1, which is expressed not in the cerebellum but in the hippocampus, remains to be characterized. Here, we report that GluD1 expressed in non-neuronal HEK cells, induced presynaptic differentiation of granule neurons through its N-terminal domain in co-cultures with cerebellar neurons, similarly to GluD2. We also show that GluD1 rescued the defect of synapse formation in GluD2-knockout Purkinje neurons, indicating the functional similarity of GluD1 and GluD2. In contrast, GluD1 expression alone did not induce presynaptic differentiation in co-cultures of HEK cells with hippocampal neurons. However, when Cbln1 was exogenously added to the culture medium, GluD1 induced presynaptic differentiation of not only glutamatergic presynaptic terminals but also GABAergic ones. Cbln1 is not expressed in hippocampal neurons but is expressed in entorhinal cortical neurons projecting to the hippocampus. In co-cultures of HEK cells expressing GluD1 and entorhinal cortical neurons, both glutamatergic and GABAergic presynaptic terminals were formed on the HEK cells without exogenous application of Cbln1. These results suggest that GluD1 might contribute to the formation of specific synapses in the hippocampus such as those formed by the projecting neurons of the entorhinal cortex.

  11. Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis.

    PubMed

    Chen, Yue; Asico, Laureano D; Zheng, Shuo; Villar, Van Anthony M; He, Duofen; Zhou, Lin; Zeng, Chunyu; Jose, Pedro A

    2013-11-01

    Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension.

  12. Differential regulation of cyclins D1 and D3 in hepatocyte proliferation.

    PubMed

    Rickheim, David G; Nelsen, Christopher J; Fassett, John T; Timchenko, Nikolai A; Hansen, Linda K; Albrecht, Jeffrey H

    2002-07-01

    Substantial evidence suggests that cyclin D1 plays a pivotal role in the control of the hepatocyte cell cycle in response to mitogenic stimuli, whereas the closely related protein cyclin D3 has not been extensively evaluated. In the current study, we examined the regulation of cyclins D1 and D3 during hepatocyte proliferation in vivo after 70% partial hepatectomy (PH) and in culture. In contrast to cyclin D1, which was nearly undetectable in quiescent liver and substantially up-regulated after PH, cyclin D3 was constitutively expressed and induced only modestly. In the regenerating liver, the concentration of cyclin D3 was only about 10% of that of cyclin D1. Cyclin D1 formed complexes primarily with cyclin-dependent kinase 4 (cdk4), which were markedly activated in the regenerating liver and readily sequestered the cell cycle inhibitory proteins, p21 and p27. Cyclin D3 bound to both cdk4 and cdk6. Cyclin D3/cdk6 activity was readily detectable in quiescent liver and changed little after PH, and this complex appeared to play a minor role in sequestering p21 and p27. In cultured hepatocytes, epidermal growth factor or insulin had little effect, but the combination of these agents substantially induced cyclin D1 and cell cycle progression. Inhibition of Mek1 or phosphoinositide 3-kinase markedly inhibited cyclin D1 expression and replication. In contrast, cyclin D3 was expressed in the absence of mitogens and was only modestly affected by these manipulations. In addition, growth-inhibitory extracellular matrix conditions inhibited cyclin D1 but not cyclin D3 expression. In conclusion, these results support the concept that cyclin D1 is critically regulated by extracellular stimuli that control proliferation, whereas cyclin D3 is regulated through different pathways and plays a distinct role in the liver.

  13. Prenatal lipopolysaccharide exposure results in dysfunction of the renal dopamine D1 receptor in offspring.

    PubMed

    Wang, Xinquan; Luo, Hao; Chen, Caiyu; Chen, Ken; Wang, Jialiang; Cai, Yue; Zheng, Shuo; Yang, Xiaoli; Zhou, Lin; Jose, Pedro A; Zeng, Chunyu

    2014-11-01

    Adverse environment in early life can modulate the adult phenotype, including blood pressure. Lipopolysaccharide (LPS) exposure in utero results in increased blood pressure in the offspring, but the exact mechanisms are not clear. Studies have shown that the renal dopamine D1 receptor (D1R) plays an important role in maintaining sodium homeostasis and normal blood pressure; dysfunction of D1R is associated with oxidative stress and hypertension. In this study, we determined if dysfunction of the renal D1R is involved in fetal-programmed hypertension, and if oxidative stress contributes to this process. Pregnant Sprague-Dawley (SD) rats were intraperitoneally injected with LPS (0.79 mg/kg) or saline at gestation days 8, 10, and 12. As compared with saline-injected (control) dams, offspring of LPS-treated dams had increased blood pressure, decreased renal sodium excretion, and increased markers of oxidative stress. In addition, offspring of LPS-treated dams had decreased renal D1R expression, increased D1R phosphorylation, and G protein-coupled receptor kinase type 2 (GRK2) and type 4 (GRK4) protein expression, and impaired D1R-mediated natriuresis and diuresis. All of the findings in the offspring of LPS-treated dams were normalized after treatment with TEMPOL, an oxygen free radical scavenger. In conclusion, prenatal LPS exposure, via an increase in oxidative stress, impairs renal D1R function and leads to hypertension in the offspring. Normalization of renal D1R function by amelioration of oxidative stress may be a therapeutic target of fetal programming of hypertension.

  14. The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors.

    PubMed

    Andringa, G; Drukarch, B; Leysen, J E; Cools, A R; Stoof, J C

    1999-01-01

    So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.

  15. [Recombination frequency in the locus Gli-D1 of common wheat T. aestivum L].

    PubMed

    Kozub, N A; Sozinov, I A; Sozinov, A A

    2003-01-01

    The recombination frequency at the gliadin locus Gli-D1 of common wheat was determined by the maximum likelihood method. Recombination was observed between the gene encoding the fastest omega-component of the allele Gli-D1j, and the genes encoding the other omega-gliadins of this allele. The frequency of recombination was 0.65 +/- 0.18% for the cross between the near-isogenic lines of winter common wheat with respect to gliadin loci Gli-D1-4 and Gli-B1-3 and 0.78 +/- 0.45% for the cross between the varieties Yunnat and B-16.

  16. Synthesis and herbicidal evaluation of novel benzothiazole derivatives as potential inhibitors of D1 protease.

    PubMed

    Huang, Tonghui; Sun, Jie; An, Lin; Zhang, Lixian; Han, Cuiping

    2016-04-01

    D1 protease is a C-terminal processing protease that has been predicted to be an ideal herbicidal target. Three novel series of benzothiazole derivatives were synthesized and evaluated for their herbicidal activities against Brassica napus (rape) and Echinochloa crusgalli (barnyard grass). The preliminary bioassay indicated that most of the synthesized compounds possess promising D1 protease inhibitory activities and considerable herbicidal activities. Molecular docking was performed to position representative compounds into the active site of D1 protease to determine a probable binding model.

  17. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

    PubMed Central

    Alao, John P

    2007-01-01

    Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed. PMID:17407548

  18. Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms.

    PubMed

    Yao, Pei-Li; Chen, Li Ping; Dobrzański, Tomasz P; Phillips, Dylan A; Zhu, Bokai; Kang, Boo-Hyon; Gonzalez, Frank J; Peters, Jeffrey M

    2015-11-03

    Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPARβ/δ in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPARβ/δ. Expression of PPARβ/δ caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPARβ/δ-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPARβ/δ competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARα-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPARβ/δ mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPARβ/δ inhibits RAR/RXR dimerization and represents a new therapeutic strategy.

  19. Origin of the Scaling Constant "d" = 1.7 in Item Response Theory.

    ERIC Educational Resources Information Center

    Camilli, Gregory

    1994-01-01

    Describes the scaling constant "d" = 1.702, used in Item Response Theory, which minimizes the maximum difference between the normal and logistic distribution functions. Recapitulates the theoretical and numerical derivation of "d" given by D. Haley (1952). (SLD)

  20. The new powder diffractometer D1B of the Institut Laue Langevin

    NASA Astrophysics Data System (ADS)

    Puente Orench, I.; Clergeau, J. F.; Martínez, S.; Olmos, M.; Fabelo, O.; Campo, J.

    2014-11-01

    D1B is a medium resolution high flux powder diffractometer located at the Institut Laue Langevin, ILL. D1B a suitable instrument for studying a large variety of polycrystalline materials. D1B runs since 1998 as a CRG (collaborating research group) instrument, being exploited by the CNRS (Centre National de la Recherche Scientifique, France) and CSIC (Consejo Superior de Investigaciones Cientificas, Spain). In 2008 the Spanish CRG started an updating program which included a new detector and a radial oscillating collimator (ROC). The detector, which has a sensitive height of 100mm, covers an angular range of 128°. Its 1280 gold wires provide a neutron detection point every 0.1°. The ROC is made of 198 gadolinium- based absorbing collimation blades, regular placed every 0.67°. Here the present characteristics of D1B are reviewed and the different experimental performances will be presented.

  1. Dual signaling regulated by calcyon, a D1 dopamine receptor interacting protein.

    PubMed

    Lezcano, N; Mrzljak, L; Eubanks, S; Levenson, R; Goldman-Rakic, P; Bergson, C

    2000-03-03

    The synergistic response of cells to the stimulation of multiple receptors has been ascribed to receptor cross talk; however, the specific molecules that mediate the resultant signal amplification have not been defined. Here a 24-kilodalton single transmembrane protein, designated calcyon, we functionally characterize that interacts with the D1 dopamine receptor. Calcyon localizes to dendritic spines of D1 receptor-expressing pyramidal cells in prefrontal cortex. These studies delineate a mechanism of Gq- and Gs-coupled heterotrimeric GTP-binding protein-coupled receptor cross talk by which D1 receptors can shift effector coupling to stimulate robust intracellular calcium (Ca2+i) release as a result of interaction with calcyon. The role of calcyon in potentiating Ca2+-dependent signaling should provide insight into the D1 receptor-modulated cognitive functions of prefrontal cortex.

  2. Mechanisms for Antagonistic Regulation of AMPA and NMDA-D1 Receptor Complexes at Postsynaptic Sites

    NASA Technical Reports Server (NTRS)

    Schumann, Johann; Scheler, Gabriele

    2004-01-01

    From the analysis of these pathways we conclude that postsynaptic processes that regulate synaptic transmission undergo significant cross-talk with respect to glutamatergic and neuromodulatory (dopamine) signals. The main hypothesis is that of a compensatory regulation, a competitive switch between the induction of increased AMPA conductance by CaMKII-dependent phosphorylation and reduced expression of PP2A, and increased D1 receptor sensitivity and expression by increased PKA, PP2A and decreased PP-1/calcineurin expression. Both types of plasticity are induced by NMDA receptor activation and increased internal calcium, they require different internal conditions to become expressed. Specifically we propose that AMPA regulation and D1 regulation are inversely coupled;The net result may be a bifurcation of synaptic state into predominantly AMPA or NMDA-D1 synapses. This could have functional consequences: stable connections for AMPA and conditional gating for NMDA-D1 synapses.

  3. 42 CFR 51d.1 - To what does this subpart apply?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.1 To what does this subpart apply? The... communities created by mental health or substance abuse emergencies, as authorized under section 501(m) of...

  4. 42 CFR 51d.1 - To what does this subpart apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.1 To what does this subpart apply? The... communities created by mental health or substance abuse emergencies, as authorized under section 501(m) of...

  5. 42 CFR 51d.1 - To what does this subpart apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.1 To what does this subpart apply? The... communities created by mental health or substance abuse emergencies, as authorized under section 501(m) of...

  6. 42 CFR 51d.1 - To what does this subpart apply?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.1 To what does this subpart apply? The... communities created by mental health or substance abuse emergencies, as authorized under section 501(m) of...

  7. 42 CFR 51d.1 - To what does this subpart apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.1 To what does this subpart apply? The... communities created by mental health or substance abuse emergencies, as authorized under section 501(m) of...

  8. Diverse functions for the semaphorin receptor PlexinD1 in development and disease

    PubMed Central

    Gay, Carl M.; Zygmunt, Tomasz; Torres-Vázquez, Jesús

    2010-01-01

    SUMMARY Plexins are a family of single pass transmembrane proteins that serve as cell surface receptors for Semaphorins during the embryonic development of animals. Semaphorin-Plexin signaling is critical for many cellular aspects of organogenesis, including cell migration, proliferation and survival. Until recently, little was known about the function of PlexinD1, the sole member of the vertebrate-specific PlexinD (PlxnD1) subfamily. Here we review novel findings about PlxnD1’s roles in the development of the cardiovascular, nervous and immune systems and salivary gland branching morphogenesis and discuss new insights concerning the molecular mechanisms of PlxnD1 activity. PMID:20880496

  9. Cyclin D1 G870A polymorphism and risk of colorectal cancer: a case control study.

    PubMed

    Sameer, Aga Syed; Parray, Fazl Q; Dar, Manzoor Ahmad; Nissar, Saniya; Banday, Mujeeb Zafar; Rasool, Sabha; Gulzar, G M; Chowdri, Nissar A; Siddiqi, Mushtaq A

    2013-03-01

    The present study aimed to analyse the role of cyclin D1 A870G polymorphism in modulating the susceptibility to colorectal cancer (CRC) in the Kashmiri population. The genotype distribution of the cyclin D1 gene in 130 CRC cases in comparison with 160 healthy controls was investigated. No direct significant association between cyclin D1 genotypes and CRC was observed; however, the AG and AA genotypes were found to be associated with an increased risk of CRC compared to the GG genotype, with an almost 2-fold increase in OR. This study suggests that the cyclin D1 polymorphism is associated with an increased risk of CRC in the Kashmiri population.

  10. Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis.

    PubMed

    Padia, Shetal H; Kemp, Brandon A; Howell, Nancy L; Keller, Susanna R; Gildea, John J; Carey, Robert M

    2012-02-01

    Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.

  11. Pharmacology of Signaling Induced by Dopamine D1-Like Receptor Activation

    PubMed Central

    Undieh, Ashiwel S.

    2010-01-01

    Dopamine D1-like receptors consisting of D1 and D5 subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D1-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D1-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D1-like receptor agonists is reliably associated with the D1 subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D5 receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D5 coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D5 versus D1 subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D1 or D5 interactions with D2-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway. PMID:20547182

  12. Adaptive evolution of the Streptococcus pyogenes regulatory aldolase LacD.1.

    PubMed

    Cusumano, Zachary; Caparon, Michael

    2013-03-01

    In the human-pathogenic bacterium Streptococcus pyogenes, the tagatose bisphosphate aldolase LacD.1 likely originated through a gene duplication event and was adapted to a role as a metabolic sensor for regulation of virulence gene transcription. Although LacD.1 retains enzymatic activity, its ancestral metabolic function resides in the LacD.2 aldolase, which is required for the catabolism of galactose. In this study, we compared these paralogous proteins to identify characteristics correlated with divergence and novel function. Surprisingly, despite the fact that these proteins have identical active sites and 82% similarity in amino acid sequence, LacD.1 was less efficient at cleaving both fructose and tagatose bisphosphates. Analysis of kinetic properties revealed that LacD.1's adaptation was associated with a decrease in k(cat) and an increase in K(m). Construction and analysis of enzyme chimeras indicated that non-active-site residues previously associated with the variable activities of human aldolase isoenzymes modulated LacD.1's affinity for substrate. Mutant LacD.1 proteins engineered to have LacD.2-like levels of enzymatic efficiency lost the ability to function as regulators, suggesting that an alteration in efficiency was required for adaptation. In competition under growth conditions that mimic a deep-tissue environment, LacD.1 conferred a significant gain in fitness that was associated with its regulatory activity. Taken together, these data suggest that LacD.1's adaptation represents a form of neofunctionalization in which duplication facilitated the gain of regulatory function important for growth in tissue and pathogenesis.

  13. Expression of Cyclin D1 and P16 in Esophageal Squamous Cell Carcinoma.

    PubMed

    Dey, Biswajit; Raphael, Vandana; Khonglah, Yookarin; GiriLynrah, Kyrshanlang

    2015-10-01

    BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Many genes including cyclin D1 and p16 play important role in its carcinogenesis. We aimed to analyze the expressions of cyclin D1 and p16 with the various clinicopathological characteristics of ESCC. METHODS We examined 30 biopsy samples of ESCC for cyclin D1 and p16 protein expressions using immunohistochemistry. Immunointensity was classified as no immunostaining (-), weakly immunostaining (+), weak immunostaining (++) and strongly positive immunostaining (+++). RESULTS Out of the 30 cases, positive expression of cyclin D1 was detected in 26 cases (86.7%). The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%), and tumors which were poorly differentiated (92.9%) were higher in cyclin D1 positive tumors than in the cyclin D1 negative tumors. However no significant association was found between cyclin D1 expression and the different clinicopathological parameters.There were 22 cases of ESCC (73.3 %) which showed negativity for p16. The percentage of tumors with invasion to the adventitia (82.4%) and poorly differentiated tumors (92.9%) were higher in the p16 negative tumors than in the p16 positive tumors. There was significant association between the histological grade and p16 expression (p=0.012). However, there were no significant association with regard to site, size and lymph node status of the tumors and p16 expression. CONCLUSION The study shows that alterations of cyclin D1 and p16 play an important role in ESCC. Loss of p16 expression was associated with poor differentiation.

  14. Effects of dopamine D1 receptor full agonists in rats trained to discriminate SKF 38393.

    PubMed

    Gleason, S D; Witkin, J M

    2004-02-01

    Although the dopaminergic pharmacology of the D1 receptor full agonists, dinapsoline, dihydrexidine and the prodrug ABT-431 have been studied, no information is available on the ability of these agonists to substitute for the D1 agonist SKF 38393 in rats trained to discriminate this compound from vehicle. The present study was designed to characterize the potential D1 discriminative stimulus effects of these compounds. The selective dopamine D1-receptor agonists dihydrexidine [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride], ABT-431 [(-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride], the diacetyl prodrug derivative of A-86929, and dinapsoline [9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline] were studied in rats trained to discriminate racemic SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a selective D1 receptor partial agonist from vehicle. All of the agonists substituted fully for the discriminative stimulus effects of SKF 38393. The rank order of potency for substitution was ABT-431 > dinapsoline > dihydrexidine > SKF 38393. The D1 receptor antagonist, SCH 23390, blocked the discriminative stimulus effects of SKF 38393. The D3/D2-receptor agonist PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol] did not substitute up to doses that produced profound rate-suppressant effects. Thus, consistent with their D1 receptor pharmacology, the full D1-receptor agonists substituted completely for the discriminative stimulus of SKF 38393.

  15. 17 CFR 270.12d1-1 - Exemptions for investments in money market funds.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) of the Act (15 U.S.C. 80a-3(c)(1) and 80a-3(c)(7)). (2) Money market fund means: (i) An open-end... as if it were a registered open-end investment company: (A) Operates in compliance with § 270.2a-7... money market funds. 270.12d1-1 Section 270.12d1-1 Commodity and Securities Exchanges SECURITIES...

  16. 17 CFR 270.12d1-1 - Exemptions for investments in money market funds.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) of the Act (15 U.S.C. 80a-3(c)(1) and 80a-3(c)(7)). (2) Money market fund means: (i) An open-end... as if it were a registered open-end investment company: (A) Operates in compliance with § 270.2a-7... money market funds. 270.12d1-1 Section 270.12d1-1 Commodity and Securities Exchanges SECURITIES...

  17. NeuroD1: developmental expression and regulated genes in the rodent pineal gland.

    PubMed

    Muñoz, Estela M; Bailey, Michael J; Rath, Martin F; Shi, Qiong; Morin, Fabrice; Coon, Steven L; Møller, Morten; Klein, David C

    2007-08-01

    NeuroD1/BETA2, a member of the bHLH transcription factor family, is known to influence the fate of specific neuronal, endocrine and retinal cells. We report here that NeuroD1 mRNA is highly abundant in the developing and adult rat pineal gland. Pineal expression begins in the 17-day embryo at which time it is also detectable in other brain regions. Expression in the pineal gland increases during the embryonic period and is maintained thereafter at levels equivalent to those found in the cerebellum and retina. In contrast, NeuroD1 mRNA decreases markedly in non-cerebellar brain regions during development. Pineal NeuroD1 levels are similar during the day and night, and do not appear to be influenced by sympathetic neural input. Gene expression analysis of the pineal glands from neonatal NeuroD1 knockout mice identifies 127 transcripts that are down-regulated (>twofold, p < 0.05) and 16 that are up-regulated (>twofold, p < 0.05). According to quantitative RT-PCR, the most dramatically down-regulated gene is kinesin family member 5C ( approximately 100-fold) and the most dramatically up-regulated gene is glutamic acid decarboxylase 1 ( approximately fourfold). Other impacted transcripts encode proteins involved in differentiation, development, signal transduction and trafficking. These findings represent the first step toward elucidating the role of NeuroD1 in the rodent pinealocyte.

  18. D1-class dopamine receptor involvement in the behavioral recovery from prefrontal cortical injury.

    PubMed

    Vargo, J M; Bromberg, B B; Best, P J; Corwin, J V; Marshall, J F

    1995-12-14

    Following unilateral aspiration of the left medial agranular cortex (AGm) region of prefrontal cortex, rats demonstrate contralateral neglect, characterized by a failure to orient to visual, tactile and auditory stimuli presented on the contralateral body side. While dopamine (DA) has been implicated in cortical neglect and its recovery, this study specifically examined D1-class DA receptors for their involvement in spontaneous recovery from neglect caused by AGm ablation. In the first experiment, left AGm-ablated rats demonstrated severe neglect of contralateral stimuli of each modality which spontaneously recovered over a period of several weeks. Recovered rats were given 7.0 micrograms/kg (s.c.) of the D1-selective antagonist SCH 23390. SCH 23390 reinstated severe neglect of contralateral stimuli, yet had no effect on orientation to ipsilateral stimuli. The same dose had no effect on the orientation behavior of controls. In a second experiment, D1 receptor characteristics were quantified via binding of [3H]SCH 23390 to tissue homogenates of the caudate-putamen of recovered AGm-ablated rats. Numbers and affinities of striatal D1 receptors of rats with unilateral AGm ablations did not differ between hemispheres or from values obtained from lesioned controls. Considered together, these findings indicate that recovery from neglect produced by cortical injury is associated with an increased dependence on D1-class receptor-mediated events, and that this increased dependence is unlikely to be mediated through changes in D1-class receptor numbers or affinities within caudate-putamen.

  19. NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program.

    PubMed

    Pataskar, Abhijeet; Jung, Johannes; Smialowski, Pawel; Noack, Florian; Calegari, Federico; Straub, Tobias; Tiwari, Vijay K

    2016-01-04

    Cell fate specification relies on the action of critical transcription factors that become available at distinct stages of embryonic development. One such factor is NeuroD1, which is essential for eliciting the neuronal development program and possesses the ability to reprogram other cell types into neurons. Given this capacity, it is important to understand its targets and the mechanism underlying neuronal specification. Here, we show that NeuroD1 directly binds regulatory elements of neuronal genes that are developmentally silenced by epigenetic mechanisms. This targeting is sufficient to initiate events that confer transcriptional competence, including reprogramming of transcription factor landscape, conversion of heterochromatin to euchromatin, and increased chromatin accessibility, indicating potential pioneer factor ability of NeuroD1. The transcriptional induction of neuronal fate genes is maintained via epigenetic memory despite a transient NeuroD1 induction during neurogenesis. NeuroD1 also induces genes involved in the epithelial-to-mesenchymal transition, thereby promoting neuronal migration. Our study not only reveals the NeuroD1-dependent gene regulatory program driving neurogenesis but also increases our understanding of how cell fate specification during development involves a concerted action of transcription factors and epigenetic mechanisms.

  20. Glycogen synthase kinase 3β and cyclin D1 expression in cervical carcinogenesis

    PubMed Central

    Park, Hyunsoo; Lee, Myunghwa; Kim, Dae Woon; Hong, Seo Yoo

    2016-01-01

    Objective Glycogen synthase kinase 3β (GSK3β) is a pluripotent protein kinase involved in the development of cancers through regulation of numerous oncogenic molecules. Cyclin D1, an important regulator of G1 to S phase transition in various cells, is one of target proteins that GSK3β regulate. Our objective was to assess the expression of GSK3β and cyclin D1 in cervical neoplasm of different histologic grades and to identify their correlation in cervical carcinogenesis. Methods Immunohistochemical analysis of GSK3β and cyclin D1 was performed in a total of 137 patients with 12 normal, 62 cervical intraepithelial neoplasia (CIN) (31 CIN1 and 31 CIN3) and 63 invasive cancers including 56 squamous cell carcinomas and 7 adenocarcinomas. Results The expression of GSK3β increased in parallel with the lesion grade, while that of cyclin D1 decreased with severity of the lesion (P<0.001). There was a significant inverse correlation between GSK3β and cyclin D1 expression in overall cervical neoplasia (Φ=-0.413, P<0.001). GSK3β expression was higher in squamous cell carcinoma than in adenocarcinoma (P=0.049). Conclusion These results suggest that the expressional increase in GSK3β plays a role in cervical carcinogenesis and has inverse correlation with cyclin D1 expression in this process. In addition, GSK3β expression appears to be associated with the histologic type of cervical cancer, especially squamous cell carcinoma. PMID:27896249

  1. Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation.

    PubMed

    Capaldo, Christopher T; Koch, Stefan; Kwon, Michael; Laur, Oskar; Parkos, Charles A; Nusrat, Asma

    2011-05-15

    Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of TJ plaque proteins sequesters cyclin D1 at TJs during mitosis, through an evolutionarily conserved class II PSD-95, Dlg, and ZO-1 (PDZ)-binding motif within cyclin D1. Disruption of the cyclin D1/ZO complex through mutagenesis or siRNA-mediated suppression of ZO-3 resulted in increased cyclin D1 proteolysis and G(0)/G(1) cell-cycle retention. This study highlights an important new role for ZO family TJ proteins in regulating epithelial cell proliferation through stabilization of cyclin D1 during mitosis.

  2. The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats.

    PubMed

    Wirtshafter, David; Osborn, Catherine V

    2005-12-28

    The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.

  3. Trans-activation of TRPV1 by D1R in mouse dorsal root ganglion neurons.

    PubMed

    Lee, Dong Woo; Cho, Pyung Sun; Lee, Han Kyu; Lee, Sang Hoon; Jung, Sung Jun; Oh, Seog Bae

    2015-10-02

    TRPV1, a ligand-gated ion channel expressed in nociceptive sensory neurons is modulated by a variety of intracellular signaling pathways. Dopamine is a neurotransmitter that plays important roles in motor control, cognition, and pain modulation in the CNS, and acts via a variety of dopamine receptors (D1R-D5R), a class of GPCRs. Although nociceptive sensory neurons express D1-like receptors, very little is known about the effect of dopamine on TRPV1 in the peripheral nervous system. Therefore, in this study, we examined the effects of D1R activation on TRPV1 in mouse DRG neurons using Ca(2+) imaging and immunohistochemical analysis. The D1R agonist SKF-38393 induced reproducible Ca(2+) responses via Ca(2+) influx through TRPV1 rather than Ca(2+) mobilization from intracellular Ca(2+) stores. Immunohistochemical analysis revealed co-expression of D1R and TRPV1 in mouse DRG neurons. The PLC-specific inhibitor blocked the SKF-38393-induced Ca(2+) response, whereas the PKC, DAG lipase, AC, and PKA inhibitors had no effect on the SKF-38393-induced Ca(2+) response. Taken together, our results suggest that the SKF-38393-induced Ca(2+) response results from the direct activation of TRPV1 by a PLC/DAG-mediated membrane-delimited pathway. These results provide evidence that the trans-activation of TRPV1 following D1R activation may contribute to the modulation of pain signaling in nociceptive sensory neurons.

  4. Cyclin D1 is an essential mediator of apoptotic neuronal cell death.

    PubMed Central

    Kranenburg, O; van der Eb, A J; Zantema, A

    1996-01-01

    Many neurons in the developing nervous system undergo programmed cell death, or apoptosis. However, the molecular mechanism underlying this phenomenon is largely unknown. In the present report, we present evidence that the cell cycle regulator cyclin D1 is involved in the regulation of neuronal cell death. During neuronal apoptosis, cyclin D1-dependent kinase activity is stimulated, due to an increase in cyclin D1 levels. Moreover, artificial elevation of cyclin D1 levels is sufficient to induce apoptosis, even in non-neural cell types. Cyclin D1-induced apoptosis, like neuronal apoptosis, can be inhibited by 21 kDa E1B, Bcl2 and pRb, but not by 55 kDa E1B. Most importantly, however, overexpression of the cyclin D-dependent kinase inhibitor p16INK4 protects neurons from apoptotic cell death, demonstrating that activation of endogenous cyclin D1-dependent kinases is essential during neuronal apoptosis. These data support a model in which neuronal apoptosis results from an aborted attempt to activate the cell cycle in terminally differentiated neurons. Images PMID:8598205

  5. Fludioxonil induced the cancer growth and metastasis via altering epithelial-mesenchymal transition via an estrogen receptor-dependent pathway in cellular and xenografted breast cancer models.

    PubMed

    Go, Ryeo-Eun; Kim, Cho-Won; Jeon, So-Ye; Byun, Yong-Sub; Jeung, Eui-Bae; Nam, Ki-Hoan; Choi, Kyung-Chul

    2017-04-01

    Fludioxonil is an antifungal agent used in agricultural applications that is present at measurable amounts in fruits and vegetables. In this study, the effects of fludioxonil on cancer cell viability, epithelial-mesenchymal transition (EMT), and metastasis were examined in MCF-7 clonal variant breast cancer cell (MCF-7 CV cells) with estrogen receptors (ERs). MCF-7 CV cells were cultured with 0.1% DMSO (control), 17β-estradiol (E2; 1 ×10(-9) M, positive control), or fludioxonil (10(-5) -10(-8) M). MTT assay revealed that fludioxonil increased MCF-7 CV cell proliferation 1.2 to 1.5 times compared to the control, while E2 markedly increased the cell proliferation by about 3.5 times. When the samples were co-treated with ICI 182,780 (10(-8) M), an ER antagonist, fludioxonil-induced cell proliferation was reversed to the level of the control. Protein levels of cyclin E1, cyclin D1, Snail, and N-cadherin increased in response to fludioxonil as the reaction to E2, but these increases were not observed when fludioxonil was administered with ICI 182,780. Moreover, the protein level of p21 and E-cadherin decreased in response to treatment with fludioxonil, but remained at the control level when co-treated with ICI 182,780. In xenografted mouse models transplanted with MCF-7 CV cells, fludioxonil significantly increased the tumor mass formation by about 2.5 times as E2 did when compared to vehicle (0.1% DMSO) during the experimental period (80 days). Immunohistochemistry revealed that the protein level of proliferating cell nuclear antigen (PCNA), Snail, and cathepsin D increased in response to fludioxonil as the reaction to E2. These results imply that fludioxonil may have a potential to induce growth or metastatic behaviors of breast cancer by regulation of the expression of cell cycle-, EMT-, and metastasis-related genes via the ER-dependent pathway. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1439-1454, 2017.

  6. Identification of a D1 dopamine receptor, not linked to adenylate cyclase, on lactotroph cells.

    PubMed Central

    Schoors, D. F.; Vauquelin, G. P.; De Vos, H.; Smets, G.; Velkeniers, B.; Vanhaelst, L.; Dupont, A. G.

    1991-01-01

    1. We studied the lactotroph cells of the rat by both in vivo and in vitro pharmacological techniques for the presence of D1-receptors. Both approaches revealed the presence of D2-receptor, stimulated by quinpirole (resulting in an inhibition of prolactin secretion) and blocked by domperidone. 2. Administration of fenoldopam, the most selective D1-receptor agonist currently available, resulted in a dose-dependent decrease of prolactin secretion in vivo (after pretreatment with alpha-methyl-p-tyrosine) and in vitro (cultured pituitary cells). This increase was dose-dependently blocked by the selective D1-receptor antagonist, SCH 23390, and although the effect of fenoldopam was less than that obtained by D2-receptor stimulation, these data suggest that a D1-receptor also controls prolactin secretion. 3. In order to detect the location of these dopamine receptors, autoradiographic studies were performed by use of [3H]-SCH 23390 and [3H]-spiperone as markers for D1- and D2-receptors, respectively. Specific binding sites for [3H]-SCH 23390 were demonstrated. Fenoldopam dose-dependently reduced [3H]-SCH 23390 binding, but had no effect on [3H]-spiperone binding. Immunocytochemical labelling of prolactin cells after incubation with [3H]-SCH 23390 revealed that the granulae and hence, D1 binding sites were present on the lactotroph cells. 4. Radioligand binding studies performed on membranes from anterior pituitary cells revealed the presence of the D2-receptor (54 fmol mg-1 protein) with a Kd of 0.58 nM for [3H]-spiperone, but failed to detect D1-receptors. 5. Finally, we studied the effect of dopamine and of fenoldopam on the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content of anterior pituitary cells.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 4 Figure 5 PMID:1833020

  7. Resolvin D1 primes the resolution process initiated by calorie restriction in obesity-induced steatohepatitis.

    PubMed

    Rius, Bibiana; Titos, Esther; Morán-Salvador, Eva; López-Vicario, Cristina; García-Alonso, Verónica; González-Périz, Ana; Arroyo, Vicente; Clària, Joan

    2014-02-01

    Insulin resistance and nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis combined with inflammation, are major sequelae of obesity. Currently, lifestyle modification (i.e., weight loss) is the first-line therapy for NASH. However, weight loss resolves steatosis but not inflammation. In this study, we tested the ability of resolvin D1 (RvD1), an anti-inflammatory and proresolving molecule, to promote the resolution initiated by calorie restriction in obese mice with NASH. Calorie restriction reduced adipose and liver weight (-56 and -13%, respectively; P<0.001), serum leptin and resistin levels, hepatic steatosis, and insulin resistance. In addition to these, mice receiving RvD1 during the dietary intervention showed increased adiponectin expression at both the mRNA and protein levels and reduced liver macrophage infiltration (-15%, P<0.01). Moreover, RvD1 skewed macrophages from an M1- to an M2-like anti-inflammatory phenotype, induced a specific hepatic miRNA signature (i.e., miR-219-5p and miR-199a-5p), and reduced inflammatory adipokine mRNA and protein expression and macrophage innate immune response. In precision-cut liver slices (PCLSs), which override the influence of circulating factors, RvD1 attenuated hypoxia-induced mRNA and protein expression of COX-2, IL-1β, IL-6, and CCR7. Of note, RvD1 anti-inflammatory actions were absent in macrophage-depleted PCLSs. In summary, RvD1 acts as a facilitator of the hepatic resolution process by reducing the inflammatory component of obesity-induced NASH.

  8. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury.

    PubMed

    Liu, Yong; Zhou, Dan; Long, Fei-Wu; Chen, Ke-Ling; Yang, Hong-Wei; Lv, Zhao-Yin; Zhou, Bin; Peng, Zhi-Hai; Sun, Xiao-Feng; Li, Yuan; Zhou, Zong-Guang

    2016-03-01

    Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.

  9. BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells

    SciTech Connect

    Nakuci, Enkeleda; Mahner, Sven; DiRenzo, James; ElShamy, Wael M. . E-mail: wael_elshamy@dfci.harvard.edu

    2006-10-01

    The regulator of cell cycle progression, cyclin D1, is up-regulated in breast cancer cells; its expression is, in part, dependent on ER{alpha} signaling. However, many ER{alpha}-negative tumors and tumor cell lines (e.g., SKBR3) also show over-expression of cyclin D1. This suggests that, in addition to ER{alpha} signaling, cyclin D1 expression is under the control of other signaling pathways; these pathways may even be over-expressed in the ER{alpha}-negative cells. We previously noticed that both ER{alpha}-positive and -negative cell lines over-express BRCA1-IRIS mRNA and protein. Furthermore, the level of over-expression of BRCA1-IRIS in ER{alpha}-negative cell lines even exceeded its over-expression level in ER{alpha}-positive cell lines. In this study, we show that: (1) BRCA1-IRIS forms complex with two of the nuclear receptor co-activators, namely, SRC1 and SRC3 (AIB1) in an ER{alpha}-independent manner. (2) BRCA1-IRIS alone, or in connection with co-activators, is recruited to the cyclin D1 promoter through its binding to c-Jun/AP1 complex; this binding activates the cyclin D1 expression. (3) Over-expression of BRCA1-IRIS in breast cells over-activates JNK/c-Jun; this leads to the induction of cyclin D1 expression and cellular proliferation. (4) BRCA1-IRIS activation of JNK/c-Jun/AP1 appears to account for this, because in cells that were depleted from BRCA1-IRIS, JNK remained inactive. However, depletion of SRC1 or SRC3 instead reduced c-Jun expression. Our data suggest that this novel signaling pathway links BRCA1-IRIS to cellular proliferation through c-Jun/AP1 nuclear pathway; finally, this culminates in the increased expression of the cyclin D1 gene.

  10. D1-D2 Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

    PubMed Central

    Chun, Lani S.; Free, R. Benjamin; Doyle, Trevor B.; Huang, Xi-Ping; Rankin, Michele L.

    2013-01-01

    The D1 dopamine receptor (D1R) has been proposed to form a hetero-oligomer with the D2 dopamine receptor (D2R), which in turn results in a complex that couples to phospholipase C–mediated intracellular calcium release. We have sought to elucidate the pharmacology and mechanism of action of this putative signaling pathway. Dopamine dose-response curves assaying intracellular calcium mobilization in cells heterologously expressing the D1 and D2 subtypes, either alone or in combination, and using subtype selective ligands revealed that concurrent stimulation is required for coupling. Surprisingly, characterization of a putative D1-D2 heteromer-selective ligand, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-(3-methylphenyl)-1H-3-benzazepine-7,8-diol (SKF83959), found no stimulation of calcium release, but it did find a broad range of cross-reactivity with other G protein–coupled receptors. In contrast, SKF83959 appeared to be an antagonist of calcium mobilization. Overexpression of Gqα with the D1 and D2 dopamine receptors enhanced the dopamine-stimulated calcium response. However, this was also observed in cells expressing Gqα with only the D1R. Inactivation of Gi or Gs with pertussis or cholera toxin, respectively, largely, but not entirely, reduced the calcium response in D1R and D2R cotransfected cells. Moreover, sequestration of Gβγ subunits through overexpression of G protein receptor kinase 2 mutants either completely or largely eliminated dopamine-stimulated calcium mobilization. Our data suggest that the mechanism of D1R/D2R–mediated calcium signaling involves more than receptor-mediated Gq protein activation, may largely involve downstream signaling pathways, and may not be completely heteromer-specific. In addition, SKF83959 may not exhibit selective activation of D1-D2 heteromers, and its significant cross-reactivity to other receptors warrants careful interpretation of its use in vivo. PMID:23680635

  11. The relevance of paternity analysis in Romanian population using the D1S80 locus.

    PubMed

    Ceacăreanu, A C; Ceacăreanu, B

    1999-01-01

    At present, DNA fingerprinting for human identification and paternity testing is a necessary and usual procedure. D1S80 is one of the best known polymorphic loci showing a VNTR, and exhibiting a high heterozygosity. This genetic locus, with a Tsp 509 I polymorphism of its 5' flanking sequence (1, 9), have been successfully amplified from human genomic DNA isolated from blood. The Tsp 509 I polymorphism was detected by restriction after PCR amplification. We tested the relevance of paternity analysis using the D1S80 locus considering the allele frequency distribution characteristic for our country. Paternal and maternal bands were compared with the children's DNA patterns. Our data include a comparison between D1S80 alleles amplified from mother, child and the supposed father for three tested families. This study was the first of this type made in Romania. We concluded a good power of discrimination and exclusion for this locus. It can be used successfully in the case of subtypes with low frequencies, and this is frequent for our population because of the high heterozygosity of D1S80 subtypes in Romanian population. We recommend the D1S80 use for exclusion paternity tests in Romanian population, as a very useful molecular tool, but we also recommend a complete set of molecular markers for confirmation paternity test in the same population.

  12. 85Rb D1-Line Coherent-Population-Trapping Atomic Clock for Low-Power Operation

    NASA Astrophysics Data System (ADS)

    Goka, Shigeyoshi

    2010-06-01

    A 85Rb D1-line coherent-population-trapping (CPT) atomic clock with a natural-mixture Rb gas cell is demonstrated. D1-line excitation can generate a larger CPT resonance amplitude, and the choice of 85Rb rather than conventional 87Rb is because of its lower ground-state hyperfine-splitting frequency. The frequency deviation for the D1 line was measured using the same experimental setup as that for the D2 line except for the vertical-cavity surface-emitting laser (VCSEL) wavelength and RF power. In the case of D1-line excitation, the CPT resonance amplitude was 1.5 times that for the D2 line, and the light shift sensitivity was one-half that for the D2 line. The Allan standard deviations for the 85Rb D1 line, estimated from the frequency deviations, are <2.5×10-12 per day. In addition, the required RF is 1.5 GHz and its power is only -8.0 dBm.

  13. 85Rb D1-Line Coherent-Population-Trapping Atomic Clock for Low-Power Operation

    NASA Astrophysics Data System (ADS)

    Shigeyoshi Goka,

    2010-06-01

    A 85Rb D1-line coherent-population-trapping (CPT) atomic clock with a natural-mixture Rb gas cell is demonstrated. D1-line excitation can generate a larger CPT resonance amplitude, and the choice of 85Rb rather than conventional 87Rb is because of its lower ground-state hyperfine-splitting frequency. The frequency deviation for the D1 line was measured using the same experimental setup as that for the D2 line except for the vertical-cavity surface-emitting laser (VCSEL) wavelength and RF power. In the case of D1-line excitation, the CPT resonance amplitude was 1.5 times that for the D2 line, and the light shift sensitivity was one-half that for the D2 line. The Allan standard deviations for the 85Rb D1 line, estimated from the frequency deviations, are <2.5× 10-12 per day. In addition, the required RF is 1.5 GHz and its power is only -8.0 dBm.

  14. Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration.

    PubMed

    Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T; Beauvais, Genevieve; Cai, Ning Sheng

    2010-11-01

    Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson's disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA.

  15. Striatal dopamine modulates song spectral but not temporal features through D1 receptors

    PubMed Central

    Leblois, Arthur; Perkel, David J

    2012-01-01

    The activity of midbrain dopaminergic neurons and their projection to the basal ganglia (BG) are thought to play a critical role in the acquisition of motor skills through reinforcement learning, as well as in the expression of learned motor behaviors. The precise role of BG dopamine in mediating and modulating motor performance and learning, however, remains unclear. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. Previously we found that dopamine acts on D1 receptors in Area X to modulate the BG output signal and thereby trigger changes in song variability. Here, we investigate the effect of D1 receptor blockade in the BG on song behavior in the zebra finch. We report that this manipulation abolishes social context-dependent changes in variability not only in harmonic stacks, but also in other types of syllables. However, song timing seems not to be modulated by this BG dopamine signal. Indeed, injections of a D1 antagonist in the BG altered neither song duration, nor the change of song duration with social context. Finally, D1 receptor activation in the BG was not necessary for the modulation of other features of song such as the number of introductory notes or motif repetitions. Together, our results suggest that activation of D1 receptors in the BG is necessary for the modulation of fine acoustic features of song with social context while it is not involved in the regulation of song timing and structure at a larger time scale. PMID:22594943

  16. Contribution of dopamine D1 and D2 receptors to amygdala activity in human.

    PubMed

    Takahashi, Hidehiko; Takano, Harumasa; Kodaka, Fumitoshi; Arakawa, Ryosuke; Yamada, Makiko; Otsuka, Tatsui; Hirano, Yoshiyuki; Kikyo, Hideyuki; Okubo, Yoshiro; Kato, Motoichiro; Obata, Takayuki; Ito, Hiroshi; Suhara, Tetsuya

    2010-02-24

    Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

  17. Dopamine D1 receptor-agonist interactions: A mutagenesis and homology modeling study.

    PubMed

    Mente, Scot; Guilmette, Edward; Salafia, Michelle; Gray, David

    2015-01-01

    The dopamine D1 receptor is a G protein-coupled receptor that regulates intracellular signaling via agonist activation. Although the number of solved GPCR X-ray structures has been steadily increasing, still no structure of the D1 receptor exists. We have used site-directed mutagenesis of 12 orthosteric vicinity residues of possible importance to G protein-coupled activation to examine the function of prototypical orthosteric D1 agonists and partial agonists. We find that residues from four different regions of the D1 receptor make significant contributions to agonist function. All compounds studied, which are catechol-amines, are found to interact with the previously identified residues: the conserved D103(3.32), as well as the trans-membrane V serine residues. Additional key interactions are found for trans-membrane VI residues F288(6.51), F289(6.52) and N292(6.55), as well as the extra-cellular loop residue L190(ECL2). Molecular dynamics simulations of a D1 homology model have been used to help put the ligand-residue interactions into context. Finally, we considered the rescaling of fold-shift data as a method to account for the change in the size of the mutated side-chain and found that this rescaling helps to relate the calculated ligand-residue energies with observed experimental fold-shifts.

  18. Diminished natriuretic response to dopamine D1 receptor agonist, SKF-38393 in obese Zucker rats.

    PubMed

    Marwaha, Aditi; Lokhandwala, Mustafa F

    2003-11-01

    Dopamine causes natriuresis and diuresis via activation of D1 receptors located on the renal proximal tubules and subsequent inhibition of the sodium transporters, Na-H exchanger and Na+/K+ ATPase. We have reported that dopamine fails to inhibit the activities of these two transporters in the obese Zucker rats (OZR). The present study was designed to examine the functional consequence of this phenomenon by determining the natriuretic and diuretic response to D1 receptor activation in lean Zucker rats (LZR) and OZR. In 11-12 week-old OZR and LZR, natriuretic and diuretic responses to intravenously administered D1 receptor agonist, SKF 38393 (3 microg/kg/min for 30 min) were measured under Inactin anesthesia. Plasma insulin and glucose levels were significantly higher in the obese rats as compared to the lean rats. Intravenous infusion of SKF 38393 caused significant increases in urine flow, urinary sodium excretion (U(Na)V), fractional excretion of sodium (FE(Na)), and glomerular filtration rate (GFR) in the lean rats. However, the natriuretic and diuretic response to SKF 38393 was markedly blunted in OZR. Infusion of SKF 38393 did not cause significant changes in the mean blood pressure and heart rate in either of the two groups. We suggest that the diminished natriuretic response to D1 receptor activation in OZR is the consequence of the previously reported defect in the D1 receptor-G-protein coupling and the failure of dopamine to inhibit the sodium transporters in these animals.

  19. Cyclin D1 and Ki-67 expression in normal, hyperplastic and neoplastic endometrium

    PubMed Central

    Shevra, CR; Ghosh, A; Kumar, M

    2015-01-01

    Background: Proliferation and differentiation of cancer cells are regulated by various cell cycle promoting and inhibiting factors. Our knowledge about these proteins and mechanisms regulating cell cycle progression has increased dramatically in recent years. Aim: The present study was undertaken to examine the expression profile of cell cycle regulatory proteins in normal proliferative endometrium, hyperplasias (simple, complex and atypical) and endometrial carcinoma in a quantitative approach as also to assess correlations of Cyclin D1 expression with Ki-67 a proliferation marker. Settings and Design: A retrospective case control study in a tertiary referral centre. Materials and Methods: We evaluated and compared the expression profile of Cyclin D1 and Ki-67 expressions in 61 endometrial samples submitted as either endometrial curetting or hysterectomy specimens, which were diagnosed as simple hyperplasia (n =11), complex hyperplasia (n = 13), atypical hyperplasia (n = 7), and endometrial carcinoma (n = 20). Results: There was increased expression of Cyclin D1 and Ki-67 in patients with endometrial carcinoma relative to proliferative endometrium and simple hyperplasia, but there was no such difference between cases of atypical hyperplasia and endometrial carcinoma. Cyclin D1 expression had a positive correlation with Ki-67 expression. Cyclin D1 together with Ki-67 may be a marker for endometrial carcinogenesis and tumor cell proliferation. PMID:25511212

  20. NMDA receptor blockade attenuates locomotion elicited by intrastriatal dopamine D1-receptor stimulation.

    PubMed

    Kreipke, Christian W; Walker, Paul D

    2004-07-01

    Previous behavioral studies suggest that the striatum mediates a hyperactive response to systemic NMDA receptor antagonism in combination with systemic D1 receptor stimulation. However, many experiments conducted at the cellular level suggest that inhibition of NMDA receptors should block D1 receptor-mediated locomotor activity. Therefore, we investigated the consequences of NMDA receptor blockade on the ability of striatal D1 receptors to elicit locomotor activity using systemic and intrastriatal injections of the NMDA antagonist MK-801 combined with intrastriatal injections of the D1 full agonist SKF 82958. Following drug treatment locomotor activity was measured via computerized activity monitors designed to quantify multiple parameters of rodent open-field behavior. Both systemic (0.1 mg/kg) and intrastriatal (1.0 microg) MK-801 pretreatments completely blocked locomotor and stereotypic activity elicited by 10 microg of SKF 82958 directly infused into the striatum. Further, increased activity triggered by intrastriatal SKF 82958 was attenuated by a posttreatment with intrastriatal infusion of 1 microg MK-801. These data suggest that D1-stimulated locomotor behaviors controlled by the striatum require functional NMDA channels.

  1. Cyclin D1 expression in acral melanoma: a case control study in Sarawak.

    PubMed

    Ibrahim, Zainal Abidin; Narihan, M Zulkarnaen A; Ojep, Dk Norlida A; Soosay, Ashley Edward Roy; Pan, Kok Long

    2012-12-01

    Acral melanoma has been reported to have distinctive clinical presentation and ethnic distribution compared to other histological types of malignant melanoma. Acral melanoma also exhibits distinctive focused gene amplifications, including cyclin D1 overexpression. We reviewed archived histological material of malignant melanoma in the Sarawak General Hospital from year 2004 to 2010. 43 tumours, comprising 28 acral melanoma and 15 non-acral melanoma, had sufficient material to be included in the study. The majority (36%) of acral melanoma tumours occurred in the heel. The tumours were analyzed for cyclin D1 expression by immunohistochemistry. 68% of acral melanoma were cyclin D1 positive compared to a positivity of 33% in non-acral tumours. This difference was statistically significant (p < 0.05). This finding may improve the histological diagnosis of acral melanoma and detection of positive resection margins.

  2. Microstates of the D1-D5-Kaluza-Klein monopole system

    SciTech Connect

    Bena, Iosif; Kraus, Per

    2005-07-15

    We find supergravity solutions corresponding to all U(1)xU(1) invariant chiral primaries of the D1-D5-KK system. These solutions are 1/8 BPS, carry angular momentum, and are asymptotically flat in the 3+1 dimensional sense. They can be thought of as representing the ground states of the four-dimensional black hole constructed from the D1-D5-KK-P system. Demanding the absence of unphysical singularities in our solutions determines all free parameters, and gives precise agreement with the quantum numbers expected from the CFT point of view. The physical mechanism behind the smoothness of the solutions is that the D1 branes and D5 branes expand into a KK-monopole supertube in the transverse space of the original KK monopole.

  3. Quantitative analysis of the interaction between lysozyme and monoclonal antibody D1.3.

    PubMed

    McInerney, T L; Howlett, G J; Gruen, L C; Jackson, D C

    1993-01-01

    The method of sedimentation equilibrium has been used to determine the stoichiometry and binding constant for the interaction between hen egg white lysozyme and monoclonal antibody D1.3. The procedures described allow the relative binding affinities of 125I-labelled lysozyme and unlabelled lysozyme to be compared. The data indicate that labelled and unlabelled lysozyme bind to monoclonal D1.3 with similar affinity (binding constant, K = 1.6 x 10(9)/M). Using solid-phase methods estimates obtained for the binding constant were lower and dependent both on the amount of antigen coated on the plate and the dilution of primary antibody (D1.3). These data were not consistent with a simple equilibrium binding model, suggesting kinetic or orientation effects. In contrast sedimentation equilibrium experiments provide a rapid and accurate method for determining both the stoichiometry and binding constants for the interaction between antigens and antibodies.

  4. D0- and D1-branes with κ- and κ+ extended symmetry

    NASA Astrophysics Data System (ADS)

    Moshe, Moshe; Sakai, Norisuke

    2000-10-01

    D0-brane (D-particle) and D1-brane actions possess first and second class constraints that result in local κ symmetry. The κ symmetry of the D-particle and the D1-brane is extended here into a larger symmetry (κ- and κ+) in a larger phase space by turning second class constraints into first class constraints. Different gauge fixings of these symmetries result in different presentations of these systems while a ``unitary'' gauge fixing of the new κ+ symmetry retrieves the original action with κ-=κ symmetry. For a D1-brane our extended phase space makes all constraints into first class constraints in the case of a vanishing world sheet electric field [namely, (0,1) string].

  5. Production of the excited charm mesons D1 and D2* at HERA

    NASA Astrophysics Data System (ADS)

    Abramowicz, H.; Abt, I.; Adamczyk, L.; Adamus, M.; Aggarwal, R.; Antonelli, S.; Antonioli, P.; Antonov, A.; Arneodo, M.; Arslan, O.; Aushev, V.; Aushev, Y.; Bachynska, O.; Bamberger, A.; Barakbaev, A. N.; Barbagli, G.; Bari, G.; Barreiro, F.; Bartosik, N.; Bartsch, D.; Basile, M.; Behnke, O.; Behr, J.; Behrens, U.; Bellagamba, L.; Bertolin, A.; Bhadra, S.; Bindi, M.; Blohm, C.; Bokhonov, V.; Bołd, T.; Bondarenko, K.; Boos, E. G.; Borras, K.; Boscherini, D.; Bot, D.; Brock, I.; Brownson, E.; Brugnera, R.; Brümmer, N.; Bruni, A.; Bruni, G.; Brzozowska, B.; Bussey, P. J.; Bylsma, B.; Caldwell, A.; Capua, M.; Carlin, R.; Catterall, C. D.; Chekanov, S.; Chwastowski, J.; Ciborowski, J.; Ciesielski, R.; Cifarelli, L.; Cindolo, F.; Contin, A.; Cooper-Sarkar, A. M.; Coppola, N.; Corradi, M.; Corriveau, F.; Costa, M.; D'Agostini, G.; Dal Corso, F.; del Peso, J.; Dementiev, R. K.; De Pasquale, S.; Derrick, M.; Devenish, R. C. E.; Dobur, D.; Dolgoshein, B. A.; Dolinska, G.; Doyle, A. T.; Drugakov, V.; Durkin, L. S.; Dusini, S.; Eisenberg, Y.; Ermolov, P. F.; Eskreys, A.; Fang, S.; Fazio, S.; Ferrando, J.; Ferrero, M. I.; Figiel, J.; Foster, B.; Gach, G.; Galas, A.; Gallo, E.; Garfagnini, A.; Geiser, A.; Gialas, I.; Gizhko, A.; Gladilin, L. K.; Gladkov, D.; Glasman, C.; Gogota, O.; Golubkov, Yu. A.; Göttlicher, P.; Grabowska-Bołd, I.; Grebenyuk, J.; Gregor, I.; Grigorescu, G.; Grzelak, G.; Gueta, O.; Guzik, M.; Gwenlan, C.; Haas, T.; Hain, W.; Hamatsu, R.; Hart, J. C.; Hartmann, H.; Hartner, G.; Hilger, E.; Hochman, D.; Hori, R.; Hüttmann, A.; Ibrahim, Z. A.; Iga, Y.; Ingbir, R.; Ishitsuka, M.; Jakob, H.-P.; Januschek, F.; Jones, T. W.; Jüngst, M.; Kadenko, I.; Kahle, B.; Kananov, S.; Kanno, T.; Karshon, U.; Karstens, F.; Katkov, I. I.; Kaur, M.; Kaur, P.; Keramidas, A.; Khein, L. A.; Kim, J. Y.; Kisielewska, D.; Kitamura, S.; Klanner, R.; Klein, U.; Koffeman, E.; Kondrashova, N.; Kononenko, O.; Kooijman, P.; Korol, Ie.; Korzhavina, I. A.; Kotański, A.; Kötz, U.; Kowalski, H.; Kuprash, O.; Kuze, M.; Lee, A.; Levchenko, B. B.; Levy, A.; Libov, V.; Limentani, S.; Ling, T. Y.; Lobodzinska, E.; Lohmann, W.; Löhr, B.; Lohrmann, E.; Long, K. R.; Longhin, A.; Lontkovskyi, D.; Lukina, O. Yu.; Maeda, J.; Magill, S.; Makarenko, I.; Malka, J.; Mankel, R.; Margotti, A.; Marini, G.; Martin, J. F.; Mastroberardino, A.; Mattingly, M. C. K.; Melzer-Pellmann, I.-A.; Mergelmeyer, S.; Miglioranzi, S.; Mohamad Idris, F.; Monaco, V.; Montanari, A.; Morris, J. D.; Mujkic, K.; Musgrave, B.; Nagano, K.; Namsoo, T.; Nania, R.; Nigro, A.; Ning, Y.; Nobe, T.; Notz, D.; Nowak, R. J.; Nuncio-Quiroz, A. E.; Oh, B. Y.; Okazaki, N.; Olkiewicz, K.; Onishchuk, Yu.; Papageorgiu, K.; Parenti, A.; Paul, E.; Pawlak, J. M.; Pawlik, B.; Pelfer, P. G.; Pellegrino, A.; Perlański, W.; Perrey, H.; Piotrzkowski, K.; Pluciński, P.; Pokrovskiy, N. S.; Polini, A.; Proskuryakov, A. S.; Przybycień, M.; Raval, A.; Reeder, D. D.; Reisert, B.; Ren, Z.; Repond, J.; Ri, Y. D.; Robertson, A.; Roloff, P.; Rubinsky, I.; Ruspa, M.; Sacchi, R.; Samson, U.; Sartorelli, G.; Savin, A. A.; Saxon, D. H.; Schioppa, M.; Schlenstedt, S.; Schleper, P.; Schmidke, W. B.; Schneekloth, U.; Schönberg, V.; Schörner-Sadenius, T.; Schwartz, J.; Sciulli, F.; Shcheglova, L. M.; Shehzadi, R.; Shimizu, S.; Singh, I.; Skillicorn, I. O.; Słomiński, W.; Smith, W. H.; Sola, V.; Solano, A.; Son, D.; Sosnovtsev, V.; Spiridonov, A.; Stadie, H.; Stanco, L.; Stefaniuk, N.; Stern, A.; Stewart, T. P.; Stifutkin, A.; Stopa, P.; Suchkov, S.; Susinno, G.; Suszycki, L.; Sztuk-Dambietz, J.; Szuba, D.; Szuba, J.; Tapper, A. D.; Tassi, E.; Terrón, J.; Theedt, T.; Tiecke, H.; Tokushuku, K.; Tomaszewska, J.; Trusov, V.; Tsurugai, T.; Turcato, M.; Turkot, O.; Tymieniecka, T.; Vázquez, M.; Verbytskyi, A.; Viazlo, O.; Vlasov, N. N.; Walczak, R.; Wan Abdullah, W. A. T.; Whitmore, J. J.; Wichmann, K.; Wiggers, L.; Wing, M.; Wlasenko, M.; Wolf, G.; Wolfe, H.; Wrona, K.; Yagües-Molina, A. G.; Yamada, S.; Yamazaki, Y.; Yoshida, R.; Youngman, C.; Zabiegalov, O.; Żarnecki, A. F.; Zawiejski, L.; Zenaiev, O.; Zeuner, W.; Zhautykov, B. O.; Zhmak, N.; Zichichi, A.; Zolkapli, Z.; Zotkin, D. S.; ZEUS Collaboration

    2013-01-01

    The production of the excited charm mesons D1(2420) and D2*(2460) in ep collisions has been measured with the ZEUS detector at HERA using an integrated luminosity of 373 pb. The masses of the neutral and charged states, the widths of the neutral states, and the helicity parameter of D1(2420 were determined and compared with other measurements and with theoretical expectations. The measured helicity parameter of the D10 allows for some mixing of S- and D-waves in its decay to Dπ∓. The result is also consistent with a pure D-wave decay. Ratios of branching fractions of the two decay modes of the D2*(2460 and D2*(2460 states were measured and compared with previous measurements. The fractions of charm quarks hadronising into D1 and D2* were measured and are consistent with those obtained in e+e- annihilations.

  6. Intrarenal dopamine D1-like receptor stimulation induces natriuresis via an angiotensin type-2 receptor mechanism.

    PubMed

    Salomone, Leslie J; Howell, Nancy L; McGrath, Helen E; Kemp, Brandon A; Keller, Susanna R; Gildea, John J; Felder, Robin A; Carey, Robert M

    2007-01-01

    We explored the effects of direct renal interstitial stimulation of dopamine D(1)-like receptors with fenoldopam, a selective D(1)-like receptor agonist, on renal sodium excretion and angiotensin type-2 (AT(2)) receptor expression and cellular distribution in rats on a high-sodium intake. In contrast to vehicle-infused rats, sodium excretion increased in fenoldopam-infused rats during each of three 1-hour experimental periods (<0.001). Blood pressure was unaffected by vehicle or fenoldopam. In plasma membranes of renal cortical cells, fenoldopam increased D(1) receptor expression by 38% (P<0.05) and AT(2) receptor expression by 69% (P<0.01). In plasma membranes of renal proximal tubule cells, fenoldopam increased AT(2) receptor expression by 108% (P<0.01). In outer apical membranes of proximal tubule cells, fenoldopam increased AT(2) receptor expression by 59% (P<0.01). No significant change in total AT(2) receptor protein expression was detectable in response to fenoldopam. Fenoldopam-induced natriuresis was abolished when either PD-123319, a specific AT(2) receptor antagonist, or SCH-23390, a potent D(1)-like receptor antagonist, was coinfused with F (P<0.001). In summary, direct renal D(1)-like receptor activation increased urinary sodium excretion and the plasma membrane expression of AT(2) receptors in renal cortical and proximal tubule cells. D(1)-like receptor-induced natriuresis was abolished by intrarenal AT(2) receptor inhibition. These findings suggest that dopaminergic regulation of sodium excretion involves recruitment of AT(2) receptors to the outer plasma membranes of renal proximal tubule cells and that dopamine-induced natriuresis requires AT(2) receptor activation.

  7. Cat (Fel d 1) and dog (Can f 1) allergen levels in cars, dwellings and schools.

    PubMed

    Niesler, A; Ścigała, G; Łudzeń-Izbińska, B

    Pets are an important source of indoor allergens. The aim of the study was to compare cat and dog allergen levels in cars, schools and homes. The study was carried out in 17 cars, 14 classrooms and 19 dwellings located in the highly industrialized and urbanized region of Poland. Dust and air samples were analyzed for Fel d 1 and Can f 1 using a double monoclonal ELISA assay. The highest amounts of cat and dog allergens (Fel d 1: 1169 μg/g; Can f 1: 277 μg/g) were found in dwellings with pets. Allergen concentrations were correlated with the number of animals kept at home. Although concentrations on automobile seats were lower, Fel d 1 levels exceeded 8 μg/g in 23.5 % of cars and high levels of Can f 1 (>10 μg/g) were found in 17.6 % of cars. The study revealed that cars of pet owners may be reservoirs of cat and dog allergens even when animals are not transported in them. In schools, concentrations of pet allergens did not reach high levels, but the moderate levels of Fel d 1 (≥1-8 μg/g) and Can f 1 (≥2-10 μg/g) were detected in 42.9 and 7.1 % of the investigated classrooms. Concentrations of cat and dog allergen in schools were higher than in homes without pets. While airborne Fel d 1 and Can f 1 levels were found low, residential allergen concentrations in settled dust and air were correlated. The study results suggest that classrooms and cars of pet owners may be important sites of exposure to cat and dog allergens, though the highest concentrations of Fel d 1 and Can f 1 are found in homes of pet owners.

  8. A transgenic mouse model of neuroepithelial cell specific inducible overexpression of dopamine D1-receptor

    PubMed Central

    Fujimoto, Kumiko; Araki, Kiyomi; McCarthy, Deirdre M.; Sims, John R.; Ren, Jia-Qian; Zhang, Xuan; Bhide, Pradeep G.

    2010-01-01

    Dopamine and its receptors appear in the brain during early embryonic period suggesting a role for dopamine in brain development. In fact, dopamine receptor imbalance resulting from impaired physiological balance between D1- and D2-receptor activities can perturb brain development and lead to persisting changes in brain structure and function. Dopamine receptor imbalance can be produced experimentally using pharmacological or genetic methods. Pharmacological methods tend to activate or antagonize the receptors in all cell types. In the traditional gene knockout models the receptor imbalance occurs during development and also at maturity. Therefore, assaying the effects of dopamine imbalance on specific cell types (e.g. precursor versus postmitotic cells) or at specific periods of brain development (e.g. pre- or postnatal periods) is not feasible in these models. We describe a novel transgenic mouse model based on the tetracycline dependent inducible gene expression system in which dopamine D1-receptor transgene expression is induced selectively in neuroepithelial cells of the embryonic brain at experimenter-chosen intervals of brain development. In this model, doxycycline-induced expression of the transgene causes significant overexpression of the D1-receptor and significant reductions in the incorporation of the S-phase marker bromodeoxyuridine into neuroepithelial cells of the basal and dorsal telencephalon indicating marked effects on telencephalic neurogenesis. The D1-receptor overexpression occurs at higher levels in the medial ganglionic eminence than the lateral ganglionic eminence or cerebral wall. Moreover, although the transgene is induced selectively in the neuroepithelium, D1-receptor protein overexpression appears to persist in postmitotic cells. The mouse model can be modified for neuroepithelial cell-specific inducible expression of other transgenes or induction of the D1-receptor transgene in other cells in specific brain regions by crossbreeding

  9. Evolutionary dynamics of HBV-D1 genotype epidemic in Turkey.

    PubMed

    Ciccozzi, Massimo; Ciccaglione, Anna Rita; Lo Presti, Alessandra; Equestre, Michele; Cella, Eleonora; Ebranati, Erika; Gabanelli, Elena; Villano, Umbertina; Bruni, Roberto; Yalcinkaya, Tulay; Tanzi, Elisabetta; Zehender, Gianguglielmo

    2014-01-01

    Hepatitis B virus (HBV), is the leading cause of liver diseases infecting an estimated 240 million persons worldwide. The HBV prevalence rates are variables between different countries, with an high level of endemicity in the south-eastern part of Europe. Seven main HBV-D subgenotypes have been described until now (D1-D7). Turkey, seems to have played an important role in the penetration of HBV-D1 in the Mediterranean area. The importance of Turkey in the European epidemiology of HBV is also suggested by the observation that the highest spread of HBV infection in the Continent are reported in Turkey with Romania, Bulgaria, Greece, Albania and some southern regions of Italy. In this paper the molecular epidemiology and the epidemiological history of HBV-D in Turkey was studied, by characterizing 34 new Turkish isolates and performing a phylogeographic reconstruction. By using a phylodynamic and phylogeographic Bayesian approach, the analysis suggested that HBV-D1 originated in Turkey about in the early 1940s. The large prevalence of D1 in comparison to the other subgenotypes in Turkey confirms the importance of this Country as epidemiological reservoir of HBV-D1 dispersion. The phylogeny suggests that after each initial introduction of the virus in a specific population, separate transmission clusters have been evolving along independent phylogenetic lineages. Better characterization and continuous monitoring of such groups are going to be crucial to understand in detail the epidemiology of HBV-D1 subgenotype in Turkey and to assess the efficacy of prevention, vaccination and therapy in controlling the epidemic.

  10. The dopamine D(1) receptor agonist SKF-82958 serves as a discriminative stimulus in the rat.

    PubMed

    Haile, C N; Carey, G; Varty, G B; Coffin, V L

    2000-01-28

    We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with the dopamine D(1)/D(5) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo-[d]naphtho -¿2, 1-b¿azepine (SCH-39166) (0.01 mg/kg) attenuated the discriminative stimulus effects of SKF-82958. Pretreatment with the dopamine D(2) receptor antagonist raclopride (0.03 mg/kg) had no effect. The high-efficacy dopamine D(1) receptor agonist R(+)6chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) fully substituted for SKF-82958, whereas the low-efficacy dopamine D(1) receptor agonist (+/-)1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) produced only partial substitution. The dopamine D(2) receptor agonist trans-(+/-)-4,4a,5,6,7,8,8a, 9-octahydro-5-propyl-1H-propyl-1H-pyrazolo[3,4-g]quinoline dihydrochloride (quinpirole) and the indirect dopamine agonist cocaine did not substitute fully for the SKF-82958 discriminative stimulus cue. These results demonstrate that the high-efficacy dopamine D(1) receptor agonist SKF-82958 can serve as an effective discriminative stimulus in the rat, and that these effects are mediated by a dopamine D(1)-like receptor mechanism.

  11. Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans.

    PubMed

    Fresnoza, Shane; Paulus, Walter; Nitsche, Michael A; Kuo, Min-Fang

    2014-02-12

    The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose-response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

  12. Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3

    PubMed Central

    Li, Xuhui; Eilers, Grant; He, Quan; Liu, Lili; Wu, Yeqing; Wu, Yuehong; Yu, Wei; Fletcher, Jonathan A.; Ou, Wen-Bin

    2016-01-01

    The MDM2-p53 pathway has a prominent oncogenic function in the pathogenesis of various cancers. Nutlin-3, a small-molecule antagonist of MDM2-p53 interaction, inhibits proliferation in cancer cells with wild-type p53. Herein, we evaluate the expression of MDM2, both the full length and a splicing variant MDM2-A, and the sensitivity of Nutlin-3 in different cancer cell lines. Included are seven cell lines with wild-type p53 (four mesothelioma, one breast cancer, one chondrosarcoma, and one leiomyosarcoma), two liposarcoma cell lines harboring MDM2 amplification and wild-type p53, and one mesothelioma cell line harboring a p53 point mutation. Nutlin-3 treatment increased expression of cyclin D1, MDM2, and p53 in cell lines with wild-type p53. Additive effects were observed in cells containing wild-type p53 through coordinated attack on MDM2-p53 binding and cyclin D1 by lentivirual shRNA knockdown or small molecule inhibition, as demonstrated by immunoblots and cell viability analyses. Further results demonstrate that MDM2 binds to cyclin D1, and that an increase in cyclin D1 expression after Nutlin-3 treatment is correlated with expression and ubiquitin E3-ligase activity of MDM2. MDM2 and p53 knockdown experiments demonstrated inhibition of cyclin D1 by MDM2 but not p53. These results indicate that combination inhibition of cyclin D1 and MDM2-p53 binding warrants clinical evaluation as a novel therapeutic strategy in cancer cells harboring wild-type p53. PMID:27129163

  13. Evaluation of Cyclin D1 expression in Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Dhingra, Vishal; Verma, Jyoti; Misra, Vatsala; Srivastav, Sapan

    2017-01-01

    Introduction Squamous Cell Carcinoma (SCC) is an aggressive epithelial malignancy of the upper aero digestive tract and comprises 90% of all Head and Neck Squamous Cell Carcinoma (HNSCC). It is the sixth leading cancer worldwide with approximately 600,000 cases reported annually. It is one of the most common cancers in India. Tumour Lymph Node and Metastases (TNM) staging has been the most useful indicator to predict prognosis in HNSCC but recently various biomolecular markers have potentially offered new methods for early diagnosis and treatment alternatives for HNSCC patients; one amongst them being cyclin D1. Aim This study has been undertaken to evaluate expression of cyclin D1 in HNSCC cases and to find out its association with various pathological prognostic factors. Materials and Methods A 48 formalin fixed paraffin embedded tumour sections, stained with Haematoxylin & Eosin were graded and staged. Immunohistochemistry for cyclin D1 was evaluated as Extent Score (ES), Intensity Score (IS) and Total Score (TS) was calculated. Statistical Analysis All the relevant data collected was transferred on to the excel sheet. Chi square test with and without Yate’s correction was used to compare various parameters. The p-value ≤ 0.05 was taken as critical level of significance. Results A significant association was seen between TS of Cyclin D1 expression with tumour stage and with lymph node metastasis but not with grade. Conclusion Higher Cyclin D1 expression is associated with higher tumour stage and lymph node metastasis. Therefore, there is value of analysing cyclin D1 amplification and expression, for prognostic evaluation. This may also be further used for targeted therapy in head and neck cancers. PMID:28384866

  14. Suberoylanilide hydroxamic acid (SAHA) inhibits EGF-induced cell transformation via reduction of cyclin D1 mRNA stability

    SciTech Connect

    Zhang, Jingjie; Ouyang, Weiming; Li, Jingxia; Zhang, Dongyun; Yu, Yonghui; Wang, York; Li, Xuejun; Huang, Chuanshu

    2012-09-01

    Suberoylanilide hydroxamic acid (SAHA) inhibiting cancer cell growth has been associated with its downregulation of cyclin D1 protein expression at transcription level or translation level. Here, we have demonstrated that SAHA inhibited EGF-induced Cl41 cell transformation via the decrease of cyclin D1 mRNA stability and induction of G0/G1 growth arrest. We found that SAHA treatment resulted in the dramatic inhibition of EGF-induced cell transformation, cyclin D1 protein expression and induction of G0/G1 growth arrest. Further studies showed that SAHA downregulation of cyclin D1 was only observed with endogenous cyclin D1, but not with reconstitutionally expressed cyclin D1 in the same cells, excluding the possibility of SAHA regulating cyclin D1 at level of protein degradation. Moreover, SAHA inhibited EGF-induced cyclin d1 mRNA level, whereas it did not show any inhibitory effect on cyclin D1 promoter-driven luciferase reporter activity under the same experimental conditions, suggesting that SAHA may decrease cyclin D1 mRNA stability. This notion was supported by the results that treatment of cells with SAHA decreased the half-life of cyclin D1 mRNA from 6.95 h to 2.57 h. Consistent with downregulation of cyclin D1 mRNA stability, SAHA treatment also attenuated HuR expression, which has been well-characterized as a positive regulator of cyclin D1 mRNA stability. Thus, our study identifies a novel mechanism responsible for SAHA inhibiting cell transformation via decreasing cyclin D1 mRNA stability and induction of G0/G1 growth arrest in Cl41 cells. -- Highlights: ► SAHA inhibits cell transformation in Cl41 cells. ► SAHA suppresses Cyclin D1 protein expression. ► SAHA decreases cyclin D1 mRNA stability.

  15. Stereoselective synthesis of protectin D1: A potent anti-inflammatory and proresolving lipid mediator

    PubMed Central

    Aursnes, M.; Tungen, J. E.; Vik, A.; Dalli, J.; Hansen, T. V.

    2014-01-01

    A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao’s chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS-MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material PMID:24253202

  16. Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents

    PubMed Central

    Dwyer, Jennifer B.; Leslie, Frances M.

    2016-01-01

    Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas prior studies have examined age-dependent changes in dopamine receptor binding, there have been fewer functional analyses. The aim of the present study was therefore to determine whether the functional consequences of D1 and D2-like activation are age-dependent. Adolescent and adult rats were given direct D1 and D2 agonists, alone and in combination. Locomotor and stereotypic behaviors were measured, and brains were collected for analysis of mRNA expression for the immediate early genes (IEGs), cfos and arc. Adolescents showed enhanced D2-like receptor control of locomotor and repetitive behaviors, which transitioned to dominant D1-like mechanisms in adulthood. When low doses of agonists were co-administered, adults showed supra-additive behavioral responses to D1/D2 combinations, whereas adolescents did not, which may suggest age differences in D1/D2 synergy. D1/D2-stimulated IEG expression was particularly prominent in the bed nucleus of the stria terminalis (BNST). Given the BNST’s function as an integrator of corticostriatal, hippocampal, and stress-related circuitry, and the importance of neural network dynamics in producing behavior, an exploratory functional network analysis of regional IEG expression was performed. This data-driven analysis demonstrated similar developmental trajectories as those described in humans and suggested that dopaminergic drugs alter forebrain coordinated gene expression age dependently. D1/D2 recruitment of stress nuclei into functional networks was associated with low behavioral output in adolescents. Network analysis presents a novel tool to assess pharmacological action, and highlights critical developmental changes in functional

  17. Alternative splicing variants of human Fbx4 disturb cyclin D1 proteolysis in human cancer

    SciTech Connect

    Chu, Xiufeng; Zhang, Ting; Wang, Jie; Li, Meng; Zhang, Xiaolei; Tu, Jing; Sun, Shiqin; Chen, Xiangmei; Lu, Fengmin

    2014-04-25

    Highlights: • The expression of Fbx4 was significantly lower in HCC tissues. • Novel splicing variants of Fbx4 were identified. • These novel variants are much more abundant in human cancer tissues and cells. • The novel Fbx4 isoforms could promote cell proliferation and migration in vitro. • These isoforms showed less capability for cyclin D1 binding and degradation. - Abstract: Fbx4 is a specific substrate recognition component of SCF ubiquitin ligases that catalyzes the ubiquitination and subsequent degradation of cyclin D1 and Trx1. Two isoforms of human Fbx4 protein, the full length Fbx4α and the C-terminal truncated Fbx4β have been identified, but their functions remain elusive. In this study, we demonstrated that the mRNA level of Fbx4 was significantly lower in hepatocellular carcinoma tissues than that in the corresponding non-tumor tissues. More importantly, we identified three novel splicing variants of Fbx4: Fbx4γ (missing 168–245nt of exon1), Fbx4δ (missing exon6) and a N-terminal reading frame shift variant (missing exon2). Using cloning sequencing and RT-PCR, we demonstrated these novel splice variants are much more abundant in human cancer tissues and cell lines than that in normal tissues. When expressed in Sk-Hep1 and NIH3T3 cell lines, Fbx4β, Fbx4γ and Fbx4δ could promote cell proliferation and migration in vitro. Concordantly, these isoforms could disrupt cyclin D1 degradation and therefore increase cyclin D1 expression. Moreover, unlike the full-length isoform Fbx4α that mainly exists in cytoplasm, Fbx4β, Fbx4γ, and Fbx4δ locate in both cytoplasm and nucleus. Since cyclin D1 degradation takes place in cytoplasm, the nuclear distribution of these Fbx4 isoforms may not be involved in the down-regulation of cytoplasmic cyclin D1. These results define the impact of alternative splicing on Fbx4 function, and suggest that the attenuated cyclin D1 degradation by these novel Fbx4 isoforms provides a new insight for aberrant

  18. Investigating the Role of Cyclin D1 in the Promotion of Genomic Instability and Breast Cancer

    DTIC Science & Technology

    2011-09-01

    20mM Tris, 40mM MgCl2, 2.5mM EGTA). Beads containing SCFFbx4 complexes 6 were then mixed with Sf9 -produced purified cyclin D1 substrate, ATP...ubiquitylation reactions with Sf9 -purified cyclin D1/CDK4 as substrate, in the presence of E1, E2, 1 ubiquitin, and ATP. 2 3 Figure 6. Fbx4 loss drives cell...kinase/methyltrans- ferase reactions with purified recombinant PRMT5/MEP50 pro- duced in Sf9 cells. PRMT5-dependent methyltransferase activity was

  19. 26 CFR 1.674(d)-1 - Excepted powers exercisable by any trustee other than grantor or spouse.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... than grantor or spouse. 1.674(d)-1 Section 1.674(d)-1 Internal Revenue INTERNAL REVENUE SERVICE... Substantial Owners § 1.674(d)-1 Excepted powers exercisable by any trustee other than grantor or spouse. Section 674(d) provides an additional exception to the general rule of section 674(a) for a power...

  20. 26 CFR 1.674(d)-1 - Excepted powers exercisable by any trustee other than grantor or spouse.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... than grantor or spouse. 1.674(d)-1 Section 1.674(d)-1 Internal Revenue INTERNAL REVENUE SERVICE... Treated As Substantial Owners § 1.674(d)-1 Excepted powers exercisable by any trustee other than grantor or spouse. Section 674(d) provides an additional exception to the general rule of section 674(a)...

  1. 26 CFR 1.6038D-1T - Reporting with respect to specified foreign financial assets, definition of terms (temporary).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Reporting with respect to specified foreign financial assets, definition of terms (temporary). 1.6038D-1T Section 1.6038D-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6038D-1T...

  2. 26 CFR 1.6038D-1T - Reporting with respect to specified foreign financial assets, definition of terms (temporary).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Reporting with respect to specified foreign financial assets, definition of terms (temporary). 1.6038D-1T Section 1.6038D-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6038D-1T...

  3. Ligation of D1-His332 and D1-Asp170 to the Manganese Cluster of Photosystem II from Synechocystis Assessed by Multifrequency Pulse EPR Spectroscopy†**

    PubMed Central

    Stich, Troy A.; Yeagle, Gregory J.; Service, Rachel J.; Debus, Richard J.; Britt, R. David

    2012-01-01

    Multifrequency electron-spin echo envelope modulation (ESEEM) spectroscopy is used to ascertain the nature of the bonding interactions of various active site amino acids with the Mn ions that compose the oxygen-evolving cluster (OEC) in photosystem II (PSII) from the cyanobacterium Synechocystis sp. PCC 6803 poised in the S2 state. Spectra of natural isotopic abundance PSII (14N-PSII), uniformly 15N-labeled PSII (15N-PSII), as well as 15N-PSII containing 14N-histidine (14N-His/15N-PSII) are compared. These complementary data sets allow for a precise determination of the spin Hamiltonian parameters of the postulated histidine nitrogen interaction with the Mn ions of the OEC. These results are compared to those from a similar study on PSII isolated from spinach. Upon mutation of His332 of the D1 polypeptide to a glutamate residue, all isotopically sensitive spectral features vanish. Additional Ka- and Q-band ESEEM experiments on the D1-D170H site-directed mutant give no indication of new 14N-based interactions. PMID:21790179

  4. Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure.

    PubMed

    Pezze, M A; Marshall, H J; Domonkos, A; Cassaday, H J

    2016-02-04

    The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05μg/side) or D1 antagonist SCH23390 (0.5μg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning.

  5. Geologic map of the McCarthy D-1 Quadrangle, Alaska

    USGS Publications Warehouse

    Richter, D.H.; Ratte, J.C.; Leeman, W.P.; Menzies, Martin

    2000-01-01

    Data set describes a 20-million-year-old shield volcano in the Wrangell volcanic field of north-central Alaska. These digital files were used to create the 1:63,360-scale geologic map of the McCarthy D-1 quadrangle.

  6. Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure

    PubMed Central

    Pezze, M.A.; Marshall, H.J.; Domonkos, A.; Cassaday, H.J.

    2016-01-01

    The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10 s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 μg/side) or D1 antagonist SCH23390 (0.5 μg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning. PMID:26343307

  7. 17 CFR 240.15d-1 - Requirement of annual reports.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Requirement of annual reports....15d-1 Requirement of annual reports. Every registrant under the Securities Act of 1933 shall file an annual report, on the appropriate form authorized or prescribed therefor, for the fiscal year in...

  8. The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression.

    PubMed

    Yang, Yong-Jin; Han, Jeung-Whan; Youn, Hong-Duk; Cho, Eun-Jung

    2010-01-01

    Parafibromin, a component of the RNA polymerase II-associated PAF1 complex, is a tumor suppressor linked to hyperparathyroidism-jaw tumor syndrome and sporadic parathyroid carcinoma. Parafibromin induces cell cycle arrest by repressing cyclin D1 via an unknown mechanism. Here, we show that parafibromin interacts with the histone methyltransferase, SUV39H1, and functions as a transcriptional repressor. The central region (128-227 amino acids) of parafibromin is important for both the interaction with SUV39H1 and transcriptional repression. Parafibromin associated with the promoter and coding regions of cyclin D1 and was required for the recruitment of SUV39H1 and the induction of H3 K9 methylation but not H3 K4 methylation. RNA interference analysis showed that SUV39H1 was critical for cyclin D1 repression. These data suggest that parafibromin plays an unexpected role as a repressor in addition to its widely known activity associated with transcriptional activation. Parafibromin as a part of the PAF1 complex might downregulate cyclin D1 expression by integrating repressive H3 K9 methylation during transcription.

  9. 17 CFR 240.12d1-2 - Effectiveness of registration.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Securities Exchange Act of 1934 Certification by Exchanges and Effectiveness of Registration § 240.12d1-2 Effectiveness of registration. (a) A request for acceleration of the effective date of registration pursuant to... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Effectiveness of...

  10. AT-RvD1 Promotes Resolution of Inflammation in NOD/ShiLtJ mice

    PubMed Central

    Wang, Ching-Shuen; Maruyama, Christina L.; Easley, Justin T.; Trump, Bryan G.; Baker, Olga J.

    2017-01-01

    Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease characterized by diminished secretory function of the exocrine glands. Treatments for hyposalivation are limited to the use of saliva substitutes and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore functioning is essential. Resolvins (Rv), which are highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. The goal of this study was to determine whether systemic preventive treatment with Aspirin-triggered RvD1 (AT-RvD1) reduces inflammation and preserves secretory functioning in NOD/ShiLtJ SS-like mice. Our results indicate that systemic treatment with AT-RvD1 diminishes the progression of the disease in salivary epithelium from female mice as follows: (a) improves secretory function, (b) reduces pro-inflammatory molecule gene expression, (c) increases anti-inflammatory molecule gene expression and (d) induces M2 macrophage polarization. Finally, AT-RvD1 decreases lymphocytic infiltration into the salivary glands when used with small doses of the steroid, dexamethasone, and promotes the tissue healing process. PMID:28361884

  11. PvD1 defensin, a plant antimicrobial peptide with inhibitory activity against Leishmania amazonensis.

    PubMed

    do Nascimento, Viviane V; Mello, Érica de O; Carvalho, Laís P; de Melo, Edésio J T; Carvalho, André de O; Fernandes, Katia V S; Gomes, Valdirene M

    2015-08-18

    Plant defensins are small cysteine-rich peptides and exhibit antimicrobial activity against a variety of both plant and human pathogens. Despite the broad inhibitory activity that plant defensins exhibit against different micro-organisms, little is known about their activity against protozoa. In a previous study, we isolated a plant defensin named PvD1 from Phaseolus vulgaris (cv. Pérola) seeds, which was seen to be deleterious against different yeast cells and filamentous fungi. It exerted its effects by causing an increase in the endogenous production of ROS (reactive oxygen species) and NO (nitric oxide), plasma membrane permeabilization and the inhibition of medium acidification. In the present study, we investigated whether PvD1 could act against the protozoan Leishmania amazonensis. Our results show that, besides inhibiting the proliferation of L. amazonensis promastigotes, the PvD1 defensin was able to cause cytoplasmic fragmentation, formation of multiple cytoplasmic vacuoles and membrane permeabilization in the cells of this organism. Furthermore, we show, for the first time, that PvD1 defensin was located within the L. amazonensis cells, suggesting the existence of a possible intracellular target.

  12. PvD1 defensin, a plant antimicrobial peptide with inhibitory activity against Leishmania amazonensis

    PubMed Central

    do Nascimento, Viviane V.; Mello, Érica de O.; Carvalho, Laís P.; de Melo, Edésio J.T.; Carvalho, André de O.; Fernandes, Katia V.S.; Gomes, Valdirene M.

    2015-01-01

    Plant defensins are small cysteine-rich peptides and exhibit antimicrobial activity against a variety of both plant and human pathogens. Despite the broad inhibitory activity that plant defensins exhibit against different micro-organisms, little is known about their activity against protozoa. In a previous study, we isolated a plant defensin named PvD1 from Phaseolus vulgaris (cv. Pérola) seeds, which was seen to be deleterious against different yeast cells and filamentous fungi. It exerted its effects by causing an increase in the endogenous production of ROS (reactive oxygen species) and NO (nitric oxide), plasma membrane permeabilization and the inhibition of medium acidification. In the present study, we investigated whether PvD1 could act against the protozoan Leishmania amazonensis. Our results show that, besides inhibiting the proliferation of L. amazonensis promastigotes, the PvD1 defensin was able to cause cytoplasmic fragmentation, formation of multiple cytoplasmic vacuoles and membrane permeabilization in the cells of this organism. Furthermore, we show, for the first time, that PvD1 defensin was located within the L. amazonensis cells, suggesting the existence of a possible intracellular target. PMID:26285803

  13. Agonist and antagonist protect sulfhydrals in the binding site of the D-1 dopamine receptor

    SciTech Connect

    Sidhu, A.; Kebabian, J.W.; Fishman, P.H.

    1986-05-01

    An iodinated compound (/sup 125/I)-SCH 23982 (8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) has been characterized as a specific, high affinity (Kd = 0.7 nM) ligand for the D-1 dopamine receptor. The ligand binding site of the D-1 receptor in rat striatum was inactivated by N-ethylmaleimide (NEM) in a time and concentration dependent manner. The inactivation was rapid and irreversible with a 70% net loss of binding sites. Scatchard analysis of binding to NEM-treated tissue showed a decrease both in receptor number and in radioligand affinity. The remaining receptors retained their selectivity for stereoisomers of both agonist and antagonist. Receptor occupancy by either a D-1 specific agonist or antagonist protected in a dose dependent manner the binding sites from inactivation by NEM; the agonist was more effective than the antagonist. The agonist high affinity site, however, was abolished in the absence or presence of protective compound, presumably because of inactivation of the GTP-binding component of adenylate cyclase. In this regard, there was a total loss of agonist- and forskolin-stimulated adenylate cyclase activity after NEM treatment. The authors conclude that the D-1 dopamine receptor contains NEM-sensitive sulfhydral group(s) at or near the vicinity of the ligand binding site.

  14. 17 CFR 270.30d-1 - Filing of copies of reports to shareholders.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.30d-1 Filing of copies of reports to shareholders. A registered management investment company, other than a small business investment company... and procedures specified therefor, of reports on Form N-CSR (§§ 249.331 and 274.128 of this...

  15. 26 CFR 301.6323(d)-1 - 45-day period for making disbursements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 18 2014-04-01 2014-04-01 false 45-day period for making disbursements. 301....6323(d)-1 45-day period for making disbursements. (a) In general. Even though a notice of a lien... made before the 46th day after the date of tax lien filing, or if earlier, before the person making...

  16. 26 CFR 301.6323(d)-1 - 45-day period for making disbursements.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 18 2011-04-01 2011-04-01 false 45-day period for making disbursements. 301....6323(d)-1 45-day period for making disbursements. (a) In general. Even though a notice of a lien... made before the 46th day after the date of tax lien filing, or if earlier, before the person making...

  17. 26 CFR 301.6323(d)-1 - 45-day period for making disbursements.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 18 2012-04-01 2012-04-01 false 45-day period for making disbursements. 301....6323(d)-1 45-day period for making disbursements. (a) In general. Even though a notice of a lien... made before the 46th day after the date of tax lien filing, or if earlier, before the person making...

  18. 26 CFR 301.6323(d)-1 - 45-day period for making disbursements.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 18 2013-04-01 2013-04-01 false 45-day period for making disbursements. 301....6323(d)-1 45-day period for making disbursements. (a) In general. Even though a notice of a lien... made before the 46th day after the date of tax lien filing, or if earlier, before the person making...

  19. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics.

  20. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells.

    PubMed

    Katz, Samuel G; Labelle, James L; Meng, Hailong; Valeriano, Regina P; Fisher, Jill K; Sun, Heather; Rodig, Scott J; Kleinstein, Steven H; Walensky, Loren D

    2014-02-06

    Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its α-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1-transgenic mice harboring Bim-deficient B cells. In response to immunization, Eμ(CycD1)CD19(CRE)Bim(fl/fl) mice manifested selective expansion of their splenic mantle zone compartment. Three distinct immune stimulation regimens induced lymphomas with histopathologic and molecular features of human MCL in a subset of mice. Thus, deletion of Bim in B cells, in the context of cyclin D1 overexpression, disrupts a critical control point in lymphoid maturation and predisposes to the development of MCL. This genetic proof of concept for MCL pathogenesis suggests an opportunity to reactivate the death pathway by pharmacologic mimicry of proapoptotic BIM.

  1. D 1 , 2 (RN) versus C (RN) local minimizer and a Hopf-type maximum principle

    NASA Astrophysics Data System (ADS)

    Carl, Siegfried; Costa, David G.; Tehrani, Hossein

    2016-08-01

    We consider functionals of the form Φ (u) =1/2∫RN | ∇u|2 -∫RN b (x) G (u) on D 1 , 2 (RN), N ≥ 3, whose critical points are the weak solutions of a corresponding elliptic equation in the whole RN. We present a Brezis-Nirenberg type result and a Hopf-type maximum principle in the context of the space D 1 , 2 (RN). More precisely, we prove that a local minimizer of Φ in the topology of the subspace V must be a local minimizer of Φ in the D 1 , 2 (RN)-topology, where V is given by V : = { v ∈D 1 , 2 (RN) : v ∈ C (RN)withsupx∈RN ⁡ (1 + | x| N - 2) | v (x) | < ∞ }. It is well-known that the Brezis-Nirenberg result has been proved a strong tool in the study of multiple solutions for elliptic boundary value problems in bounded domains. We believe that the result obtained in this paper may play a similar role for elliptic problems in RN.

  2. The Freud-1/CC2D1A family: transcriptional regulators implicated in mental retardation.

    PubMed

    Rogaeva, Anastasia; Galaraga, Kimberly; Albert, Paul R

    2007-10-01

    The CC2D1A gene family consists of two homologous genes, Freud-1/CC2D1A and Freud-2/CC2D1B, that share conserved domains, including several DM14 domains that are specific to this protein family, a C-terminal helix-loop-helix domain, and a C2 calcium-dependent phospholipid binding domain. Although the function of Freud-2 is unknown, Freud-1 has been shown to function as a transcriptional repressor of the serotonin-1A receptor gene that binds to a novel DNA element (FRE, 5'-repressor element). The DNA binding and repressor activities of Freud-1 are inhibited by calcium-calmodulin-dependent protein kinase. Recently, a deletion in the CC2D1A gene has been linked to nonsyndromic mental retardation. This deletion results in the truncation of the helix-loop-helix DNA binding and the C2 domains, crucial for Freud-1 repressor activity, and hence is predicted to generate an inactive or weakly dominant negative protein. The possible mechanisms by which inactivation of Freud-1 could lead to abnormal cortical development and cognitive impairment and the potential roles of Freud-1 gene targets are discussed.

  3. Part 3 of 3 of panorama with HABS CA2783D1 and ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Part 3 of 3 of panorama with HABS CA-2783-D-1 and HABS CA-2783-D-2. View of north elevation of Building No. 9. . Hinkley Avenue in foreground, looking south - Easter Hill Village, Building No. 11, South side of Hinkley Avenue, west of South Twenty-Sixth Street, Richmond, Contra Costa County, CA

  4. Part 2 of 3 of panorama with HABS CA2783D1 and ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Part 2 of 3 of panorama with HABS CA-2783-D-1 and HABS CA-2783-D-3. View of north elevation of Building No. 9. Hinkley Avenue in foreground, looking south - Easter Hill Village, Building No. 11, South side of Hinkley Avenue, west of South Twenty-Sixth Street, Richmond, Contra Costa County, CA

  5. 26 CFR 1.167(d)-1 - Agreement as to useful life and rates of depreciation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 2 2013-04-01 2013-04-01 false Agreement as to useful life and rates of... and Corporations § 1.167(d)-1 Agreement as to useful life and rates of depreciation. After August 16... respect to the estimated useful life, method and rate of depreciation and treatment of salvage of...

  6. 26 CFR 1.167(d)-1 - Agreement as to useful life and rates of depreciation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 2 2012-04-01 2012-04-01 false Agreement as to useful life and rates of... and Corporations § 1.167(d)-1 Agreement as to useful life and rates of depreciation. After August 16... respect to the estimated useful life, method and rate of depreciation and treatment of salvage of...

  7. Epigenetically altered miR-193b targets cyclin D1 in prostate cancer

    PubMed Central

    Kaukoniemi, Kirsi M; Rauhala, Hanna E; Scaravilli, Mauro; Latonen, Leena; Annala, Matti; Vessella, Robert L; Nykter, Matti; Tammela, Teuvo L J; Visakorpi, Tapio

    2015-01-01

    Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed in cancer and other diseases. We have previously shown that miR-193b is hypermethylated in prostate cancer (PC) and suppresses cell growth. It has been suggested that miR-193b targets cyclin D1 in several malignancies. Here, our aim was to determine if miR-193b targets cyclin D1 in prostate cancer. Our data show that miR-193b is commonly methylated in PC samples compared to benign prostate hyperplasia. We found reduced miR-193b expression (P < 0.05) in stage pT3 tumors compared to pT2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR-193b expression, the overexpression of miR-193b reduced CCND1mRNA levels and cyclin D1 protein levels. In addition, the exogenous expression of miR-193b decreased the phosphorylation level of RB, a target of the cyclin D1-CDK4/6 pathway. Moreover, according to a reporter assay, miR-193b targeted the 3’UTR of CCND1 in PC cells and the CCND1 activity was rescued by expressing CCND1 lacking its 3’UTR. Immunohistochemical analysis of cyclin D1 showed that castration-resistant prostate cancers have significantly (P = 0.0237) higher expression of cyclin D1 compared to hormone-naïve cases. Furthermore, the PC cell lines 22Rv1 and VCaP, which express low levels of miR-193b and high levels of CCND1, showed significant growth retardation when treated with a CDK4/6 inhibitor. In contrast, the inhibitor had no effect on the growth of PC-3 and DU145 cells with high miR-193b and low CCND1 expression. Taken together, our data demonstrate that miR-193b targets cyclin D1 in prostate cancer. PMID:26129688

  8. Synergistic Effects of Mutations in Cytochrome P450cam Designed to Mimic CYP101D1

    PubMed Central

    Batabyal, Dipanwita; Li, Huiying; Poulos, Thomas L.

    2013-01-01

    A close ortholog to the cytochrome P450cam (CYP101A1) that catalyzes the same hydroxylation of camphor to 5-exo hydroxycamphor is CYP101D1. There are potentially important differences in and around the active site that could contribute to subtle functional differences. Adjacent to the heme iron ligand, Cys357, is Leu358 in P450cam while this residue is Ala in CYP101D1. Leu358 plays a role in binding of the P450cam redox partner, putidaredoxin (Pdx). On the opposite side of the heme about 15 – 20 Å away Asp251 in P450cam plays a critical role in a proton relay network required for O2 activation but forms strong ion pairs with Arg186 and Lys178. In CYP101D1 a Gly replaces Lys178. Thus, the local electrostatic environment and ion pairing is substantially different in CYP101D1. These sites have been systematically mutated in P450cam to the corresponding residues in CYP101D1 and the mutants analyzed by crystallography, kinetics, and UV/Vis spectroscopy. Individually the mutants have little effect on activity or structure but in combination there is a major drop in enzyme activity. This loss in activity is due the mutants being locked in the low-spin state which prevents electron transfer from the P450cam redox partner, Pdx. These studies illustrate the strong synergistic effects on well separated parts of the structure in controlling the equilibrium between the open (low-spin) and closed (high-spin) conformational states. PMID:23865948

  9. Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation

    PubMed Central

    Odusanwo, Olutayo; Chinthamani, Sreedevi; McCall, Andrew; Duffey, Michael E.

    2012-01-01

    Sjögren's syndrome is a chronic autoimmune disorder characterized by inflammation of salivary glands resulting in impaired secretory function. Our present studies indicate that chronic exposure of salivary epithelium to TNF-α and/or IFN-γ alters tight junction integrity, leading to secretory dysfunction. Resolvins of the D-series (RvDs) are endogenous lipid mediators derived from DHA that regulate excessive inflammatory responses leading to resolution and tissue homeostasis. In this study, we addressed the hypothesis that activation of the RvD1 receptor ALX/FPR2 in salivary epithelium prevents and/or resolves the TNF-α-mediated disruption of acinar organization and enhances monolayer formation. Our results indicate that 1) the RvD1 receptor ALX/FPR2 is present in fresh, isolated cells from mouse salivary glands and in cell lines of salivary origin; and 2) the agonist RvD1 (100 ng/ml) abolished tight junction and cytoskeletal disruption caused by TNF-α and enhanced cell migration and polarity in salivary epithelium. These effects were blocked by the ALX/FPR2 antagonist butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe. The ALX/FPR2 receptor signals via modulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways since, in our study, blocking PI3K activation with LY294002, a potent and selective PI3K inhibitor, prevented RvD1-induced cell migration. Furthermore, Akt gene silencing with the corresponding siRNA almost completely blocked the ability of Par-C10 cells to migrate. Our findings suggest that RvD1 receptor activation promotes resolution of inflammation and tissue repair in salivary epithelium, which may have relevance in the restoration of salivary gland dysfunction associated with Sjögren's syndrome. PMID:22237406

  10. Establishment and initial characterization of SOX2-overexpressing NT2/D1 cell clones.

    PubMed

    Drakulic, D; Krstic, A; Stevanovic, M

    2012-05-15

    SOX2, a universal marker of pluripotent stem cells, is a transcription factor that helps control embryonic development in vertebrates; its expression persists in neural stem/progenitor cells into adulthood. Considering the critical role of the SOX2 transcription factor in the regulation of genes required for self-renewal and pluripotency of stem cells, we developed and characterized SOX2-overexpressing NT2/D1 cell clones. Using Southern blot and semi-quantitative RT-PCR, we confirmed integration and expression of exogenous SOX2 in three NT2/D1 cell clones. Overexpression of the SOX2 gene was detected in two of these clones. SOX2 overexpression in NT2/D1 cell clones resulted in altered expression of key pluripotency genes OCT4 and NANOG. Furthermore, SOX2-overexpressing NT2/D1 cell clones entered into retinoic acid-dependent neural differentiation, even when there was elevated SOX2 expression. After 21 days of induction by retinoic acid, expression of neural markers (neuroD1 and synaptophysin) was higher in induced cell clones than in induced parental cells. The cell clone with SOX2 overexpression had an approximately 1.3-fold higher growth rate compared to parental cells. SOX2 overexpression did not increase the population of cells undergoing apoptosis. Taken together, we developed two SOX2-overexpressing cell clones, with constitutive SOX2 expression after three weeks of retinoic acid treatment. SOX2 overexpression resulted in altered expression of pluripotency-related genes, increased proliferation, and altered expression of neural markers after three weeks of retinoic acid treatment.

  11. Hidden oil leg: Case study of lower D1 Miocene sandstone, Dulang field, offshore Peninsular Malaysia

    SciTech Connect

    Solomon, G.J.; Chandramohan, S.; Karra, S.; Sonrexa, K.

    1995-10-01

    The Dulang Field is located offshore east coast of Peninsular Malaysia in water depths of approximately 75 m. The field, discovered in 1981, is about 24 km by 3.5 km. After drilling 14 exploration/appraisal wells by both Carigali and its partner Esso Production Malaysia Inc., the central part of the field was developed as a unitized area in November 1990. Three 32-slot platforms have been installed in the unitized area, and development drilling is ongoing. Production commenced in March 1991 and is currently maintained at approximately 50,000 BOPD. The estimated OIIP (oil-initially-in-place) for the unitized area is in the order of 700 million barrels. There are 19 reservoir sands in Groups D and E which are of Middle-Late Miocene age. During the exploration/appraisal phase, oil and gas were encountered in the Group E and only gas in the Lower D1 reservoirs. Wireline formation pressure test data taken in the Lower D1 reservoir in these wells plotted along a common trend with a gradient of 0.06 psi/ft. The lowermost gas pressure point was only 6 m above the normal hydrostatic gradient. It was therefore concluded that an oil column, even if present, would be thin. At the time, it was understandable that the gas pressures plotted along the same trend because the hydrocarbon column of the Lower D1 reservoir was large and extended beyond the limits of the major faults, suggesting a common pool. However, during the development drilling phase, it was discovered that the Lower D1 sandstone was a major oil reservoir, with estimated oil-in-place of about 100 million barrels. Oil columns of 75 m and 40 m have been proven up in the northern and southern flanks of the field, respectively, in the Lower D1. In addition, development plans were flexible enough to be able to effectively exploit the discovery.

  12. Replication licensing promotes cyclin D1 expression and G1 progression in untransformed human cells

    PubMed Central

    Liu, Peijun; Slater, Damien M.; Lenburg, Marc; Nevis, Kathleen; Cook, Jeanette Gowen; Vaziri, Cyrus

    2011-01-01

    Defects in DNA replication are implicated as early and causal events in malignancy. However, the immediate effects of impaired DNA replication licensing on cell cycle progression of non-malignant human cells are unknown. Therefore, we have investigated the acute effects of Mcm7 ablation using synchronized cultures of untransformed Human Dermal Fibroblasts (HDF). Mcm7 ablation elicited a G1 delay associated with impaired activation of CDK4 and CDK2 and reduced Rb phosphorylation. The cell cycle delay of Mcm7-ablated cells was not associated with a DNA damage response. However, levels of cyclin D1 mRNA were specifically reduced and binding of RNA Polymerase II to the CYCD1 promoter was decreased in Mcm7-depleted cells. Similar to Mcm7-deficiency, Mcm2- or Cdc6-depletion led to impaired cyclin D expression. Ectopic overexpression of Cdc6 in quiescent cells promoted cyclin D1 expression, CDK4 activation and G1 progression. Therefore timely and efficient expression of cyclin D1 during G1 phase requires replication licensing. Reconstitution of cyclin D1 expression was insufficient to correct the G1 delay of Mcm7-depleted cells, indicating that additional cell cycle events during G1 are dependent on replication licensing. However, ectopic expression of the HPV-E7 oncoprotein, and the resulting bypass of the requirement for cyclin D1-Rb signaling enabled Mcm7-depleted cells to enter S-phase. HPV-E7-induced S-phase entry of Mcm7-depleted cells led to a DNA damage response, a hallmark of pre-malignancy. Taken together, our results suggest the existence of a ‘replication licensing restriction point’ that couples pre-RC assembly with G1 progression in normal cells to minimize replication stress, DNA damage and tumorigenesis. PMID:19106611

  13. Characterization of dopamine D1 and D2 receptor-expressing neurons in the mouse hippocampus.

    PubMed

    Gangarossa, Giuseppe; Longueville, Sophie; De Bundel, Dimitri; Perroy, Julie; Hervé, Denis; Girault, Jean-Antoine; Valjent, Emmanuel

    2012-12-01

    The hippocampal formation is part of an anatomical system critically involved in learning and memory. Increasing evidence suggests that dopamine plays an important role in learning and memory as well as in several forms of synaptic plasticity. However, the precise identification of neuronal populations expressing D1 or D2 dopamine receptors within the hippocampus is still lacking. To clarify this issue, we used BAC transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter of dopamine D1 or D2 receptors. In Drd1a-EGFP mice, sparse GFP-expressing neurons were detected among glutamatergic projecting neurons of the granular layer of the dentate gyrus and GABAergic interneurons located in the hilus. A dense immunofluorescence was observed in the outer and medial part of the molecular layer of the dentate gyrus as well as in the inner part of the molecular layer of CA1 corresponding to the terminals of pyramidal neurons of the entorhinal cortex defining the perforant and the temporo-ammonic pathway respectively. Finally, scattered D1 receptor-expressing neurons were also identified as GABAergic interneurons in the CA3/CA1 fields of the hippocampus. In Drd2-EGFP transgenic mice, GFP was exclusively detected in the glutamatergic mossy cells located in the polymorphic layer of the dentate gyrus. This pattern was confirmed in Drd2-Cre mice crossed with NLS-LacZ-Tau(mGFP) :LoxP and RCE:LoxP reporter lines. Our results demonstrate that D1 and D2 receptor-expressing neurons are strictly segregated in the mouse hippocampus. By clarifying the identity of D1 and D2 receptor-expressing neurons in the hippocampus, this study establishes a basis for future investigations aiming at elucidating their roles in the hippocampal network.

  14. Antisense inhibition of cyclin D1 expression is equivalent to flavopiridol for radiosensitization of zebrafish embryos

    SciTech Connect

    McAleer, Mary Frances; Duffy, Kevin T.; Davidson, William R.; Kari, Gabor; Dicker, Adam P.; Rodeck, Ulrich; Wickstrom, Eric . E-mail: eric@tesla.jci.tju.edu

    2006-10-01

    Purpose: Flavopiridol, a small molecule pan-cyclin inhibitor, has been shown to enhance Radiation response of tumor cells both in vitro and in vivo. The clinical utility of flavopiridol, however, is limited by toxicity, previously attributed to pleiotropic inhibitory effects on several targets affecting multiple signal transduction pathways. Here we used zebrafish embryos to investigate radiosensitizing effects of flavopiridol in normal tissues. Methods and Materials: Zebrafish embryos at the 1- to 4-cell stage were treated with 500 nM flavopiridol or injected with 0.5 pmol antisense hydroxylprolyl-phosphono nucleic acid oligomers to reduce cyclin D1 expression, then subjected to ionizing radiation (IR) or no radiation. Results: Flavopiridol-treated embryos demonstrated a twofold increase in mortality after exposure to 40 Gy by 96 hpf and developed distinct radiation-induced defects in midline development (designated as the 'curly up' phenotype) at higher rates when compared with embryos receiving IR only. Cyclin D1-deficient embryos had virtually identical IR sensitivity profiles when compared with embryos treated with flavopiridol. This was particularly evident for the IR-induced curly up phenotype, which was greatly exacerbated by both flavopriridol and cyclin D1 downregulation. Conclusions: Treatment of zebrafish embryos with flavopiridol enhanced radiation sensitivity of zebrafish embryos to a degree that was very similar to that associated with downregulation of cyclin D1 expression. These results are consistent with the hypothesis that inhibition of cyclin D1 is sufficient to account for the radiosensitizing action of flavopiridol in the zebrafish embryo vertebrate model.

  15. Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation.

    PubMed

    Devoto, Paola; Fattore, Liana; Antinori, Silvia; Saba, Pierluigi; Frau, Roberto; Fratta, Walter; Gessa, Gian Luigi

    2016-01-01

    Previous investigations indicate that the dopamine-β-hydroxylase (DBH) inhibitors disulfiram and nepicastat suppress cocaine-primed reinstatement of cocaine self-administration behaviour. Moreover, both inhibitors increase dopamine release in the rat medial prefrontal cortex (mPFC) and markedly potentiate cocaine-induced dopamine release in this region. This study was aimed to clarify if the suppressant effect of DBH inhibitors on cocaine reinstatement was mediated by the high extracellular dopamine in the rat mPFC leading to a supra-maximal stimulation of D1 receptors in the dorsal division of mPFC, an area critical for reinstatement of cocaine-seeking behaviour. In line with previous microdialysis studies in drug-naïve animals, both DBH inhibitors potentiated cocaine-induced dopamine release in the mPFC, in the same animals in which they also suppressed reinstatement of cocaine seeking. Similar to the DBH inhibitors, L-DOPA potentiated cocaine-induced dopamine release in the mPFC and suppressed cocaine-induced reinstatement of cocaine-seeking behaviour. The bilateral microinfusion of the D1 receptor antagonist SCH 23390 into the dorsal mPFC not only prevented cocaine-induced reinstatement of cocaine seeking but also reverted both disulfiram- and L-DOPA-induced suppression of reinstatement. Moreover, the bilateral microinfusion of the D1 receptor agonist chloro-APB (SKF 82958) into the dorsal mPFC markedly attenuated cocaine-induced reinstatement of cocaine seeking. These results suggest that stimulation of D1 receptors in the dorsal mPFC plays a crucial role in cocaine-induced reinstatement of cocaine seeking, whereas the suppressant effect of DBH inhibitors and L-DOPA on drug-induced reinstatement is mediated by a supra-maximal stimulation of D1 receptors leading to their inactivation.

  16. The D1-D2 region of the large subunit ribosomal DNA as barcode for ciliates.

    PubMed

    Stoeck, T; Przybos, E; Dunthorn, M

    2014-05-01

    Ciliates are a major evolutionary lineage within the alveolates, which are distributed in nearly all habitats on our planet and are an essential component for ecosystem function, processes and stability. Accurate identification of these unicellular eukaryotes through, for example, microscopy or mating type reactions is reserved to few specialists. To satisfy the demand for a DNA barcode for ciliates, which meets the standard criteria for DNA barcodes defined by the Consortium for the Barcode of Life (CBOL), we here evaluated the D1-D2 region of the ribosomal DNA large subunit (LSU-rDNA). Primer universality for the phylum Ciliophora was tested in silico with available database sequences as well as in the laboratory with 73 ciliate species, which represented nine of 12 ciliate classes. Primers tested in this study were successful for all tested classes. To test the ability of the D1-D2 region to resolve conspecific and congeneric sequence divergence, 63 Paramecium strains were sampled from 24 mating species. The average conspecific D1-D2 variation was 0.18%, whereas congeneric sequence divergence averaged 4.83%. In pairwise genetic distance analyses, we identified a D1-D2 sequence divergence of <0.6% as an ideal threshold to discriminate Paramecium species. Using this definition, only 3.8% of all conspecific and 3.9% of all congeneric sequence comparisons had the potential of false assignments. Neighbour-joining analyses inferred monophyly for all taxa but for two Paramecium octaurelia strains. Here, we present a protocol for easy DNA amplification of single cells and voucher deposition. In conclusion, the presented data pinpoint the D1-D2 region as an excellent candidate for an official CBOL barcode for ciliated protists.

  17. Diverse flavonoids stimulate NodD1 binding to nod gene promoters in Sinorhizobium meliloti.

    PubMed

    Peck, Melicent C; Fisher, Robert F; Long, Sharon R

    2006-08-01

    NodD1 is a member of the NodD family of LysR-type transcriptional regulators that mediates the expression of nodulation (nod) genes in the soil bacterium Sinorhizobium meliloti. Each species of rhizobia establishes a symbiosis with a limited set of leguminous plants. This host specificity results in part from a NodD-dependent upregulation of nod genes in response to a cocktail of flavonoids in the host plant's root exudates. To demonstrate that NodD is a key determinant of host specificity, we expressed nodD genes from different species of rhizobia in a strain of S. meliloti lacking endogenous NodD activity. We observed that nod gene expression was initiated in response to distinct sets of flavonoid inducers depending on the source of NodD. To better understand the effects of flavonoids on NodD, we assayed the DNA binding activity of S. meliloti NodD1 treated with the flavonoid inducer luteolin. In the presence of luteolin, NodD1 exhibited increased binding to nod gene promoters compared to binding in the absence of luteolin. Surprisingly, although they do not stimulate nod gene expression in S. meliloti, the flavonoids naringenin, eriodictyol, and daidzein also stimulated an increase in the DNA binding affinity of NodD1 to nod gene promoters. In vivo competition assays demonstrate that noninducing flavonoids act as competitive inhibitors of luteolin, suggesting that both inducing and noninducing flavonoids are able to directly bind to NodD1 and mediate conformational changes at nod gene promoters but that only luteolin is capable of promoting the downstream changes necessary for nod gene induction.

  18. West Valley Tank 8D-1 and 8D-2 Inventory Estimation Methodology

    SciTech Connect

    O'Brien, Robert F.; Heasler, Patrick G.; Rowell, Laurene

    2001-07-20

    This report details work funded by the West Valley Support Project (WVSP) and the Tanks Focus Area Retrieval and Closure Program. The work was conducted by the Pacific Northwest National Laboratory (PNNL) and is in support of the West Valley Demonstration Project (WVDP). The WVDP site in New York was originally the site of a commercial nuclear fuel reprocessing plant. The high-level waste (HLW), approximately 2 million liters, produced during plutonium-uranium extraction (PUREX) and thorium extraction (THOREX) reprocessing campaigns at the plant and subsequent HLW preprocessing, was stored on site in three tanks identified as 8D-1, 8D-2, and 8D-4. Waste from the PUREX process was neutralized with NaOH for storage in a carbon steel tank designated as 8D-2. Neutralization resulted in a precipitated hydroxide sludge that settled to the bottom of the tank and was covered by a supernatant salt solution. The acidic THOREX waste, approximately 55,000 L, was first stored in a stainless steel tank (8D-4) and then added to the PUREX waste in Tank 8D-2. Supernatant decontamination, primarily cesium removal, was conducted by ion-exchange using in-tank columns suspended in Tank 8D-1. The cesium-loaded zeolite, resulting from the supernatant decontamination process, was dumped to the bottom of Tank 8D-1. Approximately 90% of the spent zeolite was transferred from Tank 8D-1 into Tank 8D-2 by the start of vitrification processing in June 1996. Periodically, the remaining spent zeolite contained in Tank 8D-1 is incrementally transferred to 8D-2. The combined waste in Tank 8D-2 continues to be processed through the Vitrification Facility into canisters for final repository disposal.

  19. Sex differences in effects of dopamine D1 receptors on social withdrawal

    PubMed Central

    Campi, Katharine L.; Greenberg, Gian D.; Kapoor, Amita; Ziegler, Toni E.; Trainor, Brian C.

    2013-01-01

    Dopamine signaling in the nucleus accumbens (NAc) plays a critical role in the regulation of motivational states. Recent studies in male rodents show that social defeat stress increases the activity of ventral tegmental dopamine neurons projecting to the NAc, and that this increased activity is necessary for stress-induced social withdrawal. Domestic female mice are not similarly aggressive, which has hindered complementary studies in females. Using the monogamous California mouse (Peromyscus californicus), we found that social defeat increased total dopamine, DOPAC, and HVA content in the NAc in both males and females. These results are generally consistent with previous studies in Mus, and suggest defeat stress also increases NAc dopamine signaling in females. However, these results do not explain our previous observations that defeat stress induces social withdrawal in female but not male California mice. Pharmacological manipulations provided more insights. When 500 ng of the D1 agonist SKF38393 was infused in the NAc shell of females that were naïve to defeat, social interaction behavior was reduced. This same dose of SKF38393 had no effect in males, suggesting that D1 receptor activation is sufficient to induce social withdrawal in females but not males. Intra-accumbens infusion of the D1 antagonist SCH23390 increased social approach behavior in females exposed to defeat but not in females naïve to defeat. This result suggests that D1 receptors are necessary for defeat-induced social withdrawal. Overall, our results suggest that sex differences in molecular pathways that are regulated by D1 receptors contribute to sex differences in social withdrawal behavior. PMID:24120838

  20. SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contraction in zebrafish embryos

    PubMed Central

    Tan, Xungang; Rotllant, Josep; Li, Huiqing; DeDeyne, Patrick; Du, Shao Jun

    2006-01-01

    Histone modification has emerged as a fundamental mechanism for control of gene expression and cell differentiation. Recent studies suggest that SmyD1, a novo SET domain-containing protein, may play a critical role in cardiac muscle differentiation. However, its role in skeletal muscle development and its mechanism of actions remains elusive. Here we report that SmyD1a and SmyD1b, generated by alternative splicing of SmyD1 gene, are histone methyltransferases that play a key role in skeletal and cardiac muscle contraction. SmyD1a and SmyD1b are specifically expressed in skeletal and cardiac muscles of zebrafish embryos. Knockdown of SmyD1a and SmyD1b expression by morpholino antisense oligos resulted in malfunction of skeletal and cardiac muscles. The SmyD1 morphant embryos (embryos injected with morpholino oligos) could not swim and had no heartbeat. Myofibril organization in the morphant embryos was severely disrupted. The affected myofibers appeared as immature fibers with centrally located nuclei. Together, these data indicate that SmyD1a and SmyD1b are histone methyltransferases and play a critical role in myofibril organization during myofiber maturation. PMID:16477022

  1. Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice

    PubMed Central

    Hargett, Stefan R.; Walker, Natalie N.; Hussain, Syed S.; Hoehn, Kyle L.

    2015-01-01

    Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling. PMID:26015432

  2. Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4α.

    PubMed

    Hanse, Eric A; Mashek, Douglas G; Becker, Jennifer R; Solmonson, Ashley D; Mullany, Lisa K; Mashek, Mara T; Towle, Howard C; Chau, Anhtung T; Albrecht, Jeffrey H

    2012-07-15

    Following acute hepatic injury, the metabolic capacity of the liver is altered during the process of compensatory hepatocyte proliferation by undefined mechanisms. In this study, we examined the regulation of de novo lipogenesis by cyclin D1, a key mediator of hepatocyte cell cycle progression. In primary hepatocytes, cyclin D1 significantly impaired lipogenesis in response to glucose stimulation. Cyclin D1 inhibited the glucose-mediated induction of key lipogenic genes, and similar effects were seen using a mutant (D1-KE) that does not activate cdk4 or induce cell cycle progression. Cyclin D1 (but not D1-KE) inhibited the activity of the carbohydrate response element-binding protein (ChREBP) by regulating the glucose-sensing motif of this transcription factor. Because changes in ChREBP activity could not fully explain the effect of cyclin D1, we examined hepatocyte nuclear factor 4α (HNF4α), which regulates numerous differentiated functions in the liver including lipid metabolism. We found that both cyclins D1 and D1-KE bound to HNF4α and significantly inhibited its recruitment to the promoter region of lipogenic genes in hepatocytes. Conversely, knockdown of cyclin D1 in the AML12 hepatocyte cell line promoted HNF4α activity and lipogenesis. In mouse liver, HNF4α bound to a central domain of cyclin D1 involved in transcriptional repression. Cyclin D1 inhibited lipogenic gene expression in the liver following carbohydrate feeding. Similar findings were observed in the setting of physiologic cyclin D1 expression in the regenerating liver. In conclusion, these studies demonstrate that cyclin D1 represses ChREBP and HNF4α function in hepatocytes via Cdk4-dependent and -independent mechanisms. These findings provide a direct link between the cell cycle machinery and the transcriptional control of metabolic function of the liver.

  3. High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype.

    PubMed

    Tiberi, M; Caron, M G

    1994-11-11

    Dopamine D1A and D1B receptor subtypes belong to the superfamily of G protein-coupled receptors. Both receptors are coupled to the activation of adenylyl cyclase and exhibit distinct brain distribution. To identify functional differences, binding and stimulation of adenylyl cyclase were assessed in 293 cells expressing transiently either dopamine D1A or D1B receptors. Membranes expressing D1B receptors displayed higher affinities for agonists than those expressing D1A receptors, whereas antagonist affinities were lower at the D1B than at the D1A receptor. Basal activity of adenylyl cyclase in whole 293 cells expressing various levels of D1B receptors was significantly higher than the basal activity measured in cells expressing D1A receptors. Maximal activation of adenylyl cyclase resulting from stimulation of the D1B receptor was less than that obtained following agonist activation of the D1A receptor. In cells expressing D1B receptors, agonists displayed an increased potency for stimulating adenylyl cyclase in comparison with the potencies determined for the D1A receptor. On the other hand, certain antagonists displayed "negative efficacy" at both receptor subtypes but had a more profound inhibition on the agonist-independent signaling activity of the D1B receptor. The properties described here are reminiscent of those of constitutively active G protein-coupled receptors obtained by site-directed mutations. Thus, the D1B receptor may represent a naturally occurring receptor subtype with properties akin to those of constitutively active G protein-coupled receptors. The different anatomical distribution and biochemical properties of these D1 receptors strengthen the functional distinctions between the two subtypes and could account for the basis of heterogeneity within a given class of neurotransmitter or hormone receptors. In addition, if these properties are recapitulated in cells expressing the D1B receptors, they may underlie important role in the regulation of

  4. Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity.

    PubMed

    Centonze, Diego; Grande, Cristina; Saulle, Emilia; Martin, Ana B; Gubellini, Paolo; Pavón, Nancy; Pisani, Antonio; Bernardi, Giorgio; Moratalla, Rosario; Calabresi, Paolo

    2003-09-17

    Stimulation of dopamine (DA) receptors in the striatum is essential for voluntary motor activity and for the generation of plasticity at corticostriatal synapses. In the present study, mice lacking DA D1 receptors have been used to investigate the involvement of the D1-like class (D1 and D5) of DA receptors in locomotion and corticostriatal long-term depression (LTD) and long-term potentiation (LTP). Our results suggest that D1 and D5 receptors exert distinct actions on both activity-dependent synaptic plasticity and spontaneous motor activity. Accordingly, the ablation of D1 receptors disrupted corticostriatal LTP, whereas pharmacological blockade of D5 receptors prevented LTD. On the other side, genetic ablation of D1 receptors increased locomotor activity, whereas the D1/D5 receptor antagonist SCH 23390 decreased motor activity in both control mice and mice lacking D1 receptors. Endogenous DA stimulated D1 and D5 receptors in distinct subtypes of striatal neurons to induce, respectively, LTP and LTD. In control mice, in fact, LTP was blocked by inhibiting the D1-protein kinase A pathway in the recorded spiny neuron, whereas the striatal nitric oxide-producing interneuron was presumably the neuronal subtype stimulated by D5 receptors during the induction phase of LTD. Understanding the role of DA receptors in striatal function is essential to gain insights into the neural bases of critical brain functions and of dramatic pathological conditions such as Parkinson's disease, schizophrenia, and drug addiction.

  5. Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

    PubMed

    Tobón, Krishna E; Catuzzi, Jennifer E; Cote, Samantha R; Sonaike, Adenike; Kuzhikandathil, Eldo V

    2015-07-01

    The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady-state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within 30 min when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated with the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within 5 min of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggest a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals.

  6. Impaired nuclear export of tumor-derived c-terminal truncated cyclin D1 mutant in ESCC cancer.

    PubMed

    Hao, Meili; Chen, Xiangmei; Zhang, Ting; Shen, Tao; Xie, Qing; Xing, Xiujuan; Gu, Hongxi; Lu, Fengmin

    2011-11-01

    Cyclin D1 is a significant regulator of the G1- to S-phase transition and is often aberrant in human tumors of various origins. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms by which they contribute to neoplasia remaind to be elucidated. We previously identified a cyclin D1 mutation (Δ266-295) in esophageal cancer with deleted codons from 266 to 295 of wild-type cyclin D1, the critical COOH-terminal regulatory sequences necessary for cyclin D1 nuclear export. In the present study, this cancer-derived cyclin D1-Δ266-295 was shown to be a constitutively nuclear cyclin D1 protein with a significantly increased oncogenic potential. Moreover, the cancer-derived cyclin D1-Δ266-295 mutant was found to retain its ability to bind to and activate CDK4, which in turn phosphorylates and inactivates the pRb protein and promotes cell cycle progression. In comparison to wild-type cyclin D1a, D1-Δ266-295 exhibited enforced nuclear accumulation. In addition, the transient transfection and ectopic expression of this nuclear localized D1-Δ266-295 up-regulated endogenous Notch1 expression, indicating that the mutant retained its ability as a transcriptional regulator. Furthermore, data from the flow cytometry assay showed that D1-Δ266-295 fractionally increased >4N cell accumulation, and further analysis suggested the retriggering of DNA replication relevant to its inhibition of Cdt1 proteolysis. Therefore, the inappropriate nuclear localization of this cyclin D1 mutant may interfere with DNA replication in cultured cells, thereby contributing to genomic instability.

  7. O(D-1) production in ozone photolysis near 310 nm

    NASA Technical Reports Server (NTRS)

    Lin, C.; Demore, W. B.

    1973-01-01

    Relative quantum yields of O(D-1)production, phi, in ozone photolysis from 275 nm to 334 nm were determined in the gas phase at 233 K. The O(D-1) was monitored by means of its reaction with isobutane to form isobutyl alcohol. The light source was a high pressure mercury lamp combined with a monochromator, with a bandwidth of 1.6 nm. The results show a constant phi below 300 nm, which is taken as unity on the basis of previous work. There is a very sharp fall-off in phi which is centered at 308 nm. At 313 nm phi is not greater than 0.1.

  8. Towards the D1 protein application for the development of sensors specific for herbicides

    SciTech Connect

    Piletskaya, E.; Piletsky, S.; Lavrik, N.; Masuchi, Y.; Karube, I.

    1998-12-01

    One of the most widespread groups of pesticides are the triazine herbicides. These substances inhibit photosynthesis by blocking electron transport in plant chloroplasts. The possibility of the chloroplast D1 protein application for determination of the herbicide concentration in solution was investigated. Potentiometry and cyclic voltammetry have been selected to monitor specific interaction between the D1 protein and herbicide. It was found that membranes with well-defined structure, like Langmuir-Blongett film are more suitable for sensitive sensor construction than cross-linked membranes. After addition of atrazine, the current through these multilayers appeared to increase 5 fold. The effect was found to be fast and irreversible. It has been proposed that the toxic action of herbicides on chloroplasts, traditionally interpreted by inhibition of electron flow along the chloroplast membrane, may also be the result of the thylakoid membrane depolarization.

  9. Symmetry limits of (D+1)-dimensional Dirac equation with Möbius square potential

    NASA Astrophysics Data System (ADS)

    Ikot, Akpan N.; Yazarloo, B. H.; Zarrinkamar, S.; Hassanabadi, H.

    2014-05-01

    In this paper, we present the solutions of the Dirac equation for the Möbius square potential with arbitrary spin orbit coupling number κ under quasi-spin and quasi-pseudospin symmetry limits in ( D + 1) dimensions. The parametric Nikiforov-Uvarov method is used to obtain the energy eigenvalues and the corresponding wave functions in closed form. Useful figures and tables are included.

  10. Cerebello-cortical heterotopia in dentate nucleus, and other microdysgeneses in trisomy D1 (Patau) syndrome.

    PubMed

    Hori, A; Peiffer, J; Pfeiffer, R A; Iizuka, R

    1980-01-01

    Several new histological findings in six cases of the trisomy D1 syndrome are described: hyperplasia of fetal structures (indusium griseum, median raphe of the medulla oblongata) and completely developed cerebellar cortical heterotopia in the dentate nucleus. In one case, a heterotopic pontine nucleus was found within the cerebellar white matter. The coexistence of overdeveloped and remaining fetal structures is emphasized. Several hypotheses regarding cerebellar dysgenesis are discussed.

  11. Placental estrogen suppresses cyclin D1 expression in the nonhuman primate fetal adrenal cortex.

    PubMed

    Dumitrescu, Adina; Aberdeen, Graham W; Pepe, Gerald J; Albrecht, Eugene D

    2014-12-01

    We have previously shown that estrogen selectively suppresses growth of the fetal zone of the baboon fetal adrenal cortex, which produces the C19-steroid precursors, eg, dehydroepiandrosterone sulfate, which are aromatized to estrogen within the placenta. In the present study, we determined whether fetal adrenal expression of cell cycle regulators are altered by estrogen and thus provide a mechanism by which estrogen regulates fetal adrenocortical development. Cyclin D1 mRNA levels in the whole fetal adrenal were increased 50% (P < .05), and the number of cells in the fetal adrenal definitive zone expressing cyclin D1 protein was increased 2.5-fold (P < .05), whereas the total number of cells in the fetal zone and fetal serum dehydroepiandrosterone sulfate levels were elevated 2-fold (P < .05) near term in baboons in which fetal serum estradiol levels were decreased by 95% (P < .05) after maternal administration of the aromatase inhibitor letrozole and restored to normal by concomitant administration of letrozole plus estradiol throughout second half of gestation. However, fetal adrenocortical expression of cyclin D2, the cyclin-dependent kinase (Cdk)-2, Cdk4, and Cdk6, and Cdk regulatory proteins p27(Kip1) and p57(Kip2) were not changed by letrozole or letrozole plus estradiol administration. We suggest that estrogen controls the growth of the fetal zone of the fetal adrenal by down-regulating cyclin D1 expression and thus proliferation of progenitor cells within the definitive zone that migrate to the fetal zone. We propose that estrogen restrains growth and function of the fetal zone via cyclin D1 to maintain estrogen levels in a physiological range during primate pregnancy.

  12. The autophagy machinery restrains iNKT cell activation through CD1D1 internalization.

    PubMed

    Keller, Christian W; Loi, Monica; Ewert, Svenja; Quast, Isaak; Theiler, Romina; Gannagé, Monique; Münz, Christian; De Libero, Gennaro; Freigang, Stefan; Lünemann, Jan D

    2017-03-15

    Invariant natural killer T (iNKT) cells are innate T cells with powerful immune regulatory functions that recognize glycolipid antigens presented by the CD1D protein. While iNKT-cell-activating glycolipids are currently being explored for their efficacy to improve immunotherapy against infectious diseases and cancer, little is known about the mechanisms that control CD1D antigen presentation and iNKT cell activation in vivo. CD1D molecules survey endocytic pathways to bind lipid antigens in MHC class II containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4(+) T cell immunity. Here, we report that mice with dendritic cell (DC)-specific deletion of the essential autophagy gene Atg5 showed better CD1D1-restricted glycolipid presentation in vivo. These effects led to enhanced iNKT cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake or costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1D1 molecules via the adaptor protein complex 2 (AP2) and, thus, increased surface expression of stimulatory CD1D1-glycolipid complexes. These findings indicate that the autophagic machinery assists in the recruitment of AP2 to CD1D1 molecules resulting in attenuated iNKT cell activation, in contrast to the supporting role of macroautophagy in CD4(+) T cell stimulation.

  13. Characterization of the 5' flanking region of the human D1A dopamine receptor gene.

    PubMed Central

    Minowa, M T; Minowa, T; Monsma, F J; Sibley, D R; Mouradian, M M

    1992-01-01

    To study how the expression of the D1A dopamine receptor gene is regulated, a human genomic clone was isolated by using a rat cDNA as probe. A 2.3-kilobase genomic fragment spanning -2571 through -236 relative to the adenosine of the first methionine codon was sequenced. The gene has an intron of 116 base pairs in the 5' noncoding region, nucleotides -599 through -484 as determined by S1 mapping and reverse transcription-PCR. It has multiple transcription initiation sites located between -1061 and -1040. The promoter region lacks a TATA box and a CAAT box, is rich in G+C content, and has multiple putative binding sites for transcription factor Sp1. Thus, the promoter region of the human D1A gene has features of "housekeeping" genes. However, it also has consensus sequences for AP1 and AP2 binding sites and a putative cAMP response element. The ability of four deletion mutants of the 2.3-kilobase fragment to modulate transcription of the heterologous chloramphenicol acetyltransferase gene in the promoterless plasmid pCAT-Basic was determined. All mutants demonstrated substantial transcriptional activity in the murine neuroblastoma cell line NS20Y, which expresses the D1A gene endogenously. Transient expression assays suggested the presence of a positive modulator between nucleotides -1340 and -1102, and a negative modulator between -1730 and -1341. The four genomic fragments had no or very low transcriptional activity in NB41A3, C6, and Hep G2 cells, which are not known to express this gene. Thus, the human D1A gene belongs to the category of tissue-specific, regulated genes that have housekeeping-type promoters. Images PMID:1557411

  14. Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect

    PubMed Central

    Claussen, Catherine M; Witte, Lindsey J; Dafny, Nachum

    2015-01-01

    Methylphenidate (MPD) is a readily prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD) and moreover is used illicitly by youths for its cognitive-enhancing effects and recreation. MPD exposure in rodents elicits increased locomotor activity. Repetitive MPD exposure leads to further augmentation of their locomotor activity. This behavioral response is referred to as behavioral sensitization. Behavioral sensitization is used as an experimental marker for a drug’s ability to elicit dependence. There is evidence that dopamine (DA) is a key player in the acute and chronic MPD effect; however, the role of DA in the effects elicited by MPD is still debated. The objective of this study was to investigate the role of D1 and/or D2 DA receptors in the acute and chronic effect of MPD on locomotor activity. The study lasted for 12 consecutive days. Seven groups of male Sprague Dawley® rats were used. A single D1 or D2 antagonist was given before and after acute and chronic MPD administration. Single injection of D1 DA antagonist was able to significantly attenuate the locomotor activity when given prior to the initial MPD exposure and after repetitive MPD exposure, while the D2 DA antagonist partially attenuated the locomotor activity only when given before the second MPD exposure. The results show the role, at least in part, of the D1 DA receptor in the mechanism of behavioral sensitization, whereas the D2 DA receptor only partially modulates the response to acute and chronic MPD. PMID:27186140

  15. Placental Estrogen Suppresses Cyclin D1 Expression in the Nonhuman Primate Fetal Adrenal Cortex*

    PubMed Central

    Dumitrescu, Adina; Aberdeen, Graham W.; Pepe, Gerald J.

    2014-01-01

    We have previously shown that estrogen selectively suppresses growth of the fetal zone of the baboon fetal adrenal cortex, which produces the C19-steroid precursors, eg, dehydroepiandrosterone sulfate, which are aromatized to estrogen within the placenta. In the present study, we determined whether fetal adrenal expression of cell cycle regulators are altered by estrogen and thus provide a mechanism by which estrogen regulates fetal adrenocortical development. Cyclin D1 mRNA levels in the whole fetal adrenal were increased 50% (P < .05), and the number of cells in the fetal adrenal definitive zone expressing cyclin D1 protein was increased 2.5-fold (P < .05), whereas the total number of cells in the fetal zone and fetal serum dehydroepiandrosterone sulfate levels were elevated 2-fold (P < .05) near term in baboons in which fetal serum estradiol levels were decreased by 95% (P < .05) after maternal administration of the aromatase inhibitor letrozole and restored to normal by concomitant administration of letrozole plus estradiol throughout second half of gestation. However, fetal adrenocortical expression of cyclin D2, the cyclin-dependent kinase (Cdk)-2, Cdk4, and Cdk6, and Cdk regulatory proteins p27Kip1 and p57Kip2 were not changed by letrozole or letrozole plus estradiol administration. We suggest that estrogen controls the growth of the fetal zone of the fetal adrenal by down-regulating cyclin D1 expression and thus proliferation of progenitor cells within the definitive zone that migrate to the fetal zone. We propose that estrogen restrains growth and function of the fetal zone via cyclin D1 to maintain estrogen levels in a physiological range during primate pregnancy. PMID:25247468

  16. Inhibition of Adult Rat Retinal Ganglion Cells by D1-type Dopamine Receptor Activation

    PubMed Central

    Hayashida, Yuki; Rodríguez, Carolina Varela; Ogata, Genki; Partida, Gloria J.; Oi, Hanako; Stradleigh, Tyler W.; Lee, Sherwin C.; Colado, Anselmo Felipe; Ishida, Andrew T.

    2011-01-01

    The spike output of neural pathways can be regulated by modulating output neuron excitability and/or their synaptic inputs. Dopaminergic interneurons synapse onto cells that route signals to mammalian retinal ganglion cells, but it is unknown whether dopamine can activate receptors in these ganglion cells and, if it does, how this affects their excitability. Here, we show D1a-receptor-like immunoreactivity in ganglion cells identified in adult rats by retrogradely transported dextran, and that dopamine, D1-type receptor agonists, and cAMP analogs inhibit spiking in ganglion cells dissociated from adult rats. These ligands curtailed repetitive spiking during constant current injections, and reduced the number and rate of rise of spikes elicited by fluctuating current injections without significantly altering the timing of the remaining spikes. Consistent with mediation by D1-type receptors, SCH-23390 reversed the effects of dopamine on spikes. Contrary to a recent report, spike inhibition by dopamine was not precluded by blocking Ih. Consistent with the reduced rate of spike rise, dopamine reduced voltage-gated Na+ current (INa) amplitude and tetrodotoxin, at doses that reduced INa as moderately as dopamine, also inhibited spiking. These results provide the first direct evidence that D1-type dopamine receptor activation can alter mammalian retinal ganglion cell excitability, and demonstrate that dopamine can modulate spikes in these cells by a mechanism different from the pre- and postsynaptic means proposed by previous studies. To our knowledge, our results also provide the first evidence that dopamine receptor activation can reduce excitability without altering the temporal precision of spike firing. PMID:19940196

  17. A merger in the dusty, z = 7.5 galaxy A1689-zD1?

    NASA Astrophysics Data System (ADS)

    Knudsen, Kirsten K.; Watson, Darach; Frayer, David; Christensen, Lise; Gallazzi, Anna; Michałowski, Michał J.; Richard, Johan; Zavala, Jesús

    2017-04-01

    The gravitationally lensed galaxy A1689-zD1 is one of the most distant spectroscopically confirmed sources (z = 7.5). It is the earliest known galaxy where the interstellar medium (ISM) has been detected; dust emission was detected with the Atacama Large Millimetre Array (ALMA). A1689-zD1 is also unusual among high-redshift dust emitters as it is a sub-L★ galaxy and is therefore a good prospect for the detection of gaseous ISM in a more typical galaxy at this redshift. We observed A1689-zD1 with ALMA in bands 6 and 7 and with the Green Bank Telescope (GBT) in band Q. To study the structure of A1689-zD1, we map the mm-thermal dust emission and find two spatial components with sizes about 0.4 - 1.7 kpc (lensing-corrected). The rough spatial morphology is similar to what is observed in the near-infrared with HST and points to a perturbed dynamical state, perhaps indicative of a major merger or a disc in early formation. The ALMA photometry is used to constrain the far-infrared spectral energy distribution, yielding a dust temperature (Tdust ∼ 35-45 K for β = 1.5 - 2). We do not detect the CO(3-2) line in the GBT data with a 95 per cent upper limit of 0.3 mJy observed. We find a slight excess emission in ALMA band 6 at 220.9 GHz. If this excess is real, it is likely due to emission from the [C II] 158.8 μm line at z_[C II] = 7.603. The stringent upper limits on the [C II] LFIR luminosity ratio suggest a [C II] deficit similar to several bright quasars and massive starbursts.

  18. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects

    PubMed Central

    Bilbao, Ainhoa; Rieker, Claus; Cannella, Nazzareno; Parlato, Rosanna; Golda, Slawomir; Piechota, Marcin; Korostynski, Michal; Engblom, David; Przewlocki, Ryszard; Schütz, Günther; Spanagel, Rainer; Parkitna, Jan R.

    2014-01-01

    It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naïve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB. PMID:24966820

  19. Refined genetic mapping of autosomal dominant retinitis pigmentosa locus RP18 reduces the critical region to 2 cM between D1S442 and D1S2858 on chromosome 1q.

    PubMed

    Xu, S Y; Rosenberg, T; Gal, A

    1998-04-01

    Linkage analysis was performed on a large Danish family to refine the position of RP18, the locus for autosomal dominant retinitis pigmentosa, mapped previously between D1S534 and D1S305 in chromosome 1p13-q21. We genotyped the family members for five microsatellite-type DNA polymorphisms and mapped RP18 between D1S422 and D1S2858 to a region of less than 2 cM. No obvious candidate gene has yet been assigned to the chromosomal interval defined here.

  20. Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes.

    PubMed

    Cox, Sylvia M L; Frank, Michael J; Larcher, Kevin; Fellows, Lesley K; Clark, Crystal A; Leyton, Marco; Dagher, Alain

    2015-04-01

    The extent to which we learn from positive and negative outcomes of decisions is modulated by the neurotransmitter dopamine. Dopamine neurons burst fire in response to unexpected rewards and pause following negative outcomes. This dual signaling mechanism is hypothesized to drive both approach and avoidance behavior. Here we test a prediction deriving from a computational reinforcement learning model, in which approach is mediated via activation of the direct cortico-striatal pathway due to striatal D1 receptor stimulation, while avoidance occurs via disinhibition of indirect pathway striatal neurons secondary to a reduction of D2 receptor stimulation. Using positron emission tomography with two separate radioligands, we demonstrate that individual differences in human approach and avoidance learning are predicted by variability in striatal D1 and D2 receptor binding, respectively. Moreover, transient dopamine precursor depletion improved learning from negative outcomes. These findings support a bidirectional modulatory role for striatal dopamine in reward and avoidance learning via segregated D1 and D2 cortico-striatal pathways.

  1. Development of an immunomodulatory biomaterial: using resolvin D1 to modulate inflammation.

    PubMed

    Vasconcelos, Daniela P; Costa, Madalena; Amaral, Isabel F; Barbosa, Mário A; Águas, Artur P; Barbosa, Judite N

    2015-01-01

    In our search for immunomodulatory biomaterials capable of modulating the inflammatory response through M2 macrophage polarization, we report here on a new strategy that resulted from the incorporation of resolvin D1 (RvD1), a pro-resolution lipid mediator in porous 3D chitosan (Ch) scaffolds, followed by its lyophilisation. We have investigated the inflammatory response caused by this biomaterial in vivo using a mouse air-pouch model of inflammation. We found that this developed material caused a decrease in inflammatory cells recruited to the implant site, together with higher numbers of F4/80(+)/CD206(+) cells (M2 macrophages) and lower numbers of F4/80(+)/CCR7(+) cells (M1 macrophages). It also induced a general decrease in pro-inflammatory cytokines, and caused a decrease in the inflammatory cells observed around and within the implanted scaffolds, when compared with Ch alone or Ch not submitted to lyophilisation after RvD1 incorporation. Our results demonstrate that we were able to develop an immunomodulating biomaterial that triggers a shift in the macrophage response towards a M2 reparative response that will be advantageous for the host.

  2. SCH 23390 may alter dopamine-mediated motor behaviour via striatal D-1 receptors.

    PubMed

    Boyce, S; Kelly, E; Davis, A; Fleminger, S; Jenner, P; Marsden, C D

    1985-05-15

    SCH 23390 potently displaced the specific binding of 3H-piflutixol to D-1 sites in striatal membranes but haloperidol was only weakly effective. SCH 23390 weakly displaced specific 3H-spiperone binding to D-2 sites, but haloperidol was potent. SCH 23390 was more effective than haloperidol in inhibiting dopamine stimulated striatal adenylate cyclase activity. These results confirm the D-1 selectivity of SCH 23390. However, SCH 23390 inhibited apomorphine-induced stereotypy and climbing behaviour in rats with equal potency to haloperidol. Haloperidol dose-dependently increased striatal HVA and DOPAC concentrations without altering dopamine content. Low doses of SCH 23390 elevated striatal DOPAC concentrations but higher doses were without effect; striatal dopamine and HVA overall was unaffected by administration of SCH 23390. Haloperidol did not affect basal 3H-acetylcholine release from striatal slices but reversed the apomorphine-induced inhibition of 3H-acetylcholine release. SCH 23390 did not affect basal 3H-acetylcholine release nor did it reverse the apomorphine-induced inhibition of 3H-acetylcholine release. The ability of SCH 23390 to inhibit motor behaviour in the rat may be due to its action on D-1 receptors since the drug does not cause typical changes in parameters of striatal D-2 receptor function.

  3. Cyclin D1 and Ki-67 expression correlates to tumor staging in tongue squamous cell carcinoma

    PubMed Central

    de Carli, Marina-Lara; Sperandio, Felipe-Fornias; Hanemann, João-Adolfo-Costa; Pereira, Alessandro-Antônio-Costa

    2015-01-01

    Background The immunohistochemical expression of Cyclin D1 and Ki-67 were analyzed in tongue squamous cell carcinomas (SCC), relating them to the clinical and morphological exhibition of these tumors. Material and Methods Twenty-nine patients fulfilled the inclusion criteria; clinical data included gender, age, ethnicity and use of licit drugs such as alcohol and tobacco. The TNM staging and histopathological differentiation grading was assessed for each case. In addition, T1 patients were gathered with T2 patients; and T3 patients were gathered with T4 patients to assemble two distinct groups: (T1/T2) and (T3/T4). Results The mean follow-up time was 24 months and 30% of the patients died as a consequence of the disease, while 23.3% lived with the disease and 46.7% lived lesion-free. T1 and T2 tumors showed statistically lesser Ki-67 and Cyclin D1 staining when compared to T3 and T4 tumors. Conclusions Ki-67 and Cyclin D1 pose as auxiliary tools when determining the progression of tongue SCC at the time of diagnosis. Key words:Carcinoma, squamous cell, cyclin D, immunohistochemistry, Ki-67 antigen, prognosis. PMID:26449430

  4. Age Dependent Switching Role of Cyclin D1 in Breast Cancer

    PubMed Central

    Rinaldi, Carmela; Malara, Natalia Maria; D’Angelo, Rosalia; Sidoti, Antonina; Leotta, Attilio; Lio, Santo; Caparello, Basilio; Ruggeri, Alessia; Mollace, Vincenzo; Amato, Aldo

    2012-01-01

    Background: Cyclin D1 gene (CCND1) plays pivotal roles in the development of several human cancers, including breast cancer, functioning as an oncogene. The aim of this study was to better understand the molecular dynamics of ductal carcinomas with regard to proliferation and the ageing process. Methods: 130 cases of ductal breast cancer in postmenopausal women, aged 52–96 in 3 age classes were selected. Tumoral tissues preserved in formaldehyde solution and subsequently embedded in paraffin were subjected to analysis Fluorescence in situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT- PCR) and immuno-histochemical tests. The molecular variables studied were estimated in relation to the patients’ age. Results: The results obtained suggest that the increment of the levels of cyclin D1 in intra-ductal breast tumors in older woman that we have examined is significantly associated with a lower proliferation rate. Conclusion: Cyclin D1, which characterizes tumor in young women as molecular director involved in strengthening tumoral proliferation mechanisms, may be seen as a potential blocking molecular switch in corresponding tumours in old women. PMID:22231956

  5. Radiative Transfer Modeling of the Enigmatic Scattering Polarization in the Solar Na I D1 Line

    NASA Astrophysics Data System (ADS)

    Belluzzi, Luca; Trujillo Bueno, Javier; Landi Degl'Innocenti, Egidio

    2015-12-01

    The modeling of the peculiar scattering polarization signals observed in some diagnostically important solar resonance lines requires the consideration of the detailed spectral structure of the incident radiation field as well as the possibility of ground level polarization, along with the atom's hyperfine structure and quantum interference between hyperfine F-levels pertaining either to the same fine structure J-level, or to different J-levels of the same term. Here we present a theoretical and numerical approach suitable for solving this complex non-LTE radiative transfer problem. This approach is based on the density-matrix metalevel theory (where each level is viewed as a continuous distribution of sublevels) and on accurate formal solvers of the transfer equations and efficient iterative methods. We show an application to the D-lines of Na i, with emphasis on the enigmatic D1 line, pointing out the observable signatures of the various physical mechanisms considered. We demonstrate that the linear polarization observed in the core of the D1 line may be explained by the effect that one gets when the detailed spectral structure of the anisotropic radiation responsible for the optical pumping is taken into account. This physical ingredient is capable of introducing significant scattering polarization in the core of the Na i D1 line without the need for ground-level polarization.

  6. Molecular hijacking of siroheme for the synthesis of heme and d1 heme.

    PubMed

    Bali, Shilpa; Lawrence, Andrew D; Lobo, Susana A; Saraiva, Lígia M; Golding, Bernard T; Palmer, David J; Howard, Mark J; Ferguson, Stuart J; Warren, Martin J

    2011-11-08

    Modified tetrapyrroles such as chlorophyll, heme, siroheme, vitamin B(12), coenzyme F(430), and heme d(1) underpin a wide range of essential biological functions in all domains of life, and it is therefore surprising that the syntheses of many of these life pigments remain poorly understood. It is known that the construction of the central molecular framework of modified tetrapyrroles is mediated via a common, core pathway. Herein a further branch of the modified tetrapyrrole biosynthesis pathway is described in denitrifying and sulfate-reducing bacteria as well as the Archaea. This process entails the hijacking of siroheme, the prosthetic group of sulfite and nitrite reductase, and its processing into heme and d(1) heme. The initial step in these transformations involves the decarboxylation of siroheme to give didecarboxysiroheme. For d(1) heme synthesis this intermediate has to undergo the replacement of two propionate side chains with oxygen functionalities and the introduction of a double bond into a further peripheral side chain. For heme synthesis didecarboxysiroheme is converted into Fe-coproporphyrin by oxidative loss of two acetic acid side chains. Fe-coproporphyrin is then transformed into heme by the oxidative decarboxylation of two propionate side chains. The mechanisms of these reactions are discussed and the evolutionary significance of another role for siroheme is examined.

  7. The D1 family dopamine receptor, DopR, potentiates hind leg grooming behavior in Drosophila

    PubMed Central

    Pitmon, E.; Stephens, G.; Parkhurst, S. J.; Wolf, F. W.; Kehne, G.; Taylor, M.

    2016-01-01

    Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH‐positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted. PMID:26749475

  8. Computer program documentation D1FLTD to drive SINDA boundary nodes: User's guide

    NASA Technical Reports Server (NTRS)

    Damico, S. J.

    1980-01-01

    The thermal model correlation process begins when measured thermocouple data is available from the orbital flight tests of the shuttle. For this effort, it is necessary to convert some of the system improved numerical differencing analyzer (SINDA) diffusion or arithmetic nodes to boundary nodes and then drive these boundary nodes to the temperature profile of a flight measurement. An efficient way to provide this capability within the SINDA and OFT software systems is to provide a new SINDA routine, D1FLTD, for use in VARIABLES 1 of SINDA, to access the processed (word-addressable) orbital data reduction center flight data and store the appropriate measurement temperature in the desired SINDA temperature location. The ODRC flight data that is to be used for driving the boundary nodes must be assigned a logical unit number and must reside on a word-addressable file. The user must also provide two SINDA constants for the word positions of the first and last words of the temperature record for each measurement identifier (MID), i.e. each call to D1FLTD, used in the model. D1FLTD is then called from the VARIABLES 1 block to obtain the SINDA boundary node temperature for any MID on the file at any time point.

  9. SKF-83566, a D1-dopamine receptor antagonist, inhibits the dopamine transporter.

    PubMed

    Stouffer, Melissa A; Ali, Solav; Reith, Maarten E A; Patel, Jyoti C; Sarti, Federica; Carr, Kenneth D; Rice, Margaret E

    2011-09-01

    Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1)-receptor activation in axonal DA release regulation in dorsal striatum using a D(1)-receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single-pulse evoked extracellular DA concentration, with a maximum increase of ∼ 65% in 5 μM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration clearance time. Both effects were occluded by nomifensine (1 μM), a dopamine transporter (DAT) inhibitor, suggesting that SKF-83566 acted via the DAT. We tested this by examining [(3)H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 μM. Binding studies with [(3)H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 μM). Thus, data obtained using SKF-83566 as a D(1) DA-receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of this drug at the cocaine versus DA binding site of the DAT.

  10. Prefrontal D1 dopamine signaling is necessary for temporal expectation during reaction time performance

    PubMed Central

    Parker, Krystal L.; Alberico, Stephanie L.; Miller, Adam D.; Narayanan, Nandakumar S.

    2013-01-01

    Responses during a simple reaction time task are influenced by temporal expectation, or the ability to anticipate when a stimulus occurs in time. Here, we test the hypothesis that prefrontal D1 dopamine signaling is necessary for temporal expectation during simple reaction time task performance. We depleted dopamine projections to the medial prefrontal circuits by infusing 6-hydroxidopamine, a selective neurotoxin, into the ventral tegmental area (VTA) of rats, and studied their performance on a simple reaction time task with two delays. VTA dopamine depletion did not change movements or learning of the reaction time task. However, VTA dopamine-depleted animals did not develop delay-dependent speeding of reaction times, suggesting that mesocortical dopamine signaling is required for temporal expectation. Next, we manipulated dopamine signaling within the medial prefrontal cortex using local pharmacology. We found that SCH23390, a D1-type dopamine receptor antagonist, specifically attenuated delay-dependent speeding, while sulpiride, a D2-type receptor antagonist, did not. These data suggest that prefrontal D1 dopamine signaling is necessary for temporal expectation during performance of a simple reaction time task. Our findings provide insight into temporal processing of the prefrontal cortex, and how dopamine signaling influences prefrontal circuits that guide goal-directed behavior. PMID:24120554

  11. Immunohistochemical evaluation of chemically induced rhabdomyosarcomas in rats: diagnostic utility of MyoD1.

    PubMed

    Newsholme, S J; Zimmerman, D M

    1997-01-01

    Monoclonal antibodies (mAbs) to selected muscle proteins were assessed as potential immunohistochemical markers to assist in the definitive diagnosis of poorly differentiated soft tissue sarcomas in rats. A series of 7 rat rhabdomyosarcomas (RMS) induced with nickel subsulfide were studied by light microscopy and were evaluated for immunoreactivity to desmin, vimentin, fast (type II isoform) skeletal myosin, alpha-actin (smooth muscle isoform), or MyoD1 (myogenic regulatory protein) mAbs using an avidin-biotin-chromogen technique. Consecutive RMS slices were fixed in 10% neutral buffered formalin (the fixative routinely used in carcinogenicity bioassays) for periods of 3 days or 2 mo prior to paraffin embedding to determine the effect of fixation time on immunoreactivity. Desmin and vimentin mAbs bound to many cells of all tumors, but fixation for 2 mo resulted in irretrievable loss of desmin and vimentin binding. Fast myosin and alpha-actin mAbs bound to many cells in 1 RMS but to < 1% of the cells in the remainder. MyoD1 mAb bound to tumor cell nuclei in 5/7 RMS with no loss of staining in tissue fixed for 2 mo. Results indicate that MyoD1 immunostaining, in contrast to desmin, maintains its sensitivity following prolonged formalin fixation and may be of value to distinguish RMS from other soft tissue sarcomas in the rat.

  12. [PCR-based analysis of the D1S80 locus and its application in paternity test].

    PubMed

    Que, T; Lin, Y; Li, L

    1998-01-01

    Allelic data for the D1S80 locus was obtained by using the PCR and subsequent analysis with high-resolution horizontal PAGE technique. In a sample of 184 unrelated Chinese, the D1S80 locus had 75 phenotypes and 20 allelic. The distribution of genotype was in agreement with expected values according to the Hardy-Weinberg equilibrium. Analysis of the D1S80 locus by the PCR has been successfully applied in 150 cases of questioned paternity.

  13. Isolation and characterization of mutant Sinorhizobium meliloti NodD1 proteins with altered responses to luteolin.

    PubMed

    Peck, Melicent C; Fisher, Robert F; Bliss, Robert; Long, Sharon R

    2013-08-01

    NodD1, a member of the NodD family of LysR-type transcriptional regulators (LTTRs), mediates nodulation (nod) gene expression in the soil bacterium Sinorhizobium meliloti in response to the plant-secreted flavonoid luteolin. We used genetic screens and targeted approaches to identify NodD1 residues that show altered responses to luteolin during the activation of nod gene transcription. Here we report four types of NodD1 mutants. Type I (NodD1 L69F, S104L, D134N, and M193I mutants) displays reduced or no activation of nod gene expression. Type II (NodD1 K205N) is constitutively active but repressed by luteolin. Type III (NodD1 L280F) demonstrates enhanced activity with luteolin compared to that of wild-type NodD1. Type IV (NodD1 D284N) shows moderate constitutive activity yet can still be induced by luteolin. In the absence of luteolin, many mutants display a low binding affinity for nod gene promoter DNA in vitro. Several mutants also show, as does wild-type NodD1, increased affinity for nod gene promoters with added luteolin. All of the NodD1 mutant proteins can homodimerize and heterodimerize with wild-type NodD1. Based on these data and the crystal structures of several LTTRs, we present a structural model of wild-type NodD1, identifying residues important for inducer binding, protein multimerization, and interaction with RNA polymerase at nod gene promoters.

  14. Cyclin D1 blocks the anti-proliferative function of RUNX3 by interfering with RUNX3-p300 interaction

    SciTech Connect

    Iwatani, Kazunori; Fujimoto, Tetsuhiro; Ito, Takaaki

    2010-09-24

    Research highlights: {yields} Cyclin D1 interacts with RUNX3 and inhibits the interaction and collaboration of RUNX3 with coactivator p300. {yields} Cyclin D1 blocks the ability of RUNX3 to induce the expression of cdk inhibitor p21. {yields} Cyclin D1 releases cancer cells from the inhibition of proliferation induced by RUNX3. -- Abstract: Transcriptional function of cyclin D1, whose deregulation is frequently observed in human cancers, has been suggested to contribute to cancer formation. In the present study, we show that cyclin D1 protein inhibits RUNX3 activity by directly binding to it and interfering with its interaction with p300 interaction in lung cancer cells. Cyclin D1 inhibits p300-dependent RUNX3 acetylation and negatively regulates cyclin-dependent kinase (cdk) inhibitor p21 expression. These transcriptional effects of cyclin D1 do not require cdk4/6 kinase activation. We propose that cyclin D1 provides a transcriptional switch that allows the tumor suppressor activity of RUNX3 to be repressed in cancer cells. Since RUNX3 plays tumor suppressive roles in a wide range of cancers, a non-canonical cyclin D1 function may be critical for neoplastic transformation of the epithelial cells in which RUNX3 regulates proliferation.

  15. Stimulation of α₁-adrenoceptor or angiotensin type 1 receptor enhances DNA synthesis in human-induced pluripotent stem cells via Gq-coupled receptor-dependent signaling pathways.

    PubMed

    Ishizuka, Toshiaki; Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro

    2013-08-15

    Stimulation of either α₁-adrenoceptor or angiotensin type 1 receptor (AT₁ receptor) induces proliferation of mouse induced pluripotent stem (iPS) cells. Both α₁-adrenoceptor and AT₁ receptor are guanine nucleotide-binding protein q polypeptide (Gq)-coupled receptors. However, it is not fully understood whether stimulation of these Gq-coupled receptors exert a similar effect in human iPS cells, i.e. proliferation of human iPS cells. In this study, we evaluated the involvement of α₁-adrenoceptor and AT₁ receptor in the DNA synthesis of human iPS cells. Treatment with either l-phenylephrine (a selective α₁-adrenoceptor agonist) or angiotensin II (Ang II) significantly increased DNA synthesis in human iPS cells. Enhanced DNA synthesis was significantly inhibited by pretreatment with protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) inhibitor, or phosphatidylinositol-3 phosphate kinase (PI3K) inhibitor. Treatment with either l-phenylephrine or Ang II significantly increased Akt and p44/42 MAPK phosphorylation. Short interfering RNA (siRNA) directed against Gq significantly inhibited DNA synthesis and phosphorylation of Akt and p44/42 MAPK enhanced by l-phenylephrine or Ang II. These results suggest that stimulation of α₁-adrenoceptor or AT₁ receptor may enhance DNA synthesis in human iPS cells via Gq-coupled receptor-dependent signaling pathways.

  16. Effect of allelic variations at the Glu-D1, Glu-A3, Glu-B3 and Pinb-D1 loci on flour characteristics and bread loaf volume

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Doubled haploid wheat lines developed from a cross between Keumkang, a hard white winter wheat, and Olgeuru, soft red winter wheat were used to determine the effects of allelic variation in Glu-D1, Glu-A3, Glu-B3 and Pinb-D1 loci on physiochemical properties of flour and bread loaf volume. Variation...

  17. Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice

    PubMed Central

    Gagnon, D.; Petryszyn, S.; Sanchez, M. G.; Bories, C.; Beaulieu, J. M.; De Koninck, Y.; Parent, A.; Parent, M.

    2017-01-01

    The loss of nigrostriatal dopamine neurons in Parkinson’s disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson’s disease. PMID:28128287

  18. Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells

    PubMed Central

    Bustany, Sophie; Bourgeais, Jérôme; Tchakarska, Guergana; Body, Simon; Hérault, Olivier; Gouilleux, Fabrice; Sola, Brigitte

    2016-01-01

    The interactions of multiple myeloma (MM) cells with their microenvironment are crucial for pathogenesis. MM cells could interact differentially with their microenvironment depending on the type of cyclin D they express. We established several clones that constitutively express cyclin D1 from the parental RPMI8226 MM cell line and analyzed the impact of cyclin D1 expression on cell behavior. We performed a gene expression profiling study on cyclin D1-expressing vs. control cells and validated the results by semi-quantitative RT-PCR. The expression of cyclin D1 altered the transcription of genes that control adhesion and migration. We confirmed that cyclin D1 increases cell adhesion to stromal cells and fibronectin, stabilizes F-actin fibers, and enhances chemotaxis and inflammatory chemokine secretion. Both control and cyclin D1-expressing cells were more resistant to acute carfilzomib treatment when cultured on stromal cells than in suspension. However, this resistance was specifically reduced in cyclin D1-expressing cells after pomalidomide pre-treatment that modifies tumor cell/microenvironment interactions. Transcriptomic analysis revealed that cyclin D1 expression was also associated with changes in the expression of genes controlling metabolism. We also found that cyclin D1 expression disrupted the redox balance by producing reactive oxygen species. The resulting oxidative stress activated the p44/42 mitogen-activated protein kinase (or ERK1/2) signaling pathway, increased cell adhesion to fibronectin or stromal cells, and controlled drug sensitivity. Our results have uncovered a new function for cyclin D1 in the control of redox metabolism and interactions of cyclin D1-expressing MM cells with their bone marrow microenvironment. PMID:27286258

  19. D1/D5 dopamine receptors stimulate intracellular calcium release in primary cultures of neocortical and hippocampal neurons.

    PubMed

    Lezcano, Nelson; Bergson, Clare

    2002-04-01

    D1/D5 dopamine receptors in basal ganglia, hippocampus, and cerebral cortex modulate motor, reward, and cognitive behavior. Previous work with recombinant proteins revealed that in cells primed with heterologous G(q/11)-coupled G-protein-coupled receptor (GPCR) agonists, the typically G(s)-linked D1/D5 receptors can stimulate robust release of calcium from internal stores when coexpressed with calcyon. To learn more about the intracellular signaling mechanisms underlying these D1/D5 receptor regulated behaviors, we explored the possibility that endogenous receptors stimulate internal release of calcium in neurons. We have identified a population of neurons in primary cultures of hippocampus and neocortex that respond to D1/D5 dopamine receptor agonists with a marked increase in intracellular calcium (Ca) levels. The D1/D5 receptor stimulated responses occurred in the absence of extracellular Ca(2+) indicating the rises in Ca involve release from internal stores. In addition, the responses were blocked by D1/D5 receptor antagonists. Further, the D1/D5 agonist-evoked responses were state dependent, requiring priming with agonists of G(q/11)-coupled glutamate, serotonin, muscarinic, and adrenergic receptors or with high external K(+) solution. In contrast, D1/D5 receptor agonist-evoked Ca(2+) responses were not detected in neurons derived from striatum. However, D1/D5 agonists elevated cAMP levels in striatal cultures as effectively as in neocortical and hippocampal cultures. Further, neither forskolin nor 8-Br-cAMP stimulation following priming was able to mimic the D1/D5 agonist-evoked Ca(2+) response in neocortical neurons indicating that increased cAMP levels are not sufficient to stimulate Ca release. Our data suggest that D1-like dopamine receptors likely modulate neocortical and hippocampal neuronal excitability and synaptic function via Ca(2+) as well as cAMP-dependent signaling.

  20. A crucial role for cAMP and protein kinase A in D1 dopamine receptor regulated intracellular calcium transients.

    PubMed

    Dai, Rujuan; Ali, Mohammad K; Lezcano, Nelson; Bergson, Clare

    2008-01-01

    D1-like dopamine receptors stimulate Ca(2+) transients in neurons but the effector coupling and signaling mechanisms underlying these responses have not been elucidated. Here we investigated potential mechanisms using both HEK 293 cells that stably express D1 receptors (D1HEK293) and hippocampal neurons in culture. In D1HEK293 cells, the full D1 receptor agonist SKF 81297 evoked a robust dose-dependent increase in Ca(2+)(i) following 'priming' of endogenous G(q/11)-coupled muscarinic or purinergic receptors. The effect of SKF81297 could be mimicked by forskolin or 8-Br-cAMP. Further, cholera toxin and the cAMP-dependent protein kinase (PKA) inhibitors, KT5720 and H89, as well as thapsigargin abrogated the D1 receptor evoked Ca(2+) transients. Removal of the priming agonist and treatment with the phospholipase C inhibitor U73122 also blocked the SKF81297-evoked responses. D1R agonist did not stimulate IP(3) production, but pretreatment of cells with the D1R agonist potentiated G(q)-linked receptor agonist mobilization of intracellular Ca(2+) stores. In neurons, SKF81297 and SKF83959, a partial D1 receptor agonist, promoted Ca(2+) oscillations in response to G(q/11)-coupled metabotropic glutamate receptor (mGluR) stimulation. The effects of both D1R agonists on the mGluR-evoked Ca(2+) responses were PKA dependent. Altogether the data suggest that dopamine D1R activation and ensuing cAMP production dynamically regulates the efficiency and timing of IP(3)-mediated intracellular Ca(2+) store mobilization.

  1. SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C.

    PubMed

    Lee, Sang-Min; Kant, Andrew; Blake, Daniel; Murthy, Vishakantha; Boyd, Kevin; Wyrick, Steven J; Mailman, Richard B

    2014-11-01

    SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson's disease models, and a D1-D2 heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D1 and D2 receptors in both rat brain and heterologous systems expressing human D1 or D2 receptors. Contrary to common assumptions, SKF-83959 is similar to the classical, well-characterized partial agonist SKF38393 in all systems. It is a partial agonist (not an antagonist) at adenylate cyclase in vitro and ex vivo, and is a partial agonist in D1-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D1-mediated effects on PLC signaling in heterologous systems. Because drug metabolites can also contribute, its 3-N-demethylated analog also was synthesized and tested. As expected from the known structure-activity relationships of the benzazepines, this compound also had high affinity for the D1 receptor and somewhat higher intrinsic activity than the parent ligand, and also might contribute to in vivo effects of SKF-83959. Together, these data demonstrate that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral data can be explained solely by its partial D1 agonism in canonical signaling pathway(s). Mechanisms that have been proposed based on the purported signaling novelty of SKF-83959 at PLC should be reconsidered.

  2. Invertebrate Specific D1-like Dopamine Receptor in Control of Salivary Glands in the Black-Legged Tick Ixodes scapularis

    PubMed Central

    Šimo, Ladislav; Koči, Juraj; Kim, Donghun; Park, Yoonseong

    2014-01-01

    The control of tick salivary secretion, which plays a crucial role in compromising the host immune system, involves complex neural mechanisms. Dopamine is known to be the most potent activator of salivary secretion, as a paracrine/autocrine factor. We describe the invertebrate specific D1-like dopamine receptor (InvD1L), which is highly expressed in tick salivary glands. The InvD1L phylogenic clade was found only in invertebrates, suggesting that this receptor was lost in the vertebrates during evolution. InvD1L expressed in CHO-K1 cells was activated by dopamine with a median effective dose (EC50) of 1.34 μM. Immunohistochemistry using the antibody raised against InvD1L revealed two different types of immunoreactivities: basally located axon terminals that are colocalized with myoinhibitory peptide (MIP) and SIFamide neuropeptides, and longer axon-like processes that are positive only for the InvD1L antibody and extended to the apical parts of the acini. Both structures were closely associated with the myoepithelial cell, as visualized by beta-tubulin antibody, lining the acinar lumen in a web-like fashion. Subcellular localizations of InvD1L in the salivary gland suggest that InvD1L modulates the neuronal activities including MIP/SIFamide varicosities, and leads the contraction of myoepithelial cells and/or of the acinar valve to control the efflux of the luminal content. Combining the previously described D1 receptor with its putative function for activating an influx of fluid through the epithelial cells of acini, we propose that complex control of the tick salivary glands is mediated through two different dopamine receptors, D1 and InvD1L, for different downstream responses of the acinar cells. PMID:24307522

  3. Detection of cyclin D1 mRNA by hybridization sensitive NIC-oligonucleotide probe.

    PubMed

    Kovaliov, Marina; Segal, Meirav; Kafri, Pinhas; Yavin, Eylon; Shav-Tal, Yaron; Fischer, Bilha

    2014-05-01

    A large group of fluorescent hybridization probes, includes intercalating dyes for example thiazole orange (TO). Usually TO is coupled to nucleic acids post-synthetically which severely limits its use. Here, we have developed a phosphoramidite monomer, 10, and prepared a 2'-OMe-RNA probe, labeled with 5-(trans-N-hexen-1-yl-)-TO-2'-deoxy-uridine nucleoside, dU(TO), (Nucleoside bearing an Inter-Calating moiety, NIC), for selective mRNA detection. We investigated a series of 15-mer 2'-OMe-RNA probes, targeting the cyclin D1 mRNA, containing one or several dU(TO) at various positions. dU(TO)-2'-OMe-RNA exhibited up to 7-fold enhancement of TO emission intensity upon hybridization with the complementary RNA versus that of the oligomer alone. This NIC-probe was applied for the specific detection of a very small amount of a breast cancer marker, cyclin D1 mRNA, in total RNA extract from cancerous cells (250 ng/μl). Furthermore, this NIC-probe was found to be superior to our related NIF (Nucleoside with Intrinsic Fluorescence)-probe which could detect cyclin D1 mRNA target only at high concentrations (1840 ng/μl). Additionally, dU(T) can be used as a monomer in solid-phase oligonucleotide synthesis, thus avoiding the need for post-synthetic modification of oligonucleotide probes. Hence, we propose dU(TO) oligonucleotides, as hybridization probes for the detection of specific RNA in homogeneous solutions and for the diagnosis of breast cancer.

  4. MicroRNA-195 inhibits proliferation of cervical cancer cells by targeting cyclin D1a.

    PubMed

    Wang, Ning; Wei, Heng; Yin, Duo; Lu, Yanming; Zhang, Yao; Zhang, Qiao; Ma, Xiaoxin; Zhang, Shulan

    2016-04-01

    Cervical cancer is one of the most frequent gynecological malignancies in women worldwide. MicroRNA-195 (miR-195) was recently found highly expressed in cervical cancer. However, the role of miR-195 in the pathology of cervical cancer remains poorly understood. In this study, we first confirmed the downregulation of miR-195 in primary cervical cancer tissues. For the functional study, we introduced the sequences of miR-195 or miR-195 inhibitor into Hela and SiHa cervical cancer cell lines. Overexpression of miR-195 inhibited the proliferation of both Hela and SiHa cells. In contrast, reducing the endogenous miR-195 level by miR-195 inhibitor promoted the proliferation of cervical cancer cells. Flow cytometric assay showed that overexpression of miR-195 induced G1 phase arrest, whereas miR-195 inhibitor shortened G1 phase of cervical cancer cells. In addition, the suppressive role of miR-195 in cell cycle was also demonstrated by the western blot results of various cell cycle indicators, such as phosphorylated retinoblastoma (p-Rb) and proliferating cell nuclear antigen (PCNA), in the gain and loss of function experiments. Furthermore, Dual-Luciferase Reporter Assay revealed that miR-195 targeted the 3'-untranslated region of cyclin D1a transcript, such as to regulate cyclin D1 expression. In summary, our results suggest that miR-195 acts as a suppressor in the proliferation and cell cycle of cervical cancer cells by directly targeting cyclin D1a mRNA.

  5. RhoA promotes epidermal stem cell proliferation via PKN1-cyclin D1 signaling

    PubMed Central

    Wang, Fan; Zhan, Rixing; Chen, Liang; Dai, Xia; Wang, Wenping; Guo, Rui; Li, Xiaoge; Li, Zhe; Wang, Liang; Huang, Shupeng; Shen, Jie

    2017-01-01

    Objective Epidermal stem cells (ESCs) play a critical role in wound healing, but the mechanism underlying ESC proliferation is not well defined. Here, we explore the effects of RhoA on ESC proliferation and the possible underlying mechanism. Methods Human ESCs were enriched by rapid adhesion to collagen IV. RhoA(+/+)(G14V), RhoA(-/-)(T19N) and pGFP control plasmids were transfected into human ESCs. The effect of RhoA on cell proliferation was detected by cell proliferation and DNA synthesis assays. Induction of PKN1 activity by RhoA was determined by immunoblot analysis, and the effects of PKN1 on RhoA in terms of inducing cell proliferation and cyclin D1 expression were detected using specific siRNA targeting PKN1. The effects of U-46619 (a RhoA agonist) and C3 transferase (a RhoA antagonist) on ESC proliferation were observed in vivo. Results RhoA had a positive effect on ESC proliferation, and PKN1 activity was up-regulated by the active RhoA mutant (G14V) and suppressed by RhoA T19N. Moreover, the ability of RhoA to promote ESC proliferation and DNA synthesis was interrupted by PKN1 siRNA. Additionally, cyclin D1 protein and mRNA expression levels were up-regulated by RhoA G14V, and these effects were inhibited by siRNA-mediated knock-down of PKN1. RhoA also promoted ESC proliferation via PKN in vivo. Conclusion This study shows that the effect of RhoA on ESC proliferation is mediated by activation of the PKN1-cyclin D1 pathway in vitro, suggesting that RhoA may serve as a new therapeutic target for wound healing. PMID:28222172

  6. Effects of full D1 dopamine receptor agonists on firing rates in the globus pallidus and substantia nigra pars compacta in vivo: tests for D1 receptor selectivity and comparisons to the partial agonist SKF 38393.

    PubMed

    Ruskin, D N; Rawji, S S; Walters, J R

    1998-07-01

    Many studies have used the D1 agonist SKF 38393 to characterize D1 receptor influences on firing rates in basal ganglia nuclei in vivo. However, SKF 38393 is a partial agonist and so may not be ideal for delineating D1 receptor effects. This study characterizes the effects of four full D1 agonists, SKF 82958 (chloro-APB), SKF 81297 (6-chloro-PB), dihydrexidine and A-77636, on the firing rates of midbrain dopamine and globus pallidus neurons. Recordings were done in fully anesthetized or paralyzed, locally anesthetized rats, and drugs were given systemically intravenously. Dihydrexidine, SKF 81297 and A-77636 were free of rate effects on midbrain dopamine neurons (up to 10.2 mg/kg) and also did not antagonize the inhibitory effects of quinpirole. In contrast, SKF 82958 strongly inhibited dopamine cells through activation of D2 autoreceptors (ED50 = 0.70 mg/kg). Of these drugs, SKF 82958 also was the only one to increase pallidal unit firing rates when given alone (at 5.0 but not 1.0 mg/kg); the other compounds appeared to be selective for postsynaptic D1 receptors. The results suggest that SKF 82958 may be more properly classified as a mixed D1/D2 agonist. In addition, all four agonists strongly potentiated the pallidal response to quinpirole, demonstrating a D1 receptor potentiation of D2 receptor effects. The results support the role of D1 receptors in the midbrain and globus pallidus as previously characterized with SKF 38393. The similar actions of partial and full D1 agonists in these systems support evidence for a D1 receptor reserve and possibly an effector system other than adenylate cyclase.

  7. Carotenoids suppress proliferating cell nuclear antigen and cyclin D1 expression in oral carcinogenic models.

    PubMed

    Cheng, Hsin-Chung; Chien, Hsin; Liao, Chia-Hui; Yang, Yi-Yuan; Huang, Shih-Yi

    2007-10-01

    The purpose of this study was to investigate the chemopreventive effect of carotenoids on proliferating cell nuclear antigen (PCNA) and cyclin D(1) expression in betel (Areca catechu) quid extract (BQE)-induced hamster oral cancer and human KB cell models, respectively. In the in vivo animal study, 41 hamsters were divided into six groups and treated with 0.3 ml of 0.5% 9,10-dimethyl-1,2-benz[a]-anthracene, BQE, alpha-tocopherol, beta-carotene, lycopene, lutein and mixed carotenoids for 12 weeks. After treatment, the pouches were excised and graded using an immunohistochemical assay of PCNA. In the in vitro cell experiment, KB cells were cultured, and the inhibitory effect of carotenoids (beta-carotene, lycopene and lutein) on cell proliferation was evaluated. Cyclin D(1) and PCNA were evaluated in terms of cell differentiation. In the results, most of the animal lesions showed no overexpression of PCNA. However, in dysplastic lesions, PCNA expressions by the beta-carotene, lutein, lycopene, mixed and vitamin E groups were less than that of the control group. In papilloma lesions, PCNA expressions by the beta-carotene, mixed and vitamin E groups were less severe than that of the control group. PCNA expression by the vitamin E-treated group was less severe than that of the control group. No carcinoma was found in the lycopene or mixed groups. In the cell study, all carotenoids exerted a significant inhibitory effect on KB cell proliferation. Although lycopene suppressed KB cell proliferation at the G(0)/G(1) phase with a significant decrease in PCNA expression, beta-carotene and lutein possessed less of an inhibitory effect and even exhibited elevated cell proliferation at the G(2)/M phase. These results indicate that different carotenoids present various suppressive abilities against PCNA and cyclin D(1) expressions in cell proliferation. In conclusion, carotenoids suppressed the carcinogenesis of induced hamster oral cancer and a cancer cell line by acting as a

  8. Dopamine and dopamine receptor D1 associated with decreased social interaction.

    PubMed

    Liu, Qiang; Shi, Jieyun; Lin, Rongfei; Wen, Tieqiao

    2017-02-13

    Deficits in social interaction are hallmarks of neurological and psychiatric disorders. However, its underlying mechanism is still unclear. Here, we show that the loss of dendritic cell factor 1 (Dcf1) in the nervous system of mice induces social interaction deficiency, autism-like behaviour, and influences social interaction via the dopamine system. Dopamine receptor D1 agonist rescues this social cognition phenotype, and improves short-term plasticity. Together, this study presents a new genetic mechanism that affects social interaction and may provide a new way to improve positive social interaction and treat autism spectrum disorders.

  9. Sensitivities of dopamine D1 and D2 receptor radioligands to changes in synaptic dopamine

    SciTech Connect

    Gifford, A.N.; Gatley, S.J.; Shea, C.

    1996-05-01

    Prior studies have shown that the in vivo binding of D2 radioligands such as raclopride and IBZM is subject to competition with synaptic DA. D2 radioligands can thus be used to evaluate both direct effects of drugs at DAergic synapses, and indirect effects at these synapses mediated via neurotransmitter interactions. Competition with DA must also be a potential confounding factor in studies designed to evaluate changes in D2 receptor number. We evaluated the sensitivity of the D1 radioligands for susceptibility to alterations in synaptic DA. We evaluated the sensitivity of the D1 radioligand SCH 23390 using three different models: rat brain slices in which DA release is controlled by electrically simulation, ex vivo mouse brain uptake, and PET in the baboon brain. In slices, the order of sensitivity of DA system radioligands to synaptic DA was D1>D2>DA transporter, and the sensitivity of the low affinity (Kd = 1 nM) D2 ligand, [H-3]raclopride, was greater than that of the high affinity (Kd = 0.05 nM) D2 ligand, [I-123]epidepride (Gifford et al., Synapse, in press). In mice, striatal [H-3]SCH 23390 was decreased after administration of the DA transporter blocker RTI-55 ({beta}-CIT, 0.5 mg/kg, i/v), to a similar extent as that of co-administered [I-123]epidepride. In these experiments RTI-55 was given four hours after injection of radiotracers, after peak striatal radioactivity, to avoid the effects of the increase in delivery of radiotracer to the brain caused by RTI-55. In PET experiments, striatal binding of the D1 radioligand [C-11]SCH23390 was less sensitive to challenge with the DA transporter blocker methylphenidate (0.5 mg/kg, 7-10 min before radiotracer) than is [C-11]raclopride. Our results together indicate that SCH 23390 is not very sensitive to pharmacological challenges which decrease the in vivo binding of labeled raclopride.

  10. Hair on non-extremal D1-D5 bound states

    NASA Astrophysics Data System (ADS)

    Roy, Pratik; Srivastava, Yogesh K.; Virmani, Amitabh

    2016-09-01

    We consider a truncation of type IIB supergravity on four-torus where in addition to the Ramond-Ramond 2-form field, the Ramond-Ramond axion ( w) and the NS-NS 2-form field ( B) are also retained. In the ( w, B) sector we construct a linearised perturbation carrying only left moving momentum on two-charge non-extremal D1-D5 geometries of Jejjala, Madden, Ross and Titchener. The perturbation is found to be smooth everywhere and normalisable. It is constructed by matching to leading order solutions of the perturbation equations in the inner and outer regions of the geometry.

  11. High-precision Monte Carlo study of directed percolation in (d+1) dimensions.

    PubMed

    Wang, Junfeng; Zhou, Zongzheng; Liu, Qingquan; Garoni, Timothy M; Deng, Youjin

    2013-10-01

    We present a Monte Carlo study of the bond- and site-directed (oriented) percolation models in (d+1) dimensions on simple-cubic and body-centered-cubic lattices, with 2 ≤ d ≤ 7. A dimensionless ratio is defined, and an analysis of its finite-size scaling produces improved estimates of percolation thresholds. We also report improved estimates for the standard critical exponents. In addition, we study the probability distributions of the number of wet sites and radius of gyration, for 1 ≤ d ≤ 7.

  12. Initial observations of GeSe-xenon transport experiments performed on the D1 space flight

    NASA Technical Reports Server (NTRS)

    Wiedemeier, H.; Trivedi, S. B.

    1986-01-01

    GeSe-xenon experiments performed aboard the D1 mission at xenon pressures of 2 and 6 atm confirm the crystal growth pattern, sizes, and surface morphology of crystals previously grown aboard STS-7 for different pressures. Besides the deposition and growth of GeSe crystals on the ampoule wall, several large single-crystalline GeSe platelets with lateral dimensions much greater than those of crystals on the wall and obtained on the ground are found. The present results reemphasize the question concerning the nucleation phenomena in microgravity.

  13. Draft Genomic Analysis of an Avian Multidrug Resistant Morganella morganii Isolate Carrying qnrD1

    PubMed Central

    Jones-Dias, Daniela; Clemente, Lurdes; Moura, Inês B.; Sampaio, Daniel A.; Albuquerque, Teresa; Vieira, Luís; Manageiro, Vera; Caniça, Manuela

    2016-01-01

    Morganella morganii is a commensal bacterium and opportunistic pathogen often present in the gut of humans and animals. We report the 4.3 Mbp draft genome sequence of a M. morganii isolated in association with an Escherichia coli from broilers in Portugal that showed macroscopic lesions consistent with colisepticemia. The analysis of the genome matched the multidrug resistance phenotype and enabled the identification of several clinically important and potentially mobile acquired antibiotic resistance genes, including the plasmid-mediated quinolone resistance determinant qnrD1. Mobile genetic elements, prophages, and pathogenicity factors were also detected, improving our understanding toward this human and animal opportunistic pathogen. PMID:27826290

  14. Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

    SciTech Connect

    Chen, Jiao; Shetty, Sreerama; Zhang, Ping; Gao, Rong; Hu, Yuxin; Wang, Shuxia; Li, Zhenyu; Fu, Jian

    2014-06-01

    The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

  15. Crystal Structures and Functional Characterization of Wild Type and Active Sites Mutants of CYP101D1

    PubMed Central

    Batabyal, Dipanwita; Poulos, Thomas L.

    2014-01-01

    Although CYP101D1 and P450cam catayze the same reaction at a similar rate and share strikingly similar active site architectures, there are significance functional differences. CYP101D1 thus provides an opportunity to probe what structural and functional features must be shared and what can differ yet maintain high catalytic efficiency. Crystal structures of the cyanide complex of wild type CYP101D1 and it active site mutants, D259N and T260A, have been solved. The conformational changes in CYP101D1 upon cyanide binding are very similar to P450cam indicating a similar mechanism for proton delivery during oxygen activation using solvent assisted proton transfer. The D259N-CN− complex shows a perturbed solvent structure compared to wild type which is similar to what was observed in the oxy-complex of the corresonding D251N mutant in P450cam. As in P450cam the T260A mutant is highly uncoupled while the D259N gives barely detectable activity. Despite these similarities, CYP101D1 is able to use the P450cam redox partners while P450cam cannot use the CYP101D1 redox partners. Thus the strict requirement of P450cam for its own redox partner is relaxed in CYP101D1. Differences in the local environment of the essential Asp (Asp259 in CYP101D1) provides a strucutral basis for understanding these functional differences. PMID:24261604

  16. 15 CFR 770.3 - Interpretations related to exports of technology and software to destinations in Country Group D:1.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... technology and software to destinations in Country Group D:1. 770.3 Section 770.3 Commerce and Foreign Trade... technology and software to destinations in Country Group D:1. (a) Introduction. This section is intended to provide you additional guidance on how to determine whether your technology or software would be...

  17. 26 CFR 1.514(d)-1 - Basis of debt-financed property acquired in corporate liquidation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Basis of debt-financed property acquired in corporate liquidation. 1.514(d)-1 Section 1.514(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of...

  18. Compound 800, a natural product isolated from genetically engineered Pseudomonas: proposed structure, reactivity, and putative relation to heme d1.

    PubMed

    Youn, Hyung-Sun; Liang, Qiaoli; Cha, Jin K; Cai, Mengli; Timkovich, Russell

    2004-08-24

    Genetically engineered strains of Escherichia coli and Pseudomonas aeruginosa were prepared harboring the gene cluster nirFDLGH from Pseudomonas stutzeri substrain ZoBell on a high copy plasmid. These genes have been previously implicated as being essential for the biosynthesis of heme d(1), the prosthetic group of dissimilatory nitrite reductases in anaerobic, denitryfying bacteria. Tetrapyrroles detectable at steady-state levels were identified from both organisms, and cell-free extracts from each were also used to transform uroporphyrinogen in vitro. E. coli does not naturally produce d(1), and the engineered strain failed to produce d(1) or any tetrapyrrole foreign to E. coli. Therefore, while nirFDLGHmay be necessary for d(1) biosynthesis, it is not sufficient. In the denitrifier P. aeruginosa, the results were more positive. The presence of the plasmid led to increased levels of d(1). In addition, a previously unidentified tetrapyrrole was detected. This compound was characterized by visible absorption spectroscopy, infrared spectroscopy, X-ray photoelectron spectroscopy, mass spectrometry, and NMR, and a tentative structure was proposed for this compound. The tetrapyrrole has structural features similar to sirohydrochlorin (as precorrin-2 or sirotetrahydrochlorin, a known intermediate of d(1)) and d(1) itself. The most unusual substituents are epoxide and sulfoxide moieties. When this tetrapyrrole was treated with strong mineral acid and heat, it was converted into natural d(1).

  19. 15 CFR 770.3 - Interpretations related to exports of technology and software to destinations in Country Group D:1.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... technology and software to destinations in Country Group D:1. 770.3 Section 770.3 Commerce and Foreign Trade... technology and software to destinations in Country Group D:1. (a) Introduction. This section is intended to provide you additional guidance on how to determine whether your technology or software would be...

  20. 15 CFR 770.3 - Interpretations related to exports of technology and software to destinations in Country Group D:1.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... technology and software to destinations in Country Group D:1. 770.3 Section 770.3 Commerce and Foreign Trade... technology and software to destinations in Country Group D:1. (a) Introduction. This section is intended to provide you additional guidance on how to determine whether your technology or software would be...

  1. 17 CFR 240.14d-1 - Scope of and definitions applicable to Regulations 14D and 14E.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... a minimum acceptance condition included in the terms of the offer has been satisfied by counting...) shall apply to any tender offer that is subject to section 14(d)(1) of the Act (15 U.S.C. 78n(d)(1)), including, but not limited to, any tender offer for securities of a class described in that section that...

  2. Apple (Malus domestica L. Borkh.) allergen Mal d 1: effect of cultivar, cultivation system, and storage conditions.

    PubMed

    Matthes, Anne; Schmitz-Eiberger, Michaela

    2009-11-25

    It has been reported on the basis of skin prick tests and gene expression studies that apple cultivars differ in their allergenic potential. Only a few studies have tried to measure the amount of the major apple allergen Mal d 1 so far. Mal d 1 belongs to the pathogenesis-related proteins, a family of proteins that are induced by pathogens and environmental stress. Due to cross-reactivity between Bet v 1 and proteins present in several plant-derived foods, birch pollen allergic patients develop food allergies, most frequently to apples. Mal d 1 content was quantified in different apple cultivars, cultivated at the research stations Klein-Altendorf and Bavendorf, dependent on cultivation method and storage conditions by sandwich-ELISA. Apple cultivars differ considerably in their Mal d 1 content. A high variability in Mal d 1 content was determined within one cultivar and between the two locations for the same apple cultivar. In most cases organically cultivated fruit showed lower Mal d 1 content in comparison to fruit from integrated production. At harvest the detected concentration of Mal d 1 was low, but during storage the Mal d 1 content increased significantly.

  3. 15 CFR 770.3 - Interpretations related to exports of technology and software to destinations in Country Group D:1.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... technology and software to destinations in Country Group D:1. 770.3 Section 770.3 Commerce and Foreign Trade... technology and software to destinations in Country Group D:1. (a) Introduction. This section is intended to provide you additional guidance on how to determine whether your technology or software would be...

  4. 15 CFR 770.3 - Interpretations related to exports of technology and software to destinations in Country Group D:1.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... technology and software to destinations in Country Group D:1. 770.3 Section 770.3 Commerce and Foreign Trade... technology and software to destinations in Country Group D:1. (a) Introduction. This section is intended to provide you additional guidance on how to determine whether your technology or software would be...

  5. Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

    USGS Publications Warehouse

    Cueva, J.P.; Chemel, B.R.; Juncosa, J.I.; Lill, M.A.; Watts, V.J.; Nichols, D.E.

    2012-01-01

    Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.

  6. Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

    PubMed Central

    Cueva, Juan Pablo; Chemel, Benjamin R.; Juncosa, Jose I.; Lill, Markus A.; Watts, Val J.; Nichols, David E.

    2012-01-01

    Efforts to develop selective agonists for dopamine D1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric β-phenyldopamine-type full agonist ligands that display selectivity and potency at D1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D1- and D2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D1-like receptor binding, suggesting important differences between the interactions of these ligands with the D1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. PMID:22204903

  7. Rewarding effects of ethanol combined with low doses of morphine through dopamine D1 receptors.

    PubMed

    Ise, Yuya; Mori, Tomohisa; Katayama, Shirou; Nagase, Hiroshi; Suzuki, Tsutomu

    2013-01-01

    This study investigated whether ethanol combined with low doses of morphine produces rewarding effects in rats. Ethanol (0.075-1.2 g/kg, intraperitoneal [i.p.]) alone did not induce place preference. A moderate dose (1 mg/kg, s.c.), but not a low dose (0.1 mg/kg), of morphine induced a significant place preference. The combination of ethanol (0.075-0.6 g/kg, i.p.) and 0.1 mg/kg of morphine, as well as low doses of morphine (0.03-0.1 mg/kg, subcutaneous [s.c.]) combined with ethanol (0.3 g/kg, i.p.), induced a significant place preference. The combined effect of ethanol and morphine was significantly attenuated by naloxone (0.3 mg/kg, s.c.), naltrindole (1.0 mg/kg, s.c.), or long-term administration of the dopamine D1 receptor antagonist SCH23390 (1.0 mg/kg/day, s.c.). These results suggest that the rewarding effect induced by ethanol and a low dose of morphine is mediated by activation of the central opioidergic and dopaminergic systems through dopamine D1 receptors.

  8. Characterization of cytoplasmic cyclin D1 as a marker of invasiveness in cancer

    PubMed Central

    Santacana, Maria; Fernández-Hernández, Rita; Gatius, Sònia; Pedraza, Neus; Pallarés, Judit; Cemeli, Tània; Valls, Joan; Tarres, Marc; Ferrezuelo, Francisco; Dolcet, Xavier; Matias-Guiu, Xavier; Garí, Eloi

    2016-01-01

    Cyclin D1 (Ccnd1) is a proto-oncogen amplified in many different cancers and nuclear accumulation of Ccnd1 is a characteristic of tumor cells. Ccnd1 activates the transcription of a large set of genes involved in cell cycle progress and proliferation. However, Ccnd1 also targets cytoplasmic proteins involved in the regulation of cell migration and invasion. In this work, we have analyzed by immunohistochemistry the localization of Ccnd1 in endometrial, breast, prostate and colon carcinomas with different types of invasion. The number of cells displaying membranous or cytoplasmic Ccnd1 was significantly higher in peripheral cells than in inner cells in both collective and pushing invasion patterns of endometrial carcinoma, and in collective invasion pattern of colon carcinoma. Also, the cytoplasmic localization of Ccnd1 was higher when tumors infiltrated as single cells, budding or small clusters of cells. To evaluate cytoplasmic function of cyclin D1, we have built a variant (Ccnd1-CAAX) that remains attached to the cell membrane therefore sequestering this cyclin in the cytoplasm. Tumor cells harboring Ccnd1-CAAX showed high levels of invasiveness and metastatic potential compared to those containing the wild type allele of Ccnd1. However, Ccnd1-CAAX expression did not alter proliferative rates of tumor cells. We hypothesize that the role of Ccnd1 in the cytoplasm is mainly associated with the invasive capability of tumor cells. Moreover, we propose that subcellular localization of Ccnd1 is an interesting guideline to measure cancer outcome. PMID:27105504

  9. Identification and characterization of major cat allergen Fel d 1 mimotopes on filamentous phage carriers.

    PubMed

    Luzar, Jernej; Molek, Peter; Šilar, Mira; Korošec, Peter; Košnik, Mitja; Štrukelj, Borut; Lunder, Mojca

    2016-03-01

    Cat allergy is one of the most prevalent allergies worldwide and can lead to the development of rhinitis and asthma. Thus far, only allergen extracts from natural sources have been used for allergen-specific immunotherapy. However, extracts and whole allergens in immunotherapy present an anaphylaxis risk. Identification of allergen epitopes or mimotopes has an important role in development of safe and effective allergen-specific immunotherapy. Moreover, with a suitable immunogenic carrier, the absence of sufficient immune response elicited by short peptides could be surmounted. In this study, we identified five structural mimotopes of the major cat allergen Fel d 1 by immunoscreening with random peptide phage libraries. The mimotopes were computationally mapped to the allergen surface, and their IgE reactivity was confirmed using sera from cat-allergic patients. Importantly, the mimotopes showed no basophil activation of the corresponding cat-allergic patients, which makes them good candidates for the development of hypoallergenic vaccine. As bacteriophage particles are becoming increasingly recognized as immunogenic carriers, we constructed bacteriophage particles displaying multiple copies of each selected mimotope on major phage coat protein. These constructed phages elicited T cell-mediated immune response, which was predominated by the type 1 T cell response. Mimotopes alone contributed to the type 1 T cell response by promoting IL-2 production. Fel d 1 mimotopes, as well as their filamentous phage immunogenic carriers, represent promising candidates in the development of hypoallergenic vaccine against cat allergy.

  10. Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide.

    PubMed

    Blattes, Roxane; Monod, Caroline; Susbielle, Guillaume; Cuvier, Olivier; Wu, Jian-hong; Hsieh, Tao-shih; Laemmli, Ulrich K; Käs, Emmanuel

    2006-06-07

    The functions of DNA satellites of centric heterochromatin are difficult to assess with classical molecular biology tools. Using a chemical approach, we demonstrate that synthetic polyamides that specifically target AT-rich satellite repeats of Drosophila melanogaster can be used to study the function of these sequences. The P9 polyamide, which binds the X-chromosome 1.688 g/cm3 satellite III (SAT III), displaces the D1 protein. This displacement in turn results in a selective loss of HP1 and topoisomerase II from SAT III, while these proteins remain bound to the adjacent rDNA repeats and to other regions not targeted by P9. Conversely, targeting of (AAGAG)n satellite V repeats by the P31 polyamide results in the displacement of HP1 from these sequences, indicating that HP1 interactions with chromatin are sensitive to DNA-binding ligands. P9 fed to larvae suppresses the position-effect variegation phenotype of white-mottled adult flies. We propose that this effect is due to displacement of the heterochromatin proteins D1, HP1 and topoisomerase II from SAT III, hence resulting in stochastic chromatin opening and desilencing of the nearby white gene.

  11. Neurochemical abnormalities in unmedicated bipolar depression and mania: a 2D 1H MRS investigation.

    PubMed

    Xu, Jun; Dydak, Ulrike; Harezlak, Jaroslaw; Nixon, Jonathan; Dzemidzic, Mario; Gunn, Abigail D; Karne, Harish S; Anand, Amit

    2013-09-30

    The neurobiology and neurochemistry of bipolar disorder and its different phases are poorly understood. This study investigated metabolite abnormalities in both unmedicated bipolar depression as well as mania using 2D 1H magnetic resonance spectroscopy imaging (MRSI). MRSI data were obtained from 24 unmedicated bipolar disorder (BP) subjects (12 (hypo)manic (BPM)) and 12 depressed (BPD), and 20 closely matched healthy controls. 2D 1H MRSI data were collected from a 15-mm axial slice placed along the anterior commissure-posterior commissure (AC-PC) line to measure brain metabolites bilaterally in the thalamus and also the anterior and posterior cingulate cortex (ACC and PCC). Brain Lac/Cr levels were significantly increased in the BP group as a whole compared to healthy controls. Glutamate abnormalities varied across bipolar state as well as brain region: significantly increased Glx/Cr values were found in the left thalamus in BPD, but BPM had decreased Glu/Cr and Glx/Cr levels in the PCC when compared to healthy controls and decreased Glu/Cr levels even when compared to the BPD subjects group. The findings of the study point to state-related abnormalities of oxidative and glutamate metabolism in bipolar disorder.

  12. Possible role of phosphorylation in the function of chicken MyoD1.

    PubMed

    Nakamura, S

    1993-06-05

    Chicken MyoD1 (CMD1), an equivalent to the mouse MyoD1, expressed in chicken skeletal muscle (Lin, Z.-Y., Dechesne, C. A., Eldridge, J., and Paterson, B. M. (1989) Genes & Dev. 3, 986-996), was produced in Spodoptera frugiperda (Sf9) cells by Baculovirus expression vector and purified to almost homogeneity. This CMD1 was directly demonstrated to be a phosphoprotein by a 32P-labeling experiment. Phosphoamino acid analysis revealed that only serine residue was phosphorylated. Phosphoamino acid of CMD1 from chick primary culture of 11-day embryonic breast muscle was also serine. Electrophoretic mobility on SDS-polyacrylamide gel electrophoresis of the phosphorylated CMD1 produced in Sf9 cells and that obtained from primary culture of muscle were indistinguishable. Gel retardation and methylation interference assays showed that purified CMD1 bound specifically to the mouse muscle creatine kinase enhancer in combination with the in vitro translated E12. CMD1 alone had almost no affinity to the target DNA. When purified CMD1 was treated with calf intestinal phosphatase, its affinity to the target DNA in combination with E12 was reduced by approximately 5-fold. The affinity recovered at least partially by possible rephosphorylation of CMD1 by kinase(s) contained in wheat germ extract. These results suggested that phosphorylation of CMD1 could be involved in the regulation of muscle differentiation.

  13. Subplane-based Control Rod Decusping Techniques for the 2D/1D Method in MPACT

    SciTech Connect

    Graham, Aaron M; Collins, Benjamin S; Downar, Thomas

    2017-01-01

    The MPACT transport code is being jointly developed by Oak Ridge National Laboratory and the University of Michigan to serve as the primary neutron transport code for the Virtual Environment for Reactor Applications Core Simulator. MPACT uses the 2D/1D method to solve the transport equation by decomposing the reactor model into a stack of 2D planes. A fine mesh flux distribution is calculated in each 2D plane using the Method of Characteristics (MOC), then the planes are coupled axially through a 1D NEM-P$_3$ calculation. This iterative calculation is then accelerated using the Coarse Mesh Finite Difference method. One problem that arises frequently when using the 2D/1D method is that of control rod cusping. This occurs when the tip of a control rod falls between the boundaries of an MOC plane, requiring that the rodded and unrodded regions be axially homogenized for the 2D MOC calculations. Performing a volume homogenization does not properly preserve the reaction rates, causing an error known as cusping. The most straightforward way of resolving this problem is by refining the axial mesh, but this can significantly increase the computational expense of the calculation. The other way of resolving the partially inserted rod is through the use of a decusping method. This paper presents new decusping methods implemented in MPACT that can dynamically correct the rod cusping behavior for a variety of problems.

  14. The Protein Elicitor PevD1 Enhances Resistance to Pathogens and Promotes Growth in Arabidopsis

    PubMed Central

    Liu, Mengjie; Khan, Najeeb Ullah; Wang, Ningbo; Yang, Xiufen; Qiu, Dewen

    2016-01-01

    The protein elicitor PevD1, isolated from Verticillium dahlia, could enhance resistance to TMV in tobacco and Verticillium wilt in cotton. Here, the pevd1 gene was over-expressed in wild type (WT) Arabidopsis, and its biological functions were investigated. Our results showed that the transgenic lines were more resistant to Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000 than the WT line was. In transgenic plants, both the germination time and bolting time required were significantly shorter and fresh weights and plant heights were significantly higher than those in the WT line. A transcriptomics study using digital gene expression profiling (DGE) was performed in transgenic and WT Arabidopsis. One hundred and thirty-six differentially expressed genes were identified. In transgenic Arabidopsis, three critical regulators of JA biosynthesis were up-regulated and JA levels were slightly increased. Three important repressors of the ABA-responsive pathway were up-regulated, indicating that ABA signal transduction may be suppressed. One CML and two WRKY TFs involved in Ca2+-responsive pathways were up-regulated, indicating that this pathway may have been triggered. In conclusion, we show that PevD1 is involved in regulating several plant endogenous signal transduction pathways and regulatory networks to enhance resistance and promote growth and development in Arabidopsis. PMID:27489497

  15. Dorsal striatum D1-expressing neurons are involved with sensorimotor gating on prepulse inhibition test.

    PubMed

    Rodrigues, Samanta; Salum, Cristiane; Ferreira, Tatiana L

    2017-04-01

    Prepulse inhibition (PPI) is a behavioral test in which the startle reflex response to a high-intensity stimulus (pulse) is inhibited by the prior presentation of a weak stimulus (prepulse). The classic neural circuitry that mediates startle response is localized in the brainstem; however, recent studies point to the contribution of structures involved in higher cognitive functions in regulating the sensorimotor gating, particularly forebrain regions innervated by dopaminergic nuclei. The aim of the present study was to verify the role of dorsal striatum (DS) and dopaminergic transmitting mediated by D1 and D2 receptors on PPI test in rats. DS inactivation induced by muscimol injection did not affect PPI (%PPI and startle response), although it impaired the locomotor activity and caused catalepsy. Infusion of D1-like antagonist SCH23390 impaired %PPI but did not disturb the startle response and locomotor activity evaluated immediately after PPI test. D2 antagonist microinjection (sulpiride) did not affect %PPI and startle response, but impaired motor activity. These results point to an important role of DS, probably mediated by direct basal ganglia pathway, on modulation of sensorimotor gating, in accordance with clinical studies showing PPI deficits in schizophrenia, Tourette syndrome, and compulsive disorders - pathologies related to basal ganglia dysfunctions.

  16. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis.

    PubMed

    Kuwabara, Tomoko; Hsieh, Jenny; Muotri, Alysson; Yeo, Gene; Warashina, Masaki; Lie, Dieter Chichung; Moore, Lynne; Nakashima, Kinichi; Asashima, Makoto; Gage, Fred H

    2009-09-01

    In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.

  17. PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells

    PubMed Central

    Rehman, Michael; Capparuccia, Lorena

    2016-01-01

    The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays. We found that Notch ligands and constitutively activated intracellular forms of Notch receptors upregulated PlexinD1 expression; conversely RNAi-based knock-down, or pharmacological inhibition of Notch signaling by gamma-secretase inhibitors, downregulated PlexinD1 levels. Notably, both Notch1 and Notch3 expression positively correlates with PlexinD1 levels in prostate cancer, as well as in other tumor types. In prostate cancer cells, Sema3E-PlexinD1 axis was previously reported to regulate migration; however, implicated mechanisms were not elucidated. Here we show that in these cells PlexinD1 activity induces the expression of the transcription factor Slug, downregulates E-cadherin levels and enhances cell migration. Moreover, our mechanistic data identify PlexinD1 as a pivotal mediator of this signaling axis downstream of Notch in prostate cancer cells. In fact, on one hand, PlexinD1 is required to mediate cell migration and E-cadherin regulation elicited by Notch. On the other hand, PlexinD1 upregulation is sufficient to induce prostate cancer cell migration and metastatic potential in mice, leading to functional rescue in the absence of Notch. In sum, our work identifies PlexinD1 as a novel transcriptional target induced by Notch signaling, and reveals its role promoting prostate cancer cell migration and downregulating E-cadherin levels in Slug-dependent manner. Collectively, these findings suggest that

  18. Pharmacological and biochemical characterization of the D-1 dopamine receptor mediating acetylcholine release in rabbit retina

    SciTech Connect

    Hensler, J.G.; Cotterell, D.J.; Dubocovich, M.L.

    1987-12-01

    Superfusion with dopamine (0.1 microM-10 mM) evokes calcium-dependent (/sup 3/H)acetylcholine release from rabbit retina labeled in vitro with (/sup 3/H)choline. This effect is antagonized by the D-1 dopamine receptor antagonist SCH 23390. Activation or blockade of D-2 dopamine, alpha-2 or beta receptors did not stimulate or attenuate the release of (/sup 3/H)acetylcholine from rabbit retina. Dopamine receptor agonists evoke the release of (/sup 3/H)acetylcholine with the following order of potency: apomorphine less than or equal to SKF(R)82526 < SKF 85174 < SKF(R)38393 less than or equal to pergolide less than or equal to dopamine (EC50 = 4.5 microM) < SKF(S)82526 less than or equal to SKF(S)38393. Dopamine receptor antagonists inhibited the dopamine-evoked release of (/sup 3/H)acetylcholine: SCH 23390 (IC50 = 1 nM) < (+)-butaclamol less than or equal to cis-flupenthixol < fluphenazine < perphenazine < trans-flupenthixol < R-sulpiride. The potencies of dopamine receptor agonists and antagonists at the dopamine receptor mediating (/sup 3/H)acetylcholine release is characteristic of the D-1 dopamine receptor. These potencies were correlated with the potencies of dopamine receptor agonists and antagonists at the D-1 dopamine receptor in rabbit retina as labeled by (/sup 3/H)SCH 23390, or as determined by adenylate cyclase activity. (/sup 3/H)SCH 23390 binding in rabbit retinal membranes was stable, saturable and reversible. Scatchard analysis of (/sup 3/H)SCH 23390 saturation data revealed a single high affinity binding site (Kd = 0.175 +/- 0.002 nM) with a maximum binding of 482 +/- 12 fmol/mg of protein. The potencies of dopamine receptor agonists to stimulate (/sup 3/H)acetylcholine release were correlated with their potencies to stimulate adenylate cyclase (r = 0.784, P less than .05, n = 7) and with their affinities at (/sup 3/H)SCH 23390 binding sites (r = 0.755, P < .05, n = 8).

  19. A jumonji (Jarid2) protein complex represses cyclin D1 expression by methylation of histone H3-K9.

    PubMed

    Shirato, Haruki; Ogawa, Satoko; Nakajima, Kuniko; Inagawa, Masayo; Kojima, Mizuyo; Tachibana, Makoto; Shinkai, Yoichi; Takeuchi, Takashi

    2009-01-09

    Covalent modifications of histone tails have critical roles in regulating gene expression. Previously, we identified the jumonji (jmj, Jarid2) gene, the jmjC domain, and a Jmj family. Recently, many Jmj family proteins have been shown to be histone demethylases, and jmjC is the catalytic domain. However, Jmj does not have histone demethylase activity because the jmjC domain lacks conserved residues for binding to cofactors. Independently of these studies, we previously showed that Jmj binds to the cyclin D1 promoter and represses the transcription of cyclin D1. Here, we show the mechanisms by which Jmj represses the transcription of cyclin D1. We found that a protein complex of Jmj had histone methyltransferase activity toward histone H3 lysine 9 (H3-K9). We also found that Jmj bound to the H3-K9 methyltransferases G9a and GLP. Expression of Jmj recruited G9a and GLP to the cyclin D1 promoter and increased H3-K9 methylation. Inactivation of both G9a and GLP, but not of only G9a, inhibited the methylation of H3-K9 in the cyclin D1 promoter and repression of cyclin D1 expression by Jmj. These results suggest that Jmj methylates H3-K9 and represses cyclin D1 expression through G9a and GLP, and that Jmj family proteins can regulate gene expression by not only histone demethylation but also other histone modification.

  20. The role of MIF, cyclinD1 and ERK in the development of pulmonary hypertension in broilers.

    PubMed

    Li, Haoyun; Wang, Yanmei; Chen, Lingli; Han, Lijuan; Li, Lifang; He, Han; Li, Yuan; Huang, Nan; Ren, Hao; Pei, Fangying; Li, Guilan; Cheng, Jia; Wang, Wenkui

    2017-04-01

    Pulmonary hypertension (PH) is a major disease in the broiler breeding industry. During PH, the pulmonary artery undergoes remodelling, which is caused by pulmonary vascular smooth muscle cell proliferation. CyclinD1 regulates cell proliferation. This study investigated the role of cyclinD1 in the development of PH in broilers, and which bioactivators and signalling pathway are involved in the pathological process. The PH group contained 3-4-week-old broilers with clinical PH, and the healthy group broilers from the same flock without PH. Histopathology indicated pulmonary arterial walls were thicker in the PH group compared with the healthy group. Target gene expressions of macrophage migration inhibitory factor (MIF), extracellular signal-regulated kinase (ERK), and cyclinD1 detected by quantitative real-time PCR were upregulated in the PH group compared with the healthy group. Immunohistochemistry showed MIF, phosphorylated ERK (p-ERK) and cyclinD1 were present on pulmonary vascular walls; MIF was present in the cytoplasm of arterial endothelial cells and smooth muscle cells; p-ERK and cyclinD1 were present in smooth muscle cell cytoplasm. Western blotting demonstrated that MIF, p-ERKand cyclinD1 levels were significantly higher (P < 0.01) in the PH group compared with the healthy group. In summary, increased MIF in PH broiler pulmonary arteries upregulated cyclinD1 via the ERK signalling pathway to induce pulmonary vascular smooth muscle cell proliferation, causing pulmonary artery remodelling and hypertension.

  1. Correlation of cyclin D1 expression with aggressive DNA pattern in patients with tobacco-related intraoral squamous cell carcinoma

    PubMed Central

    Das, Satya N.; Khare, Pratima; Singh, Manoj K; Sharma, Suresh C.

    2011-01-01

    Background & objectives: Cyclin D1 has been strongly implicated in cell proliferation particularly in the G1/S checkpoint of the cell cycle, and prognoses in human malignancies. We investigated the correlation between cyclin D1 overexpression and clinicopathological features as well as cell cycle parameters to understand its clinical significance in patients with tobacco-related oral squamous cell carcinoma (OSCC). Methods: Immunohistochemistry for cyclin D1 and DNA flowcytometry for cell cycle parameters was done on paraffin embedded tumour samples from 45 patients with OSCC Results: Higher expression of cyclin D1 was observed only in 30 (66.6%) of 45 cases that correlated with advanced age (P <0.02), higher tumour stage ((P<0.01), histological differentiation and lymph node metastasis (P <0.01). Analysis of nuclear DNA pattern revealed cyclin D1 immunoreactivity in tumours with aggressive DNA pattern such as aneuploidy ((P<0.05) and higher S phase fraction ((P<0.04). Interpretation & conclusions: Higher expression of cyclin D1 in oral cancer appears to be closely linked to cell proliferation, differentiation and lymph node invasion. Pre-operative evaluation of cyclin D1 in biopsy specimen may be useful in planning the most appropriate treatment strategies in patients with tobacco-related OSCC. PMID:21537090

  2. Autoradiography: (/sup 125/I)SCH 23982 binds with picomolar affinity to D1 sites on striatonigral neurons

    SciTech Connect

    Altar, C.A.; Marien, M.R.

    1986-03-01

    SCH 23390 is selective D1 antagonist. The authors show for the first time, with iodinated SCH 23390, (/sup 125/I)SCH 23982, D1 binding sites on striatonigral neurons. Rat brain sections were covered for 1 hr by a pH 7.6 TRIS buffer containing 2-770 pM (/sup 125/I)SCH 23982, rinsed 2 min at 4 /sup 0/C, dried, and exposed to film for 18 hr. (/sup 125/I)SCH 23982 was displaced by D1 (SCH 23390; IC50= 200 pM; cis-flupenthixol, 10 nM; SKF 38393, 90 nM) but not D2 (sulpiride, LY171555) ligands. Intermediate D1 binding was found in the internal capsule and entopeduncular nucleus. Striatal quinolinate (100 nmol) decreased nigral and striatal D1 binding. Intranigral 6-hydroxydopamine (6 ..mu..g) that destroyed > 90% of nigrostriatal dopamine neurons did not alter nigral or striatal D1 binding. Thus, (/sup 125/I)SCH 23982 labels with pM affinity D1 sites that reside on striatonigral neurons.

  3. UGT74D1 Catalyzes the Glucosylation of 2-Oxindole-3-Acetic Acid in the Auxin Metabolic Pathway in Arabidopsis

    PubMed Central

    Tanaka, Keita; Hayashi, Ken-ichiro; Natsume, Masahiro; Kamiya, Yuji; Sakakibara, Hitoshi; Kawaide, Hiroshi; Kasahara, Hiroyuki

    2014-01-01

    IAA is a naturally occurring auxin that plays a crucial role in the regulation of plant growth and development. The endogenous concentration of IAA is spatiotemporally regulated by biosynthesis, transport and its inactivation in plants. Previous studies have shown that the metabolism of IAA to 2-oxindole-3-acetic acid (OxIAA) and OxIAA-glucoside (OxIAA-Glc) may play an important role in IAA homeostasis, but the genes involved in this metabolic pathway are still unknown. In this study, we show that UGT74D1 catalyzes the glucosylation of OxIAA in Arabidopsis. By screening yeasts transformed with Arabidopsis UDP-glycosyltransferase (UGT) genes, we found that OxIAA-Glc accumulates in the culture media of yeasts expressing UGT74D1 in the presence of OxIAA. Further, we showed that UGT74D1 expressed in Escherichia coli converts OxIAA to OxIAA-Glc. The endogenous concentration of OxIAA-Glc decreased by 85% while that of OxIAA increased 2.5-fold in ugt74d1-deficient mutants, indicating the major role of UGT74D1 in OxIAA metabolism. Moreover, the induction of UGT74D1 markedly increased the level of OxIAA-Glc and loss of root gravitropism. These results indicate that UGT74D1 catalyzes a committed step in the OxIAA-dependent IAA metabolic pathway in Arabidopsis. PMID:24285754

  4. Field resistance to Fusarium oxysporum and Verticillium dahliae in transgenic cotton expressing the plant defensin NaD1

    PubMed Central

    Anderson, Marilyn A.

    2014-01-01

    The plant defensin NaD1, from Nicotiana alata, has potent antifungal activity against a range of filamentous fungi including the two important cotton pathogens, Fusarium oxysporum f. sp. vasinfectum (Fov) and Verticillium dahliae. Transgenic cotton plants expressing NaD1 were produced and plants from three events were selected for further characterization. Homozygous plants were assessed in greenhouse bioassays for resistance to Fov. One line (D1) was selected for field trial testing over three growing seasons in soils naturally infested with Fov and over two seasons in soils naturally infested with V. dahliae. In the field trials with Fov-infested soil, line D1 had 2–3-times the survival rate, a higher tolerance to Fov (higher disease rank), and a 2–4-fold increase in lint yield compared to the non-transgenic Coker control. When transgenic line D1 was planted in V. dahliae-infested soil, plants had a higher tolerance to Verticillium wilt and up to a 2-fold increase in lint yield compared to the non-transgenic Coker control. Line D1 did not exhibit any detrimental agronomic features compared to the parent Coker control when plants were grown in non-diseased soil. This study demonstrated that the expression of NaD1 in transgenic cotton plants can provide substantial resistance to two economically important fungal pathogens. PMID:24502957

  5. Dopamine D1 sensitivity in the prefrontal cortex predicts general cognitive abilities and is modulated by working memory training

    PubMed Central

    Wass, Christopher; Pizzo, Alessandro; Sauce, Bruno; Kawasumi, Yushi; Sturzoiu, Tudor; Ree, Fred; Otto, Tim; Matzel, Louis D.

    2013-01-01

    A common source of variance (i.e., “general intelligence”) underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to co-vary with general intelligence, and dopamine D1 signaling in prefrontal cortex can modulate attentional abilities. Based on their aggregate performance across five diverse tests of learning, here we characterized the general cognitive ability (GCA) of CD-1 outbred mice. In response to a D1 agonist (SKF82958, 1 mg/kg), we then assessed the relationship between GCA and activation of D1 receptor (D1R)-containing neurons in the prelimbic region of the medial prefrontal cortex, the agranular insular cortex, and the dorsomedial striatum. Increased activation of D1R-containing neurons in the prelimbic cortex (but not the agranular insular cortex or dorsomedial striatum) was observed in animals of high GCA relative to those of low GCA (quantified by c-Fos activation in response to the D1 agonist). However, a Western blot analysis revealed no differences in the density of D1Rs in the prelimbic cortex between animals of high and low GCA. Last, it was observed that working memory training promoted an increase in animals’ GCA and enhanced D1R-mediated neuronal activation in the prelimbic cortex. These results suggest that the sensitivity (but not density) of D1Rs in the prelimbic cortex may both regulate GCA and be a target for working memory training. PMID:24129098

  6. Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain.

    PubMed

    Bergson, C; Mrzljak, L; Smiley, J F; Pappy, M; Levenson, R; Goldman-Rakic, P S

    1995-12-01

    The pathways governing signal transduction in the mesocortical and nigrostriatal dopamine systems of the brain are of central importance in a variety of drug actions and neurological diseases. We have analyzed the regional, cellular, and subcellular distribution of the closely related D1 and D5 subtypes of dopamine receptors in the cerebral cortex and selected subcortical structures of rhesus monkey using subtype specific antibodies. The distribution of D1 and D5 receptors was highly differentiated in subcortical structures. In the neostriatum, both D1 and to a lesser extent D5 antibodies labeled medium spiny neurons, while only D5 antibodies labeled the large aspiny neurons typical of cholinergic interneurons. In the caudate nucleus, D1 labeling was concentrated in the spines and shafts of projection neurons, whereas D5 antibodies predominantly labeled the shafts, and less commonly, the spines of these cells. The D1 receptor was abundantly expressed in the neuropil of the substantia nigra pars reticulata while the D5 antibodies labeled only a few scattered cell bodies in this structure. Conversely, D5 antibodies labeled cholinergic neurons in the basal forebrain more intensely than D1 antibodies. Within the cerebral cortex and hippocampus, D1 and D5 antibody labeling was prominent in pyramidal cells. Double-label experiments revealed that the two receptors were frequently coexpressed in neurons of both structures. Ultrastructurally, D1 receptors were especially prominent in dendritic spines whereas dendritic shafts were more prominently labeled by the D5 receptor. The anatomical segregation of the D1 and D5 receptors at the subcellular level in cerebral cortex and at the cellular level in subcortical areas suggest that these closely related receptors may be preferentially associated with different circuit elements and may play distinct regulatory roles in synaptic transmission.

  7. Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice.

    PubMed

    Xie, Wanli; Wang, Huiqing; Wang, Lei; Yao, Chengye; Yuan, Ruixia; Wu, Qingping

    2013-09-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary permeability with high mortality. Resolvin D1 (RvD1), which has potent anti-inflammatory and pro-resolving activity, can attenuate pulmonary edema in the animal model of ALI. However, the mechanism underlying the protection of RvD1 on pulmonary edema is still unknown. Here we explore the effects and mechanism of RvD1 on the disruption of tight junction protein that results in the permeability edema in a model of lipopolysaccharide (LPS)-induced ALI. The severity of pulmonary edema was assessed by wet-to-dry rate and Evans blue infiltration; expressions of tight junction (TJ) proteins occludin and zona occludin-1 (ZO-1) were examined by immunofluorescence staining and western blot; mRNA in lung tissue was studied by real time-PCR; the TUNEL kit was performed for the detection of apoptosis of pulmonary barrier. Twenty-four hours after LPS inhalation by mice, wet-to-dry rate and Evans blue infiltration indicated that pretreatment with RvD1 relieved the pulmonary edema and pulmonary capillary permeability. Moreover, RvD1 attenuated the LPS-induced deterioration of TJ protein ZO-1 and occludin significantly. And we found that RvD1 increased heme oxygenase-1 (HO-1) expression contributed to the protection on the deterioration of TJs. In addition, we found that RvD1 could reduce pulmonary cellular apoptosis in LPS-induced mice. In conclusion, RvD1 possesses the ability that relieves the pulmonary edema and restores pulmonary capillary permeability and reduces disruption of TJs in LPS-induced ALI of mice, at least in part, by upregulating HO-1 expression.

  8. The effect of cell passage number on osteogenic and adipogenic characteristics of D1 cells.

    PubMed

    Kwist, K; Bridges, W C; Burg, K J L

    2016-08-01

    Cell line passage number is an important consideration when designing an experiment. At higher passages, it is generally understood that cell health begins to decline and, when this occurs, the result can be variable data. However, there are no specific guidelines regarding optimal passage range, and this information is dependent on cell type. To explore these variabilities, low passage D1 cells were thawed (passage 3) and passaged serially until a much higher number (passage 34). Samples were taken every five passages and analyzed for alkaline phosphatase and triglyceride; also, the gene expression of both adipogenic and osteogenic markers was tested. The results indicate that the growth rate of these cells did slow down after passage 30. However, expression of the osteogenic characteristics seemed to cycle, with the highest levels seen at passage 4 and 24. The adipocyte expression levels remained the same throughout the study.

  9. Complete Genome Sequence of a thermotolerant sporogenic lactic acid bacterium, Bacillus coagulans strain 36D1

    PubMed Central

    Rhee, Mun Su; Moritz, Brélan E.; Xie, Gary; Glavina del Rio, T.; Dalin, E.; Tice, H.; Bruce, D.; Goodwin, L.; Chertkov, O.; Brettin, T.; Han, C.; Detter, C.; Pitluck, S.; Land, Miriam L.; Patel, Milind; Ou, Mark; Harbrucker, Roberta; Ingram, Lonnie O.; Shanmugam, K. T.

    2011-01-01

    Bacillus coagulans is a ubiquitous soil bacterium that grows at 50-55 °C and pH 5.0 and ferments various sugars that constitute plant biomass to L (+)-lactic acid. The ability of this sporogenic lactic acid bacterium to grow at 50-55 °C and pH 5.0 makes this organism an attractive microbial biocatalyst for production of optically pure lactic acid at industrial scale not only from glucose derived from cellulose but also from xylose, a major constituent of hemicellulose. This bacterium is also considered as a potential probiotic. Complete genome sequence of a representative strain, B. coagulans strain 36D1, is presented and discussed. PMID:22675583

  10. Hyper sensitive protein detection by Tandem-HTRF reveals Cyclin D1 dynamics in adult mouse

    PubMed Central

    Zampieri, Alexandre; Champagne, Julien; Auzemery, Baptiste; Fuentes, Ivanna; Maurel, Benjamin; Bienvenu, Frédéric

    2015-01-01

    We present here a novel method for the semi-quantitative detection of low abundance proteins in solution that is both fast and simple. It is based on Homogenous Time Resolved Förster Resonance Energy Transfer (HTRF), between a lanthanide labeled donor antibody and a d2 or XL665 labeled acceptor antibody that are both raised against different epitopes of the same target. This novel approach we termed “Tandem-HTRF”, can specifically reveal rare polypeptides from only a few microliters of cellular lysate within one hour in a 384-well plate format. Using this sensitive approach, we observed surprisingly that the core cell cycle regulator Cyclin D1 is sustained in fully developed adult organs and harbors an unexpected expression pattern affected by environmental challenge. Thus our method, Tandem-HTRF offers a promising way to investigate subtle variations in the dynamics of sparse proteins from limited biological material. PMID:26503526

  11. Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia

    NASA Astrophysics Data System (ADS)

    Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B.; Panayiotou, Richard; Scotti Buzhardt, Michele; Radisky, Derek C.; Crawford, Howard C.; Fields, Alan P.; Murray, Nicole R.; Wang, Q. Jane; Leitges, Michael; Storz, Peter

    2015-02-01

    The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.

  12. Phospholipase D1-regulated autophagy supplies free fatty acids to counter nutrient stress in cancer cells

    PubMed Central

    Cai, Ming; He, Jingquan; Xiong, Jian; Tay, Li Wei Rachel; Wang, Ziqing; Rog, Colin; Wang, Jingshu; Xie, Yizhao; Wang, Guobin; Banno, Yoshiko; Li, Feng; Zhu, Michael; Du, Guangwei

    2016-01-01

    Cancer cells utilize flexible metabolic programs to maintain viability and proliferation under stress conditions including nutrient deprivation. Here we report that phospholipase D1 (PLD1) participates in the regulation of metabolic plasticity in cancer cells. PLD1 activity is required for cancer cell survival during prolonged glucose deprivation. Blocking PLD1 sensitizes cancer cells to glycolysis inhibition by 2-deoxy-D-glucose (2-DG) and results in decreased autophagic flux, enlarged lysosomes, and increased lysosomal pH. Mechanistically, PLD1-regulated autophagy hydrolyzes bulk membrane phospholipids to supply fatty acids (FAs) for oxidation in mitochondria. In low glucose cultures, the blockade of fatty acid oxidation (FAO) by PLD1 inhibition suppresses adenosine triphosphate (ATP) production and increases reactive oxygen species (ROS), leading to cancer cell death. In summary, our findings reveal a novel role of PLD1 in sustaining cancer cell survival during metabolic stress, and suggest PLD1 as a potential target for anticancer metabolism therapy. PMID:27809301

  13. Analysis of ocular torsion data from Space Labs D-1 and SL-1

    NASA Technical Reports Server (NTRS)

    Oman, C. M.

    1990-01-01

    A series of preflight, inflight, and postflight vestibular experiments were conducted on Spacelab missions SL-1 and D-1. Two portions of the investigation, the 'sled' and 'dome' functional objectives, involved recording the torsional motion of human subject's eyes. In the SL-1 sled and dome experiments, preflight and postflight ocular torsion was recorded on 35 mm film using a Nikon motor driven camera (2.6 frames/sec). The film was to be analyzed by measuring the motion of contact lens landmarks using a Hermes senior film scanner. However, an inflight failure of the dome experiment camera flash unit led the crew to utilize the Spacelab video camera as an alternative contingency method for imaging the eye in this FO. A suitable method for analysis of the video data was developed. Results of the analysis are presented.

  14. Generation of Narrow-Band Polarization-Entangled Photon Pairs at a Rubidium D1 Line

    NASA Astrophysics Data System (ADS)

    Tian, Long; Li, Shujing; Yuan, Haoxiang; Wang, Hai

    2016-12-01

    Using the process of cavity-enhanced spontaneous parametric down-conversion (SPDC), we generate a narrow-band polarization-entangled photon pair resonant on the rubidium (Rb) D1 line (795 nm). The degenerate single-mode photon pair is selected by multiple temperature controlled etalons. The linewidth of generated polarization-entangled photon pairs is 15 MHz which matches the typical atomic memory bandwidth. The measured Bell parameter for the polarization-entangled photons S = 2.73 ± 0.04 which violates the Bell-CHSH inequality by ˜18 standard deviations. The presented entangled photon pair source could be utilized in quantum communication and quantum computing based on quantum memories in atomic ensemble.

  15. Smooth non-extremal D1-D5-P solutions as charged gravitational instantons

    NASA Astrophysics Data System (ADS)

    Chakrabarty, Bidisha; Rocha, Jorge V.; Virmani, Amitabh

    2016-08-01

    We present an alternative and more direct construction of the non-super-symmetric D1-D5-P supergravity solutions found by Jejjala, Madden, Ross and Titchener. We show that these solutions — with all three charges and both rotations turned on — can be viewed as a charged version of the Myers-Perry instanton. We present an inverse scattering construction of the Myers-Perry instanton metric in Euclidean five-dimensional gravity. The angular momentum bounds in this construction turn out to be precisely the ones necessary for the smooth microstate geometries. We add charges on the Myers-Perry instanton using appropriate SO(4, 4) hidden symmetry transformations. The full construc-tion can be viewed as an extension and simplification of a previous work by Katsimpouri, Kleinschmidt and Virmani.

  16. Evidence for a unique PTSD construct represented by PTSD's D1-D3 symptoms.

    PubMed

    Elhai, Jon D; Biehn, Tracey L; Armour, Cherie; Klopper, Jessica J; Frueh, B Christopher; Palmieri, Patrick A

    2011-04-01

    Two models of posttraumatic stress disorder (PTSD) have received the most empirical support in confirmatory factor analytic studies: King, Leskin, King, and Weathers' (1998) Emotional Numbing model of reexperiencing, avoidance, emotional numbing and hyperarousal; and Simms, Watson, and Doebbeling's (2002) Dysphoria model of reexperiencing, avoidance, dysphoria and hyperarousal. These models only differ in placement of three PTSD symptoms: sleep problems (D1), irritability (D2), and concentration problems (D3). In the present study, we recruited 252 women victims of domestic violence and tested whether there is empirical support to separate these three PTSD symptoms into a fifth factor, while retaining the Emotional Numbing and Dysphoria models' remaining four factors. Confirmatory factor analytic findings demonstrated that separating the three symptoms into a separate factor significantly enhanced model fit for the Emotional Numbing and Dysphoria models. These three symptoms may represent a unique latent construct. Implications are discussed.

  17. Effect of Bacillus circulans D1 thermostable xylanase on biobleaching of eucalyptus kraft pulp.

    PubMed

    Bocchini, Daniela A; Damiano, Valquiria B; Gomes, Eleni; Da Silva, Roberto

    2003-01-01

    The alkalophilic Bacillus circulans D1 was isolated from decayed wood. It produced high levels of extracellular cellulase-free xylanase. The enzyme was thermally stable up to 60 degrees C, with an optimal hydrolysis temperature of 70 degrees C. It was stable over a wide pH range (5.5-10.5), with an optimum pH at 5.5 and 80% of its activity at pH 9.0. This cellulase-free xylanase preparation was used to biobleach kraft pulp. Enzymatic treatment of kraft pulp decreased chlorine dioxide use by 23 and 37% to obtain the same kappa number (kappa number) and brightness, respectively. Separation on Sephadex G-50 isolated three fractions with xylanase activity with distinct molecular weights.

  18. Mutation scan of the D1 dopamine receptor gene in 22 cases of bipolar I disorder

    SciTech Connect

    Shah, M.; Coon, H.; Holik, J.; Hoff, M.

    1995-04-24

    In a previous study we found suggestive evidence of linkage between manic-depressive illness (MDI) in eight multiplex pedigrees and D5S62, a DNA marker mapping to the telomeric region of 5q. As the D1 dopamine receptor gene (DRDI) maps to this region and as alterations in dopaminergic neurotransmission have been indirectly implicated in the pathogenesis of MDI, we directly searched for mutations in the coding region of the DRDI gene in 22 unrelated cases of bipolar I (BPI) disorder derived from multiplex families. Using single strand conformation polymorphism (SSCP) analysis, we did not observe any abnormal SSCP variants in the BPI cases that differed from controls. 30 refs., 1 fig.

  19. Complete Genome Sequence of a thermotolerant sporogenic lactic acid bacterium, Bacillus coagulans strain 36D1

    SciTech Connect

    Xie, Gary; Dalin, Eileen; Tice, Hope; Chertkov, Olga; Land, Miriam L

    2011-01-01

    Bacillus coagulans is a ubiquitous soil bacterium that grows at 50-55 C and pH 5.0 and fer-ments various sugars that constitute plant biomass to L (+)-lactic acid. The ability of this sporogenic lactic acid bacterium to grow at 50-55 C and pH 5.0 makes this organism an attractive microbial biocatalyst for production of optically pure lactic acid at industrial scale not only from glucose derived from cellulose but also from xylose, a major constituent of hemi-cellulose. This bacterium is also considered as a potential probiotic. Complete genome squence of a representative strain, B. coagulans strain 36D1, is presented and discussed.

  20. Complete Genome Sequence of a thermotolerant sporogenic lactic acid bacterium, Bacillus coagulans strain 36D1

    SciTech Connect

    Rhee, Mun Su; Moritz, Brelan E.; Xie, Gary; Glavina Del Rio, Tijana; Dalin, Eileen; Tice, Hope; Bruce, David; Goodwin, Lynne A.; Chertkov, Olga; Brettin, Thomas S; Han, Cliff; Detter, J. Chris; Pitluck, Sam; Land, Miriam L; Patel, Milind; Ou, Mark; Harbrucker, Roberta; Ingram, Lonnie O.; Shanmugam, Keelnathan T.

    2011-01-01

    Bacillus coagulans is a ubiquitous soil bacterium that grows at 50-55 C and pH 5.0 and fer- ments various sugars that constitute plant biomass to L (+)-lactic acid. The ability of this spo- rogenic lactic acid bacterium to grow at 50-55 C and pH 5.0 makes this organism an attrac- tive microbial biocatalyst for production of optically pure lactic acid at industrial scale not only from glucose derived from cellulose but also from xylose, a major constituent of hemi- cellulose. This bacterium is also considered as a potential probiotic. Complete genome se- quence of a representative strain, B. coagulans strain 36D1, is presented and discussed.

  1. Complete Genome Sequence of a thermotolerant sporogenic lactic acid bacterium, Bacillus coagulans strain 36D1.

    PubMed

    Rhee, Mun Su; Moritz, Brélan E; Xie, Gary; Glavina Del Rio, T; Dalin, E; Tice, H; Bruce, D; Goodwin, L; Chertkov, O; Brettin, T; Han, C; Detter, C; Pitluck, S; Land, Miriam L; Patel, Milind; Ou, Mark; Harbrucker, Roberta; Ingram, Lonnie O; Shanmugam, K T

    2011-12-31

    Bacillus coagulans is a ubiquitous soil bacterium that grows at 50-55 °C and pH 5.0 and ferments various sugars that constitute plant biomass to L (+)-lactic acid. The ability of this sporogenic lactic acid bacterium to grow at 50-55 °C and pH 5.0 makes this organism an attractive microbial biocatalyst for production of optically pure lactic acid at industrial scale not only from glucose derived from cellulose but also from xylose, a major constituent of hemicellulose. This bacterium is also considered as a potential probiotic. Complete genome sequence of a representative strain, B. coagulans strain 36D1, is presented and discussed.

  2. Evidence against a role for dopamine D1 receptors in the myocardium of the pig.

    PubMed Central

    Van Woerkens, L. J.; Duncker, D. J.; Den Boer, M. O.; McFalls, E. O.; Sassen, L. M.; Saxena, P. R.; Verdouw, P. D.

    1991-01-01

    1. We investigated the presence of dopamine D1 receptors in the myocardium of anesthetized pigs using intravenous infusions of dopamine, alone and after alpha- and beta-adrenoceptor blockade and intracoronary infusions of the selective D1 receptor agonist, fenoldopam. 2. Intravenous infusion of dopamine (2.5, 5 and 10 micrograms kg-1 min-1 for 10 min, n = 6) caused dose-dependent changes in heart rate (from 94 +/- 6 to 132 +/- 10 beats min-1, P less than 0.05), the maximal rate of rise of left ventricular pressure (LVdP/dtmax; from 2280 +/- 170 to 4800 +/- 410 mmHgs-1, P less than 0.05), mean arterial blood pressure (from 87 +/- 5 to 62 +/- 3 mmHg) and systemic vascular resistance (from 40 +/- 4 to 28 +/- 2 mmHgl-1 min, P less than 0.05). The increases in heart rate and LVdP/dtmax were abolished when dopamine was infused after alpha- and beta-adrenoceptor blockade. The vasodilator response was, however, only minimally affected. 3. Intravenous infusions of dopamine decreased coronary vascular resistance from 0.90 +/- 0.06 to 0.53 +/- 0.07 mmHg ml-1 min 100 g (P less than 0.05). This action of dopamine was not observed when dopamine was infused after blockade of the alpha- and beta-adrenoceptors. 4. Pretreatment with alpha- and beta-adrenoceptor blockade had no effect or only slightly attenuated the dopamine-induced decrease in vascular resistance of the brain, kidneys, adrenals and small intestine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1686206

  3. SOX2 overexpression affects neural differentiation of human pluripotent NT2/D1 cells.

    PubMed

    Klajn, A; Drakulic, D; Tosic, M; Pavkovic, Z; Schwirtlich, M; Stevanovic, M

    2014-11-01

    SOX2 is one of the key transcription factors involved in maintenance of neural progenitor identity. However, its function during the process of neural differentiation, including phases of lineage-specification and terminal differentiation, is still poorly understood. Considering growing evidence indicating that SOX2 expression level must be tightly controlled for proper neural development, the aim of this research was to analyze the effects of constitutive SOX2 overexpression on outcome of retinoic acid-induced neural differentiation of pluripotent NT2/D1 cells. We demonstrated that in spite of constitutive SOX2 overexpression, NT2/D1 cells were able to reach final phases of neural differentiation yielding both neuronal and glial cells. However, SOX2 overexpression reduced the number of mature MAP2-positive neurons while no difference in the number of GFAP-positive astrocytes was detected. In-depth analysis at single-cell level showed that SOX2 downregulation was in correlation with both neuronal and glial phenotype acquisitions. Interestingly, while in mature neurons SOX2 was completely downregulated, astrocytes with low level of SOX2 expression were detected. Nevertheless, cells with high level of SOX2 expression were incapable of entering in either of two differentiation pathways, neurogenesis or gliogenesis. Accordingly, our results indicate that fine balance between undifferentiated state and neural differentiation depends on SOX2 expression level. Unlike neurons, astrocytes could maintain low level of SOX2 expression after they acquired glial fate. Further studies are needed to determine whether differences in the level of SOX2 expression in GFAP-positive astrocytes are in correlation with their self-renewal capacity, differentiation status, and/or their phenotypic characteristics.

  4. Catalysis of nitrosyl transfer reactions by a dissimilatory nitrite reductase (cytochrome c,d1).

    PubMed

    Kim, C H; Hollocher, T C

    1984-02-25

    The dissimilatory nitrite reductase (cytochrome c,d1) from Pseudomonas aeruginosa was observed at pH 7.5 to catalyze nitrosyl transfer (nitrosation) between [15N]nitrite and several N-nucleophiles or H2 18O, with rate enhancement of the order of 10(8) relative to analogous chemical reactions. The reducing system (ascorbate, N,N,N',N'-tetramethylphenylenediamine) could reduce nitrite (but not NO) enzymatically and had essentially no direct chemical reactivity toward nitrite or NO. The N-nitrosations showed saturation kinetics with respect to the nucleophile and, while exhibiting Vmax values which varied by about 40-fold, nevertheless showed little or no dependence of Vmax on nucleophile pKa. The N-nitrosations and NO-2/H2O-18O exchange required the reducing system, whereas NO/H2O-18O exchange was inhibited by the reducing system. NO was not detected to serve as a nitrosyl donor to N-nucleophiles. These and other kinetic observations suggest that the enzymatic nitrosyl donor is an enzyme-bound species derived from reduced enzyme and one molecule of nitrite, possibly a heme-nitrosyl compound (E-FeII X NO+) for which there is precedence. Nitrosyl transfer to N-nucleophiles may occur within a ternary complex of enzyme, nitrite, and nucleophile. Catalysis of nitrosyl transfer by nitrite reductase represents a new class of enzymatic reactions and may present another example of electrophilic catalysis by a metal center. The nitrosyl donor trapped by these reactions is believed to represent an intermediate in the reduction of nitrite by cytochrome c,d1.

  5. Differential expression of Cyclin D1 in keratin-producing odontogenic cysts

    PubMed Central

    Vera-Sirera, Beatriz; Forner-Navarro, Leopoldo

    2015-01-01

    Objetives: The aim of the present study was to analyze the expression levels of Cyclin D1 (CCD1), a nuclear protein that plays a crucial role in cell cycle progression, in a series of keratin-producing odontogenic cysts. Study Design: A total of 58 keratin-producing odontogenic cysts, diagnosed over ten years and classified according to the WHO 2005 criteria, were immunohistochemically analyzed in terms of CCD1 expression, which was quantified in the basal, suprabasal and intermediate/superficial epithelial compartments. The extent of immunostaining was measured as a proportion of total epithelial thickness. Quantified immunohistochemical data were correlated with clinicopathological features and clinical recurrence. Results: Keratin-producing odontogenic cysts were classified as 6 syndromic keratocystic odontogenic tumors (S-KCOT), 40 sporadic or non-syndromic KCOT (NS-KCOT) and 12 orthokeratinized odontogenic cysts (OOC). Immunohistochemically, CCD1 staining was evident predominantly in the parabasal region of all cystic lesions, but among-lesion differences were apparent, showing a clear expansion of parabasal compartment especially in the S-KCOT, followed to a lesser extent in the NS-KCOT, and being much more reduced in the OOC, which had the greatest average epithelial thickness. Conclusions: The differential expression of CCD1 noted in the present study suggests that dysregulation of cell cycle progression from G1 to the S phase contributes to the different aggressiveness of these lesions. However, CCD1 expression levels did not predict NS-KCOT recurrence, which is likely influenced by factors unrelated to lesion biology. Key words:Keratin-producing odontogenic cyst, keratocyst, keratocystic odontogenic tumor, nevoid basal cell carcinoma syndrome, orthokeratinized odontogenic cyst, cyclin D1, immunohistochemistry. PMID:25475773

  6. Improvement of the 2D/1D Method in MPACT Using the Sub-Plane Scheme

    SciTech Connect

    Graham, Aaron M; Collins, Benjamin S; Downar, Thomas

    2017-01-01

    Oak Ridge National Laboratory and the University of Michigan are jointly developing the MPACTcode to be the primary neutron transport code for the Virtual Environment for Reactor Applications (VERA). To solve the transport equation, MPACT uses the 2D/1D method, which decomposes the problem into a stack of 2D planes that are then coupled with a 1D axial calculation. MPACT uses the Method of Characteristics for the 2D transport calculations and P3 for the 1D axial calculations, then accelerates the solution using the 3D Coarse mesh Finite Dierence (CMFD) method. Increasing the number of 2D MOC planes will increase the accuracy of the alculation, but will increase the computational burden of the calculations and can cause slow convergence or instability. To prevent these problems while maintaining accuracy, the sub-plane scheme has been implemented in MPACT. This method sub-divides the MOC planes into sub-planes, refining the 1D P3 and 3D CMFD calculations without increasing the number of 2D MOC planes. To test the sub-plane scheme, three of the VERA Progression Problems were selected: Problem 3, a single assembly problem; Problem 4, a 3x3 assembly problem with control rods and pyrex burnable poisons; and Problem 5, a quarter core problem. These three problems demonstrated that the sub-plane scheme can accurately produce intra-plane axial flux profiles that preserve the accuracy of the fine mesh solution. The eigenvalue dierences are negligibly small, and dierences in 3D power distributions are less than 0.1% for realistic axial meshes. Furthermore, the convergence behavior with the sub-plane scheme compares favorably with the conventional 2D/1D method, and the computational expense is decreased for all calculations due to the reduction in expensive MOC calculations.

  7. Purification, Characterization, and Overexpression of Flavin Reductase Involved in Dibenzothiophene Desulfurization by Rhodococcus erythropolis D-1

    PubMed Central

    Matsubara, Toshiyuki; Ohshiro, Takashi; Nishina, Yoshihiro; Izumi, Yoshikazu

    2001-01-01

    The dibenzothiophene (DBT)-desulfurizing bacterium, Rhodococcus erythropolis D-1, removes sulfur from DBT to form 2-hydroxybiphenyl using four enzymes, DszC, DszA, DszB, and flavin reductase. In this study, we purified and characterized the flavin reductase from R. erythropolis D-1 grown in a medium containing DBT as the sole source of sulfur. It is conceivable that the enzyme is essential for two monooxygenase (DszC and DszA) reactions in vivo. The purified flavin reductase contains no chromogenic cofactors and was found to have a molecular mass of 86 kDa and four identical 22-kDa subunits. The enzyme catalyzed NADH-dependent reduction of flavin mononucleotide (FMN), and the Km values for NADH and FMN were 208 and 10.8 μM, respectively. Flavin adenine dinucleotide was a poor substrate, and NADPH was inert. The enzyme did not catalyze reduction of any nitroaromatic compound. The optimal temperature and optimal pH for enzyme activity were 35°C and 6.0, respectively, and the enzyme retained 30% of its activity after heat treatment at 80°C for 30 min. The N-terminal amino acid sequence of the purified flavin reductase was identical to that of DszD of R. erythropolis IGTS8 (K. A. Gray, O. S. Pogrebinsky, G. T. Mrachko, L. Xi, D. J. Monticello, and C. H. Squires, Nat. Biotechnol. 14:1705–1709, 1996). The flavin reductase gene was amplified with primers designed by using dszD of R. erythropolis IGTS8, and the enzyme was overexpressed in Escherichia coli. The specific activity in crude extracts of the overexpressed strain was about 275-fold that of the wild-type strain. PMID:11229908

  8. Histaminergic receptors of medial septum and conditioned place preference: D1 dopamine receptor mechanism.

    PubMed

    Zarrindast, Mohammad-Reza; Moghimi, Maryam; Rostami, Parvin; Rezayof, Ameneh

    2006-09-13

    In the present study, the effects of intra-medial septum injections of histamine and/or the histamine H1 or H2 receptor antagonists on the acquisition of conditioned place preference (CPP) in male Wistar rats have been investigated. Our data showed that the conditioning treatments with intra-medial septum injection of different doses of histamine (0.5-15 microg/rat) induced a significant CPP for the drug-associated place. Using a 3-day schedule of conditioning, it was found that the histamine H1 receptor antagonist, pyrilamine (10 and 15 microg/rat, intra-medial septum) also induced a significant place preference. In addition, pyrilamine inhibited the histamine (7.5 microg/rat)-induced place preference. Intra-medial septum administration of the histamine H2 receptor antagonist, ranitidine (5-15 microg/rat) alone or in combination with histamine did not produce a significant place preference or place aversion. On the other hand, intra-medial septum administration of the dopamine D1 receptor antagonist, SCH 233390 (0.5, 0.75 and 1 microg/rat) inhibited the histamine (7.5 microg/rat) or pyrilamine (15 microg/rat)-induced place preference in a dose-dependent manner, but no effect was observed for the dopamine D2 receptor antagonist, sulpiride on the histamine or pyrilamine response. The administration of histamine (2.5-15 microg/rat) or pyrilamine (10 and 15 microg/rat) during acquisition increased locomotor activity of the animals on the testing days. The results suggest that histaminergic receptors of the medial septum may be involved in CPP and thus it is postulated that dopamine D1 receptors may play an important role in this effect.

  9. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine

    PubMed Central

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  10. Sequence variation at the oxygen-evolving centre of photosystem II: a new class of 'rogue' cyanobacterial D1 proteins.

    PubMed

    Murray, James W

    2012-02-01

    Photosystem II is the oxygen-evolving enzyme of photosynthesis. It is a membrane-bound protein-pigment complex. The oxygen is produced at the oxygen-evolving centre (OEC), a Mn(4)CaO(5) metallocluster, which is largely ligated by amino acids of the D1 protein. The OEC-ligating residues are invariant between most cyanobacteria and higher plants. In this study, a new class of cyanobacterial D1 proteins has been identified in which the OEC metal-ligating residues are very different to the consensus. This new class of 'rogue' D1 proteins is associated with diazotrophic cyanobacteria. Their function, activity and origins are discussed.

  11. Hairy cell leukemia with translocation (11;20)(q13;q11) and overexpression of cyclin D1.

    PubMed

    Ishida, F; Kitano, K; Ichikawa, N; Ito, T; Kohara, Y; Taniguchi, T; Motokura, T; Kiyosawa, K

    1999-08-01

    We report on a male Japanese patient with hairy cell leukemia (HCL). A cytogenetic study with lipopolysaccharide stimuli showed a novel translocation (11;20)(q13;q11) in 10% of the analyzed cells. Northern blot analysis and RT-PCR analysis for cyclin D1 revealed the overexpression of cyclin D1, although the southern blot analysis of PRAD1 gene showed no rearrangement. In this particular case, the t(11;20)(q13;q11) might play some role in the oncogenesis of HCL and the overexpression of cyclin D1.

  12. Enhanced antifungal and insect α-amylase inhibitory activities of Alpha-TvD1, a peptide variant of Tephrosia villosa defensin (TvD1) generated through in vitro mutagenesis.

    PubMed

    Vijayan, S; Imani, J; Tanneeru, K; Guruprasad, L; Kogel, K H; Kirti, P B

    2012-02-01

    TvD1 is a small, cationic, and highly stable defensin from the weedy legume, Tephrosia villosa with demonstrated in vitro antifungal activity. We show here peptide modifications in TvD1 that lead to enhanced antifungal activities. Three peptide variants, S32R, D37R, and Alpha-TvD1 (-G-M-T-R-T-) with variations in and around the β2-β3 loop region that imposes the two β-strands, β2 and β3 were generated through in vitro mutagenesis. Alpha-TvD1 exhibited enhanced antifungal activity against the fungal pathogens, Fusarium culmorum and Fusarium oxysporum with respective IC(50) values of 2.5 μM and 3.0 μM, when compared to S32R (<5.0 μM and >5.0 μM), D37R (5.5 μM and 4.5 μM), and the wild type TvD1 (6.5 μM). Because of the enhanced antifungal activity, this variant peptide was characterized further. Growth of F. culmorum in the presence of Alpha-TvD1 showed deformities in hyphal walls and nuclear damage. With respect to the plant pathogenic bacterium, Pseudomonas syringae pv. tomato strain DC3000, both Alpha-TvD1 and the wild type TvD1 showed comparable antibacterial activity. Both wild type TvD1 and Alpha-TvD1 displayed inhibitory activity against the α-amylase of the mealworm beetle, Tenebrio molitor (TMA) with the latter showing enhanced activity. The human salivary as well as barley α-amylase activities were not inhibited even at concentrations of up to 50 μM, which has been predicted to be due to differences in the pocket size and the size of the interacting loops. Present study shows that the variant Alpha-TvD1 exhibits enhanced antifungal as well as insect α-amylase inhibitory activity.

  13. Cloning, molecular characterization, and chromosomal assignment of a gene encoding a second D1 dopamine receptor subtype: differential expression pattern in rat brain compared with the D1A receptor.

    PubMed Central

    Tiberi, M; Jarvie, K R; Silvia, C; Falardeau, P; Gingrich, J A; Godinot, N; Bertrand, L; Yang-Feng, T L; Fremeau, R T; Caron, M G

    1991-01-01

    Multiple D1 dopaminergic receptor subtypes have been postulated on the basis of pharmacological, biochemical, and genetic studies. We describe the isolation and characterization of a rat gene encoding a dopamine receptor that is structurally and functionally similar to the D1 dopamine receptor. The coding region, which is intronless, encodes a protein of 475 amino acids (Mr 52,834) with structural features that are consistent with receptors coupled to guanine nucleotide-binding regulatory proteins. The expressed protein binds dopaminergic ligands and mediates stimulation of adenylyl cyclase with pharmacological properties similar to those of the D1 dopamine receptor. The gene encoding the human homologue of this receptor subtype is located to the short arm of chromosome 4 (4p16.3), the same region as the Huntington disease gene. In striking contrast to the previously cloned D1 receptor, little or no mRNA for the receptor described here was observed in striatum, nucleus accumbens, olfactory tubercle, and frontal cortex. High levels of mRNA for this receptor were found in distinct layers of the hippocampus, the mammillary nuclei, and the anterior pretectal nuclei, brain regions that have been shown to exhibit little or no D1 dopamine receptor binding. On the basis of its properties we propose that this dopamine receptor subtype be called D1B. Images PMID:1831904

  14. Degradation pattern of photosystem II reaction center protein D1 in intact leaves. The major photoinhibition-induced cleavage site in D1 polypeptide is located amino terminally of the DE loop.

    PubMed Central

    Kettunen, R; Tyystjärvi, E; Aro, E M

    1996-01-01

    Photoinhibition-induced degradation of the D1 protein of the photosystem II reaction center was studied in intact pumpkin (Cucurbita pepo L.) leaves. Photoinhibition was observed to cause the cleavage of the D1 protein at two distinct sites. The main cleavage generated an 18-kD N-terminal and a 20-kD C-terminal degradation fragment of the D1 protein. this cleavage site was mapped to be located clearly N terminally of the DE loop. The other, less-frequent cleavage occurred at the DE loop and produced the well-documented 23-kD, N-terminal D1 degradation product. Furthermore, the 23-kD, N-terminal D1 fragment appears to be phosphorylated and can be detected only under severe photoinhibition in vivo. Comparison of the D1 degradation pattern after in vivo photoinhibition to that after in vitro acceptor-side and donor-side photoinhibition, performed with isolated photosystem II core particles, gives indirect evidence in support of donor-side photoinhibition in intact leaves. PMID:8756500

  15. A toxaphene-degrading bacterium related to Enterobacter cloacae, strain D1 isolated from aged contaminated soil in Nicaragua.

    PubMed

    Lacayo-Romero, Martha; Quillaguamán, Jorge; van Bavel, Bert; Mattiasson, Bo

    2005-09-01

    Enterobacter sp. strain D1 is a facultative anaerobic, Gram-negative heterotrophic bacterium isolated from toxaphene-contaminated soil. This organism was identified and characterized through phylogenetic and taxonomic studies. Based on 16S rDNA analysis, the strain D1 was clustered closely with the species Enterobacter cloacae subsp. dissolvens (LMG 2683) and E. cloacae (ATCC 13047T). Strain D1 resembled these E. cloacae strains with respect to various biochemical and nutritional characteristics, but also exhibited differences. Moreover, strain D1 is able to grow and survive with toxaphene supplied in the medium in the range 3-96 mg/L. Amongst the chemical components of toxaphene, octachlorocamphenes, nonachlorobornanes and decachlorobornanes were seen to be rapidly metabolized, although levels of hexachlorocamphenes and heptachlorobornanes were found to be slowly degraded, and subsequently accumulated during the last stage of the cultivation.

  16. Hadronic production of D (2550 ) , D*(2600 ) , D (2750 ) , D1*(2760 ) , and D3*(2760 )

    NASA Astrophysics Data System (ADS)

    Zhao, Ze; Tian, Yu; Zhang, Ailin

    2016-12-01

    Hadronic decays of radially excited 2 D D (2 3D1) , D (2 3D3) , D (2 D2) , and D (2 D2') have been studied in a 3P0 model. All Okubo-Zweig-Iizuka-allowed decay channels of these 2 D D resonances have been given, and relevant decay widths have been calculated. D (2550 ), D*(2600 ), D (2750 ), D1*(2760 ), and D3*(2760 ) can be produced in hadronic decays of D (2 3D1) , D (2 3D3) , D (2 D2), and D (2 D2'). In different assignments, hadronic decay widths and some relevant ratios from the 2 D D resonances to D (2550 ), D*(2600 ), D (2750 ), D1*(2760 ), or D3*(2760 ) final states have been predicted, which may provide more information to identify these resonances in forthcoming experiments.

  17. The Calcium Goes Meow: Effects of Ions and Glycosylation on Fel d 1, the Major Cat Allergen

    PubMed Central

    Pol-Fachin, Laércio; Verli, Hugo

    2015-01-01

    The major cat allergen, Fel d 1, is a structurally complex protein with two N-glycosylation sites that may be filled by different glycoforms. In addition, the protein contains three putative Ca2+ binding sites. Since the impact of these Fel d 1 structure modifications on the protein dynamics, physiology and pathology are not well established, the present work employed computational biology techniques to tackle these issues. While conformational effects brought upon by glycosylation were identified, potentially involved in cavity volume regulation, our results indicate that only the central Ca2+ ion remains coordinated to Fel d 1 in biological solutions, impairing its proposed role in modulating phospholipase A2 activity. As these results increase our understanding of Fel d 1 structural biology, they may offer new support for understanding its physiological role and impact into cat-promoted allergy. PMID:26134118

  18. F5D-1 on ramp with Neil Armstrong preparing to fly a Dyna-Soar simulation

    NASA Technical Reports Server (NTRS)

    1962-01-01

    The Douglas F5D-1 Skylancer being pre-flighted by the pilot while the crew chief prepares to pull the wheel chocks on the 'hot gun' ramp at Edwards Air Force Base, California. The aircraft was one of two prototype F5D-1s obtained by NASA Flight Research Center in 1961. The F5D-1 Skylancer (Bu. No. 142350) had a red and white paint pattern with a NASA identification number of 213 which later became NASA 708. The Douglas F5D-1 Skylancer was built by the Navy as an all-weather fighter interceptor that never made the jump to production. Four test aircraft were developed with the same basic airframe as the Douglas F4D Skyray. With increasing modifications the four aircraft were re-designated F5D-1s before their first flights. Future Astronaut Neil Armstrong was one of the NASA research pilots assigned to support duties for the Dyna-Soar program. In addition to working at the Boeing facility in Washington state, Armstrong also tested the Dyna-Soar launch abort profile using this F5D-1, which had a similar wing shape to the Dyna-Soar. The aircraft arrived at the Flight Research Center on June 15, 1961. After the Dyna-Soar program was cancelled in December 1963, this F5D-1 continued to be used, serving as a flying simulator for the M2-F2 and as a chase plane for lifting-body flights (providing the lifting-body pilot with an extra set of eyes to assist in emergencies and avert potential crashes) This F5D-1 left the Flight Research Center (later designated the Dryden Flight Research Center) on May 19, 1970, and was donated to the Neil A. Armstrong Museum in Wapakoneta, Ohio.

  19. The Nuclear Ribonucleoprotein SmD1 Interplays with Splicing, RNA Quality Control, and Posttranscriptional Gene Silencing in Arabidopsis.

    PubMed

    Elvira-Matelot, Emilie; Bardou, Florian; Ariel, Federico; Jauvion, Vincent; Bouteiller, Nathalie; Le Masson, Ivan; Cao, Jun; Crespi, Martin D; Vaucheret, Hervé

    2016-02-01

    RNA quality control (RQC) eliminates aberrant RNAs based on their atypical structure, whereas posttranscriptional gene silencing (PTGS) eliminates both aberrant and functional RNAs through the sequence-specific action of short interfering RNAs (siRNAs). The Arabidopsis thaliana mutant smd1b was identified in a genetic screen for PTGS deficiency, revealing the involvement of SmD1, a component of the Smith (Sm) complex, in PTGS. The smd1a and smd1b single mutants are viable, but the smd1a smd1b double mutant is embryo-lethal, indicating that SmD1 function is essential. SmD1b resides in nucleoli and nucleoplasmic speckles, colocalizing with the splicing-related factor SR34. Consistent with this, the smd1b mutant exhibits intron retention at certain endogenous mRNAs. SmD1 binds to RNAs transcribed from silenced transgenes but not nonsilenced ones, indicating a direct role in PTGS. Yet, mutations in the RQC factors UPFRAMESHIFT3, EXORIBONUCLEASE2 (XRN2), XRN3, and XRN4 restore PTGS in smd1b, indicating that SmD1 is not essential for but rather facilitates PTGS. Moreover, the smd1b mtr4 double mutant is embryo-lethal, suggesting that SmD1 is essential for mRNA TRANSPORT REGULATOR4-dependent RQC. These results indicate that SmD1 interplays with splicing, RQC, and PTGS. We propose that SmD1 facilitates PTGS by protecting transgene-derived aberrant RNAs from degradation by RQC in the nucleus, allowing sufficient amounts to enter cytoplasmic siRNA bodies to activate PTGS.

  20. Expression and cellular localization of the transcription factor NeuroD1 in the developing and adult rat pineal gland.

    PubMed

    Castro, Analía E; Benitez, Sergio G; Farias Altamirano, Luz E; Savastano, Luis E; Patterson, Sean I; Muñoz, Estela M

    2015-05-01

    Circadian rhythms govern many aspects of mammalian physiology. The daily pattern of melatonin synthesis and secretion is one of the classic examples of circadian oscillations. It is mediated by a class of neuroendocrine cells known as pinealocytes which are not yet fully defined. An established method to evaluate functional and cytological characters is through the expression of lineage-specific transcriptional regulators. NeuroD1 is a basic helix-loop-helix transcription factor involved in the specification and maintenance of both endocrine and neuronal phenotypes. We have previously described developmental and adult regulation of NeuroD1 mRNA in the rodent pineal gland. However, the transcript levels were not influenced by the elimination of sympathetic input, suggesting that any rhythmicity of NeuroD1 might be found downstream of transcription. Here, we describe NeuroD1 protein expression and cellular localization in the rat pineal gland during development and the daily cycle. In embryonic and perinatal stages, protein expression follows the mRNA pattern and is predominantly nuclear. Thereafter, NeuroD1 is mostly found in pinealocyte nuclei in the early part of the night and in cytoplasm during the day, a rhythm maintained into adulthood. Additionally, nocturnal nuclear NeuroD1 levels are reduced after sympathetic disruption, an effect mimicked by the in vivo administration of α- and β-adrenoceptor blockers. NeuroD1 phosphorylation at two sites, Ser(274) and Ser(336) , associates with nuclear localization in pinealocytes. These data suggest that NeuroD1 influences pineal phenotype both during development and adulthood, in an autonomic and phosphorylation-dependent manner.

  1. Evidence for limited D1 and D2 receptor coexpression and colocalization within the dorsal striatum of the neonatal mouse.

    PubMed

    Biezonski, Dominik K; Trifilieff, Pierre; Meszaros, Jozsef; Javitch, Jonathan A; Kellendonk, Christoph

    2015-06-01

    The striatum is the major input nucleus of the basal ganglia involved in reward processing, goal-directed behaviors, habit learning, and motor control. The striatum projects to the basal ganglia output nuclei via the "direct" and "indirect" pathways, which can be distinguished by their projection fields and their opposing effects on behavior. In adult animals, the functional opposition is modulated by the differential actions of D1 and D2 dopamine receptors (D1R, D2R), the expression of which is largely separated between these pathways. To determine whether a similar degree of separation exists earlier in development, we used dual-label immunohistochemistry to map dorsal-striatal D1R and D2R expression at the promoter level in postnatal day 0 (PD0) Drd1a-tdTomato/Drd2-GFP BAC transgenic mice, and at the receptor level by costaining for native D1R and D2R in wildtype (WT) PD0 animals. To assess for potential molecular interactions between D1R and D2R we also employed a recently developed proximity-ligation assay (PLA). Limited coexpression and colocalization of the D1R and D2R proteins was found in clusters of neurons endemic to the "patch" compartment as identified by costaining with tyrosine hydroxylase, but not outside these clusters. Moreover, in contrast to our recent findings where we failed to detect a D1R-D2R PLA signal in the adult striatum, in PD0 striatum we did identify a clear PLA signal for this pair of receptors. This colocalization at close proximity points to a possible role for D1R/D2R-mediated crosstalk in early striatal ontogeny.

  2. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

    PubMed Central

    Ceglia, Ilaria; Lee, Ko-Woon; Cahill, Michael E.; Graves, Steven M.; Dietz, David; Surmeier, Dalton J.; Nestler, Eric J.; Nairn, Angus C.; Kim, Yong

    2017-01-01

    Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses. PMID:28115704

  3. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward.

    PubMed

    Calipari, Erin S; Bagot, Rosemary C; Purushothaman, Immanuel; Davidson, Thomas J; Yorgason, Jordan T; Peña, Catherine J; Walker, Deena M; Pirpinias, Stephen T; Guise, Kevin G; Ramakrishnan, Charu; Deisseroth, Karl; Nestler, Eric J

    2016-03-08

    The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.

  4. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype

    PubMed Central

    Mozos, Ana; Royo, Cristina; Hartmann, Elena; De Jong, Daphne; Baró, Cristina; Valera, Alexandra; Fu, Kai; Weisenburger, Dennis D.; Delabie, Jan; Chuang, Shih-Sung; Jaffe, Elaine S.; Ruiz-Marcellan, Carmen; Dave, Sandeep; Rimsza, Lisa; Braziel, Rita; Gascoyne, Randy D.; Solé, Francisco; López-Guillermo, Armando; Colomer, Dolors; Staudt, Louis M.; Rosenwald, Andreas; Ott, German; Jares, Pedro; Campo, Elias

    2009-01-01

    Background Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors. Design and Methods The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms. Results SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt’s lymphoma but not in any other mature lymphoid neoplasm. SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt’s lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma. Conclusions SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma. PMID:19880778

  5. Enhanced Resolution of Hyperoxic Acute Lung Injury as a result of Aspirin Triggered Resolvin D1 Treatment

    PubMed Central

    Cox, Ruan; Phillips, Oluwakemi; Fukumoto, Jutaro; Fukumoto, Itsuko; Parthasarathy, Prasanna Tamarapu; Arias, Stephen; Cho, Young; Lockey, Richard F.

    2015-01-01

    Acute lung injury (ALI), which presents as acute respiratory failure, is a major clinical problem that requires aggressive care, and patients who require prolonged oxygen exposure are at risk of developing this disease. Although molecular determinants of ALI have been reported, the molecules involved in disease catabasis associated with oxygen toxicity have not been well studied. It has been reported that lung mucosa is rich in omega-3 fatty acid dicosahexanoic acid (DHA), which has antiinflammatory properties. Aspirin-triggered resolvin D1 (AT-RvD1) is a potent proresolution metabolite of DHA that can curb the inflammatory effects in various acute injuries, yet the effect of AT-RvD1 on hyperoxic acute lung injury (HALI) or in the oxygen toxicity setting in general has not been investigated. The effects of AT-RvD1 on HALI were determined for the first time in 8- to 10-week-old C57BL/6 mice that were exposed to hyperoxia (≥95% O2) for 48 hours. Mice were given AT-RvD1 (100 ng) in saline or a saline vehicle for 24 hours in normoxic (≈21% O2) conditions after hyperoxia. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected for analysis associated with proinflammatory signaling and lung inflammation. AT-RvD1 treatment resulted in reduced oxidative stress, increased glutathione production, and significantly decreased tissue inflammation. AT-RvD1 treatment also significantly reduced the lung wet/dry ratio, protein in BAL fluid, and decreased apoptotic and NF-κB signaling. These results show that AT-RvD1 curbs oxygen-induced lung edema, permeability, inflammation, and apoptosis and is thus an effective therapy for prolonged hyperoxia exposure in this murine model. PMID:25647402

  6. The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

    PubMed Central

    Martin, Yvonne Connolly

    2011-01-01

    The novel selective D1 dopaminergic full agonists A-68930, A-77636 were discovered by the synthesis of molecules to probe the bioactive conformation of the partial agonist SKF-38393, by the use of this information to add D1 affinity and selectivity to a screening hit, and by traditional medicinal chemistry exploration of structure-activity relationships. The subsequent design of A-86929 and ABT-413 capitalized on these results, recently disclosed agonists, and traditional medicinal chemistry. PMID:25954518

  7. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward

    PubMed Central

    Calipari, Erin S.; Bagot, Rosemary C.; Purushothaman, Immanuel; Davidson, Thomas J.; Yorgason, Jordan T.; Peña, Catherine J.; Walker, Deena M.; Pirpinias, Stephen T.; Guise, Kevin G.; Ramakrishnan, Charu; Deisseroth, Karl; Nestler, Eric J.

    2016-01-01

    The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context–reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse. PMID:26831103

  8. The HTLV-1 HBZ protein inhibits cyclin D1 expression through interacting with the cellular transcription factor CREB.

    PubMed

    Ma, Yunyun; Zheng, Shangen; Wang, Yuanyuan; Zang, Wenqiao; Li, Min; Wang, Na; Li, Ping; Jin, Jing; Dong, Ziming; Zhao, Guoqiang

    2013-10-01

    Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that can cause adult T-cell leukemia (ATL) and other diseases. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, interacts with several transcription factors and is involved in T cell proliferation, viral gene transcription and cellular transformation. Cyclin D1 is a pivotal regulatory protein involved in cell cycle progression, and its depressed expression correlates with cell cycle prolongation or arrested at the G1/S transition. In our present study, we observed that HBZ expression suppressed cyclin D1 level. To investigate the role of HBZ on cyclin D1 depression, we transduced HBZ with lentivirus vector into 293T cells, CEM cells and Jurkat cells. The results of Western blot, RT-PCR and luciferase assays showed that transcriptional activity of the cyclin D1 promoter was suppressed by the bZIP domain of HBZ (HBZ-bZIP) through cyclic AMP response element (CRE) site. Immunoprecipitation and GST pull-down assays showed the binding of HBZ-bZIP to CRE-binding protein (CREB), which confirmed that the cyclin D1 promoter activity inhibition via the CRE-site was mediated by HBZ-bZIP. The results suggested that HBZ suppressed cyclin D1 transcription through interactions with CREB and along with other viral protein, HBZ may play a causal role for leukemogenesis.

  9. MiR-15b Targets Cyclin D1 to Regulate Proliferation and Apoptosis in Glioma Cells

    PubMed Central

    Sun, Guan; Shi, Lei; Yan, Shushan; Wan, Zhengqiang; Jiang, Nan; Fu, Linshan; Li, Min; Guo, Jun

    2014-01-01

    Aim. To investigate the role and mechanism of miR-15b in the proliferation and apoptosis of glioma. Methods. The miR-15b mimics were transfected into human glioma cells to upregulate the miR-15b expression. Cyclin D1 was determined by both western blotting analysis and luciferase reporter assay. Methylthiazol tetrazolium (MTT) and flow cytometry were employed to detect the cell proliferation, cell cycle, and apoptosis. Results. Overexpression of miR-15b inhibits proliferation by arrested cell cycle progression and induces apoptosis, possibly by directly targeting Cyclin D1. Both luciferase assay and bioinformatics search revealed a putative target site of miR-15b binding to the 3′-UTR of Cyclin D1. Moreover, expression of miR-15b in glioma tissues was found to be inversely correlated with Cyclin D1 expression. Enforced Cyclin D1 could abrogate the miR-15b-mediated cell cycle arrest and apoptosis. Conclusions. Our findings identified that miR-15b may function as a glioma suppressor by targeting the Cyclin D1, which may provide a novel therapeutic strategy for treatment of glioma. PMID:24995320

  10. The impact of catechin and epicatechin, total phenols and PPO activity on the Mal d 1 content in apple fruit.

    PubMed

    Kiewning, Daniela; Wollseifen, Rainer; Schmitz-Eiberger, Michaela

    2013-09-01

    The most important apple allergen in Central Europe and North America is Mal d 1. Apples are a very important source of secondary plant metabolites like polyphenols in human nutrition. It is known that oxidised phenols can bind proteins. These irreversible bindings can lead to a reduced allergenicity. The most important phenols in apple are epicatechin, catechin and their polymeric structures, which have been identified as substrates of the polyphenoloxidase (PPO). The aim of this study was to analyse the influence of naturally occurring catechin and epicatechin contents in apple on the allergenicity of apple fruits. Fruits of the cultivars 'Elstar', 'Diwa' and 'Boskoop' were harvested and stored for 8 and 12 weeks in a cold-chamber at 2 °C. Mal d 1-, catechin-, epicatechin- and total phenol content as well as the activity of PPO were determined. Correlation analysis showed that naturally occurring catechin as well as epicatechin has no impact on the Mal d 1 content of the tested cultivars: correlation coefficient ranged from -0.203 to 0.501 for the correlation between Mal d 1 and catechin. The results further indicated that the activity of PPO is more important than the content of total phenols to reduce the Mal d 1 level. If there is a high PPO activity, Mal d 1 could be reduced even if the total phenol concentration is low.

  11. Protocatechualdehyde possesses anti-cancer activity through downregulating cyclin D1 and HDAC2 in human colorectal cancer cells

    SciTech Connect

    Jeong, Jin Boo; Lee, Seong-Ho

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Protocatechualdehyde (PCA) suppressed cell proliferation and induced apoptosis in human colorectal cancer cells. Black-Right-Pointing-Pointer PCA enhanced transcriptional downregulation of cyclin D1 gene. Black-Right-Pointing-Pointer PCA suppressed HDAC2 expression and activity. Black-Right-Pointing-Pointer These findings suggest that anti-cancer activity of PCA may be mediated by reducing HDAC2-derived cyclin D1 expression. -- Abstract: Protocatechualdehyde (PCA) is a naturally occurring polyphenol found in barley, green cavendish bananas, and grapevine leaves. Although a few studies reported growth-inhibitory activity of PCA in breast and leukemia cancer cells, the underlying mechanisms are still poorly understood. Thus, we performed in vitro study to investigate if treatment of PCA affects cell proliferation and apoptosis in human colorectal cancer cells and define potential mechanisms by which PCA mediates growth arrest and apoptosis of cancer cells. Exposure of PCA to human colorectal cancer cells (HCT116 and SW480 cells) suppressed cell growth and induced apoptosis in dose-dependent manner. PCA decreased cyclin D1 expression in protein and mRNA level and suppressed luciferase activity of cyclin D1 promoter, indicating transcriptional downregulation of cyclin D1 gene by PCA. We also observed that PCA treatment attenuated enzyme activity of histone deacetylase (HDAC) and reduced expression of HDAC2, but not HDAC1. These findings suggest that cell growth inhibition and apoptosis by PCA may be a result of HDAC2-mediated cyclin D1 suppression.

  12. Dopamine D1 agonist R-[11C]SKF 82957: synthesis and in vivo characterization in rats.

    PubMed

    DaSilva, J N; Schwartz, R A; Greenwald, E R; Lourenco, C M; Wilson, A A; Houle, S

    1999-07-01

    The active enantiomer R-SKF 82957 was labeled with 11C by N-[11C]methylation of the full dopamine (D1) agonist R-SKF 81297, using [11C]methyl iodide in the presence of N-ethyldiisopropylamine, in high specific activity, radiochemical purity and yields. Compared with the D1 agonist R/S-[11C]SKF 82957, R-[11C]SKF 82957 showed higher binding in the D1 rich regions, such as striatum and olfactory tubercles (approximately 1.7 times), thereby improving the tissue contrast. R-[11C]SKF 82957 exhibited high in vivo binding selectivity for D1 receptors in rats, because only high doses of D1 competitors, but not D2 or serotonin (5-HT2) blockers, significantly reduced the radioactivity levels in all brain areas. No labeled metabolites were detected in rat brain. These results indicate that R-[11C]SKF 82957 will provide more sensitive measurements of D1 receptors in in vivo studies than the racemic mixture.

  13. Activity of D1/2 Receptor Expressing Neurons in the Nucleus Accumbens Regulates Running, Locomotion, and Food Intake

    PubMed Central

    Zhu, Xianglong; Ottenheimer, David; DiLeone, Ralph J.

    2016-01-01

    While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The nucleus accumbens (NAc) is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure. Specific manipulation of D1 vs. D2 neurons was done in both low expenditure and high expenditure (wheel running) conditions to assess behavioral effects in these different states. Direct control of neural activity was achieved using a designer receptors exclusively activated by designer drugs (DREADD) strategy. Activation of NAc D1 neurons increased food intake, wheel running and locomotor activity. In contrast, activation of D2 neurons in the NAc reduced running and locomotion while D2 neuron inhibition had opposite effects. These results highlight the importance of considering both intake and expenditure in the analysis of D1 and D2 neuronal manipulations. Moreover, the behavioral outcomes from NAc D1 neuronal manipulations depend upon the activity state of the animals (wheel running vs. non-running). The data support and complement the hypothesis of specific NAc dopamine pathways facilitating energy expenditure and suggest a potential strategy for human weight control. PMID:27147989

  14. Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    SciTech Connect

    Meng, Xiangbao; Wang, Min; Sun, Guibo; Ye, Jingxue; Zhou, Yanhui; Dong, Xi; Wang, Tingting; Lu, Shan; Sun, Xiaobo

    2014-08-15

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens or

  15. New, tritium-release assay for 25-hydroxyvitamin D-1. cap alpha. -hydroxylase

    SciTech Connect

    Brown, A.J.; Perlman, K.; DeLuca, H.F.

    1986-05-01

    A new, rapid assay for 25-hydroxyvitamin D (25-OH-D)-1..cap alpha..-hydroxylase has been developed using 25-OH-(1..cap alpha..-/sup 3/H)D/sub 3/ as substrate. This compound was prepared by reduction of 1-oxo-25-hydroxycyclovitamin D/sub 3/ with (/sup 3/H)NaBH/sub 4/, separation of the 1..cap alpha..- and 1..beta..-hydroxy products by HPLC, subsequent treatments with methylsulfonylchloride and lithium aluminum hydride, cycloreversion, and saponification. The 1..cap alpha..- and 1..beta..-tritiated substrates were tested in the solubilized and reconstituted chick 1..cap alpha..-hydroxylase system. After incubation, the reaction mixture was passed through a reversed phase silica cartridge to separate (/sup 3/H)H/sub 2/O from the labeled substrate. The cartridges were then washed with methanol to elute all vitamin D metabolites, and the amount of 1,25-(OH)/sub 2/(/sup 3/H)D/sub 3/ was measured by HPLC. In addition, identical reaction mixtures using 25-OH-(26,27-/sup 3/H)D/sub 3/ as substrate were extracted and analyzed by HPLC for 1,25-(OH)/sub 2/(/sup 3/H)D/sub 3/. Reactions with 25-OH-(1..cap alpha..-/sup 3/H)D/sub 3/ produced (/sup 3/H)H/sub 2/O comparable to the amount of 1,25-(OH)/sub 2/(26,27-/sup 3/H)D/sub 3/ and negligible (/sup 3/H) in 1,25-(OH)/sub 2/D/sub 3/. Conversely, reactions with 25-OH-(1..beta..-/sup 3/H)D/sub 3/ produced negligible (/sup 3/H)H/sub 2/O but produced 1,25-(OH)/sub 2/(/sup 3/H)D/sub 3/ comparable to that from reactions with 25-OH-(26,27-/sup 3/H)D/sub 3/. The results indicate that 1..cap alpha..-hydroxylation specifically displaces the 1..cap alpha..-hydrogen of 25-OH-D/sub 3/ and that the release of the 1..cap alpha..-/sup 3/H provides an accurate measure of vitamin D 1..cap alpha..-hydroxylation.

  16. PKCα TUMOR SUPPRESSION IN THE INTESTINE IS ASSOCIATED WITH TRANSCRIPTIONAL AND TRANSLATIONAL INHIBITION OF CYCLIN D1

    PubMed Central

    Pysz, Marybeth A.; Leontieva, Olga V.; Bateman, Nicholas W.; Uronis, Joshua M.; Curry, Kathryn J.; Threadgill, David W.; Janssen, Klaus-Peter; Robine, Sylvie; Velcich, Anna; Augenlicht, Leonard; Black, Adrian R.; Black, Jennifer D.

    2009-01-01

    Alterations in PKC isozyme expression and aberrant induction of cyclin D1 are early events in intestinal tumorigenesis. Previous studies have identified cyclin D1 as a major target in the antiproliferative effects of PKCα in non-transformed intestinal cells; however, a link between PKC signaling and cyclin D1 in colon cancer remained to be established. The current study further characterized PKC isozyme expression in intestinal neoplasms and explored the consequences of restoring PKCα or PKCδ in a panel of colon carcinoma cell lines. Consistent with patterns of PKC expression in primary tumors, PKCα and δ levels were generally reduced in colon carcinoma cell lines, PKCβII was elevated and PKCε showed variable expression, thus establishing the suitability of these models for analysis of PKC signaling. While colon cancer cells were insensitive to the effects of PKC agonists on cyclin D1 levels, restoration of PKCα downregulated cyclin D1 by two independent mechanisms. PKCα expression consistently (a) reduced steady-state levels of cyclin D1 by a novel transcriptional mechanism not previously seen in non-transformed cells, and (b) re-established the ability of PKC agonists to activate the translational repressor 4E-BP1 and inhibit cyclin D1 translation. In contrast, PKCδ had modest and variable effects on cyclin D1 steady state levels and failed to restore responsiveness to PKC agonists. Notably, PKCα expression blocked anchorage-independent growth in colon cancer cells via a mechanism partially dependent on cyclin D1 deficiency, while PKCδ had only minor effects. Loss of PKCα and effects of its re-expression were independent of the status of the APC/β-catenin signaling pathway or known genetic alterations, indicating that they are a general characteristic of colon tumors. Thus, PKCα is a potent negative regulator of cyclin D1 expression and anchorage-independent cell growth in colon tumor cells, findings that offer important perspectives on the

  17. Cyclin D1 down-regulation is essential for DBC2's tumor suppressor function

    SciTech Connect

    Yoshihara, Takashi; Collado, Denise; Hamaguchi, Masaaki . E-mail: hamaguchi@fordham.edu

    2007-07-13

    The expression of tumor suppressor gene DBC2 causes certain breast cancer cells to stop growing [M. Hamaguchi, J.L. Meth, C. Von Klitzing, W. Wei, D. Esposito, L. Rodgers, T. Walsh, P. Welcsh, M.C. King, M.H. Wigler, DBC2, a candidate for a tumor suppressor gene involved in breast cancer, Proc. Natl. Acad. Sci. USA 99 (2002) 13647-13652]. Recently, DBC2 was found to participate in diverse cellular functions such as protein transport, cytoskeleton regulation, apoptosis, and cell cycle control [V. Siripurapu, J.L. Meth, N. Kobayashi, M. Hamaguchi, DBC2 significantly influences cell cycle, apoptosis, cytoskeleton, and membrane trafficking pathways. J. Mol. Biol. 346 (2005) 83-89]. Its tumor suppression mechanism, however, remains unclear. In this paper, we demonstrate that DBC2 suppresses breast cancer proliferation through down-regulation of Cyclin D1 (CCND1). Additionally, the constitutional overexpression of CCND1 prevented the negative impact of DBC2 expression on their growth. Under a CCND1 promoter, the expression of CCNE1 exhibited the same protective effect. Our results indicate that the down-regulation of CCND1 is an essential step for DBC2's growth suppression of cancer cells. We believe that this discovery contributes to a better understanding of DBC2's tumor suppressor function.

  18. 1D-1D Coulomb drag in a 6 Million Mobility Bi-layer Heterostructure

    NASA Astrophysics Data System (ADS)

    Bilodeau, Simon; Laroche, Dominique; Xia, Jian-Sheng; Lilly, Mike; Reno, John; Pfeiffer, Loren; West, Ken; Gervais, Guillaume

    We report Coulomb drag measurements in vertically-coupled quantum wires. The wires are fabricated in GaAs/AlGaAs bilayer heterostructures grown from two different MBE chambers: one at Sandia National Laboratories (1.2M mobility), and the other at Princeton University (6M mobility). The previously observed positive and negative drag signals are seen in both types of devices, demonstrating the robustness of the result. However, attempts to determine the temperature dependence of the drag signal in the 1D regime proved challenging in the higher mobility heterostructure (Princeton), in part because of difficulties in aligning the wires within the same transverse subband configuration. Nevertheless, this work, performed at the Microkelvin laboratory of the University of Florida, is an important proof-of-concept for future investigations of the temperature dependence of the 1D-1D drag signal down to a few mK. Such an experiment could confirm the Luttinger charge density wave interlocking predicted to occur in the wires. Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under Contract DE-AC04-94AL8500.

  19. Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

    PubMed Central

    Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai-Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki

    2017-01-01

    Dopaminergic signaling plays a critical role in the nervous system, but little is known about its potential role in breast cancer and bone metabolism. A screening of ~1,000 biologically active compounds revealed that a selective agonist of dopamine receptor D1 (DRD1), A77636, inhibited proliferation of 4T1.2 mammary tumor cells as well as MDA-MB-231 breast cancer cells. Herein, we examined the effect of A77636 on bone quality using a mouse model of bone metastasis from mammary tumor. A77636 inhibited migration of cancer cells in a DRD1-dependent fashion and suppressed development of bone-resorbing osteoclasts by downregulating NFATc1 through the elevation of phosphorylation of eIF2α. In the mouse model of bone metastasis, A77636 reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Collectively, we expect that dopaminergic signaling might provide a novel therapeutic target for breast cancer and bone metastasis. PMID:28374823

  20. Isotope shift measurements on the D1 line in francium isotopes at TRIUMF

    NASA Astrophysics Data System (ADS)

    Collister, R.; Tandecki, M.; Gwinner, G.; Behr, J. A.; Pearson, M. R.; Gomez, E.; Aubin, S.; Zhang, J.; Orozco, L. A.

    2013-05-01

    Francium is the heaviest alkali and has no stable isotopes. The longest-lived among them, with half-lives from seconds to a few minutes, are now available in the new Francium Trapping Facility at TRIUMF, Canada, for future weak interaction studies. We present isotope shift measurements on the 7S1 / 2 --> 7P1 / 2 (D 1) transition on three isotopes, 206, 207 and 213 in a magneto-optical trap. The shifts are measured using a c.w. Ti:sapphire laser locked to a stabilized cavity at the mid-point between two hyperfine transitions of the reference isotope 209Fr. Scanning tunable microwave sidebands locate transitions in the other isotopes. In combination with the D 2 isotope shifts, analysis can provide a separation of the field shift, due to a changing nuclear charge radius, and specific mass shift, due to changing electron correlations, in these isotopes. Work supported by NSERC and NRC from Canada, NSF and DOE from USA, CONYACT from Mexico.

  1. Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines.

    PubMed

    Mohanty, Suchismita; Mohanty, Atish; Sandoval, Natalie; Tran, Thai; Bedell, Victoria; Wu, Jun; Scuto, Anna; Murata-Collins, Joyce; Weisenburger, Dennis D; Ngo, Vu N

    2017-03-01

    Elevated cyclin D1 (CCND1) expression levels in mantle cell lymphoma (MCL) are associated with aggressive clinical manifestations related to chemoresistance, but little is known about how this important proto-oncogene contributes to the resistance of MCL. Here, we showed that RNA interference-mediated depletion of CCND1 increased caspase-3 activities and induced apoptosis in the human MCL lines UPN-1 and JEKO-1. In vitro and xenotransplant studies revealed that the toxic effect of CCND1 depletion in MCL cells was likely due to increase in histone H2AX phosphorylation, a DNA damage marker. DNA fiber analysis suggested deregulated replication initiation after CCND1 depletion as a potential cause of DNA damage. Finally, in contrast to depletion or inhibition of cyclin-dependent kinase 4, CCND1 depletion increased chemosensitivity of MCL cells to replication inhibitors hydroxyurea and cytarabine. Our findings have an important implication for CCND1 as a potential therapeutic target in MCL patients who are refractory to standard chemotherapy.

  2. Simultaneous Faraday filtering of the Mollow triplet sidebands with the Cs-D1 clock transition

    PubMed Central

    Portalupi, Simone Luca; Widmann, Matthias; Nawrath, Cornelius; Jetter, Michael; Michler, Peter; Wrachtrup, Jörg; Gerhardt, Ilja

    2016-01-01

    Hybrid quantum systems integrating semiconductor quantum dots (QDs) and atomic vapours become important building blocks for scalable quantum networks due to the complementary strengths of individual parts. QDs provide on-demand single-photon emission with near-unity indistinguishability comprising unprecedented brightness—while atomic vapour systems provide ultra-precise frequency standards and promise long coherence times for the storage of qubits. Spectral filtering is one of the key components for the successful link between QD photons and atoms. Here we present a tailored Faraday anomalous dispersion optical filter based on the caesium-D1 transition for interfacing it with a resonantly pumped QD. The presented Faraday filter enables a narrow-bandwidth (Δω=2π × 1 GHz) simultaneous filtering of both Mollow triplet sidebands. This result opens the way to use QDs as sources of single as well as cascaded photons in photonic quantum networks aligned to the primary frequency standard of the caesium clock transition. PMID:27886194

  3. BCS instability and finite temperature corrections to tachyon mass in intersecting D1-branes

    NASA Astrophysics Data System (ADS)

    Chowdhury, Sudipto Paul; Sarkar, Swarnendu; Sathiapalan, B.

    2014-09-01

    A holographic description of BCS superconductivity is given in [1]. This model was constructed by insertion of a pair of D8-branes on a D4-background. The spectrum of intersecting D8-branes has tachyonic modes indicating an instability which is identified with the BCS instability in superconductors. Our aim is to study the stability of the intersecting branes under finite temperature effects. Many of the technical aspects of this problem are captured by a simpler problem of two intersecting D1-branes on flat background. In the simplified set-up we compute the one-loop finite temperature corrections to the tree-level tachyon mass-squared-squared using the frame-work of SU(2) Yang-Mills theory in (1 + 1)-dimensions. We show that the one-loop two-point functions are ultraviolet finite due to cancellation of ultraviolet divergence between the amplitudes containing bosons and fermions in the loop. The amplitudes are found to be infrared divergent due to the presence of massless fields in the loops. We compute the finite temperature mass-squared correction to all the massless fields and use these temperature dependent masses-squared to compute the tachyonic mass-squared correction. We show numerically the existence of a transition temperature at which the effective mass-squared of the tree-level tachyons becomes zero, thereby stabilizing the brane configuration.

  4. Stimulatory effect of ethanol on libertellenone H biosynthesis by Arctic fungus Eutypella sp. D-1.

    PubMed

    Shen, Chu; Xu, Ning; Gao, Yanyun; Sun, Xiaoyue; Yin, Ying; Cai, Menghao; Zhou, Xiangshan; Zhang, Yuanxing

    2016-02-01

    Libertellenone H (1) was a promising antitumor diterpenoid isolated from Arctic fungus Eutypella sp. D-1, however, its production was very limited. In this study, we investigated the effects of ethanol on cell growth and libertellenone H production. The mycelium in ethanol-feeding cultures was fragmented and dispersed, and the titer of libertellenone H was remarkably increased to 4.88 mg l(-1) in an optimal feeding manner, which was 16.4-fold higher than the control group. To provide an insight into the cell response to ethanol, genes critical to the libertellenone H biosynthesis were successfully cloned and their transcription levels were determined. The results suggested that the gene transcription levels of 3-hydroxy-3-methyl glutaric acyl coenzyme A reductase and geranylgeranyl diphosphate synthase were up-regulated by ethanol stimulation. The results from this study were helpful for further understanding of the ethanol function on diterpenes biosynthesis as well as developing more effective strategies for over-production of these desired secondary metabolites.

  5. Aggregation of LoD 1 building models as an optimization problem

    NASA Astrophysics Data System (ADS)

    Guercke, R.; Götzelmann, T.; Brenner, C.; Sester, M.

    3D city models offered by digital map providers typically consist of several thousands or even millions of individual buildings. Those buildings are usually generated in an automated fashion from high resolution cadastral and remote sensing data and can be very detailed. However, not in every application such a high degree of detail is desirable. One way to remove complexity is to aggregate individual buildings, simplify the ground plan and assign an appropriate average building height. This task is computationally complex because it includes the combinatorial optimization problem of determining which subset of the original set of buildings should best be aggregated to meet the demands of an application. In this article, we introduce approaches to express different aspects of the aggregation of LoD 1 building models in the form of Mixed Integer Programming (MIP) problems. The advantage of this approach is that for linear (and some quadratic) MIP problems, sophisticated software exists to find exact solutions (global optima) with reasonable effort. We also propose two different heuristic approaches based on the region growing strategy and evaluate their potential for optimization by comparing their performance to a MIP-based approach.

  6. A Deconstruction Lattice Description of the D1/D5 Brane World-Volume Gauge Theory

    DOE PAGES

    Giedt, Joel

    2011-01-01

    I genermore » alize the deconstruction lattice formulation of Endres and Kaplan to two-dimensional super-QCD with eight supercharges, denoted by (4,4), and bifundamental matter. I specialize to a particularly interesting (4,4) gauge theory, with gauge group U ( N c ) × U ( N f ) , and U ( N f ) being weakly gauged. It describes the infrared limit of the D1/D5 brane system, which has been studied extensively as an example of the AdS 3 /CFT 2 correspondence. The construction here preserves two supercharges exactly and has a lattice structure quite similar to that which has previously appeared in the deconstruction approach, that is, site, link, and diagonal fields with both the Bose and Fermi statistics. I remark on possible applications of the lattice theory that would test the AdS 3 /CFT 2 correspondence, particularly one that would exploit the recent worldsheet instanton analysis of Chen and Tong.« less

  7. D1 Receptor Activation in the Mushroom Bodies Rescues Sleep Loss Induced Learning Impairments in Drosophila

    PubMed Central

    Seugnet, Laurent; Suzuki, Yasuko; Vine, Lucy; Gottschalk, Laura; Shaw, Paul J

    2008-01-01

    Background Extended wakefulness disrupts acquisition of short term memories in mammals. However, the underlying molecular mechanisms triggered by extended waking and restored by sleep are unknown. Moreover, the neuronal circuits that depend on sleep for optimal learning remain unidentified. Results Learning was evaluated using Aversive Phototaxic Suppression (APS). In this task, flies learn to avoid light that is paired with an aversive stimulus (quinine /humidity). We demonstrate extensive homology in sleep deprivation induced learning impairment between flies and humans. Both 6 h and 12 h of sleep deprivation are sufficient to impair learning in Canton-S (Cs) flies. Moreover, learning is impaired at the end of the normal waking-day in direct correlation with time spent awake. Mechanistic studies indicate that this task requires intact mushroom bodies (MBs) and requires the Dopamine D1-like receptor (dDA1). Importantly, sleep deprivation induced learning impairments could be rescued by targeted gene expression of the dDA1 receptor to the MBs. Conclusion These data provide direct evidence that extended wakefulness disrupts learning in Drosophila. These results demonstrate that it is possible to prevent the effects of sleep deprivation by targeting a single neuronal structure and identify cellular and molecular targets adversely affected by extended waking in a genetically tractable model organism. PMID:18674913

  8. Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect

    PubMed Central

    Hur, Jang Ho; Park, Shi-Young; Dall’Armi, Claudia; Lee, Jae Sung; Di Paolo, Gilbert; Lee, Hui-Young; Yoon, Mee-Sup; Min, Do Sik; Choi, Cheol Soo

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1−/− hepatocytes, with decreased β-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1−/− hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1−/− liver significantly reduced hepatic lipid accumulation, compared with Pld1−/− liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy. PMID:27976696

  9. Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration.

    PubMed

    Teng, Shuzhi; Stegner, David; Chen, Qin; Hongu, Tsunaki; Hasegawa, Hiroshi; Chen, Li; Kanaho, Yasunori; Nieswandt, Bernhard; Frohman, Michael A; Huang, Ping

    2015-02-01

    Myoblast differentiation and fusion is a well-orchestrated multistep process that is essential for skeletal muscle development and regeneration. Phospholipase D1 (PLD1) has been implicated in the initiation of myoblast differentiation in vitro. However, whether PLD1 plays additional roles in myoblast fusion and exerts a function in myogenesis in vivo remains unknown. Here we show that PLD1 expression is up-regulated in myogenic cells during muscle regeneration after cardiotoxin injury and that genetic ablation of PLD1 results in delayed myofiber regeneration. Myoblasts derived from PLD1-null mice or treated with PLD1-specific inhibitor are unable to form mature myotubes, indicating defects in second-phase myoblast fusion. Concomitantly, the PLD1 product phosphatidic acid is transiently detected on the plasma membrane of differentiating myocytes, and its production is inhibited by PLD1 knockdown. Exogenous lysophosphatidylcholine, a key membrane lipid for fusion pore formation, partially rescues fusion defect resulting from PLD1 inhibition. Thus these studies demonstrate a role for PLD1 in myoblast fusion during myogenesis in which PLD1 facilitates the fusion of mononuclear myocytes with nascent myotubes.

  10. Cytoplasmic cyclin D1 regulates cell invasion and metastasis through the phosphorylation of paxillin

    PubMed Central

    Fusté, Noel P.; Fernández-Hernández, Rita; Cemeli, Tània; Mirantes, Cristina; Pedraza, Neus; Rafel, Marta; Torres-Rosell, Jordi; Colomina, Neus; Ferrezuelo, Francisco; Dolcet, Xavier; Garí, Eloi

    2016-01-01

    Cyclin D1 (Ccnd1) together with its binding partner Cdk4 act as a transcriptional regulator to control cell proliferation and migration, and abnormal Ccnd1·Cdk4 expression promotes tumour growth and metastasis. While different nuclear Ccnd1·Cdk4 targets participating in cell proliferation and tissue development have been identified, little is known about how Ccnd1·Cdk4 controls cell adherence and invasion. Here, we show that the focal adhesion component paxillin is a cytoplasmic substrate of Ccnd1·Cdk4. This complex phosphorylates a fraction of paxillin specifically associated to the cell membrane, and promotes Rac1 activation, thereby triggering membrane ruffling and cell invasion in both normal fibroblasts and tumour cells. Our results demonstrate that localization of Ccnd1·Cdk4 to the cytoplasm does not simply act to restrain cell proliferation, but constitutes a functionally relevant mechanism operating under normal and pathological conditions to control cell adhesion, migration and metastasis through activation of a Ccnd1·Cdk4-paxillin-Rac1 axis. PMID:27181366

  11. One-loop transition amplitudes in the D1D5 CFT

    NASA Astrophysics Data System (ADS)

    Carson, Zaq; Hampton, Shaun; Mathur, Samir D.

    2017-01-01

    We consider the issue of thermalization in the D1D5 CFT. Thermalization is expected to correspond to the formation of a black hole in the dual gravity theory. We start from the orbifold point, where the theory is essentially free, and does not thermalize. In earlier work it was noted that there was no clear thermalization effect when the theory was deformed off the orbifold point to first order in the relevant twist perturbation. In this paper we consider the deformation to second order in the twist, where we do find effects that can cause thermalization of an initial perturbation. We consider a 1-loop process where two untwisted copies of the CFT are twisted to one copy and then again untwisted to two copies. We start with a single oscillator excitation on the initial CFT, and compute the effect of the two twists on this state. We find simple approximate expressions for the Bogoliubov coefficients and the behavior of the single oscillator excitation in the continuum limit, where the mode numbers involved are taken to be much larger than unity. We also prove a number of useful relationships valid for processes with an arbitrary number of twist insertions.

  12. Dopamine suppresses persistent network activity via D1-like dopamine receptors in rat medial entorhinal cortex

    PubMed Central

    Mayne, Elizabeth W; Craig, Michael T; McBain, Chris J; Paulsen, Ole

    2013-01-01

    Cortical networks display persistent activity in the form of periods of sustained synchronous depolarizations (‘UP states’) punctuated by periods of relative hyperpolarization (‘DOWN states’), which together form the slow oscillation. UP states are known to be synaptically generated and are sustained by a dynamic balance of excitation and inhibition, with fast ionotropic glutamatergic excitatory and GABAergic inhibitory conductances increasing during the UP state. Previously, work from our group demonstrated that slow metabotropic GABA receptors also play an important role in terminating the UP state, but the effects of other neuromodulators on this network phenomenon have received little attention. Given that persistent activity is a neural correlate of working memory and that signalling through dopamine receptors has been shown to be critical for working memory tasks, we examined whether dopaminergic neurotransmission affected the slow oscillation. Here, using an in vitro model of the slow oscillation in rat medial entorhinal cortex, we showed that dopamine strongly and reversibly suppressed cortical UP states. We showed that this effect was mediated through D1-like and not D2-like dopamine receptors, and we found no evidence that tonic dopaminergic transmission affected UP states in our model. PMID:23336973

  13. Simultaneous Faraday filtering of the Mollow triplet sidebands with the Cs-D1 clock transition.

    PubMed

    Portalupi, Simone Luca; Widmann, Matthias; Nawrath, Cornelius; Jetter, Michael; Michler, Peter; Wrachtrup, Jörg; Gerhardt, Ilja

    2016-11-25

    Hybrid quantum systems integrating semiconductor quantum dots (QDs) and atomic vapours become important building blocks for scalable quantum networks due to the complementary strengths of individual parts. QDs provide on-demand single-photon emission with near-unity indistinguishability comprising unprecedented brightness-while atomic vapour systems provide ultra-precise frequency standards and promise long coherence times for the storage of qubits. Spectral filtering is one of the key components for the successful link between QD photons and atoms. Here we present a tailored Faraday anomalous dispersion optical filter based on the caesium-D1 transition for interfacing it with a resonantly pumped QD. The presented Faraday filter enables a narrow-bandwidth (Δω=2π × 1 GHz) simultaneous filtering of both Mollow triplet sidebands. This result opens the way to use QDs as sources of single as well as cascaded photons in photonic quantum networks aligned to the primary frequency standard of the caesium clock transition.

  14. Prognostic relevance of melanoma antigen D1 expression in colorectal carcinoma

    PubMed Central

    2012-01-01

    Background Melanoma antigen D1 (MAGED1) is a member of the type II melanoma antigen (MAGE) family. The down-regulation of MAGED1 expression has been shown in breast carcinoma cell lines and in glioma stem cells and may play an important role in apoptosis and anti-tumorigenesis. However, there is no report on its clinical role in colorectal cancer (CRC). Methods We examined the expression of MAGED1 by qPCR in colorectal cancer tissues and their adjacent non-tumorous tissues taken from 6 cases and performed Western blotting and IHC analyses. In addition, we analyzed MAGED1 expression in 285 clinicopathologically characterized colorectal cancer patients. Results MAGED1 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues and was associated with clinical stage (p < 0.001), T classification (p = 0.001), N classification (p < 0.001), M classification (p < 0.001) and pathologic differentiation (p = 0.002). Patients with lower MAGED1 expression had a shorter survival time than those with higher MAGED1 expression. Univariate and multivariate analyses indicated that MAGED1 expression was an independent prognostic factors (p < 0.001). Conclusions MAGED1 may serve as a novel prognostic biomarker of human colorectal cancer. PMID:22935435

  15. Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect.

    PubMed

    Hur, Jang Ho; Park, Shi-Young; Dall'Armi, Claudia; Lee, Jae Sung; Di Paolo, Gilbert; Lee, Hui-Young; Yoon, Mee-Sup; Min, Do Sik; Choi, Cheol Soo

    2016-12-15

    Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1(-/-) hepatocytes, with decreased β-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1(-/-) hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1(-/-) liver significantly reduced hepatic lipid accumulation, compared with Pld1(-/-) liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.

  16. Phospholipase D1 decreases type I collagen levels in hepatic stellate cells via induction of autophagy.

    PubMed

    Seo, H-Y; Jang, B-K; Jung, Y-A; Lee, E-J; Kim, H-S; Jeon, J-H; Kim, J-G; Lee, I-K; Kim, M-K; Park, K-G

    2014-06-20

    Hepatic stellate cells (HSCs) are major players in liver fibrogenesis. Accumulating evidence shows that suppression of autophagy plays an important role in the development and progression of liver disease. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA) and choline, was recently shown to modulate autophagy. However, little is known about the effects of PLD1 on the production of type I collagen that characterizes liver fibrosis. Here, we examined whether PLD1 regulates type I collagen levels in HSCs through induction of autophagy. Adenovirus-mediated overexpression of PLD-1 (Ad-PLD1) reduced type I collagen levels in the activated human HSC lines, hTERT and LX2. Overexpression of PLD1 in HSCs led to induction of autophagy as demonstrated by increased LC3-II conversion and formation of LC3 puncta, and decreased p62 abundance. Moreover, inhibiting the induction of autophagy by treating cells with bafilomycin or a small interfering (si)RNA for ATG7 rescued Ad-PLD1-induced suppression of type I collagen accumulation in HSCs. The effects of PLD on type I collagen levels were not related to TGF-β/Smad signaling. Furthermore, treatment of cells with PA induced autophagy and inhibited type I collagen accumulation. The present study indicates that PLD1 plays a role in regulating type I collagen accumulation through induction of autophagy.

  17. Simultaneous Faraday filtering of the Mollow triplet sidebands with the Cs-D1 clock transition

    NASA Astrophysics Data System (ADS)

    Portalupi, Simone Luca; Widmann, Matthias; Nawrath, Cornelius; Jetter, Michael; Michler, Peter; Wrachtrup, Jörg; Gerhardt, Ilja

    2016-11-01

    Hybrid quantum systems integrating semiconductor quantum dots (QDs) and atomic vapours become important building blocks for scalable quantum networks due to the complementary strengths of individual parts. QDs provide on-demand single-photon emission with near-unity indistinguishability comprising unprecedented brightness--while atomic vapour systems provide ultra-precise frequency standards and promise long coherence times for the storage of qubits. Spectral filtering is one of the key components for the successful link between QD photons and atoms. Here we present a tailored Faraday anomalous dispersion optical filter based on the caesium-D1 transition for interfacing it with a resonantly pumped QD. The presented Faraday filter enables a narrow-bandwidth (Δω=2π × 1 GHz) simultaneous filtering of both Mollow triplet sidebands. This result opens the way to use QDs as sources of single as well as cascaded photons in photonic quantum networks aligned to the primary frequency standard of the caesium clock transition.

  18. Xylanase Production by Bacillus circulans D1 Using Maltose as Carbon Source

    NASA Astrophysics Data System (ADS)

    Bocchini, D. A.; Gomes, E.; da Silva, R.

    Bacillus circulans D1 is a good producer of extracellular thermostable xylanase. Xylanase production in different carbon sources was evaluated and the enzyme synthesis was induced by various carbon sources. It was found that d-maltose is the best inducer of the enzyme synthesis (7.05 U/mg dry biomass at 48 h), while d-glucose and d-arabinose lead to the production of basal levels of xylanase. The crude enzyme solution is free of cellulases, even when the microorganism was cultivated in a medium with d-cellobiose. When oat spelt xylan was supplemented with d-glucose, the repressive effect of this sugar on xylanase production was observed at 24 h, only when used at 5.0 g/L, leading to a reduction of 60% on the enzyme production. On the other hand, when the xylan medium was supplemented with d-xylose (3.0 or 5.0 g/L), this effect was more evident (80 and 90% of reduction on the enzyme production, respectively). Unlike that observed in the xylan medium, glucose repressed xylanase production in the maltose medium, leading to a reduction of 55% on the enzyme production at 24 h of cultivation. Xylose, at 1.0 g/L, induced xylanase production on the maltose medium. On this medium, the repressive effect of xylose, at 3.0 or 5.0 g/L, was less expressive when compared to its effect on the xylan medium.

  19. Xylanase production by Bacillus circulans D1 using maltose as carbon source.

    PubMed

    Bocchini, D A; Gomes, E; Da Silva, R

    2008-03-01

    Bacillus circulans D1 is a good producer of extracellular thermostable xylanase. Xylanase production in different carbon sources was evaluated and the enzyme synthesis was induced by various carbon sources. It was found that D-maltose is the best inducer of the enzyme synthesis (7.05 U/mg dry biomass at 48 h), while D-glucose and D-arabinose lead to the production of basal levels of xylanase. The crude enzyme solution is free of cellulases, even when the microorganism was cultivated in a medium with D-cellobiose. When oat spelt xylan was supplemented with D-glucose, the repressive effect of this sugar on xylanase production was observed at 24 h, only when used at 5.0 g/L, leading to a reduction of 60% on the enzyme production. On the other hand, when the xylan medium was supplemented with D-xylose (3.0 or 5.0 g/L), this effect was more evident (80 and 90% of reduction on the enzyme production, respectively). Unlike that observed in the xylan medium, glucose repressed xylanase production in the maltose medium, leading to a reduction of 55% on the enzyme production at 24 h of cultivation. Xylose, at 1.0 g/L, induced xylanase production on the maltose medium. On this medium, the repressive effect of xylose, at 3.0 or 5.0 g/L, was less expressive when compared to its effect on the xylan medium.

  20. D1S80 polymorphism in Amerindians from the Amazon region of Brazil.

    PubMed

    Vallinoto, A C; Cayres-Vallinoto, I M; Zago, M A; Santos, S E; Guerreiro, J F

    1998-06-01

    The allele frequency distribution at the D1S80 locus (pMCT118) was analyzed in five Amerindian tribes from the Brazilian Amazon (Zoé, Awá-Guajá, Urubú-Kaapór, Katuena, and Xikrin of Bacajá) and was compared with distributions described for other worldwide populations. Nine different segregating alleles were identified in a sample of 139 individuals; alleles *18, *25, and *30 predominated in all tribes. Although the tribes are usually characterized by a low within-population diversity, they have a high interpopulational diversity, probably because of genetic drift acting on small isolated populations. Our data are similar to data for other Brazilian Amerindian tribes; these were combined for comparison with other human populations. Brazilian Amerindians are similar to the Pehuenche from Chile and to North American natives. However, the closest similarity was observed between Brazilian Amerindians and Polynesian populations (Samoans), probably reflecting common ancestry. Brazilian Amerindians and Asian populations have some similarities in terms of allele distribution (high frequencies of alleles *18 and *30), but the values of heterozygosity and the number of alleles are higher in Asians. Brazilian Amerindians are also clearly different from Europeans.

  1. Dynamics of H Atom Production from Photodissociation of Acetic Acid-d(1).

    PubMed

    Park, Sung Man; Kwon, Chan Ho; Kim, Hong Lae

    2015-09-10

    Detailed dissociation dynamics of H(D) from acetic acid-d1 (CH3COOD) has been investigated upon electronic excitation to the (1)(n,π*), S1 state at 205 nm by measuring laser-induced fluorescence spectra of the fragment H(D) atoms. In addition, quantum yields for the H(D) atom dissociation channels, CH3COO + D and CH2COOD + H, were measured, which are 0.07 ± 0.03 and 0.17 ± 0.03, respectively. From the Doppler broadened spectra, the center-of-mass translational energy releases into products were obtained. To determine the detailed dissociation dynamics, two-dimensional potential energy surfaces along the reaction coordinate including the coordinate directly coupled to the dissociation coordinate were examined by employing quantum chemical calculations. For the CH3COO + D channel, the coupled coordinate is the dihedral angle of D against the COO plane. The dissociation of D(H) from acetic acid should take place along the triplet surface via surface crossing from the initially excited S1 state. Along the triplet surface, an exit channel barrier exists, which originates from the structural difference between the T1 and the product asymptotes, especially the dihedral angle of D against the COO plane. The observed translational energy releases were successfully estimated by the barrier impulsive model based upon the calculated two-dimensional potential energy surfaces at the B3LYP/cc-pVDZ level of theory.

  2. Non-supersymmetric D1/D5, F/NS5 and closed string tachyon condensation

    NASA Astrophysics Data System (ADS)

    Lu, J. X.; Roy, Shibaji; Wang, Zhao-Long; Wu, Rong-Jun

    2009-09-01

    We construct the intersecting non-supersymmetric (non-susy) D1/D5 solution of type IIB string theory. While, as usual, the solution is charged under an electric two-form and an electric six-form gauge field, it also contains a non-susy chargeless (non-BPS) D0-brane. The S-dual of this solution is the non-susy F/NS5 solution. We show how these solutions nicely interpolate between the corresponding black (or non-extremal) solutions and the Kaluza-Klein (KK) "bubble of nothing" (BON) by continuously changing some parameters characterizing the solutions from one set of values to another. We show, by a time symmetric general bubble initial data analysis, that the final bubbles in these cases are static and stable and the interpolations can be physically interpreted as closed string tachyon condensation. As special cases, we recover the transition of two charge black F-string to BON, considered by Horowitz, and also the transition from AdS 3 black hole to global AdS 3.

  3. Activation of the EGFR/Akt/NF-κB/cyclinD1 survival signaling pathway in human cholesteatoma epithelium.

    PubMed

    Liu, Wei; Yin, Tuanfang; Ren, Jihao; Li, Lihua; Xiao, Zian; Chen, Xing; Xie, Dinghua

    2014-02-01

    Cholesteatoma is a benign keratinizing squamous epithelial lesion characterized by the hyper-proliferation of keratinocytes with abundant production of keratin debris in the middle ear. The epidermal growth factor receptor (EGFR)/Akt/nuclear factor-kappa B (NF-κB)/cyclinD1 signaling pathway is one of the most important pathways in regulating cell survival and proliferation. We hypothesized that the EGFR/Akt/NF-κB/cyclinD1 signaling pathway may be activated and involved in the cellular hyperplasia mechanism in acquired cholesteatoma epithelium. Immunohistochemical staining of phosphorylated EGFR (p-EGFR), phosphorylated Akt (p-Akt), activated NF-κB and cyclinD1 protein was performed in 40 cholesteatoma samples and 20 samples of normal external auditory canal (EAC) epithelium. Protein expression of p-EGFR, p-Akt, activated NF-κB and cyclinD1 in cholesteatoma epithelium was significantly increased when compared with normal EAC epithelium (p < 0.01). In cholesteatoma epithelium, a significant positive association was observed between p-EGFR and p-Akt expression and between the expressions of p-Akt and NF-κB, NF-κB and cyclinD1, respectively (p < 0.01). No significant relationships were observed between the levels of investigated proteins and the degree of bone destruction (p > 0.05). The increased protein expression of p-EGFR, p-Akt, NF-κB and cyclinD1 and their associations in cholesteatoma epithelium suggest that the EGFR/Akt/NF-κB/cyclinD1 survival signaling pathway is active and may be involved in the regulatory mechanisms of cellular hyperplasia in cholesteatoma epithelium.

  4. The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process.

    PubMed

    Baxter, Amy A; Poon, Ivan Kh; Hulett, Mark D

    2017-01-01

    Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigated as potential anticancer agents. The anti-fungal plant defensin from ornamental tobacco, Nicotiana alata Defensin 1 (NaD1), was recently shown to induce necrotic-like cell death in a number of tumor cell types within 30 min of treatment, at a concentration of 10 μM. NaD1-mediated cell killing within these experimental parameters has been shown to occur via binding to the plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) in target cells to facilitate membrane destabilization and subsequent lysis. Whether NaD1 is also capable of inducing apoptosis in tumor cells has not been reported previously. In this study, treatment of MM170 (melanoma) and Jurkat T (leukemia) cells with subacute (<10 μM) concentrations of NaD1 over 6-24 h was investigated to determine whether NaD1 could induce cell death via apoptosis. At subacute concentrations, NaD1 did not efficiently induce membrane permeabilization within 30 min, but markedly reduced cell viability over 24 h. In contrast to other CAPs that have been shown to induce apoptosis through caspase activation, dying cells were not sensitive to a pancaspase inhibitor nor did they display caspase activity or DNA fragmentation over the 24 h treatment time. Furthermore, over the 24 h period, cells exhibited necrotic phenotypes and succumbed to membrane permeabilization. These results indicate that the cytotoxic mechanism of NaD1 at subacute concentrations is membranolytic rather than apoptotic and is also likely to be mediated through a PIP2-targeting cell lytic pathway.

  5. DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1

    PubMed Central

    Sun, Xin; Tang, Shou-Ching; Xu, Chongwen; Wang, Chenguang; Qin, Sida; Du, Ning; Liu, Jian; Zhang, Yiwen; Li, Xiang; Luo, Gang; Zhou, Jie; Xu, Fei; Ren, Hong

    2015-01-01

    Let-7 miRNAs act as tumour suppressors by directly binding to the 3′UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response. PMID:25702703

  6. The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process

    PubMed Central

    Baxter, Amy A; Poon, Ivan KH; Hulett, Mark D

    2017-01-01

    Cationic anti-microbial peptides (CAPs) have an important role in host innate defense against pathogens such as bacteria and fungi. Many CAPs including defensins also exhibit selective cytotoxic activity towards mammalian cells via both apoptotic and non-apoptotic processes, and are being investigated as potential anticancer agents. The anti-fungal plant defensin from ornamental tobacco, Nicotiana alata Defensin 1 (NaD1), was recently shown to induce necrotic-like cell death in a number of tumor cell types within 30 min of treatment, at a concentration of 10 μM. NaD1-mediated cell killing within these experimental parameters has been shown to occur via binding to the plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) in target cells to facilitate membrane destabilization and subsequent lysis. Whether NaD1 is also capable of inducing apoptosis in tumor cells has not been reported previously. In this study, treatment of MM170 (melanoma) and Jurkat T (leukemia) cells with subacute (<10 μM) concentrations of NaD1 over 6–24 h was investigated to determine whether NaD1 could induce cell death via apoptosis. At subacute concentrations, NaD1 did not efficiently induce membrane permeabilization within 30 min, but markedly reduced cell viability over 24 h. In contrast to other CAPs that have been shown to induce apoptosis through caspase activation, dying cells were not sensitive to a pancaspase inhibitor nor did they display caspase activity or DNA fragmentation over the 24 h treatment time. Furthermore, over the 24 h period, cells exhibited necrotic phenotypes and succumbed to membrane permeabilization. These results indicate that the cytotoxic mechanism of NaD1 at subacute concentrations is membranolytic rather than apoptotic and is also likely to be mediated through a PIP2-targeting cell lytic pathway. PMID:28179997

  7. Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis

    PubMed Central

    Fussbroich, Daniela; Mueller, Klaus; Serve, Friederike; Smaczny, Christina; Zielen, Stefan; Schubert, Ralf

    2017-01-01

    Background Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects multiple organs, including the lungs, pancreas, liver and intestine. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) locus lead to defective proteins and reduced Cl- secretion and Na+ hyperabsorption in the affected organs. In addition, patients suffering from CF display chronic inflammation that contributes to the pathogenesis of CF. Recent work suggests that CF patients have a reduced capacity to biosynthesize specialized pro-resolving lipid mediators (SPMs), which contributes to the development and duration of the unwanted inflammation. Alterations in the metabolism of arachidonic acid (AA) and docosahexaenoic acid (DHA) to specialized pro-resolving mediators (SPMs), like lipoxins (LXs), maresins (MaRs), protectins (PDs) and resolvins (Rvs), may play a major role on clinical impact of airway inflammation in CF. Methods In this study, our aims were to detect and quantitate Resolvin D1 (RvD1) in sputum and plasma from patients with CF and compare levels of RvD1 with biomarkers of inflammation and lung function. We studied 27 CF patients aged 6 to 55 years (median 16 years) in a prospective approach. Results DHA can be found in the plasma of our CF patients in the milligram range and is decreased in comparison to a healthy control group. The DHA-derived pro-resolving mediator Resolvin D1 (RvD1) was also present in the plasma (286.4 ± 50 pg/ mL, mean ± SEM) and sputum (30.0 ± 2.6 pg/ mL, mean ± SEM) samples from our patients with CF and showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations. Interestingly, sputum RvD1/ IL-8 levels showed a positive correlation with FEV1 (rs = 0.3962, p< 0.05). Conclusions SPMs, like RvD1, are well known to down-regulate inflammatory pathways. Our study shows that the bioactive lipid mediator RvD1, derived from DHA, was

  8. Anti-inflammatory effects of resolvin-D1 on human corneal epithelial cells: in vitro study

    PubMed Central

    2014-01-01

    Background This study evaluated the anti-inflammatory effects of Resolvin-D1 (RV-D1) and its mechanism of action in human corneal epithelial (HCE) cells. Methods HCE cells were incubated with different concentrations of RV-D1 for different time periods. Oleic acid (OA) and Dexamethasone (DM) served as negative and positive controls, respectively. Cells were stimulated with polyriboinosinic:polyribocytidylic acids (poly I:C). The protein contents and mRNA expression levels of Tumor necrosis factor-α (TNF-α), Interleukin (IL)-6, IL-1β and IL-8 were evaluated with multiplex fluorescent bead immunoassay (FBI) and real time-PCR, respectively. In addition, the expression of inhibitory factor-κBα (I-κBα) was evaluated with real time-PCR. Results The protein level of pro-inflammatory cytokines TNF-α, IL-6, IL-1β and IL-8 significantly increased after stimulation with Poly I:C. RV-D1 treatment at concentration of 1 μM decreased the protein level of TNF-α to 20.76 ± 9.3% (P < 0.05), IL-6 to 43.54 ± 14.16% (P < 0.001), IL-1β to 46.73 ± 15.93% (P > 0.05) and IL-8 to 51.15 ± 13.01% (P < 0.05) compared with cells stimulated with poly I:C alone. Similarly, the mRNA levels of TNF-α, IL-6, IL-1β and IL-8 were significantly reduced after treatment with RV-D1. A highly significant dose response curve was demonstrated for RV-D1 treated HCE cells for TNF-α and IL-1β. DM treatment decreased the protein content for all of the pro-inflammatory cytokines, similar results were demonstrated at the mRNA level. The anti-inflammatory effects of RV-D1 were similar to those of DM for TNF-α, IL-6 and IL-8. Conclusions RV-D1 may serve as a potent anti-inflammatory agent in ocular surface inflammation, as evaluated in cultured HCE cells. The anti-inflammatory effects of RV-D1 were comparable to those of DM, and were mediated through nuclear factor kappa B (NF-κB) signal transduction. PMID:24580770

  9. Synergistic effects of AKAP95, Cyclin D1, Cyclin E1, and Cx43 in the development of rectal cancer

    PubMed Central

    Qi, Fengjie; Yuan, Yangyang; Zhi, Xuehong; Huang, Qian; Chen, Yuexin; Zhuang, Wenxin; Zhang, Dengcheng; Teng, Bogang; Kong, Xiangyu; Zhang, Yongxing

    2015-01-01

    Objective: To explore the expression of A-kinase anchor protein 95 (AKAP95), Cyclin D1, Cyclin E1, and Connexin43 (Cx43) in rectal cancer tissues and assess the associations between each of the proteins and pathological parameters, as well as their inter-relationships. Methods: AKAP95, Cyclin D1, Cyclin E1, and Cx43 protein expression rates were evaluated by immunohistochemistry in 50 rectal cancer specimens and 16 pericarcinoma tissues. Results: The positive rates of AKAP95, Cyclin E1, and Cyclin D1 proteins were 54.00 vs. 18.75%, 62.00 vs. 6.25%, and 72.00 vs. 31.25% in rectal cancer specimens and pericarcinoma tissues, respectively, representing statistically significant differences (P < 0.05). The positive rate of Cx43 protein expression in rectal cancer tissues was 44.00% and 62.50% in pericarcinoma tissues, and the difference between them was not significant (P > 0.05). No significant associations were found between protein expression of AKAP95, Cyclin E1, Cyclin D1, and Cx43, and the degree of differentiation, histological type, and lymph node metastasis of rectal cancer (P > 0.05). However, significant correlations were obtained between the expression rates of AKAP95 and Cyclin E1, Cyclin E1 and Cyclin D1, Cyclin E1 and Cx43 protein, and Cyclin D1 and Cx43, respectively (P < 0.05). Conclusion: AKAP95, Cyclin E1, and Cyclin D1 protein expression rates were significantly higher in rectal cancer tissues compared with pericarcinoma samples, suggesting an association between these proteins and the development and progression of rectal cancer. In addition, the significant correlations between the proteins (AKAP95 and Cyclin E1, Cyclin E1 and Cyclin D1, Cyclin E1 and Cx43 protein, and Cyclin D1 and Cx43) indicate the possible synergistic effects of these factors in the development and progression of rectal cancer. PMID:25973052

  10. MicroRNA-193b Represses Cell Proliferation and Regulates Cyclin D1 in Melanoma

    PubMed Central

    Chen, Jiamin; Feilotter, Harriet E.; Paré, Geneviève C.; Zhang, Xiao; Pemberton, Joshua G.W.; Garady, Cherif; Lai, Dulcie; Yang, Xiaolong; Tron, Victor A.

    2010-01-01

    Cutaneous melanoma is an aggressive form of human skin cancer characterized by high metastatic potential and poor prognosis. To better understand the role of microRNAs (miRNAs) in melanoma, the expression of 470 miRNAs was profiled in tissue samples from benign nevi and metastatic melanomas. We identified 31 miRNAs that were differentially expressed (13 up-regulated and 18 down-regulated) in metastatic melanomas relative to benign nevi. Notably, miR-193b was significantly down-regulated in the melanoma tissues examined. To understand the role of miR-193b in melanoma, functional studies were undertaken. Overexpression of miR-193b in melanoma cell lines repressed cell proliferation. Gene expression profiling identified 314 genes down-regulated by overexpression of miR-193b in Malme-3M cells. Eighteen of these down-regulated genes, including cyclin D1 (CCND1), were also identified as putative miR-193b targets by TargetScan. Overexpression of miR-193b in Malme-3M cells down-regulated CCND1 mRNA and protein by ≥50%. A luciferase reporter assay confirmed that miR-193b directly regulates CCND1 by binding to the 3′untranslated region of CCND1 mRNA. These studies indicate that miR-193b represses cell proliferation and regulates CCND1 expression and suggest that dysregulation of miR-193b may play an important role in melanoma development. PMID:20304954

  11. Hippocampal Neuro-Networks and Dendritic Spine Perturbations in Epileptogenesis Are Attenuated by Neuroprotectin D1

    PubMed Central

    Musto, Alberto E.; Walker, Chelsey P.; Petasis, Nicos A.; Bazan, Nicolas G.

    2015-01-01

    Purpose Limbic epileptogenesis triggers molecular and cellular events that foster the establishment of aberrant neuronal networks that, in turn, contribute to temporal lobe epilepsy (TLE). Here we have examined hippocampal neuronal network activities in the pilocarpine post-status epilepticus model of limbic epileptogenesis and asked whether or not the docosahexaenoic acid (DHA)-derived lipid mediator, neuroprotectin D1 (NPD1), modulates epileptogenesis. Methods Status epilepticus (SE) was induced by intraperitoneal administration of pilocarpine in adult male C57BL/6 mice. To evaluate simultaneous hippocampal neuronal networks, local field potentials were recorded from multi-microelectrode arrays (silicon probe) chronically implanted in the dorsal hippocampus. NPD1 (570 μg/kg) or vehicle was administered intraperitoneally daily for five consecutive days 24 hours after termination of SE. Seizures and epileptiform activity were analyzed in freely-moving control and treated mice during epileptogenesis and epileptic periods. Then hippocampal dendritic spines were evaluated using Golgi-staining. Results We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis. These aberrant activities were attenuated following systemic NPD1 administration, with concomitant hippocampal dendritic spine protection. Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures. Conclusions Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis. Insight into the molecular signaling mediated by neuroprotective bioactivity of NPD1 on neuronal network dysfunction may contribute to the development of anti-epileptogenic therapeutic strategies. PMID:25617763

  12. Molecular characterization, expression profile, and polymorphism of goose dopamine D1 receptor gene.

    PubMed

    Wang, Cui; Liu, Yi; Wang, Huiying; Wu, Huali; Gong, Shaoming; He, Daqian

    2014-05-01

    Dopamine D1 receptor (DRD1) is one of the dopamine receptors with seven transmembrane domains that are coupled to the G protein. In the present study, we cloned the full coding region of DRD1 gene by the reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends from the goose hypothalamus tissues. Results showed that the goose DRD1 cDNA (GenBank: KF156790) contained a 1,356 bp open reading frame encoding a protein 452 amino acid with a molecular weight of 50.52 kDa and a isoelectric point of 6.96. Bioinformatics analysis indicated that the deduced amino acid sequence was 71-98% identical to the DRD1 protein of other species, contained seven transmembrane domains and four N-glycosylation sites. A phylogenetic tree analysis revealed that the deduced goose DRD1 protein had a close genetic relationship and evolutional distance with that of duck, chicken, and zebra finch. The semi-quantitative RT-PCR analysis displayed goose DRD1 gene was widely expressed in all detected tissues, including heart, lung, liver, spleen, kidney, breast muscle, duodenum, sebum, pituitary, hypothalamus, ovary and oviduct. Eighteen single nucleotide polymorphisms were indentified in 3,169 bp length of this gene. For G90A mutation, the genotyping analysis of PCR-TspRI-RFLP showed the allele G was in dominance in all detected goose breeds, and the allele frequencies of this polymorphism were significantly different between Chinese goose breeds and foreign breeds (P<0.01). These findings will help us understand the functions of the DRD1 gene and the molecular breeding in geese.

  13. Characterization of the mmsAB-araD1 (gguABC) genes of Agrobacterium tumefaciens.

    PubMed

    Zhao, Jinlei; Binns, Andrew N

    2011-12-01

    The chvE-gguABC operon plays a critical role in both virulence and sugar utilization through the activities of the periplasmic ChvE protein, which binds to a variety of sugars. The roles of the GguA, GguB, and GguC are not known. While GguA and GguB are homologous to bacterial ABC transporters, earlier genetic analysis indicated that they were not necessary for utilization of sugars as the sole carbon source. To further examine this issue, in-frame deletions were constructed separately for each of the three genes. Our growth analysis clearly indicated that GguA and GguB play a role in sugar utilization and strongly suggests that GguAB constitute an ABC transporter with a wide range of substrates, including L-arabinose, D-fucose, D-galactose, D-glucose, and D-xylose. Site-directed mutagenesis showed that a Walker A motif was vital to the function of GguA. We therefore propose renaming gguAB as mmsAB, for multiple monosaccharide transport. A gguC deletion affected growth only on L-arabinose medium, suggesting that gguC encodes an enzyme specific to L-arabinose metabolism, and this gene was renamed araD1. Results from bioinformatics and experimental analyses indicate that Agrobacterium tumefaciens uses a pathway involving nonphosphorylated intermediates to catabolize L-arabinose via an L-arabinose dehydrogenase, AraA(At), encoded at the Atu1113 locus.

  14. Integrated Power and Attitude Control System Demonstrated With Flywheels G2 and D1

    NASA Technical Reports Server (NTRS)

    Jansen, Ralph H.

    2005-01-01

    On September 14, 2004, NASA Glenn Research Center's Flywheel Development Team experimentally demonstrated a full-power, high-speed, two-flywheel system, simultaneously regulating a power bus and providing a commanded output torque. Operation- and power-mode transitions were demonstrated up to 2000 W in charge and 1100 W in discharge, while the output torque was simultaneously regulated between plus or minus 0.8 N-m. The G2 and D1 flywheels--magnetically levitated carbon-fiber wheels with permanent magnet motors--were used for the experiment. The units were mounted on an air bearing table in Glenn's High Energy Flywheel Facility. The operational speed range for these tests was between 20,000 and 60,000 rpm. The bus voltage was regulated at 125 V during charge and discharge, and charge-discharge and discharge-charge transitions were demonstrated by changing the amount of power that the power supply provided between 300 and 0 W. In a satellite system, this would be the equivalent of changing the amount of energy that the solar array provides to the spacecraft. In addition to regulating the bus voltage, we simultaneously controlled the net torque produced by the two flywheel modules. Both modules were mounted on an air table that was restrained by a load cell. The load cell measured the force on the table, and the torque produced by the two flywheels on the table could be calculated from that measurement. This method was used to measure the torque produced by the modules, yielding net torques from -0.8 to 0.8 N-m. This was the first Glenn demonstration of the Integrated Power and Attitude Control System (IPACS) at high power levels and speeds.

  15. Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits

    PubMed Central

    Fung, Maple M.; Rana, Brinda K.; Tang, Chih-Min; Shiina, Tetsuo; Nievergelt, Caroline M.; Rao, Fangwen; Salem, Rany M.; Waalen, Jill; Ziegler, Michael G.; Insel, Paul A.; O'Connor, Daniel T.

    2009-01-01

    Because dopamine D1 receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5′-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5′-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease. PMID:19675531

  16. Isoelectrophoretic characterization of Pseudomonas cytochrome oxidase/nitrite reductase and its heme d1-containing domain.

    PubMed

    Hull, H H; Wharton, D C

    1993-02-15

    The cytochrome oxidase/nitrite reductase of Pseudomonas aeruginosa has been purified to homogeneity as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When this "homogeneous" protein is subjected to electrophoretic titration curve analysis in ampholines or to isoelectric focusing in immobilized pH gradient gels it is resolved into several bands, each of which possesses the olive-green color of the holoenzyme. Although the patterns of resolution replicate for a given enzyme preparation differences occur among different preparations. Furthermore, storage for several months at -20 degrees C leads to an increase in the number of isoelectrophoretic forms. All preparations, however, have two primary bands, one with a pI of 6.97 and the other of 7.02. Both these bands possess significant cytochrome oxidase activity after elution from the gels. When each of the primary bands is eluted and again subjected to isoelectric focusing under the same conditions as before, each band interconverts into two bands with pIs of 6.97 and 7.02. The addition of the ligand cyanide to the holoenzyme produces a shift in the pI of the two bands to pIs 7.04 and 7.12 while the addition of nitrite shifts some of the band at pI 6.97 into that at pI 7.02. The heme d1-containing dipeptide of the enzyme, produced by treatment with subtilisin, also exhibits considerable heterogeneity upon electrophoretic titration curve analysis and by isoelectric focusing in immobiline gels. Possible explanations for the observed isoelectrophoretic behavior in terms of protein conformation and heme chemistry are discussed.

  17. Cyclin D1 G870A polymorphism: Association with uterine leiomyoma risk and in silico analysis

    PubMed Central

    Salimi, Saeedeh; Shahrakipour, Mahnaz; Hajizadeh, Azam; Mokhtari, Mojgan; Mousavi, Mahdieh; Teimoori, Batool; Yaghmaei, Minoo

    2017-01-01

    Uterine leiomyoma (UL) is the most common benign tumor causing considerable morbidity during the reproductive years in women. Cyclin D1 (CCND1) is a cell cycle regulatory protein that is required for the G1 phase, and increased expression levels of this protein may affect tumorigenesis. The present study aimed to assess the possible effect of the CCND1 G870A polymorphism on UL susceptibility. A total of 154 women with UL and 197 healthy women who were age-, body mass index (BMI)- and ethnicity-matched were genotyped for the CCND1 G870A (rs9344) polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. The effects of G870A transition on the structure of mRNA and proteins of CCND1 was evaluated using bioinformatics tools. The frequency of the CCND1 870AA genotype was significantly higher in women with UL compared with the control subjects, and the risk of UL was 1.4-fold higher in women with the AA genotype when compared with the GG genotype before and after adjusting for age, BMI, and ethnicity [odds ratio (OR), 1.4; 95% confidence interval (CI), 1.1–2 (P=0.02)]. The frequency of CCND1 870GA genotype was not significantly different between the two groups. The frequency of the CCND1 870A allele was significantly higher in the women with UL when compared with the control subjects (57 vs. 48%; P=0.02). The in silico analysis revealed that the G870A transition may fundamentally alter the structure of the CCND1-mRNA. Thus, the CCND1 870AA genotype was associated with UL susceptibility in a sample of women from the southeast of Iran. PMID:28357079

  18. Phospholipase D1 in caveolae: regulation by protein kinase Calpha and caveolin-1.

    PubMed

    Kim, J H; Han, J M; Lee, S; Kim, Y; Lee, T G; Park, J B; Lee, S D; Suh, P G; Ryu, S H

    1999-03-23

    Caveolae are small plasma membrane invaginations that have been implicated in cell signaling, and caveolin is a principal structural component of the caveolar membrane. Previously we have demonstrated that protein kinase Calpha (PKCalpha) directly interacts with phospholipase D1 (PLD1), activating the enzymatic activity of PLD1 in the presence of phorbol 12-myristate 13-acetate (PMA) [Lee, T. G., et al. (1997) Biochim. Biophys. Acta 1347, 199-204]. In this study, using a detergent-free procedure for the purification of a caveolin-enriched membrane fraction (CEM) and immunoblot analysis, we show that PLD1 is enriched in the CEMs of 3Y1 rat fibroblasts. Purified PLD1 directly bound to a glutathione S-transferase-caveolin-1 fusion protein in in vitro binding assays. The association of PLD1 with caveolin-1 could be completely eliminated by preincubation of PLD1 with an oligopeptide corresponding to the scaffolding domain (amino acids 82-101) of caveolin-1, indicating that caveolin-1 interacts with PLD1 through the scaffolding domain. The peptide also inhibited PKCalpha-stimulated PLD1 activity and the interaction between PLD1 and PKCalpha with an IC50 of 0.5 microM. PMA elicits translocation of PKCalpha to the CEMs, inducing PLD activation through the interaction of PKCalpha with PLD1 in the CEMs. Caveolin-1 also coimmunoprecipitated with PLD1 in the absence of PMA, and the amounts of coimmunoprecipitated caveolin-1 decreased in response to treatment with PMA. Taken together, our results suggest a new mechanism for the regulation of the PKCalpha-dependent PLD activity through the molecular interaction between PLD1, PKCalpha, and caveolin-1 in caveolae.

  19. Gone in a Blaze of Glory: the Demise of Comet C/2015 D1 (SOHO)

    NASA Astrophysics Data System (ADS)

    Hui, Man-To; Ye, Quan-Zhi; Manning Knight, Matthew; Battams, Karl; Clark, David

    2015-11-01

    We present studies of C/2015 D1 (SOHO), the first sunskirting comet ever seen from ground stations over the past half century. The Solar and Heliospheric Observatory (SOHO) witnessed its peculiar light curve with a huge dip followed by a flareup around perihelion: the dip was likely caused by sublimation of olivines, directly evidenced by a coincident temporary disappearance of the tail. The flareup likely reflects a disintegration event, which we suggest was triggered by intense thermal stress established within the nucleus interior. Photometric data reveal an increasingly dusty coma, indicative of volatile depletion. A catastrophic mass loss rate of ~105 kg s-1 around perihelion was seen. Ground-based Xingming Observatory spotted the post-perihelion debris cloud. Our morphological simulations of post-perihelion images find newly released dust grains of size a >~ 15 μm in radius, however, a temporal increase in amin was also witnessed, possibly due to swift dispersions of smaller grains swept away by radiation forces without replenishment. Together with the fading profile of the light curve, a power law dust size distribution with index γ = 3.2 ± 0.1 is derived. We detected no active remaining cometary nuclei over ~0.1 km in radius in post-perihelion images acquired at Lowell Observatory. Applying radial non-gravitational parameter, A1 = (1.209 ± 0.118) × 10-6 AU day-2, from an isothermal water-ice sublimation model to the SOHO astrometry significantly reduces residuals and sinusoidal trends in the orbit determination. The nucleus mass ~108--109 kg, and the radius ~50--150 m (bulk density ρd = 0.4 g cm-3 assumed) before the disintegration are deduced from the photometric data; consistent results were determined from the non-gravitational effects.

  20. Gone in a Blaze of Glory: The Demise of Comet C/2015 D1 (SOHO)

    NASA Astrophysics Data System (ADS)

    Hui, Man-To; Ye, Quan-Zhi; Knight, Matthew; Battams, Karl; Clark, David

    2015-11-01

    We present studies of C/2015 D1 (SOHO), the first sunskirting comet ever seen from ground stations over the past half century. The Solar and Heliospheric Observatory (SOHO) witnessed its peculiar light curve with a huge dip followed by a flare-up around perihelion: the dip was likely caused by sublimation of olivines, directly evidenced by a coincident temporary disappearance of the tail. The flare-up likely reflects a disintegration event, which we suggest was triggered by intense thermal stress established within the nucleus interior. Photometric data reveal an increasingly dusty coma, indicative of volatile depletion. A catastrophic mass-loss rate of ˜105 kg s-1 around perihelion was seen. Ground-based Xingming Observatory spotted the post-perihelion debris cloud. Our morphological simulations of post-perihelion images find newly released dust grains of size a ≳ 10 μm in radius however, a temporal increase in amin was also witnessed, possibly owing to swift dispersions of smaller grains swept away by radiation forces without replenishment. Together with the fading profile of the light curve, a power-law dust size distribution with index γ = 3.2 ± 0.1 is derived. We detected no active remaining cometary nuclei over ˜0.1 km in radius in post-perihelion images acquired at Lowell Observatory. Applying a radial nongravitational parameter, {{A}}1=≤ft(1.209+/- 0.118\\right)× {10}-6 AU day-2, from an isothermal water-ice sublimation model to the SOHO astrometry significantly reduces residuals and sinusoidal trends in the orbit determination. The nucleus mass ˜108-109 kg and the radius ˜50-150 m (bulk density ρd = 0.4 g cm-3 assumed) before the disintegration are deduced from the photometric data; consistent results were determined from the nongravitational effects.

  1. First D1-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring

    PubMed Central

    Granda, Michael L.; Schroeder, Frederick A.; Borra, Ronald H. J.; Schauer, Nathan; Aisaborhale, Ehimen; Guimaraes, Alexander R.

    2014-01-01

    The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin-angiotensin-aldosterone system. Here, we show the first in vivo measurement of D1-like receptors in the renal cortex of Sprague-Dawley rat and Papio anubis baboon using [11C]NNC 112, a positron emission tomography radioligand for D1-like receptors. In addition, we show a D1-like binding potential response to angiotensin II blockade in rats using losartan. Demonstration of self-saturable binding in the rat as well as specific and saturable binding in Papio anubis validate the use of [11C]NNC 112 in the first in vivo measurement of renal dopamine D1-like receptors. Furthermore, [11C]NNC 112 is a radioligand tool already validated for use in probing human central nervous system (CNS) D1-like receptors. Our work demonstrates specific and saturable non-CNS binding in higher animals and the ability to quantify physiological response to drug treatment and provides a clear path to extend use of [11C]NNC 112 to study renal dopamine in humans. PMID:24808534

  2. First D1-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring.

    PubMed

    Granda, Michael L; Schroeder, Frederick A; Borra, Ronald H J; Schauer, Nathan; Aisaborhale, Ehimen; Guimaraes, Alexander R; Hooker, Jacob M

    2014-07-01

    The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin-angiotensin-aldosterone system. Here, we show the first in vivo measurement of D1-like receptors in the renal cortex of Sprague-Dawley rat and Papio anubis baboon using [(11)C]NNC 112, a positron emission tomography radioligand for D1-like receptors. In addition, we show a D1-like binding potential response to angiotensin II blockade in rats using losartan. Demonstration of self-saturable binding in the rat as well as specific and saturable binding in Papio anubis validate the use of [(11)C]NNC 112 in the first in vivo measurement of renal dopamine D1-like receptors. Furthermore, [(11)C]NNC 112 is a radioligand tool already validated for use in probing human central nervous system (CNS) D1-like receptors. Our work demonstrates specific and saturable non-CNS binding in higher animals and the ability to quantify physiological response to drug treatment and provides a clear path to extend use of [(11)C]NNC 112 to study renal dopamine in humans.

  3. Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70

    PubMed Central

    Wang, Ying; Lam, Wing; Chen, Shao-Ru; Guan, Fu-Lan; Dutchman, Ginger E.; Francis, Samson; Baker, David C.; Cheng, Yung-Chi

    2016-01-01

    Tylophorine analog DCB-3503 is a potential anticancer and immunosuppressive agent that suppresses the translation of cellular regulatory proteins, including cyclin D1, at the elongation step. However, the molecular mechanism underlying this phenomenon remains unknown. This study demonstrates that DCB-3503 preferentially binds to heat shock cognate protein 70 (HSC70), which is a determinant for cyclin D1 translation by binding to the 3′-untranslated region (3′ UTR) of its mRNA. DCB-3503 allosterically regulates the ATPase and chaperone activities of HSC70 by promoting ATP hydrolysis in the presence of specific RNA binding motifs (AUUUA) of cyclin D1 mRNA. The suppression of cyclin D1 translation by DCB-3503 is not solely caused by perturbation of the homeostasis of microRNAs, although the microRNA processing complex is dissociated with DCB-3503 treatment. This study highlights a novel regulatory mechanism of protein translation with AUUUA motifs in the 3′ UTR of mRNA by HSC70, and its activity can be allosterically modulated by DCB-3503. DCB-3503 may be used to treat malignancies, such as hepatocellular carcinoma or breast cancer with elevated expression of cyclin D1. PMID:27596272

  4. HTLV-1 basic leucine zipper factor downregulates cyclin D1 expression via interactions with NF-κB.

    PubMed

    Ma, Yunyun; Zhang, Bo; Wang, Dong; Qian, Lili; Song, Xianmei; Wang, Xueyin; Yang, Chaokuan; Zhao, Guoqiang

    2017-03-01

    Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus. It can cause adult T cell leukemia (ATL) and other diseases. The HTLV-1 basic leucine zipper (bZIP) factor (HBZ), which is encoded by the minus-strand of the provirus, is expressed in all cases of ATL and involved in T cell proliferation. However, the exact mechanism underlying its growth-promoting activity is poorly understood. Herein, we demonstrated that HBZ suppressed cyclin D1 expression by inhibiting the nuclear factor (NF)-κB signaling pathway. Among the potential mechanisms of cyclin D1 inhibition mediated by HBZ, we found that HBZ suppressed cyclin D1 promoter activity. Luciferase assay analysis revealed that HBZ repressed cyclin D1 promoter activity by suppressing NF-κB‑driven transcription mediated by the p65 subunit. Using an immunoprecipitation assay, we found that HBZ could bind to p65, but not p50. Finally, we showed that HBZ selectively interacted with p65 via its AD+bZIP domains. By suppressing cyclin D1 expression, HBZ can alter cell cycle progression of HTLV-1-infected cells, which may be critical for oncogenesis.

  5. Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: Role of the prelimbic cortex

    PubMed Central

    Pezze, Marie A.; Marshall, Hayley J.; Fone, Kevin C.F.; Cassaday, Helen J.

    2015-01-01

    Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8 mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24 h later. The same treatments also reduced novel object recognition memory tested 24 h after the sampling phase and when given 15 min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory. PMID:26277743

  6. Plant Defensins NaD1 and NaD2 Induce Different Stress Response Pathways in Fungi

    PubMed Central

    Dracatos, Peter M.; Payne, Jennifer; Di Pietro, Antonio; Anderson, Marilyn A.; Plummer, Kim M.

    2016-01-01

    Nicotiana alata defensins 1 and 2 (NaD1 and NaD2) are plant defensins from the ornamental tobacco that have antifungal activity against a variety of fungal pathogens. Some plant defensins interact with fungal cell wall O-glycosylated proteins. Therefore, we investigated if this was the case for NaD1 and NaD2, by assessing the sensitivity of the three Aspergillus nidulans (An) O-mannosyltransferase (pmt) knockout (KO) mutants (An∆pmtA, An∆pmtB, and An∆pmtC). An∆pmtA was resistant to both defensins, while An∆pmtC was resistant to NaD2 only, suggesting NaD1 and NaD2 are unlikely to have a general interaction with O-linked side chains. Further evidence of this difference in the antifungal mechanism was provided by the dissimilarity of the NaD1 and NaD2 sensitivities of the Fusarium oxysporum f. sp. lycopersici (Fol) signalling knockout mutants from the cell wall integrity (CWI) and high osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) pathways. HOG pathway mutants were sensitive to both NaD1 and NaD2, while CWI pathway mutants only displayed sensitivity to NaD2. PMID:27598152

  7. Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: Role of the prelimbic cortex.

    PubMed

    Pezze, Marie A; Marshall, Hayley J; Fone, Kevin C F; Cassaday, Helen J

    2015-11-01

    Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8 mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24 h later. The same treatments also reduced novel object recognition memory tested 24 h after the sampling phase and when given 15 min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory.

  8. Dopamine D1 and D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration.

    PubMed

    Yan, Y; Newman, A H; Xu, M

    2014-10-10

    Memories of drug experience and drug-associated environmental cues can elicit drug-seeking and taking behaviors in humans. Disruption of reconsolidation of drug memories dampens previous memories and therefore may provide a useful way to treat drug abuse. We and others previously demonstrated that dopamine D1 and D3 receptors play differential roles in acquiring cocaine-induced behaviors. Moreover, D3 receptors contribute to the reconsolidation of cocaine-induced conditioned place preference. In the present study, we examined effects of manipulating D1 or D3 receptors on reconsolidation of cocaine memories in mouse models of drug self-administration. We found that pharmacological blockade of D1 receptors or a genetic mutation of the D3 receptor gene attenuated reconsolidation that lasted for at least 1week after the memory retrieval. In contrast, with no memory retrieval, pharmacological antagonism of D1 receptors or the D3 receptor gene mutation did not significantly affect reconsolidation of cocaine memories. Pharmacological blockade of D3 receptors also attenuated reconsolidation in wild-type mice that lasted for at least 1week after the memory retrieval. These results suggest that D1 and D3 receptors and related signaling mechanisms play key roles in reconsolidation of cocaine memories in mice, and that these receptors may serve as novel targets for the treatment of cocaine abuse in humans.

  9. Localization of the human 64kD autoantigen D1 to myofibrils in a subset of extraocular muscle fibers

    NASA Technical Reports Server (NTRS)

    Conley, C. A.; Fowler, V. M.

    1999-01-01

    PURPOSE. To evaluate the tissue-specific expression pattern of the 64kD human autoantigen D1, a tropomodulin-related protein that may be involved in thyroid-associated ophthalmopathy. METHODS. Recombinant 64kD human autoantigen D1 was generated in a bacterial expression system and used to immunize rabbits. Specific antibodies were affinity-purified and used for Western blots on normal and hyperthyroid rat and rabbit tissue, and immunofluorescence localization on cryosections of rat tissue. RESULTS. Anti-64kD human autoantigen D1 antibodies recognize specifically a approximately 70kD polypeptide in western blots of extraocular muscle, sternothyroid muscle, and smooth muscle. Immunofluorescence staining demonstrates that the 64kD human autoantigen D1 localizes to myofibrils in slow fibers from rat extraocular and sternothyroid muscle. The level of this protein is not altered in extraocular muscles from hyperthyroid rabbits. CONCLUSIONS. The 64kD human autoantigen D1 is expressed in slow fibers of extraocular and sternothyroid muscles as a component of myofibrils, and is not upregulated in conditions of hyperthyroidism.

  10. Rotation and immediate-early gene expression in rats treated with the atypical D1 dopamine agonist SKF 83822.

    PubMed

    Wirtshafter, David

    2007-03-01

    Classical agonists of the dopamine D1 receptor activate both adenylyl cyclase and phospholipase C (PLC) signaling pathways. As a result, the extent to which these two pathways are essentially involved in various effects produced by D1 receptor agonists is currently uncertain. In the present report we examined the effects of SKF 83822, a dopamine D1 agonist which has been reported to activate adenylyl cyclase, but not PLC, on behavior and immediate early gene (IEG) expression in rats with unilateral 6-hydroxydopamine lesions. SKF 83822 (25-100 microg/kg) induced dose dependent contralateral rotation in these subjects, and, additionally, stimulated strong expression of the IEG products c-Fos, Fra2, Zif/268 and Arc in the deinnervated striatum. All of these effects could be antagonized by pretreatment with the selective D1 dopamine antagonist SCH 23390 (0.5 mg/kg). Although PLC may be involved in many effects mediated through dopamine D1 receptors, these results suggest that direct activation of PLC is not necessary for the induction of either rotation or IEG expression in dopamine depleted rats.

  11. Differences between A 68930 and SKF 82958 could suggest synergistic roles of D1 and D5 receptors.

    PubMed

    Nergårdh, R; Oerther, S; Fredholm, B B

    2005-11-01

    The isochroman A 68930 and the benzazepine SKF 82958 are two full dopamine D1 receptor agonists. Responses to these compounds are different in several important aspects. When given to rats in a novel environment, A 68930 caused a dose-dependent (0.019-4.9 mg/kg) suppression of locomotion. SKF 82958 had no such effect at any dose studied (0.051-3.3 mg/kg). In animals habituated to the environment, A 68930 had no effect but SKF 82958 increased locomotor activity. Both A 68930 and SKF 82958 caused a decrease in core temperature at early time points. Both agonists increased c-fos and NGFI-A expression in caudate putamen but only SKF 82958 did so in the accumbens nucleus (at 1.6 mg/kg). Quantitative receptor autoradiography showed that A 68930 is 9-13 times more potent than SKF 82958 at displacing the selective dopamine D1 antagonist [3H]SCH 23390. This difference agrees with the difference observed when the agonists were used to stimulate cAMP formation in cells transfected with the D1 receptor. In contrast, SKF 82958 was 5 times more potent than A 68930 in cells transfected with the D5 receptor. We suggest that the balance between signaling via dopamine D1 and D5 receptors determines the functional effects of agonists at D1/D5 receptors.

  12. Dopaminergic D1 receptor agonist SKF 38393 induces GAP-43 expression and long-term potentiation in hippocampus in vivo.

    PubMed

    Williams, Shimere; Mmbaga, Natu; Chirwa, Sanika

    2006-07-10

    We evaluated whether activating dopamine D1 receptors (D1R) with an agonist will mimic the effects of long-term potentiation (LTP)-inducing electrical stimulation and trigger the expression of the presynaptic growth-associated protein 43 (GAP-43), a putative synaptic plasticity factor. Thus, we conducted GAP-43 protein analyses together with assessments of LTP across CA3/CA1 synapses in guinea pigs administered with SKF38393 (the D1R agonist) and/or SCH23390 (the D1R antagonist). Our results showed that guinea pigs treated with SKF38393 coupled with low-frequency stimulation gradually exhibited an LTP-like potentiation in correlation with increased GAP-43 protein expression. However, when SKF38393 treatment was preceded by administration of SCH23390, this antagonized the occurrence of both synaptic potentiation and GAP-43 up-regulation. By comparison, persistent LTP was readily expressed after brief high frequency tetanic stimulation in control guinea pigs, whereas animals injected with SCH23390 and tetanized only developed early-LTP but not late-LTP. Western blot analyses showed GAP-43 up-regulation in the tetanized control guinea pigs but not those injected with SCH23390. We conclude that direct D1R activations with an agonist can mimic LTP-inducing electrical stimulation to produce GAP-43 up-regulation and synaptic plasticity.

  13. Alterations in photosynthetic pigments and amino acid composition of D1 protein change energy distribution in photosystem II.

    PubMed

    Yokono, Makio; Tomo, Tatsuya; Nagao, Ryo; Ito, Hisashi; Tanaka, Ayumi; Akimoto, Seiji

    2012-05-01

    The marine cyanobacterium Prochlorococcus marinus accumulates divinyl chlorophylls instead of monovinyl chlorophylls to harvest light energy. As well as this difference in its chromophore composition, some amino acid residues in its photosystem II D1 protein were different from the conserved amino acid residues in other photosynthetic organisms. We examined PSII complexes isolated from mutants of Synechocystis sp. PCC 6803, in which chromophore and D1 protein were altered (Hisashi Ito and Ayumi Tanaka, 2011) to clarify the effects of chromophores/D1 protein composition on the excitation energy distribution. We prepared the mutants accumulating divinyl chlo