Note: This page contains sample records for the topic tieg1 regulates bmal1 from Science.gov.
While these samples are representative of the content of Science.gov,
they are not comprehensive nor are they the most current set.
We encourage you to perform a real-time search of Science.gov
to obtain the most current and comprehensive results.
Last update: August 15, 2014.
1

Cryptochrome and Period Proteins Are Regulated by the CLOCK/BMAL1 Gene: Crosstalk between the PPARs/RXR?-Regulated and CLOCK/BMAL1-Regulated Systems  

PubMed Central

Feeding and the circadian system regulate lipid absorption and metabolism, and the expression of enzymes involved in lipid metabolism is believed to be directly controlled by the clock system. To investigate the interaction between the lipid metabolism system and the circadian system, we analyzed the effect of a CLOCK/BMAL1 heterodimer on the transcriptional regulation of PPAR-controlled genes through PPAR response elements (PPREs). Transcription of acyl-CoA oxidase, cellular retinol binding protein II (CRBPII), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase was altered by CLOCK/BMAL1, and transcriptional activity via PPRE by PPARs/RXR? was enhanced by CLOCK/BMAL1 and/or by PPARs ligand/activators. We also found that CLOCK/BMAL1-mediated transcription of period (PER) and cryptochrome (CRY) was modulated by PPAR?/RXR?. These results suggest that there may be crosstalk between the PPARs/RXR?-regulated system and the CLOCK/BMAL1-regulated system.

Nakamura, Koh-ichi; Inoue, Ikuo; Takahashi, Seiichiro; Komoda, Tsugikazu; Katayama, Shigehiro

2008-01-01

2

CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1.  

PubMed

The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol. Conclusion: These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders. (Hepatology 2014;59:2196-2206). PMID:24442997

Zhou, Ben; Zhang, Yi; Zhang, Fang; Xia, Yulei; Liu, Jun; Huang, Rui; Wang, Yuangao; Hu, Yanan; Wu, Jingxia; Dai, Changgui; Wang, Hui; Tu, Yanyang; Peng, Xiaozhong; Wang, Yiqian; Zhai, Qiwei

2014-06-01

3

Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes.  

PubMed

Circadian clocks have evolved to regulate physiologic and behavioral rhythms in anticipation of changes in the environment. Although the molecular clock is present in innate immune cells, its role in monocyte homeostasis remains unknown. Here, we report that Ly6C(hi) inflammatory monocytes exhibit diurnal variation, which controls their trafficking to sites of inflammation. This cyclic pattern of trafficking confers protection against Listeria monocytogenes and is regulated by the repressive activity of the circadian gene Bmal1. Accordingly, myeloid cell-specific deletion of Bmal1 induces expression of monocyte-attracting chemokines and disrupts rhythmic cycling of Ly6C(hi) monocytes, predisposing mice to development of pathologies associated with acute and chronic inflammation. These findings have unveiled a critical role for BMAL1 in controlling the diurnal rhythms in Ly6C(hi) monocyte numbers. PMID:23970558

Nguyen, Khoa D; Fentress, Sarah J; Qiu, Yifu; Yun, Karen; Cox, Jeffery S; Chawla, Ajay

2013-09-27

4

The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1.  

PubMed

Transforming growth factor-beta (TGF-beta) signaling in naive T cells induces expression of the transcription factor Foxp3, a 'master' regulator of regulatory T cells (T(reg) cells). However, the molecular mechanisms leading to Foxp3 induction remain unclear. Here we show that Itch-/- T cells were resistant to TGF-beta treatment and had less Foxp3 expression. The E3 ubiquitin ligase Itch associated with and promoted conjugation of ubiquitin to the transcription factor TIEG1. Itch cooperated with TIEG1 to induce Foxp3 expression, which was reversed by TIEG1 deficiency. Functionally, 'TGF-beta-converted' T(reg) cells generated from TIEG1-deficient mice were unable to suppress airway inflammation in vivo. These results suggest TIEG and Itch contribute to a ubiquitin-dependent nonproteolytic pathway that regulates inducible Foxp3 expression and the control of allergic responses. PMID:18278048

Venuprasad, K; Huang, Haining; Harada, Yousuke; Elly, Chris; Subramaniam, Malayannan; Spelsberg, Thomas; Su, Jin; Liu, Yun-Cai

2008-03-01

5

Bidirectional CLOCK/BMAL1-dependent circadian gene regulation by retinoic acid in vitro  

SciTech Connect

A central circadian clock located in the suprachiasmatic nucleus (SCN) of the mammalian hypothalamus entrains peripheral clocks through both neural and humoral factors. Although candidates for entrainment factors have been described, their details remain obscure. Here, we screened ligands for nuclear receptors that affect CLOCK/BMAL1-dependent transactivation of the mouse Period1 (mPer1) gene in NIH3T3 cells. We found that retinoic acids (RAs) significantly up-regulate mPer1 expression in an E-box-dependent manner. We also found that RAs up-regulate the expression of other E-box-dependent circadian genes such as mPer2, arginine vasopressin (mAVP), and peroxisome proliferator-activated receptor {alpha} (mPPAR{alpha}). Surprisingly, the effect of RAs on CLOCK/BMAL1 (E-box)-dependent mRNA expression was bidirectional and depended on the presence of exogenous retinoic acid receptor {alpha} (RAR{alpha}). These results suggest that RAs regulate the CLOCK/BMAL1-dependent transcription of circadian genes in a complex manner.

Shirai, Hidenori [Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566 (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8502 (Japan); Oishi, Katsutaka [Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566 (Japan); Ishida, Norio [Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566 (Japan) and Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8502 (Japan)]. E-mail: n.ishida@aist.go.jp

2006-12-15

6

Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1  

SciTech Connect

Small heterodimer partner (SHP; NR0B2) is an orphan nuclear receptor and acts as a repressor for wide variety of nuclear hormone receptors. We demonstrated here that mouse SHP mRNA showed a circadian expression pattern in the liver. Transient transfection of the mSHP promoter demonstrated that CLOCK-BMAL1, core circadian clock components, bound to E-box (CACGTG), and stimulated the promoter activity by 4-fold. Liver receptor homologue-1 (LRH-1; NR5A2) stimulated the mSHP promoter, and CLOCK-BMAL1 synergistically enhanced the LRH-1-mediated transactivation. Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1. Furthermore, in vitro pull-down assays revealed the existence of direct protein-protein interaction between LRH-1 and CLOCK. In summary, this study shows that CLOCK-BMAL1, LRH-1 and SHP coordinately regulate the mSHP gene to generate the circadian oscillation. The cyclic expression of mSHP may affect daily activity of other nuclear receptors and contribute to circadian liver functions.

Oiwa, Ako [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan); Kakizawa, Tomoko [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan)]. E-mail: tkaki@hsp.md.shinshu-u.ac.jp; Miyamoto, Takahide [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan); Yamashita, Koh [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan); Jiang, Wei [Department of Endocrinology, First Clinical College, Harbin Medical University, 150001 (China); Takeda, Teiji [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan); Suzuki, Satoru [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan); Hashizume, Kiyoshi [Shinshu University Graduate School of Medicine, Institute on Aging and Adaptation, Department of Aging Medicine and Geriatrics, Matsumoto 390-8621 (Japan)

2007-02-23

7

TIEG1/KLF10 Modulates Runx2 Expression and Activity in Osteoblasts  

PubMed Central

Deletion of TIEG1/KLF10 in mice results in a gender specific osteopenic skeletal phenotype with significant defects in both cortical and trabecular bone, which are observed only in female animals. Calvarial osteoblasts isolated from TIEG1 knockout (KO) mice display reduced expression levels of multiple bone related genes, including Runx2, and exhibit significant delays in their mineralization rates relative to wildtype controls. These data suggest that TIEG1 plays an important role in regulating Runx2 expression in bone and that decreased Runx2 expression in TIEG1 KO mice is in part responsible for the observed osteopenic phenotype. In this manuscript, data is presented demonstrating that over-expression of TIEG1 results in increased expression of Runx2 while repression of TIEG1 results in suppression of Runx2. Transient transfection and chromatin immunoprecipitation assays reveal that TIEG1 directly binds to and activates the Runx2 promoter. The zinc finger containing domain of TIEG1 is necessary for this regulation supporting that activation occurs through direct DNA binding. A role for the ubiquitin/proteasome pathway in fine tuning the regulation of Runx2 expression by TIEG1 is also implicated in this study. Additionally, the regulation of Runx2 expression by cytokines such as TGF?1 and BMP2 is shown to be inhibited in the absence of TIEG1. Co-immunoprecipitation and co-localization assays indicate that TIEG1 protein associates with Runx2 protein resulting in co-activation of Runx2 transcriptional activity. Lastly, Runx2 adenoviral infection of TIEG1 KO calvarial osteoblasts leads to increased expression of Runx2 and enhancement of their ability to differentiate and mineralize in culture. Taken together, these data implicate an important role for TIEG1 in regulating the expression and activity of Runx2 in osteoblasts and suggest that decreased expression of Runx2 in TIEG1 KO mice contributes to the observed osteopenic bone phenotype.

Hawse, John R.; Cicek, Muzaffer; Grygo, Sarah B.; Bruinsma, Elizabeth S.; Rajamannan, Nalini M.; van Wijnen, Andre J.; Lian, Jane B.; Stein, Gary S.; Oursler, Merry Jo; Subramaniam, Malayannan; Spelsberg, Thomas C.

2011-01-01

8

The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor  

PubMed Central

Post-translational modifications (such as ubiquitination) of clock proteins are critical in maintaining the precision and robustness of the evolutionarily conserved circadian clock. Ubiquitination of the core clock transcription factor BMAL1 (brain and muscle Arnt-like 1) has recently been reported. However, it remains unknown whether BMAL1 ubiquitination affects circadian pacemaking and what ubiquitin ligase(s) is involved. Here, we show that activating UBE3A (by expressing viral oncogenes E6/E7) disrupts circadian oscillations in mouse embryonic fibroblasts, measured using PER2::Luc dynamics, and rhythms in endogenous messenger ribonucleic acid and protein levels of BMAL1. Over-expression of E6/E7 reduced the level of BMAL1, increasing its ubiquitination and proteasomal degradation. UBE3A could bind to and degrade BMAL1 in a ubiquitin ligase-dependent manner. This occurred both in the presence and absence of E6/E7. We provide in vitro (knockdown/over-expression in mammalian cells) and in vivo (genetic manipulation in Drosophila) evidence for an endogenous role of UBE3A in regulating circadian dynamics and rhythmic locomotor behaviour. Together, our data reveal an essential and conserved role of UBE3A in the regulation of the circadian system in mammals and flies and identify a novel mechanistic link between oncogene E6/E7-mediated cell transformation and circadian (BMAL1) disruption.

Gossan, Nicole C.; Zhang, Feng; Guo, Baoqiang; Jin, Ding; Yoshitane, Hikari; Yao, Aiyu; Glossop, Nick; Zhang, Yong Q.; Fukada, Yoshitaka; Meng, Qing-Jun

2014-01-01

9

TGF?-Inducible Early Gene-1 (TIEG1) Mutations in Hypertrophic Cardiomyopathy  

PubMed Central

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGF? Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's 4 translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in 6 patients (2 males/4 females, mean age at diagnosis 56.2 ± 23 years, MLVWT 20.8 ± 4 mm). Compared to WT TIEG1, 5 TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first paper to associate mutations in TIEG1 to human disease with the discovery of 6 novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM.

Bos, J. Martijn; Subramaniam, Malayannan; Hawse, John R.; Christiaans, I.; Rajamannan, Nalini M; Maleszewski, Joseph J.; Edwards, William D.; Wilde, Arthur A.M.; Spelsberg, Thomas C.; Ackerman, Michael J.

2012-01-01

10

Clock gene Bmal1 is dispensable for intrinsic properties of murine hematopoietic stem cells  

PubMed Central

Background Circadian rhythms are known to influence a variety of biological phenomena such as cell cycle, sleep-wake rhythm, hormone release and other important physiological functions. Given that cell cycle entry of hibernating hematopoietic stem cells (HSCs) plays a critical role in controlling hematopoiesis, we asked functional significance of the clock gene Bmal1, which plays a central role in regulating circadian rhythms as a transcription factor. Here we investigated the necessity of Bmal1 for HSC functions using Bmal1 deficient (Bmal1?/?) mice. Findings Using colony-forming assays in vitro, we found that the frequency of mixed colony formation between Bmal1+/+ and Bmal1?/? CD34?KSL cells does not differ significantly. Competitive bone marrow assays also revealed that Bmal1?/? bone marrow cells competed normally with wild-type cells and displayed long-term multi-hematopoietic lineage reconstitution. In addition, there were no significant differences in the frequencies and hibernation state of bone marrow HSCs between Bmal1+/+ and Bmal1?/? mice, suggesting that they are independent of circadian rhythms. Conclusions This paper discusses the necessity of circadian rhythms for HSC functions. Our data clearly shows that a key circadian clock gene Bmal1 is dispensable for intrinsic functions of HSCs, such as differentiation, proliferation and repopulating ability.

2014-01-01

11

The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma  

PubMed Central

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21WAF1/CIP1 and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.

Elshazley, Momen; Sato, Mitsuo; Hase, Tetsunari; Yamashita, Ryo; Yoshida, Kenya; Toyokuni, Shinya; Ishiguro, Futoshi; Osada, Hirotaka; Sekido, Yoshitaka; Yokoi, Kohei; Usami, Noriyasu; Shames, David S.; Kondo, Masashi; Gazdar, Adi F.; Minna, John D.; Hasegawa, Yoshinori

2012-01-01

12

O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination  

PubMed Central

SUMMARY Circadian clocks are coupled to metabolic oscillations through nutrient-sensing pathways. Nutrient flux into the hexosamine biosynthesis pathway triggers covalent protein modification by O-linked ?-D-N-acetylglucosamine (O-GlcNAc). Here we show that the hexosamine/O-GlcNAc pathway modulates peripheral clock oscillation. O-GlcNAc transferase (OGT) promotes expression of BMAL1/CLOCK target genes and affects circadian oscillation of clock genes in vitro and in vivo. Both BMAL1 and CLOCK are rhythmically O-GlcNAcylated and this protein modification stabilizes BMAL1 and CLOCK by inhibiting their ubiquitination. In vivo analysis of genetically modified mice with perturbed hepatic OGT expression shows aberrant circadian rhythms of glucose homeostasis. These results establish the counteraction between O-GlcNAcylation and ubiquitination as a key mechanism that regulates the circadian clock and suggest a crucial role for O-GlcNAc signaling in transducing nutritional signals to the core circadian timing machinery.

Li, Min-Dian; Ruan, Hai-Bin; Hughes, Michael E.; Lee, Jeong-Sang; Singh, Jay P.; Jones, Steven P.; Nitabach, Michael N.; Yang, Xiaoyong

2013-01-01

13

The Circadian Regulatory Proteins BMAL1 and Cryptochromes Are Substrates of Casein Kinase I?*  

PubMed Central

The serine/threonine protein kinase casein kinase I ? (CKI?) is a key regulator of metazoan circadian rhythm. Genetic and biochemical data suggest that CKI? binds to and phosphorylates the PERIOD proteins. However, the PERIOD proteins interact with a variety of circadian regulators, suggesting the possibility that CKI? may interact with and phosphorylate additional clock components as well. We find that CRY1 and BMAL1 are phosphoproteins in cultured cells. Mammalian PERIOD proteins act as a scaffold with distinct domains that simultaneously bind CKI? and mCRY1 and mCRY2 (mCRY). mCRY is phosphorylated by CKI? only when both proteins are bound to mammalian PERIOD proteins. BMAL1 is also a substrate for CKI? in vitro, and CKI? kinase activity positively regulates BMAL1-dependent transcription from circadian promoters in reporter assays. We conclude that CKI? phosphorylates multiple circadian substrates and may exert its effects on circadian rhythm in part by a direct effect on BMAL1-dependent transcription.

Eide, Erik J.; Vielhaber, Erica L.; Hinz, William A.; Virshup, David M.

2006-01-01

14

BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice  

PubMed Central

The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14/10 h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence of time-of-day on electrical seizure threshold in mice and suggest that this effect is under the control of genes that are known to regulate circadian behaviors. Furthermore, low seizure thresholds in BMAL1 KO mice suggest that BMAL1 itself is directly involved in controlling neuronal excitability.

Gerstner, Jason R.; Smith, George G.; Lenz, Olivia; Perron, Isaac J.; Buono, Russell J.; Ferraro, Thomas N.

2014-01-01

15

Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression  

Microsoft Academic Search

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent

Marina M. Bellet; Marquis P. Vawter; Blynn G. Bunney; William E. Bunney; Paolo Sassone-Corsi

2011-01-01

16

Food anticipation in Bmal1-/- and AAV-Bmal1 rescued mice: a reply to Fuller et al  

PubMed Central

Evidence that circadian food-anticipatory activity and temperature rhythms are absent in Bmal1 knockout mice and rescued by restoration of Bmal1 expression selectively in the dorsomedial hypothalamus was published in 2008 by Fuller et al and critiqued in 2009 by Mistlberger et al. Fuller et al have responded to the critique with new information. Here we update our critique in the light of this new information. We also identify and correct factual and conceptual errors in the Fuller et al response. We conclude that the original results of Fuller et al remain inconclusive and fail to clarify the role of Bmal1 or the dorsomedial hypothalamus in the generation of food-entrainable rhythms in mice.

Mistlberger, Ralph E; Buijs, Ruud M; Challet, Etienne; Escobar, Carolina; Landry, Glenn J; Kalsbeek, Andries; Pevet, Paul; Shibata, Shigenobu

2009-01-01

17

O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination.  

PubMed

Circadian clocks are coupled to metabolic oscillations through nutrient-sensing pathways. Nutrient flux into the hexosamine biosynthesis pathway triggers covalent protein modification by O-linked ?-D-N-acetylglucosamine (O-GlcNAc). Here we show that the hexosamine/O-GlcNAc pathway modulates peripheral clock oscillation. O-GlcNAc transferase (OGT) promotes expression of BMAL1/CLOCK target genes and affects circadian oscillation of clock genes in vitro and in vivo. Both BMAL1 and CLOCK are rhythmically O-GlcNAcylated, and this protein modification stabilizes BMAL1 and CLOCK by inhibiting their ubiquitination. In vivo analysis of genetically modified mice with perturbed hepatic OGT expression shows aberrant circadian rhythms of glucose homeostasis. These results establish the counteraction between O-GlcNAcylation and ubiquitination as a key mechanism that regulates the circadian clock and suggest a crucial role for O-GlcNAc signaling in transducing nutritional signals to the core circadian timing machinery. PMID:23395176

Li, Min-Dian; Ruan, Hai-Bin; Hughes, Michael E; Lee, Jeong-Sang; Singh, Jay P; Jones, Steven P; Nitabach, Michael N; Yang, Xiaoyong

2013-02-01

18

Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway.  

PubMed

Patients with obstructive lung diseases display abnormal circadian rhythms in lung function. We determined the mechanism whereby environmental tobacco/cigarette smoke (CS) modulates expression of the core clock gene BMAL1, through Sirtuin1 (SIRT1) deacetylase during lung inflammatory and injurious responses. Adult C57BL6/J and various mice mutant for SIRT1 and BMAL1 were exposed to both chronic (6 mo) and acute (3 and 10 d) CS, and we measured the rhythmic expression of clock genes, circadian rhythms of locomotor activity, lung function, and inflammatory and emphysematous responses in the lungs. CS exposure (100-300 mg/m(3) particulates) altered clock gene expression and reduced locomotor activity by disrupting the central and peripheral clocks and increased lung inflammation, causing emphysema in mice. BMAL1 was acetylated and degraded in the lungs of mice exposed to CS and in patients with chronic obstructive pulmonary disease (COPD), compared with lungs of the nonsmoking controls, linking it mechanistically to CS-induced reduction of SIRT1. Targeted deletion of Bmal1 in lung epithelium augmented inflammation in response to CS, which was not attenuated by the selective SIRT1 activator SRT1720 (EC50=0.16 ?M) in these mice. Thus, the circadian clock, specifically the enhancer BMAL1 in epithelium, plays a pivotal role, mediated by SIRT1-dependent BMAL1, in the regulation of CS-induced lung inflammatory and injurious responses. PMID:24025728

Hwang, Jae-Woong; Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

2014-01-01

19

Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions  

Microsoft Academic Search

Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day-dependent gene expression1 .H ere we show that circadian regulation of the mouse albumin D element-binding protein (Dbp) gene involves rhythmic

Jürgen A Ripperger; Ueli Schibler

2006-01-01

20

Cistanches Herba aqueous extract affecting serum BGP and TRAP and bone marrow Smad1 mRNA, Smad5 mRNA, TGF-?1 mRNA and TIEG1 mRNA expression levels in osteoporosis disease.  

PubMed

We studied molecular mechanism of Cistanches Herba aqueous extract (CHAE) in ovariectomized (OVX) rats, as an experimental model of postmenopausal osteoporosis. Female rats were either sham-operated or bilaterally OVX; and at 60 days postoperatively. The OVX group (n = 8) received an ovariectomy and treatment with normal saline for 90 days commencing from 20th post ovariectomy day. The ovariectomized +CHAE (OVX + CHAE) group (n = 8) received an ovariectomy and were treated with Cistanches Herba aqueous extract of 100 mg/kg body weight daily for 90 days commencing from 22nd post ovariectomy day. The ovariectomy +CHAE (OVX + CHAE) group (n = 8) received an ovariectomy, and were treated with the of 200 mg/kg body weight daily for 90 days commencing from 20th post ovariectomy day. Serum BGP and TRAP, E2, FSH and LH level, bone marrow Smad1, Smad5, TGF-?1 and TIEG1 mRNA expression levels were examined. Results showed that serum BGP and TRAP, FSH and LH levels were significantly increased, whereas E2, Smad1, Smad5, TGF-?1 and TIEG1 mRNA and proteins expression levels were significantly decreased in OVX rats compared to sham rats. 90 days of CHAE treatment could significantly decrease serum BGP and TRAP, FSH and LH levels, and increase E2, Smad1, Smad5, TGF-?1 and TIEG1 mRNA and proteins expression levels in OVX rats. It can be concluded that CHAE play its protective effect against OVX-induced bone degeneration partly by regulating some bone metabolism related genes, e.g. Smad1, Smad5, TGF-?1 and TIEG1. PMID:23232713

Liang, Hai-Dong; Yu, Fang; Tong, Zhi-Hong; Zhang, Hong-Quan; Liang, Wu

2013-02-01

21

Suppression of serotonin N-acetyltransferase transcription and melatonin secretion from chicken pinealocytes transfected with Bmal1 antisense oligonucleotides containing locked nucleic acid in superfusion system.  

PubMed

In birds, rhythmic changes in pineal serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, Aanat) transcripts are controlled by an oscillator located in the pinealocytes themselves which is comprised by clock genes. Our previous data indicated a temporal association between the expressions of chicken Bmal1 clock gene and Aanat suggesting a functional molecular link between them. Here, we studied the effect of cBmal1 antisense oligonucleotides containing locked nucleic acid on cAanat transcripts and melatonin production in cultured chicken pinealocytes transfected in superfusion system. These oligonucleotides synthesized for activating RNase H or blocking the binding of the translation machinery were able to reduce significantly cAanat transcription and melatonin secretion, whereas control inverted oligonucleotides were ineffective. These results indicate the key role of cBmal1 in the regulation of indole metabolism. The superfusion cell culture with reduced transfection toxicity may provide a useful tool for antisense drug design to influence the highly conserved clockwork also in man. PMID:16517056

Rekasi, Zoltan; Horvath, Reka A; Klausz, Barbara; Nagy, Eniko; Toller, Gabor L

2006-04-25

22

Influence of aging on Bmal1 and Per2 expression in extra-SCN oscillators in hamster brain  

PubMed Central

Deletion of the core clock gene, Bmal1, ablates circadian rhythms and accelerates aging, leading to cognitive deficits and tissue atrophy (e.g., skeletal muscle) (Kondratov et al., 2006, Kondratova et al, 2010). Although normal aging has been shown to attenuate Bmal1 expression in the master circadian pacemaker in the suprachiasmatic nucleus (SCN), relatively little is known about age-related changes in Bmal1 expression in other tissues, where Bmal1 may have multiple functions. This study tested the hypothesis that aging reduces Bmal1 expression in extra-SCN oscillators including brain substrates for memory and in skeletal muscle. Brains and gastrocnemius muscles were collected from young (3–5 months) and old hamsters (17–21 months) euthanized at four times of day. Bmal1 mRNA expression was determined by conducting in situ hybridization on brain sections or real-time PCR on muscle samples. The results showed age-related attenuation of Bmal1 expression in many brain regions, and included loss of diurnal rhythms in the hippocampal CA2 and CA3 subfields, but no change in muscle. In situ hybridization for Per2 mRNA was also conducted and showed age-related reduction of diurnal rhythm amplitude selectively in the hippocampal CA1 and DG subfields. In conclusion, aging has tissue-dependent effects on Bmal1 expression in extra-SCN oscillators. These finding on normal aging will provide a reference for comparing potential changes in Bmal1 and Per2 expression in age-related pathologies. In conjunction with previous reports, the results suggest the possibility that attenuation of clock gene expression in some brain regions (the hippocampus, cingulate cortex and SCN) may contribute to age-related cognitive deficits.

Duncan, Marilyn J.; Prochot, Jeffrey R.; Cook, Daniel H.; Smith, J. Tyler; Franklin, Kathleen M.

2012-01-01

23

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis  

PubMed Central

The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day–dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers.

Geyfman, Mikhail; Kumar, Vivek; Liu, Qiang; Ruiz, Rolando; Gordon, William; Espitia, Francisco; Cam, Eric; Millar, Sarah E.; Smyth, Padhraic; Ihler, Alexander; Takahashi, Joseph S.; Andersen, Bogi

2012-01-01

24

Bmal1 and ?-Cell Clock Are Required for Adaptation to Circadian Disruption, and Their Loss of Function Leads to Oxidative Stress-Induced ?-Cell Failure in Mice  

PubMed Central

Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in ?-cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in ? cells. To address this, we generated mice with ?-cell clock disruption by deleting Bmal1 in ? cells (?-Bmal1?/?). ?-Bmal1?/? mice develop diabetes due to loss of glucose-stimulated insulin secretion (GSIS). This loss of GSIS is due to the accumulation of reactive oxygen species (ROS) and consequent mitochondrial uncoupling, as it is fully rescued by scavenging of the ROS or by inhibition of uncoupling protein 2. The expression of the master antioxidant regulatory factor Nrf2 (nuclear factor erythroid 2-related factor 2) and its targets, Sesn2, Prdx3, Gclc, and Gclm, was decreased in ?-Bmal1?/? islets, which may contribute to the observed increase in ROS accumulation. In addition, by chromatin immunoprecipitation experiments, we show that Nrf2 is a direct transcriptional target of Bmal1. Interestingly, simulation of shift work-induced circadian misalignment in mice recapitulates many of the defects seen in Bmal1-deficient islets. Thus, the cell-autonomous function of Bmal1 is required for normal ?-cell function by mitigating oxidative stress and serves to preserve ?-cell function in the face of circadian misalignment.

Lee, Jeongkyung; Moulik, Mousumi; Fang, Zhe; Saha, Pradip; Zou, Fang; Xu, Yong; Nelson, David L.; Ma, Ke; Moore, David D.

2013-01-01

25

Standards of evidence in chronobiology: critical review of a report that restoration of Bmal1 expression in the dorsomedial hypothalamus is sufficient to restore circadian food anticipatory rhythms in Bmal1-/- mice  

PubMed Central

Daily feeding schedules generate food anticipatory rhythms of behavior and physiology that exhibit canonical properties of circadian clock control. The molecular mechanisms and location of food-entrainable circadian oscillators hypothesized to control food anticipatory rhythms are unknown. In 2008, Fuller et al reported that food-entrainable circadian rhythms are absent in mice bearing a null mutation of the circadian clock gene Bmal1 and that these rhythms can be rescued by virally-mediated restoration of Bmal1 expression in the dorsomedial nucleus of the hypothalamus (DMH) but not in the suprachiasmatic nucleus (site of the master light-entrainable circadian pacemaker). These results, taken together with controversial DMH lesion results published by the same laboratory, appear to establish the DMH as the site of a Bmal1-dependent circadian mechanism necessary and sufficient for food anticipatory rhythms. However, careful examination of the manuscript reveals numerous weaknesses in the evidence as presented. These problems are grouped as follows and elaborated in detail: 1. data management issues (apparent misalignments of plotted data), 2. failure of evidence to support the major conclusions, and 3. missing data and methodological details. The Fuller et al results are therefore considered inconclusive, and fail to clarify the role of either the DMH or Bmal1 in the expression of food-entrainable circadian rhythms in rodents.

Mistlberger, Ralph E; Buijs, Ruud M; Challet, Etienne; Escobar, Carolina; Landry, Glenn J; Kalsbeek, Andries; Pevet, Paul; Shibata, Shigenobu

2009-01-01

26

Detection of the CLOCK/BMAL1 heterodimer using a nucleic acid probe with cycling probe technology.  

PubMed

An isothermal signal amplification technique for specific DNA sequences, known as cycling probe technology (CPT), has enabled rapid acquisition of genomic information. Here we report an analogous technique for the detection of an activated transcription factor, a transcription element-binding assay with fluorescent amplification by apurinic/apyrimidinic (AP) site lysis cycle (TEFAL). This simple amplification assay can detect activated transcription factors by using a unique nucleic acid probe containing a consensus binding sequence and an AP site, which enables the CPT reaction with AP endonuclease. In this article, we demonstrate that this method detects the functional CLOCK/BMAL1 heterodimer via the TEFAL probe containing the E-box consensus sequence to which the CLOCK/BMAL1 heterodimer binds. Using TEFAL combined with immunoassays, we measured oscillations in the amount of CLOCK/BMAL1 heterodimer in serum-stimulated HeLa cells. Furthermore, we succeeded in measuring the circadian accumulation of the functional CLOCK/BMAL1 heterodimer in human buccal mucosa cells. TEFAL contributes greatly to the study of transcription factor activation in mammalian tissues and cell extracts and is a powerful tool for less invasive investigation of human circadian rhythms. PMID:20507820

Nakagawa, Kazuhiro; Yamamoto, Takuro; Yasuda, Akio

2010-09-15

27

Comparative analysis of Avian BMAL1 and CLOCK protein sequences: a search for features associated with owl nocturnal behaviour  

Microsoft Academic Search

Animals differ widely in the phasing of their daily rhythms with respect to daily environmental rhythms. While birds are predominantly day-active, nocturnal activity is a characteristic feature of the order Strigiformes (owls). To study the evolution of owl night-activity cDNA sequences encoding the circadian core oscillator (CCO) proteins BMAL1 and CLOCK were obtained from barn owl (Tyto alba). The predicted

Andrew E Fidler; Eberhard Gwinner

2003-01-01

28

Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex  

PubMed Central

The circadian clock controls many aspects of mammalian physiology, including responses to cancer therapy. We find that wild-type and circadian mutant mice demonstrate striking differences in their response to the anticancer drug cyclophosphamide (CY). While the sensitivity of wild-type mice varies greatly, depending on the time of drug administration, Clock mutant and Bmal1 knockout mice are highly sensitive to treatment at all times tested. On the contrary, mice with loss-of-function mutations in Cryptochrome (Cry1-/-Cry2-/- double knockouts) were more resistant to CY compared with their wild-type littermates. Thus, both time-of-day and allelic-dependent variations in response to chemotherapy correlate with the functional status of the circadian CLOCK/BMAL1 transactivation complex. Pharmacokinetic analysis of plasma concentration of different CY metabolites shows that, in contrast to the traditional view, circadian variations in drug sensitivity cannot be attributed to the changes in the rates of CY metabolic activation and/or detoxification. At the same time, mice of different circadian genotypes demonstrate significant differences in B cell responses to toxic CY metabolites: B cell survival/recovery rate was directly correlated with the in vivo drug sensitivity. Based on these results, we propose that the CLOCK/BMAL1 transcriptional complex affects the lethality of chemotherapeutic agents by modulating the survival of the target cells necessary for the viability of the organism.

Gorbacheva, Victoria Y.; Kondratov, Roman V.; Zhang, Renliang; Cherukuri, Srujana; Gudkov, Andrei V.; Takahashi, Joseph S.; Antoch, Marina P.

2005-01-01

29

Brain and muscle Arnt-like 1 is a key regulator of myogenesis  

PubMed Central

Summary The circadian clock network is an evolutionarily conserved mechanism that imparts temporal regulation to diverse biological processes. Brain and muscle Arnt-like 1 (Bmal1), an essential transcriptional activator of the clock, is highly expressed in skeletal muscle. However, whether this key clock component impacts myogenesis, a temporally regulated event that requires the sequential activation of myogenic regulatory factors, is not known. Here we report a novel function of Bmal1 in controlling myogenic differentiation through direct transcriptional activation of components of the canonical Wnt signaling cascade, a major inductive signal for embryonic and postnatal muscle growth. Genetic loss of Bmal1 in mice leads to reduced total muscle mass and Bmal1-deficient primary myoblasts exhibit significantly impaired myogenic differentiation accompanied by markedly blunted expression of key myogenic regulatory factors. Conversely, forced expression of Bmal1 enhances differentiation of C2C12 myoblasts. This cell-autonomous effect of Bmal1 is mediated by Wnt signaling as both expression and activity of Wnt components are markedly attenuated by inhibition of Bmal1, and activation of the Wnt pathway partially rescues the myogenic defect in Bmal1-deficient myoblasts. We further reveal direct association of Bmal1 with promoters of canonical Wnt pathway genes, and as a result of this transcriptional regulation, Wnt signaling components exhibit intrinsic circadian oscillation. Collectively, our study demonstrates that the core clock gene, Bmal1, is a positive regulator of myogenesis, which may represent a temporal regulatory mechanism to fine-tune myocyte differentiation.

Chatterjee, Somik; Nam, Deokhwa; Guo, Bingyan; Kim, Ji M.; Winnier, Glen E.; Lee, Jeongkyung; Berdeaux, Rebecca; Yechoor, Vijay K.; Ma, Ke

2013-01-01

30

Direct Regulation of CLOCK Expression by REV-ERB  

PubMed Central

Circadian rhythms are regulated at the cellular level by transcriptional feedback loops leading to oscillations in expression of key proteins including CLOCK, BMAL1, PERIOD (PER), and CRYPTOCHROME (CRY). The CLOCK and BMAL1 proteins are members of the bHLH class of transcription factors and form a heterodimer that regulates the expression of the PER and CRY genes. The nuclear receptor REV-ERB? plays a key role in regulation of oscillations in BMAL1 expression by directly binding to the BMAL1 promoter and suppressing its expression at certain times of day when REV-ERB? expression levels are elevated. We recently demonstrated that REV-ERB? also regulates the expression of NPAS2, a heterodimer partner of BMAL1. Here, we show that REV-ERB? also regulates the expression another heterodimer partner of BMAL1, CLOCK. We identified a REV-ERB? binding site within the 1st intron of the CLOCK gene using a chromatin immunoprecipitation – microarray screen. Suppression of REV-ERB? expression resulted in elevated CLOCK mRNA expression consistent with REV-ERB?'s role as a transcriptional repressor. A REV-ERB response element (RevRE) was identified within this region of the CLOCK gene and was conserved between humans and mice. Additionally, the CLOCK RevRE conferred REV-ERB responsiveness to a heterologous reporter gene. Our data suggests that REV-ERB? plays a dual role in regulation of the activity of the BMAL1/CLOCK heterodimer by regulation of expression of both the BMAL1 and CLOCK genes.

Crumbley, Christine; Burris, Thomas P.

2011-01-01

31

PER and TIM Inhibit the DNA Binding Activity of a Drosophila CLOCK-CYC\\/dBMAL1 Heterodimer without Disrupting Formation of the Heterodimer: a Basis for Circadian Transcription  

Microsoft Academic Search

The Drosophila CLOCK (dCLOCK) and CYCLE (CYC) (also referred to as dBMAL1) proteins are members of the basic helix-loop-helix PAS (PER-ARNT-SIM) superfamily of transcription factors and are required for high-level expression of the circadian clock genes period (per) and timeless (tim). Several lines of evidence indicate that PER, TIM, or a PER-TIM heterodimer somehow inhibit the transcriptional activity of a

CHOOGON LEE; KIHO BAE; ISAAC EDERY

32

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration  

PubMed Central

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator–like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Musiek, Erik S.; Lim, Miranda M.; Yang, Guangrui; Bauer, Adam Q.; Qi, Laura; Lee, Yool; Roh, Jee Hoon; Ortiz-Gonzalez, Xilma; Dearborn, Joshua T.; Culver, Joseph P.; Herzog, Erik D.; Hogenesch, John B.; Wozniak, David F.; Dikranian, Krikor; Giasson, Benoit I.; Weaver, David R.; Holtzman, David M.; FitzGerald, Garret A.

2013-01-01

33

Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis.  

PubMed

Altered estrogen receptor ? (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process. PMID:22935699

Rossetti, Stefano; Corlazzoli, Francesca; Gregorski, Alex; Azmi, Nurul Hidayah A; Sacchi, Nicoletta

2012-10-01

34

Regulation of Circadian Behavior and Metabolism by Rev-erb? and Rev-erb?  

PubMed Central

The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERB? and ? have been proposed to form an accessory feedback loop that contributes to clock function1,2, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both REV-ERB isoforms, which revealed shared recognition at over 50% of their total sites and extensive overlap with the master circadian regulator BMAL1. While Rev-erb? has been shown to directly regulate Bmal1 expression1,2, the cistromic analysis reveals a direct connection between Bmal1 and Rev-erb? and ? regulatory circuits than previously suspected. Genes within the intersection of the BMAL1, REV-ERB? and REV-ERB? cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb?/? function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data now ally Rev-erb?/? with Per, Cry and other components of the principal feedback loop that drives circadian expression and suggest a more integral mechanism for the coordination of circadian rhythm and metabolism.

Cho, Han; Zhao, Xuan; Hatori, Megumi; Yu, Ruth T.; Barish, Grant D.; Lam, Michael T.; Chong, Ling-Wa; DiTacchio, Luciano; Atkins, Annette R.; Glass, Christopher K.; Liddle, Christopher; Auwerx, Johan; Downes, Michael; Panda, Satchidananda; Evans, Ronald M.

2012-01-01

35

JNK regulates the photic response of the mammalian circadian clock  

PubMed Central

The posttranslational regulation of mammalian clock proteins has been assigned a time-keeping function, but seems to have more essential roles. Here we show that c-Jun N-terminal kinase (JNK), identified by inhibitor screening of BMAL1 phosphorylation at Ser 520/Thr 527/Ser 592, confers dynamic regulation on the clock. Knockdown of JNK1 and JNK2 abrogates BMAL1 phosphorylation and lengthens circadian period in fibroblasts. Mice deficient for neuron-specific isoform JNK3 have altered behavioural rhythms, with longer free-running period and compromised phase shifts to light. The locomotor rhythms are insensitive to intensity variance of constant light, deviating from Aschoff's rule. Thus, JNK regulates a core characteristic of the circadian clock by controlling the oscillation speed and the phase in response to light.

Yoshitane, Hikari; Honma, Sato; Imamura, Kiyomichi; Nakajima, Hiroto; Nishide, Shin-ya; Ono, Daisuke; Kiyota, Hiroshi; Shinozaki, Naoya; Matsuki, Hirokazu; Wada, Naoya; Doi, Hirofumi; Hamada, Toshiyuki; Honma, Ken-ichi; Fukada, Yoshitaka

2012-01-01

36

Resveratrol regulates circadian clock genes in Rat-1 fibroblast cells.  

PubMed

Circadian clocks, especially peripheral clocks, can be strongly entrained by daily feedings, but few papers have reported the effects of food components on circadian rhythm. The effects of resveratrol, a natural polyphenol, on circadian clocks of Rat-1 cells were analyzed. A dose of 100 muM resveratrol, which did not show cytotoxicity, regulated the expression of clock genes Per1, Per2, and Bmal1. PMID:18997419

Oike, Hideaki; Kobori, Masuko

2008-11-01

37

Circadian regulation of ATP release in astrocytes  

PubMed Central

Circadian clocks sustain daily oscillations in gene expression, physiology and behavior, relying on transcription-translation feedback loops of clock genes for rhythm generation. Cultured astrocytes display daily oscillations of extracellular ATP, suggesting that ATP release is a circadian output. We hypothesized that the circadian clock modulates ATP release via mechanisms that regulate acute ATP release from glia. To test the molecular basis for circadian ATP release, we developed methods to measure in real-time ATP release and Bmal1::dLuc circadian reporter expression in cortical astrocyte cultures from mice of different genotypes. Daily rhythms of gene expression required functional Clock and Bmal1, both Per1 and Per2, and both Cry1 and Cry2 genes. Similarly, high level, circadian ATP release also required a functional clock mechanism. Whereas blocking IP3 signaling significantly disrupted ATP rhythms with no effect on Bmal1::dLuc cycling, blocking vesicular release did not alter circadian ATP release or gene expression. We conclude that astrocytes depend on circadian clock genes and IP3 signaling to express daily rhythms in ATP release.

Marpegan, Luciano; Swanstrom, Adrienne E.; Chung, Kevin; Simon, Tatiana; Haydon, Philip G.; Khan, Sanjoy K.; Liu, Andrew C.; Herzog, Erik D.; Beaule, Christian

2011-01-01

38

Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene expression in the liver and kidney.  

PubMed

Mounting evidence suggests that the circadian clock plays an integral role in the regulation of many physiological processes including blood pressure, renal function, and metabolism. The canonical molecular clock functions via activation of circadian target genes by Clock/Bmal1 and repression of Clock/Bmal1 activity by Per1-3 and Cry1/2. However, we have previously shown that Per1 activates genes important for renal sodium reabsorption, which contradicts the canonical role of Per1 as a repressor. Moreover, Per1 knockout (KO) mice exhibit a lowered blood pressure and heavier body weight phenotype similar to Clock KO mice, and opposite that of Cry1/2 KO mice. Recent work has highlighted the potential role of Per1 in repression of Cry2. Therefore, we postulated that Per1 potentially activates target genes through a Cry2-Clock/Bmal1-dependent mechanism, in which Per1 antagonizes Cry2, preventing its repression of Clock/Bmal1. This hypothesis was tested in vitro and in vivo. The Per1 target genes ?ENaC and Fxyd5 were identified as Clock targets in mpkCCDc14 cells, a model of the renal cortical collecting duct. We identified PPAR? and DEC1 as novel Per1 targets in the mouse hepatocyte cell line, AML12, and in the liver in vivo. Per1 knockdown resulted in upregulation of Cry2 in vitro, and this result was confirmed in vivo in mice with reduced expression of Per1. Importantly, siRNA-mediated knockdown of Cry2 and Per1 demonstrated opposing actions for Cry2 and Per1 on Per1 target genes, supporting the potential Cry2-Clock/Bmal1-dependent mechanism underlying Per1 action in the liver and kidney. PMID:23824961

Richards, Jacob; All, Sean; Skopis, George; Cheng, Kit-Yan; Compton, Brandy; Srialluri, Nitya; Stow, Lisa; Jeffers, Lauren A; Gumz, Michelle L

2013-10-01

39

Circadian rhythms regulate amelogenesis.  

PubMed

Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of the development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24 h) intervals both at RNA and protein levels. This study also reveals that the two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory stage ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation stage ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stages of amelogenesis might be under circadian control. Changes in clock gene expression patterns might result in significant alterations of enamel apposition and mineralization. PMID:23486183

Zheng, Li; Seon, Yoon Ji; Mourão, Marcio A; Schnell, Santiago; Kim, Doohak; Harada, Hidemitsu; Papagerakis, Silvana; Papagerakis, Petros

2013-07-01

40

The De-Ubiquitinylating Enzyme, USP2, Is Associated with the Circadian Clockwork and Regulates Its Sensitivity to Light  

PubMed Central

We have identified a novel component of the circadian clock that regulates its sensitivity to light at the evening light to dark transition. USP2 (Ubiquitin Specific Protease 2), which de-ubiquitinylates and stabilizes target proteins, is rhythmically expressed in multiple tissues including the SCN. We have developed a knockout model of USP2 and found that exposure to low irradiance light at ZT12 increases phase delays of USP2?/? mice compared to wildtype. We additionally show that USP2b is in a complex with several clock components and regulates the stability and turnover of BMAL1, which in turn alters the expression of several CLOCK/BMAL1 controlled genes. Rhythmic expression of USP2 in the SCN and other tissues offers a new level of control of the clock machinery through de-ubiqutinylation and suggests a role for USP2 during circadian adaptation to environmental day length changes.

Scoma, Heather Dehlin; Humby, Monica; Yadav, Geetha; Zhang, Qingjiong; Fogerty, Joseph; Besharse, Joseph C.

2011-01-01

41

p53 Regulates Period2 Expression and the Circadian Clock  

PubMed Central

The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2), a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviorally, p53?/? mice have a shorter period length that lacks stability and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behavior.

Miki, Takao; Matsumoto, Tomoko; Zhao, Zhaoyang; Lee, Cheng Chi

2013-01-01

42

p75 Neurotrophin Receptor Is a Clock Gene That Regulates Oscillatory Components of Circadian and Metabolic Networks  

PubMed Central

The p75 neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor superfamily with a widespread pattern of expression in tissues such as the brain, liver, lung, and muscle. The mechanisms that regulate p75NTR transcription in the nervous system and its expression in other tissues remain largely unknown. Here we show that p75NTR is an oscillating gene regulated by the helix-loop-helix transcription factors CLOCK and BMAL1. The p75NTR promoter contains evolutionarily conserved noncanonical E-box enhancers. Deletion mutagenesis of the p75NTR-luciferase reporter identified the ?1039 conserved E-box necessary for the regulation of p75NTR by CLOCK and BMAL1. Accordingly, gel-shift assays confirmed the binding of CLOCK and BMAL1 to the p75NTR?1039 E-box. Studies in mice revealed that p75NTR transcription oscillates during dark and light cycles not only in the suprachiasmatic nucleus (SCN), but also in peripheral tissues including the liver. Oscillation of p75NTR is disrupted in Clock-deficient and mutant mice, is E-box dependent, and is in phase with clock genes, such as Per1 and Per2. Intriguingly, p75NTR is required for circadian clock oscillation, since loss of p75NTR alters the circadian oscillation of clock genes in the SCN, liver, and fibroblasts. Consistent with this, Per2::Luc/p75NTR?/? liver explants showed reduced circadian oscillation amplitude compared with those of Per2::Luc/p75NTR+/+. Moreover, deletion of p75NTR also alters the circadian oscillation of glucose and lipid homeostasis genes. Overall, our findings reveal that the transcriptional activation of p75NTR is under circadian regulation in the nervous system and peripheral tissues, and plays an important role in the maintenance of clock and metabolic gene oscillation.

Baeza-Raja, Bernat; Eckel-Mahan, Kristin; Zhang, Luoying; Vagena, Eirini; Tsigelny, Igor F.; Sassone-Corsi, Paolo; Ptacek, Louis J.

2013-01-01

43

Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation1  

PubMed Central

Foxp3, a winged-helix family transcription factor, serves as the master switch for CD4+ regulatory T cells (Treg). We identified a unique and evolutionarily conserved CpG-rich island of the Foxp3 nonintronic upstream enhancer and discovered that a specific site within it was unmethylated in natural Treg (nTreg) but heavily methylated in naive CD4+ T cells, activated CD4+ T cells, and peripheral TGF?-induced Treg in which it was bound by DNMT1, DNMT3b, MeCP2, and MBD2. Demethylation of this CpG site using the DNA methyltransferase inhibitor 5-aza-2?-deoxycytidine (Aza) induced acetylation of histone 3, interaction with TIEG1 and Sp1, and resulted in strong and stable induction of Foxp3. Conversely, IL-6 resulted in methylation of this site and repression of Foxp3 expression. Aza plus TGF?-induced Treg resembled nTreg, expressing similar receptors, cytokines, and stable suppressive activity. Strong Foxp3 expression and suppressor activity could be induced in a variety of T cells, including human CD4+CD25? T cells. Epigenetic regulation of Foxp3 can be predictably controlled with DNMT inhibitors to generate functional, stable, and specific Treg.

Lal, Girdhari; Zhang, Nan; van der Touw, William; Ding, Yaozhong; Ju, Wenjun; Bottinger, Erwin P.; Reid, St. Patrick; Levy, David E.; Bromberg, Jonathan S.

2013-01-01

44

Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation.  

PubMed

Foxp3, a winged-helix family transcription factor, serves as the master switch for CD4(+) regulatory T cells (Treg). We identified a unique and evolutionarily conserved CpG-rich island of the Foxp3 nonintronic upstream enhancer and discovered that a specific site within it was unmethylated in natural Treg (nTreg) but heavily methylated in naive CD4(+) T cells, activated CD4(+) T cells, and peripheral TGFbeta-induced Treg in which it was bound by DNMT1, DNMT3b, MeCP2, and MBD2. Demethylation of this CpG site using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza) induced acetylation of histone 3, interaction with TIEG1 and Sp1, and resulted in strong and stable induction of Foxp3. Conversely, IL-6 resulted in methylation of this site and repression of Foxp3 expression. Aza plus TGFbeta-induced Treg resembled nTreg, expressing similar receptors, cytokines, and stable suppressive activity. Strong Foxp3 expression and suppressor activity could be induced in a variety of T cells, including human CD4(+)CD25(-) T cells. Epigenetic regulation of Foxp3 can be predictably controlled with DNMT inhibitors to generate functional, stable, and specific Treg. PMID:19109157

Lal, Girdhari; Zhang, Nan; van der Touw, William; Ding, Yaozhong; Ju, Wenjun; Bottinger, Erwin P; Reid, St Patrick; Levy, David E; Bromberg, Jonathan S

2009-01-01

45

Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis.  

PubMed

During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)?. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes. PMID:20852621

Zhang, Eric E; Liu, Yi; Dentin, Renaud; Pongsawakul, Pagkapol Y; Liu, Andrew C; Hirota, Tsuyoshi; Nusinow, Dmitri A; Sun, Xiujie; Landais, Severine; Kodama, Yuzo; Brenner, David A; Montminy, Marc; Kay, Steve A

2010-10-01

46

The RelB subunit of NF?B acts as a negative regulator of circadian gene expression  

PubMed Central

The circadian system controls a large array of physiological and metabolic functions. The molecular organization of the circadian clock is complex, involving various elements organized in feedback regulatory loops. Here we demonstrate that the RelB subunit of NF?B acts as a repressor of circadian transcription. RelB physically interacts with the circadian activator BMAL1 in the presence of CLOCK to repress circadian gene expression at the promoter of the clock-controlled gene Dbp. The repression is independent of the circadian negative regulator CRY. Notably, RelB ?/? fibroblasts have profound alterations of circadian genes expression. These findings reveal a previously unforeseen function for RelB as an important regulator of the mammalian circadian system in fibroblasts.

Bellet, Marina M.; Zocchi, Loredana; Sassone-Corsi, Paolo

2012-01-01

47

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility  

PubMed Central

The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCS?Bmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCS?Bmal1?/?) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCS?Bmal1?/? hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na+ channel (NaV1.5), was circadianly expressed in control mouse and rat hearts but not in iCS?Bmal1?/? hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCS?Bmal1?/? hearts was associated with decreased levels of NaV1.5 and Na+ current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans.

Lefta, Mellani; Zhang, Xiping; Bartos, Daniel; Feng, Han-Zhong; Zhao, Yihua; Patwardhan, Abhijit; Jin, Jian-Ping; Esser, Karyn A.; Delisle, Brian P.

2013-01-01

48

Circadian Regulation of Lipid Mobilization in White Adipose Tissues  

PubMed Central

In mammals, a network of circadian clocks regulates 24-h rhythms of behavior and physiology. Circadian disruption promotes obesity and the development of obesity-associated disorders, but it remains unclear to which extent peripheral tissue clocks contribute to this effect. To reveal the impact of the circadian timing system on lipid metabolism, blood and adipose tissue samples from wild-type, Clock?19, and Bmal1?/? circadian mutant mice were subjected to biochemical assays and gene expression profiling. We show diurnal variations in lipolysis rates and release of free fatty acids (FFAs) and glycerol into the blood correlating with rhythmic regulation of two genes encoding the lipolysis pacemaker enzymes, adipose triglyceride (TG) lipase and hormone-sensitive lipase, by self-sustained adipocyte clocks. Circadian clock mutant mice show low and nonrhythmic FFA and glycerol blood content together with decreased lipolysis rates and increased sensitivity to fasting. Instead circadian clock disruption promotes the accumulation of TGs in white adipose tissue (WAT), leading to increased adiposity and adipocyte hypertrophy. In summary, circadian modulation of lipolysis rates regulates the availability of lipid-derived energy during the day, suggesting a role for WAT clocks in the regulation of energy homeostasis.

Shostak, Anton; Meyer-Kovac, Judit; Oster, Henrik

2013-01-01

49

Temporal Regulation of Cytokines by the Circadian Clock  

PubMed Central

Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to “circadian rhythms.” Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system “circadian clock” plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK) temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines.

Nakao, Atsuhito

2014-01-01

50

Regulation of period 1 expression in cultured rat pineal  

NASA Technical Reports Server (NTRS)

The aim of the present study was to investigate the in vitro expression of Period 1 (Per1), Period 2 (Per2) and arylalkylamine N-acetyltransferase (AA-NAT) genes in the rat pineal gland to understand the mechanism(s) regulating the expression of these genes in this organ. Pineals, when maintained in vitro for 5 days, did not show circadian rhythmicity in the expression of any of the three genes monitored. Norepinephrine (NE) induced AA-NAT and Per1, whereas its effect on Per2 was negligible. Contrary to what was observed in other systems, NE stimulation did not induce circadian expression of Per1. The effect of NE on Per1 level was dose- and receptor subtype-dependent, and both cAMP and cGMP induced Per1. Per1 was not induced by repeated NE - or forskolin - stimulation. Protein synthesis was not necessary for NE-induced Per1, but it was for reduction of Per1 following NE stimulation. Per1 transcription in pinealocytes was activated by BMAL1/CLOCK. Our results indicate that important differences are present in the regulation of these genes in the mammalian pineal. Copyright 2002 S. Karger AG, Basel.

Fukuhara, Chiaki; Dirden, James C.; Tosini, Gianluca

2002-01-01

51

24-hour rhythm of aquaporin-3 function in the epidermis is regulated by molecular clocks.  

PubMed

Aquaporin 3 (AQP3) is located in the basal layer of the epidermis and regulates biological functions of skin such as water content and trans-epidermal water loss. A recent study showed that the biological function of skin exhibits a 24-hour rhythm, but the molecular mechanism of the variation remains poorly understood. Here we show that mice mutated in the core clock component CLOCK (Clk/Clk) show decreased stratum corneum hydration. An extensive search for the underlying cause led us to identify AQP3 as a new regulator to control the 24-hour variation in biological functions of skin. In mouse epidermis of wild-type mice, mAqp3 exhibits circadian rhythms; however, these are significantly decreased in Clk/Clk. Luciferase reporter gene analysis revealed that transcription of mAqp3 is activated by D-site-binding protein, a clock gene. A human homolog, hAQP3, also exhibited significant oscillation in human keratinocyte (HaCaT) cells synchronized with medium containing 50% serum, and this rhythm was regulated by the endogenous CLOCK/BMAL1 heterodimer. These data indicate that although the molecular mechanisms underlying the rhythmic expression of mAqp3 and hAQP3 are different, clock genes are involved in time-dependent skin hydration. Our current findings provide a molecular link between the circadian clock and AQP3 function in mouse dorsal skin and HaCaT cells. PMID:24418925

Matsunaga, Naoya; Itcho, Kazufumi; Hamamura, Kengo; Ikeda, Eriko; Ikeyama, Hisako; Furuichi, Yoko; Watanabe, Miyako; Koyanagi, Satoru; Ohdo, Shigehiro

2014-06-01

52

Role of Type II Protein Arginine Methyltransferase 5 in the Regulation of Circadian Per1 Gene  

PubMed Central

Circadian clocks are the endogenous oscillators that regulate rhythmic physiological and behavioral changes to correspond to daily light-dark cycles. Molecular dissections have revealed that transcriptional feedback loops of the circadian clock genes drive the molecular oscillation, in which PER/CRY complexes inhibit the transcriptional activity of the CLOCK/BMAL1 heterodimer to constitute a negative feedback loop. In this study, we identified the type II protein arginine methyltransferase 5 (PRMT5) as an interacting molecule of CRY1. Although the Prmt5 gene was constitutively expressed, increased interaction of PRMT5 with CRY1 was observed when the Per1 gene was repressed both in synchronized mouse liver and NIH3T3 cells. Moreover, rhythmic recruitment of PRMT5 and CRY1 to the Per1 gene promoter was found to be associated with an increased level of histone H4R3 dimethylation and Per1 gene repression. Consistently, decreased histone H4R3 dimethylation and altered rhythmic Per1 gene expression were observed in Prmt5-depleted cells. Taken together, these findings provide an insight into the link between histone arginine methylation by PRMT5 and transcriptional regulation of the circadian Per1 gene.

Na, Jungtae; Lee, Kwanghyun; Kim, Hwan-Gon; Shin, Jee-Yoon; Na, Wonho; Jeong, Hayan; Lee, Jong-Woo; Cho, Sehyung; Kim, Won-Sun; Ju, Bong-Gun

2012-01-01

53

The molecular mechanism regulating the autonomous circadian expression of Topoisomerase I in NIH3T3 cells.  

PubMed

To identify whether Topoisomerase I (TopoI) has autonomous circadian rhythms regulated by clock genes, we tested mouse TopoI (mTopoI) promoter oscillation in NIH3T3 cells using a real-time monitoring assay and TopoI mRNA oscillations using real-time RT-PCR. Analysis of the mTopoI promoter region with Matlnspector software revealed two putative E-box (E1 and E2) and one DBP/E4BP4-binding element (D-box). Luciferase assays indicated that mTopoI gene expression was directly regulated by clock genes. The real-time monitoring assay showed that E-box and D-box response elements participate in the regulation of the circadian expression of mTopoI. Furthermore, a gel-shift assay showed that E2 is a direct target of the BMAL1/CLOCK heterodimer and DBP binds to the putative D-site. These results indicate that TopoI is expressed in an autonomous circadian rhythm in NIH3T3 cells. PMID:19138663

Yang, Fang; Nakajima, Yoshihiro; Kumagai, Megumi; Ohmiya, Yoshihiro; Ikeda, Masaaki

2009-02-27

54

Mistimed sleep disrupts circadian regulation of the human transcriptome  

PubMed Central

Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic processes, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep–wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized. Desynchrony of sleep–wake timing and other circadian rhythms, such as occurs in shift work and jet lag, is associated with disruption of rhythmicity in physiology and endocrinology. However, to what extent mistimed sleep affects the molecular regulators of circadian rhythmicity remains to be established. Here, we show that mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony of sleep and centrally driven circadian rhythms. Transcripts affected are key regulators of gene expression, including those associated with chromatin modification (methylases and acetylases), transcription (RNA polymerase II), translation (ribosomal proteins, initiation, and elongation factors), temperature-regulated transcription (cold inducible RNA-binding proteins), and core clock genes including CLOCK and ARNTL (BMAL1). We also estimated the separate contribution of sleep and circadian rhythmicity and found that the sleep–wake cycle coordinates the timing of transcription and translation in particular. The data show that mistimed sleep affects molecular processes at the core of circadian rhythm generation and imply that appropriate timing of sleep contributes significantly to the overall temporal organization of the human transcriptome.

Archer, Simon N.; Laing, Emma E.; Moller-Levet, Carla S.; van der Veen, Daan R.; Bucca, Giselda; Lazar, Alpar S.; Santhi, Nayantara; Slak, Ana; Kabiljo, Renata; von Schantz, Malcolm; Smith, Colin P.; Dijk, Derk-Jan

2014-01-01

55

Mistimed sleep disrupts circadian regulation of the human transcriptome.  

PubMed

Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic processes, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep-wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized. Desynchrony of sleep-wake timing and other circadian rhythms, such as occurs in shift work and jet lag, is associated with disruption of rhythmicity in physiology and endocrinology. However, to what extent mistimed sleep affects the molecular regulators of circadian rhythmicity remains to be established. Here, we show that mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony of sleep and centrally driven circadian rhythms. Transcripts affected are key regulators of gene expression, including those associated with chromatin modification (methylases and acetylases), transcription (RNA polymerase II), translation (ribosomal proteins, initiation, and elongation factors), temperature-regulated transcription (cold inducible RNA-binding proteins), and core clock genes including CLOCK and ARNTL (BMAL1). We also estimated the separate contribution of sleep and circadian rhythmicity and found that the sleep-wake cycle coordinates the timing of transcription and translation in particular. The data show that mistimed sleep affects molecular processes at the core of circadian rhythm generation and imply that appropriate timing of sleep contributes significantly to the overall temporal organization of the human transcriptome. PMID:24449876

Archer, Simon N; Laing, Emma E; Möller-Levet, Carla S; van der Veen, Daan R; Bucca, Giselda; Lazar, Alpar S; Santhi, Nayantara; Slak, Ana; Kabiljo, Renata; von Schantz, Malcolm; Smith, Colin P; Dijk, Derk-Jan

2014-02-11

56

Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver  

PubMed Central

Background The circadian clock is a critical regulator of biological functions controlling behavioral, physiological and biochemical processes. Because the liver is the primary regulator of metabolites within the mammalian body and the disruption of circadian rhythms in liver is associated with severe illness, circadian regulators would play a strong role in maintaining liver function. However, the regulatory structure that governs circadian dynamics within the liver at a transcriptional level remains unknown. To explore this aspect, we analyzed hepatic transcriptional dynamics in Sprague-Dawley rats over a period of 24 hours to assess the genome-wide responses. Results Using an unsupervised consensus clustering method, we identified four major gene expression clusters, corresponding to central carbon and nitrogen metabolism, membrane integrity, immune function, and DNA repair, all of which have dynamics which suggest regulation in a circadian manner. With the assumption that transcription factors (TFs) that are differentially expressed and contain CLOCK:BMAL1 binding sites on their proximal promoters are likely to be clock-controlled TFs, we were able to use promoter analysis to putatively identify additional clock-controlled TFs besides PARF and RORA families. These TFs are both functionally and temporally related to the clusters they regulate. Furthermore, we also identified significant sets of clock TFs that are potentially transcriptional regulators of gene clusters. Conclusions All together, we were able to propose a regulatory structure for circadian regulation which represents alternative paths for circadian control of different functions within the liver. Our prediction has been affirmed by functional and temporal analyses which are able to extend for similar studies.

2014-01-01

57

Mammalian clock gene Cryptochrome regulates arthritis via proinflammatory cytokine TNF-alpha.  

PubMed

The mammalian clock genes, Period and Cryptochrome (Cry), regulate circadian rhythm. We show that circadian rhythmicity and rhythmic expression of Period in the nuclei of inflammatory synovial cells and spleen cells are disturbed in mouse models of experimental arthritis. Expressions of other clock genes, Bmal1 and Dbp, are also disturbed in spleen cells by arthritis induction. Deletion of Cry1 and Cry2 results in an increase in the number of activated CD3(+) CD69(+) T cells and a higher production of TNF-alpha from spleen cells. When arthritis is induced, Cry1(-/-)Cry2(-/-) mice develop maximal exacerbation of joint swelling, and upregulation of essential mediators of arthritis, including TNF-alpha, IL-1beta and IL-6, and matrix metalloproteinase-3. Wee-1 kinase is solely upregulated in Cry1(-/-)Cry2(-/-) mice, in line with upregulation of c-Fos and Wee-1 kinase in human rheumatoid arthritis. The treatment with anti-TNF-alpha Ab significantly reduced the severity and halted the progression of the arthritis of Cry1(-/-)Cry2(-/-) mice and vice versa, ectopic expression of Cry1 in the mouse embryonic fibroblast from Cry1(-/-)Cry2(-/-) mice significantly reduced the trans activation of TNF-alpha gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease. PMID:20042581

Hashiramoto, Akira; Yamane, Takashi; Tsumiyama, Ken; Yoshida, Kohsuke; Komai, Koichiro; Yamada, Hiroyuki; Yamazaki, Fumiyoshi; Doi, Masao; Okamura, Hitoshi; Shiozawa, Shunichi

2010-02-01

58

The Autophagy-related Gene 14 (Atg14) Is Regulated by Forkhead Box O Transcription Factors and Circadian Rhythms and Plays a Critical Role in Hepatic Autophagy and Lipid Metabolism*  

PubMed Central

Autophagy plays a critical role in cell survival from prolonged starvation and recycling of aggregated proteins and damaged organelles. One of the essential genes involved in the autophagic initiation is autophagy-related 14 (Atg14), also called Barkor for Beclin 1-associated autophagy-related key regulator. Although its crucial role in the autophagic process has been reported, the gene regulation of Atg14 and its metabolic functions remain unclear. In this work we have identified that the Atg14 gene is regulated by forkhead box O (FoxO) transcription factors and circadian rhythms in the mouse liver. Luciferase reporter analyses and chromatin immunoprecipitation assays have revealed well conserved cis-elements for FoxOs and Clock/Bmal1 in the proximal promoter of the Atg14 gene. To examine the functions of hepatic Atg14, we have performed the gene knockdown and overexpression in the mouse livers. Remarkably, knockdown of Atg14 leads to elevated levels of triglycerides in the liver and serum as well. Conversely, overexpression of Atg14 improves hypertriglyceridemia in both high fat diet-treated wild-type mice and FoxO1/3/4 liver-specific knock-out mice. In summary, our data suggest that Atg14 is a new target gene of FoxOs and the core clock machinery, and this gene plays an important role in hepatic lipid metabolism.

Xiong, Xiwen; Tao, Rongya; DePinho, Ronald A.; Dong, X. Charlie

2012-01-01

59

Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts.  

PubMed Central

Recent advances suggest that the molecular components of the circadian clock generate a self-sustaining transcriptional-translational feedback loop with a period of approx. 24 h. The precise expression profiles of human clock genes and their products have not been elucidated. We cloned human clock genes, including per1, per2, per3, cry2 and clock, and evaluated their circadian mRNA expression profiles in WI-38 fibroblasts stimulated with serum. Transcripts of hPer1, hPer2, hPer3, hBMAL1 and hCry2 (where h is human) underwent circadian oscillation. Serum-stimulation also caused daily oscillations of hPER1 protein and the apparent molecular mass of hPER1 changed. Inhibitor studies indicated that the CKI (casein kinase I) family, including CKIepsilon and CKIdelta, phosphorylated hPER1 and increased the apparent molecular mass of hPER1. The inhibition of hPER1 phosphorylation by CKI-7 [ N -(2-aminoethyl)-5-chloro-isoquinoline-8-sulphonamide], a CKI inhibitor, disturbed hPER1 degradation, delayed the nuclear entry of hPER1 and allowed it to persist for longer in the nucleus. Furthermore, proteasome inhibitors specifically blocked hPER1 degradation. However leptomycin B, an inhibitor of nuclear export, did not alter the degradation state of hPER1 protein. These findings indicate that circadian hPER1 degradation through a proteasomal pathway can be regulated through phosphorylation by CKI, but not by subcellular localization.

Miyazaki, Koyomi; Nagase, Takahiro; Mesaki, Miho; Narukawa, Junko; Ohara, Osamu; Ishida, Norio

2004-01-01

60

SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm  

PubMed Central

SUMMARY Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1: CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circa-dian clock.

Stashi, Erin; Lanz, Rainer B.; Mao, Jianqiang; Michailidis, George; Zhu, Bokai; Kettner, Nicole M.; Putluri, Nagireddy; Reineke, Erin L.; Reineke, Lucas C.; Dasgupta, Subhamoy; Dean, Adam; Stevenson, Connor R.; Sivasubramanian, Natarajan; Sreekumar, Arun; DeMayo, Francesco; York, Brian; Fu, Loning; O'Malley, Bert W.

2014-01-01

61

Cooperation of luteinizing hormone signaling pathways in preovulatory avian follicles regulates circadian clock expression in granulosa cell.  

PubMed

Ovulation in birds is triggered by a surge of luteinizing hormone (LH), and the ovulatory cycle is affected by the circadian rhythms of clock genes transcription levels in follicles. The influence of LH signaling cascades action on circadian clock genes was investigated using granulosa cells of preovulatory follicles from Roman hens cultured in a serum-free system. The expression of core oscillators (Bmal1, Clock, Cry1, Per2, and Rev-erb?), clock-controlled gene (Star), Egr-1 and LHr was measured by quantitative real-time PCR. Significant changes in clock genes transcription levels were observed in control groups over 24 h, indicating that cell-autonomous rhythms exist in granulosa cells. Intriguingly, the transcript levels of clock genes increased with LH treatment during 24 h of culture; they peaked 4 h in advance of controls and second but weaker oscillations were also observed. It appeared that LH changed the cell-autonomous rhythm and cycle time of clock genes. To further investigate the LH signaling cascades, inhibitors of cyclic adenosine monophosphate (cAMP), p38 mitogen-activated protein kinases (p38MAPK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways were used. The transcript levels of clock genes were suppressed by blocking cAMP, but increased with similar expression patterns by blocking the p38MPAK and ERK1/2 pathways over 24 h. Thus, the influence of LH signaling cascades in chicken ovulation is mediated by the cAMP pathway and also involves the p38MAPK and ERK1/2 pathways. PMID:24825178

Li, Liang; Zhang, Zhichao; Peng, Jiyun; Wang, Yagang; Zhu, Qing

2014-09-01

62

Clock genes regulate neurogenic transcription factors, including NeuroD1, and the neuronal differentiation of adult neural stem\\/progenitor cells  

Microsoft Academic Search

The circadian clock system plays multiple roles in our bodies, and clock genes are expressed in various brain regions, including the lateral subventricular zone (SVZ) where neural stem\\/progenitor cells (NSPCs) persist and postnatal neurogenesis continues. However, the functions of clock genes in adult NSPCs are not well understood. Here, we first investigated the expression patterns of Clock and Bmal1 in

Tomomi Kimiwada; Mikako Sakurai; Hiroki Ohashi; Shunsuke Aoki; Teiji Tominaga; Keiji Wada

2009-01-01

63

Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1? gene expression in pancreatic islet ?-cells  

SciTech Connect

Highlights: •Arnt mRNA expressed in a circadian manner in mouse pancreatic islets. •Expressions of Dbp and Arnt damped in the islets of a diabetic model mouse. •DBP and E4BP4 regulate Arnt promoter activity by direct binding. •Arnt may have a role in connecting circadian rhythm and metabolism. -- Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1? (HIF-1?) has emerged as a potential determinant of pancreatic ?-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1{sup ?/?} A{sup y}/a mice that develop severe diabetes due to ?-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the Arnt promoter in MIN6 cells. These results suggest that in mouse pancreatic islets mRNA expression of Arnt fluctuates significantly in a circadian manner and that the down-regulation of Dbp and up-regulation E4bp4 contribute to direct suppression of Arnt expression in diabetes.

Nakabayashi, Hiroko; Ohta, Yasuharu, E-mail: yohta@yamaguchi-u.ac.jp; Yamamoto, Masayoshi; Susuki, Yosuke; Taguchi, Akihiko; Tanabe, Katsuya; Kondo, Manabu; Hatanaka, Masayuki; Nagao, Yuko; Tanizawa, Yukio, E-mail: tanizawa@yamaguchi-u.ac.jp

2013-05-03

64

Sleep and circadian rhythm regulation in early Parkinson disease.  

PubMed

IMPORTANCE Sleep disturbances are recognized as a common nonmotor complaint in Parkinson disease but their etiology is poorly understood. OBJECTIVE To define the sleep and circadian phenotype of patients with early-stage Parkinson disease. DESIGN, SETTING, AND PARTICIPANTS Initial assessment of sleep characteristics in a large population-representative incident Parkinson disease cohort (N=239) at the University of Cambridge, England, followed by further comprehensive case-control sleep assessments in a subgroup of these patients (n=30) and matched controls (n=15). MAIN OUTCOMES AND MEASURES Sleep diagnoses and sleep architecture based on polysomnography studies, actigraphy assessment, and 24-hour analyses of serum cortisol, melatonin, and peripheral clock gene expression (Bmal1, Per2, and Rev-Erb?). RESULTS Subjective sleep complaints were present in almost half of newly diagnosed patients and correlated significantly with poorer quality of life. Patients with Parkinson disease exhibited increased sleep latency (P?=?.04), reduced sleep efficiency (P?=?.008), and reduced rapid eye movement sleep (P?=?.02). In addition, there was a sustained elevation of serum cortisol levels, reduced circulating melatonin levels, and altered Bmal1 expression in patients with Parkinson disease compared with controls. CONCLUSIONS AND RELEVANCE Sleep dysfunction seen in early Parkinson disease may reflect a more fundamental pathology in the molecular clock underlying circadian rhythms. PMID:24687146

Breen, David P; Vuono, Romina; Nawarathna, Upekshani; Fisher, Kate; Shneerson, John M; Reddy, Akhilesh B; Barker, Roger A

2014-05-01

65

Metabolic Jet Lag when the Fat Clock is out of Sync  

PubMed Central

There is a growing appreciation of the importance of circadian regulation in energy homeostasis, and the dysregulation of the circadian clock has been associated with obesity and metabolic abnormalities. A new study shows that adipocyte-specific deletion of a core circadian clock gene, Bmal1, in mice shifts the timing of their feeding behavior, resulting in obesity (aaa-bbb).

Asterholm, Ingrid Wernstedt; Scherer, Philipp E.

2013-01-01

66

Telomerase Regulation  

PubMed Central

The intimate connection between telomerase regulation and human disease is now well established. The molecular basis for telomerase regulation is highly complex and entails multiple layers of control. While the major target of enzyme regulation is the catalytic subunit TERT, the RNA subunit of telomerase is also implicated in telomerase control. In addition, alterations in gene dosage and alternative isoforms of core telomerase components have been described. Finally, telomerase localization, recruitment to the telomere and enzymology at the chromosome terminus are all subject to modulation. In this review we summarize recent advances in understanding fundamental mechanisms of telomerase regulation.

Cifuentes-Rojas, Catherine; Shippen, Dorothy E.

2011-01-01

67

Preschool Regulations.  

ERIC Educational Resources Information Center

Published by the Department of Health and Human Services, as required by Nebraska law, this guide details regulations for the physical well-being, safety, and protection of children and defines the minimum levels of acceptable services to be provided in Nebraska preschools. The first section of the guide lists specific preschool regulations,…

Nebraska State Dept. of Health and Human Services, Lincoln.

68

Vacuum regulator  

Microsoft Academic Search

This patent describes a vacuum regulator for automotive vehicles of the type having an engine exhaust system and a computer controlled exhaust gas recirculation system. The vacuum regulator consists of: a housing having separate interconnected upper and lower portions; a solenoid in the housing including a bobbin having a valve seat; a mechanism for defining an inlet for atmospheric air

M. Slavin; R. P. Fontecchio

1986-01-01

69

PPARs Integrate the Mammalian Clock and Energy Metabolism  

PubMed Central

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of numerous target genes. PPARs play an essential role in various physiological and pathological processes, especially in energy metabolism. It has long been known that metabolism and circadian clocks are tightly intertwined. However, the mechanism of how they influence each other is not fully understood. Recently, all three PPAR isoforms were found to be rhythmically expressed in given mouse tissues. Among them, PPAR? and PPAR? are direct regulators of core clock components, Bmal1 and Rev-erb?, and, conversely, PPAR? is also a direct Bmal1 target gene. More importantly, recent studies using knockout mice revealed that all PPARs exert given functions in a circadian manner. These findings demonstrated a novel role of PPARs as regulators in correlating circadian rhythm and metabolism. In this review, we summarize advances in our understanding of PPARs in circadian regulation.

Chen, Lihong; Yang, Guangrui

2014-01-01

70

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors  

PubMed Central

During cerebellum development, Sonic hedgehog (Shh)-induced proliferation of cerebellar granular neuronal precursors (CGNPs) is potently inhibited by bone morphogenetic proteins (BMPs). We have previously reported the upregulation of TIEG-1 and Mash1, two antimitotic factors that modulate MYCN transcription and N-Myc activity, in response to BMP2. To gain further insight into the BMP antimitotic mechanism, we used microRNA (miRNA) arrays to compare the miRNAs of CGNPs proliferating in response to Shh with those of CGNPs treated with Shh plus BMP2. The array analysis revealed that miRNA 11 (miR-22) levels significantly increased in cells treated with BMP2. Additionally, in P7 mouse cerebellum, miR-22 distribution mostly recapitulated the combination of BMP2 and BMP4 expression patterns. Accordingly, in CGNP cultures, miR-22 overexpression significantly reduced cell proliferation, whereas miR-22 suppression diminished BMP2 antiproliferative activity. In contrast to BMP2, miR-22 did not induce neural differentiation but instead significantly increased cell cycle length. Consistent with the central role played by N-myc on CGNP proliferation, Max was revealed as a direct target of miR-22, and miR-22 expression caused a significant reduction of Max protein levels and N-myc/Max-dependent promoter activity. Therefore, we conclude that, in addition to the previously described mechanisms, miR-22 plays a specific role on downstream BMPs through cerebellum growth.

Berenguer, Jordi; Herrera, Antonio; Vuolo, Laura; Torroba, Blanca; Llorens, Franc; Sumoy, Lauro

2013-01-01

71

Florida Seafood Regulations and Regulators.  

National Technical Information Service (NTIS)

This article is intended to explain the pertinent regulations and responsible regulatory authorities which have some monitoring role for the seafood industry in Florida. The primary concerns are proper use of the respective natural resources, product qual...

W. S. Otwell

1985-01-01

72

Circadian clock, cancer and lipid metabolism  

Microsoft Academic Search

Genetic analysis has revealed that mammalian circadian oscillator is driven by a cell autonomous transcription\\/translation-based negative feedback loop, wherein positive elements (CLOCK and BMAL1) induce the expression of negative regulators (Periods, CRY1 and CRY2) that inhibit the transactivation of positive regulators. Recent research reveals that this clock feedback loop affects many aspects of our physiology, such as cell cycle and

Norio Ishida

2007-01-01

73

Circadian clock gene regulation of steroidogenic acute regulatory protein gene expression in preovulatory ovarian follicles.  

PubMed

It is now known that circadian clocks are localized not only in the central pacemaker but also in peripheral organs. An example of a clock-dependent peripheral organ is the ovary of domestic poultry in which ovulation is induced by the positive feedback action of ovarian progesterone on the neuroendocrine system to generate a preovulatory release of LH during a daily 6-10 h "open period" of the ovulatory cycle. It has been assumed previously that the timing of ovulation in poultry is controlled solely by a clock-dependent mechanism within the neuroendocrine system. Here, we question this assumption by demonstrating the expression of the clock genes, Per2 (Period 2) and Per3, Clock, and Bmal1 (brain and muscle Arnt-like protein 1), in preovulatory follicles in laying quail. Diurnal changes in Per2 and Per3 expression were seen in the largest preovulatory follicle (F1) but not in smaller follicles. We next sought to identify clock-driven genes in preovulatory follicles focusing on those involved in the synthesis of progesterone. One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24-h changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock driven was obtained by showing that its 5' flanking region contains E-box enhancers that bind to CLOCK/BMAL1 heterodimers to activate gene transcription. We also showed that LH administration increased the promoter activity of chicken StAR. We therefore suggest that the timing of ovulation in poultry involves an LH-responsive F1 follicular clock that is involved in the timing of the preovulatory release of progesterone. PMID:17431006

Nakao, Nobuhiro; Yasuo, Shinobu; Nishimura, Atsuko; Yamamura, Takashi; Watanabe, Tsuyoshi; Anraku, Tsubasa; Okano, Toshiyuki; Fukada, Yoshitaka; Sharp, Peter J; Ebihara, Shizufumi; Yoshimura, Takashi

2007-07-01

74

Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3  

Microsoft Academic Search

Background: The Arnt3 (also termed as BMAL1 or MOP3)\\/Clock heterodimer is a positive regulator of circadian rhythm and activates the transcription of target genes such as per1 and vasopressin. Results: We investigated the transcriptional mechan- ism of mArnt3\\/mClock heterodimer. While mClock did not possess any distinct activation domain, mArnt3 contained a transcriptional activation domain at the most C-terminal end, the

Sho Takahata; Takahiro Ozaki; Junsei Mimura; Yasuo Kikuchi; Kazuhiro Sogawa; Yoshiaki Fujii-Kuriyama

2000-01-01

75

A non-canonical E-box within the MyoD core enhancer is necessary for circadian expression in skeletal muscle  

PubMed Central

The myogenic differentiation 1 (MyoD) gene is a master regulator of myogenesis. We previously reported that the expression of MyoD mRNA oscillates over 24?h in skeletal muscle and that the circadian clock transcription factors, BMAL1 (brain and muscle ARNT-like 1) and CLOCK (circadian locomotor output cycles kaput), were bound to the core enhancer (CE) of the MyoD gene in vivo. In this study, we provide in vivo and in vitro evidence that the CE is necessary for circadian expression of MyoD in adult muscle. Gel shift assays identified a conserved non-canonical E-box within the CE that is bound by CLOCK and BMAL1. Functional analysis revealed that this E-box was required for full activation by BMAL1/CLOCK and for in vitro circadian oscillation. Expression profiling of muscle of CEloxP/loxP mice found approximately 1300 genes mis-expressed relative to wild-type. Based on the informatics results, we analyzed the respiratory function of mitochondria isolated from wild-type and CEloxP/loxP mice. These assays determined that State 5 respiration was significantly reduced in CEloxP/loxP muscle. The results of this work identify a novel element in the MyoD enhancer that confers circadian regulation to MyoD in skeletal muscle and suggest that loss of circadian regulation leads to changes in myogenic expression and downstream mitochondrial function.

Zhang, Xiping; Patel, Samir P.; McCarthy, John J.; Rabchevsky, Alexander G.; Goldhamer, David J.; Esser, Karyn A.

2012-01-01

76

The orphan receptor Rev-erb? gene is a target of the circadian clock pacemaker  

PubMed Central

Rev-erb? is a ubiquitously expressed orphan nuclear receptor which functions as a constitutive transcriptional repressor and is expressed in vertebrates according to a robust circadian rhythm. We report here that two Rev-erb? mRNA isoforms, namely Rev-erb?1 and Rev-erb?2, are generated through alternative promoter usage and that both show a circadian expression pattern in an in vitro system using serum-shocked fibroblasts. Both promoter regions P1 (Rev-erb?1) and P2 (Rev-erb?2) contain several E-box DNA sequences, which function as response elements for the core circadian-clock components: CLOCK and BMAL1. The CLOCK–BMAL1 heterodimer stimulates the activity of both P1 and P2 promoters in transient transfection assay by 3–6-fold. This activation was inhibited by the overexpression of CRY1, a component of the negative limb of the circadian transcriptional loop. Critical E-box elements were mapped within both promoters. This regulation is conserved in vertebrates since we found that the CLOCK–BMAL1 heterodimer also regulates the zebrafish Rev-erb? gene. In line with these data Rev-erb? circadian expression was strongly impaired in the livers of Clock mutant mice and in the pineal glands of zebrafish embryos treated with Clock and Bmal1 antisense oligonucleotides. Together these data demonstrate that CLOCK is a critical regulator of Rev-erb? circadian gene expression in evolutionarily distant vertebrates and suggest a role for Rev-erb? in the circadian clock output.

Triqueneaux, Gerard; Thenot, Sandrine; Kakizawa, Tomoko; Antoch, Marina P; Safi, Rachid; Takahashi, Joseph S; Delaunay, Franck; Laudet, Vincent

2013-01-01

77

Changes in the Daily Rhythm of Lipid Metabolism in the Diabetic Retina  

PubMed Central

Disruption of circadian regulation was recently shown to cause diabetes and metabolic disease. We have previously demonstrated that retinal lipid metabolism contributed to the development of diabetic retinopathy. The goal of this study was to determine the effect of diabetes on circadian regulation of clock genes and lipid metabolism genes in the retina and retinal endothelial cells (REC). Diabetes had a pronounced inhibitory effect on the negative clock arm with lower amplitude of the period (per) 1 in the retina; lower amplitude and a phase shift of per2 in the liver; and a loss of cryptochrome (cry) 2 rhythmic pattern in suprachiasmatic nucleus (SCN). The positive clock arm was increased by diabetes with higher amplitude of circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1 (bmal1) and phase shift in bmal1 rhythmic oscillations in the retina; and higher bmal1 amplitude in the SCN. Peroxisome proliferator-activated receptor (PPAR) ? exhibited rhythmic oscillation in retina and liver; PPAR? had lower amplitude in diabetic liver; sterol regulatory element-binding protein (srebp) 1c had higher amplitude in the retina but lower in the liver in STZ- induced diabetic animals. Both of Elongase (Elovl) 2 and Elovl4 had a rhythmic oscillation pattern in the control retina. Diabetic retinas lost Elovl4 rhythmic oscillation and had lower amplitude of Elovl2 oscillations. In line with the in vivo data, circadian expression levels of CLOCK, bmal1 and srebp1c had higher amplitude in rat REC (rREC) isolated from diabetic rats compared with control rats, while PPAR? and Elovl2 had lower amplitude in diabetic rREC. In conclusion, diabetes causes dysregulation of circadian expression of clock genes and the genes controlling lipid metabolism in the retina with potential implications for the development of diabetic retinopathy.

Wang, Qi; Tikhonenko, Maria; Bozack, Svetlana N.; Lydic, Todd A.; Yan, Lily; Panchy, Nicholas L.; Mcsorley, Kelly M.; Faber, Matthew S.; Yan, Yuanqing; Boulton, Michael E.; Grant, Maria B.; Busik, Julia V.

2014-01-01

78

Altered Stra13 and Dec2 circadian gene expression in hypoxic cells  

SciTech Connect

The circadian system regulates rhythmically most of the mammalian physiology in synchrony with the environmental light/dark cycle. Alteration of circadian clock gene expression has been associated with tumour progression but the molecular links between the two mechanisms remain poorly defined. Here we show that Stra13 and Dec2, two circadian transcriptional regulators which play a crucial role in cell proliferation and apoptosis are overexpressed and no longer rhythmic in serum shocked fibroblasts treated with CoCl{sub 2,} a substitute of hypoxia. This effect is associated with a loss of circadian expression of the clock genes Rev-erb{alpha} and Bmal1, and the clock-controlled gene Dbp. Consistently, cotransfection assays demonstrate that STRA13 and DEC2 both antagonize CLOCK:BMAL1 dependent transactivation of the Rev-erb{alpha} and Dbp promoters. Using a transplantable osteosarcoma tumour model, we show that hypoxia is associated with altered circadian expression of Stra13, Dec2, Rev-erb{alpha}, Bmal1 and Dbp in vivo. These observations collectively support the notion that overexpression of Stra13 and Dec2 links hypoxia signalling to altered circadian clock gene expression.

Guillaumond, Fabienne; Lacoche, Samuel; Dulong, Sandrine; Grechez-Cassiau, Aline [Universite de Nice-Sophia Antipolis, CNRS FRE3094, 28 Av. Valrose, 06108 Nice (France); Filipski, Elisabeth; Li, Xiao-Mei; Levi, Francis [Universite Paris-Sud, INSERM U776, Hopital Paul Brousse, 14 Av. P.V. Couturier, 94800 Villejuif (France); Berra, Edurne [Cell Biology and Stem Cells Unit, CIC BioGUNE, Technologic Park of Bizkaia, 48160-Derio (Spain); Delaunay, Franck [Universite de Nice-Sophia Antipolis, CNRS FRE3094, 28 Av. Valrose, 06108 Nice (France); Teboul, Michele [Universite de Nice-Sophia Antipolis, CNRS FRE3094, 28 Av. Valrose, 06108 Nice (France)], E-mail: teboulm@unice.fr

2008-05-16

79

Survival of Adult Generated Hippocampal Neurons Is Altered in Circadian Arrhythmic Mice  

PubMed Central

The subgranular zone of the hippocampal formation gives rise to new neurons that populate the dentate gyrus throughout life. Cells in the hippocampus exhibit rhythmic clock gene expression and the circadian clock is known to regulate the cycle of cell division in other areas of the body. These facts suggest that the circadian clock may regulate adult neurogenesis in the hippocampus as well. In the present study, neurogenesis in the hippocampal subgranular zone was examined in arrhythmic Bmal1 knockout (-KO) mice and their rhythmic heterozygous and wildtype littermates. Proliferation and survival of newly generated subgranular zone cells were examined using bromodeoxyuridine labelling, while pyknosis (a measure of cell death) and hippocampal volume were examined in cresyl violet stained sections. There was no significant difference in cellular proliferation between any of the groups, yet survival of proliferating cells, 6 weeks after the bromodeoxyuridine injection, was significantly greater in the BMAL1-KO animals. The number of pyknotic cells was significantly decreased in Bmal1-KO animals, yet hippocampal volume remained the same across genotypes. These findings suggest that while a functional circadian clock is not necessary for normal proliferation of neuronal precursor cells, the normal pruning of newly generated neurons in the hippocampus may require a functional circadian clock.

Rakai, Brooke D.; Chrusch, Michael J.; Spanswick, Simon C.; Dyck, Richard H.; Antle, Michael C.

2014-01-01

80

Effect of premature aging on murine adipose tissue.  

PubMed

To evaluate the effect of aging on adipose tissue development, subcutaneous (SC) and gonadal (GON) white and peri-aortic brown adipose tissues were analyzed of 10 and 30 week old mice deficient in the clock gene Bmal1 (brain and muscle arnt like protein 1) (Bmal1(-/-)) and wild-type littermates (Bmal1(+/+)) kept on a standard fat diet. At both ages, daily food intake was significantly decreased for Bmal1(-/-) mice, associated with reduced hypothalamic expression of PPAR?. Between 10 and 30 weeks of age, the total body weight of Bmal1(+/+) mice increased significantly, but that of Bmal1(-/-) mice did not change. Whereas for Bmal1(+/+) mice, both SC and GON fat mass increased with age, these decreased for Bmal1(-/-) mice. This was associated with increased adipocyte size with age for Bmal1(+/+) but not for Bmal1(-/-) mice. Adipose tissue related angiogenesis was not affected by genotype or aging. Peri-aortic brown adipose tissue mass in 30 week old Bmal1(-/-) mice was significantly reduced as compared to age-matched Bmal1(+/+) mice. Comparison of gene expression profiles in SC and GON adipose tissues of both genotypes revealed very marked effects of Bmal1 gene deletion in itself on PAI-1 (4- to 13-fold downregulation), whereas the associated effect of premature aging was striking for leptin (90- to 130-fold downregulation). Thus, premature aging in Bmal1(-/-) mice kept on normal chow was associated with reduced adiposity. PMID:22265801

Hemmeryckx, Bianca; Hoylaerts, Marc F; Lijnen, H Roger

2012-03-01

81

Lead regulation handbook  

SciTech Connect

This comprehensive book details lead regulations and litigation -- including all the related EPA and OSHA statutes. With examples of lead litigation, one can apply these legal interpretations to one's own questions of product regulation, liability, and workplace regulation.

Shea, E.E.

1996-01-01

82

A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock  

PubMed Central

Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Here, we explore the role of Chrono in cellular timekeeping. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Overexpression of Chrono leads to suppression of BMAL1–CLOCK activity in a histone deacetylase (HDAC) –dependent manner. In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO) mice display a longer circadian period of locomotor activity. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress. CHRONO forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Our comprehensive study spotlights a previously unrecognized clock component of an unsuspected negative circadian feedback loop that is independent of another negative regulator, Cry2, and that integrates behavioral stress and epigenetic control for efficient metabolic integration of the clock.

Myung, Jihwan; Kim, Jae Kyoung; Yoritaka, Takashi; Tanoue, Shintaro; Abe, Takaya; Kiyonari, Hiroshi; Fujimoto, Katsumi; Kato, Yukio; Todo, Takashi; Matsubara, Akio; Forger, Daniel; Takumi, Toru

2014-01-01

83

Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm  

PubMed Central

Glucocorticoid (GC) signaling synchronizes the circadian rhythm of individual peripheral cells and induces the expression of circadian genes, including Period1 (Per1) and Period2 (Per2). However, no GC response element (GRE) has been reported in the Per2 promoter region. Here we report the molecular mechanisms of Per2 induction by GC signaling and its relevance to the regulation of circadian timing. We found that GC prominently induced Per2 expression and delayed the circadian phase. The overlapping GRE and E-box (GE2) region in the proximal Per2 promoter was responsible for GC-mediated Per2 induction. The GRE in the Per2 promoter was unique in that brain and muscle ARNT-like protein-1 (BMAL1) was essential for GC-induced Per2 expression, whereas other GRE-containing promoters, such as Per1 and mouse mammary tumor virus, responded to dexamethasone in the absence of BMAL1. This specialized regulatory mechanism was mediated by BMAL1-dependent binding of the GC receptor to GRE in Per2 promoter. When Per2 induction was abrogated by the mutation of the GRE or E-box, the circadian oscillation phase failed to be delayed compared with that of the wild-type. Therefore, the current study demonstrates that the rapid Per2 induction mediated by GC is crucial for delaying the circadian rhythm.

Cheon, Solmi; Park, Noheon; Cho, Sehyung; Kim, Kyungjin

2013-01-01

84

Radioactive Material Regulations Review.  

National Technical Information Service (NTIS)

This review provides guidance on the DOT Hazardous Materials Regulations contained in Title 49, Code of Federal Regulations (HMR; 49 CFR) which govern the packaging and shipment of radioactive material. These materials have an excellent safety record when...

2012-01-01

85

Emotion Regulation and Stress  

Microsoft Academic Search

This paper examines the similarities and differences between emotion regulation and stress coping and reviews research that\\u000a suggests that the association between emotion regulation and stress may be explained by the common neural structures. Developmental\\u000a changes related to emotion regulation and stress are also discussed. Overall, the research suggests that individuals vary\\u000a in their ability to regulate emotions and cope

Manjie Wang; Kimberly J. Saudino

2011-01-01

86

Cyclin dependent kinase regulation  

Microsoft Academic Search

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and their activities are consequently tightly regulated. Recent developments in the field of CDK regulation have included the discovery and characterization of CDK inhibitors. These developments have had an impact on our understanding of how other signalling pathways may be linked to the cell cycle machinery.

Emma Lees

1995-01-01

87

Regulation of Drug Intake  

Microsoft Academic Search

Regulation of drug intake refers to the maintenance of relatively constant levels of drug over a specified time period. An understanding of regulation of drug intake may be critical in determining how drugs function as reinforcers and how their reinforcing effects may be modified. However, little is known about regulation of drug intake, and the mechanisms underlying it are poorly

Wendy J. Lynch; Marilyn E. Carroll

2001-01-01

88

Cytokines in sleep regulation  

Microsoft Academic Search

The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified

James M. Krueger; Satoshi Takahashi; Levente Kapás; Sebastian Bredow; Rachida Roky; Jidong Fang; Rachael Floyd; Kathryn B. Renegar; Nandita Guha-Thakurta; Sergei Novitsky; Ferenc Obál

1995-01-01

89

Load regulating expansion fixture  

DOEpatents

A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils is disclosed. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located therebetween. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components. 1 fig.

Wagner, L.M.; Strum, M.J.

1998-12-15

90

Load regulating expansion fixture  

DOEpatents

A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located therebetween. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components.

Wagner, Lawrence M. (San Jose, CA) [San Jose, CA; Strum, Michael J. (San Jose, CA) [San Jose, CA

1998-01-01

91

76 FR 35739 - Foreign Assets Control Regulations; Transaction Control Regulations (Regulations Prohibiting...  

Federal Register 2010, 2011, 2012, 2013

...Control Regulations; Transaction Control Regulations (Regulations Prohibiting Transactions Involving the Shipment of Certain Merchandise Between Foreign Countries) AGENCY: Office of Foreign Assets Control, Treasury. ACTION: Final...

2011-06-20

92

Regulators of NFAT  

US Patent & Trademark Office Database

Disclosed are methods of identifying an agent that modulates an NFAT regulator protein. One such method comprises contacting at least one test agent with a recombinant cell comprising at least one NFAT regulator protein or fragment or derivative thereof, assessing the effect of the test agent on an activity, interaction, expression, or binding to the NFAT regulator protein or fragment or derivative thereof, and identifying the test agent that has an effect on an activity, interaction, expression, or binding to the NFAT regulator protein or fragment or derivative thereof, whereby the identified test agent is characterized as an agent that modulates an NFAT regulator protein. Methods of identifying an agent that modulates intracellular calcium, methods to screen for an agent that modulates NFAT regulator function, methods to diagnose unexplained immunodeficiency in a subject, and methods for identifying an agent for treating or preventing a disease or disorder associated with a NFAT regulator protein or calcium signaling are also disclosed.

2013-03-19

93

The nuclear receptor REV-ERB? mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines.  

PubMed

Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erb? expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERB? activity. Circadian gating of endotoxin response was lost in rev-erb?(-/-) mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erb? expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERB? as the key link between the clock and immune function. REV-ERB? may therefore represent a unique therapeutic target in human inflammatory disease. PMID:22184247

Gibbs, Julie E; Blaikley, John; Beesley, Stephen; Matthews, Laura; Simpson, Karen D; Boyce, Susan H; Farrow, Stuart N; Else, Kathryn J; Singh, Dave; Ray, David W; Loudon, Andrew S I

2012-01-10

94

Pressure reducing regulator  

DOEpatents

A pressure reducing regulator that controls its downstream or outlet pressure to a fixed fraction of its upstream or inlet pressure. The regulator includes a housing which may be of a titanium alloy, within which is located a seal or gasket at the outlet end which may be made of annealed copper, a rod, and piston, each of which may be made of high density graphite. The regulator is insensitive to temperature by virtue of being without a spring or gas sealed behind a diaphragm, and provides a reference for a system in which it is being used. The rod and piston of the regulator are constructed, for example, to have a 1/20 ratio such that when the downstream pressure is less than 1/20 of the upstream pressure the regulator opens and when the downstream pressure exceeds 1/20 of the upstream pressure the regulator closes.

Whitehead, John C. (Davis, CA); Dilgard, Lemoyne W. (Willits, CA)

1995-01-01

95

Plant Growth Regulation  

NSDL National Science Digital Library

Plant growth regulators, including auxin, gibberellin, cytokinin, abscisic acid, and ethylene, are investigated in this learning activity to demonstrate how these chemicals (hormones) affect plant growth and development.

This page authored by Jim Bidlack, University of Central Oklahoma, based on original activities by Long Ashton Research Station, KScience, Cynthia Herbrandson, Kellogg Community College, Ross Koning, Eastern Connecticut State University, and A.G. Scientific, Inc.

96

Novel regulators of spermatogenesis.  

PubMed

Spermatogenesis is a multistep process that supports the production of millions of sperm daily. Understanding of the molecular mechanisms that regulate spermatogenesis has been a major focus for decades. Yet, the regulators involved in different cellular processes of spermatogenesis remain largely unknown. Human diseases that result in defective spermatogenesis have provided hints on the molecular mechanisms regulating this process. In this review, we have summarized recent findings on the function and signaling mechanisms of several genes that are known to be associated with disease or pathological processes, including CFTR, CD147, YWK-II and CT genes, and discuss their potential roles in regulating different processes of spermatogenesis. PMID:24594193

Fok, Kin Lam; Chen, Hao; Ruan, Ye Chun; Chan, Hsiao Chang

2014-05-01

97

Subdivision Regulations, Foley, Alabama.  

National Technical Information Service (NTIS)

The report presents the Subdivision Regulations for the City of Foley. The main purpose of such regulations is to insure that the City has some guarantee that the design of streets, lot layouts, installation of utilities, reservation or dedication of park...

1973-01-01

98

Plant Growth Regulators.  

ERIC Educational Resources Information Center

Describes the effect of "plant growth regulators" on plants, such as controlling the flowering, fruit development, plant size, and increasing crop yields. Provides a list of plant growth regulators which includes their chemical, common, and trade names, as well as their different use(s). (GA)

Nickell, Louis G.

1978-01-01

99

Child Care Center Regulations.  

ERIC Educational Resources Information Center

This guide enumerates regulations for anyone caring for four or more children, from families other than their own, for compensation and on a regular basis, in the state of Nebraska. The purpose of the regulations is to protect and promote the health and safety of children in child care facilities. The first section of the guide lists specific…

Nebraska State Dept. of Health and Human Services, Lincoln.

100

Health practitioner regulation  

Microsoft Academic Search

A number of patterns in the regulation of health practitioners can be identified internationally since the early 1990s. This period of time has seen a significant homogenization and globalization in regulation but it has also seen the emergence of complex new trends and difficulties. Significant changes in “consumer culture” and the emergence of the “information age” have engendered new attitudes

IAN FRECKELTON

101

Regulating Consumer Lending  

Microsoft Academic Search

In order to promulgate effective consumer credit regulation, policy makers must understand the supply and demand for consumer\\u000a credit as well as the economic and sociological benefits and detriments. After an explanation of each of these factors, the\\u000a article proposes legislation and regulation that will reduce the damage but allow nonsuspect transactions to continue to occur.

David A. Lander

102

Controlling contradictions among regulations  

SciTech Connect

The decade of the 1970s imposed environmental and health and safety regulations throughout the economy, adding to the economic regulation, equal opportunity regulation, and other prior government regulation. Different parts of the Environmental Protection Agency dictate how a company will handle its liquid, gaseous, and solid wastes, while the Occupational Safety and Health Administration requires that workers be protected against harmful exposures to the chemicals. Although the depressed auto industry received national attention, many other aspects of the economy are subject to contradictory regulations generated by the ''one at a time'' approach of Congress to externalities. Although the more general analysis proposed by the author is more difficult to implement, the effort is necessary. 8 references.

Lave, L.B.

1984-06-01

103

Pressure regulating valve controller  

SciTech Connect

In an aircraft cabin air conditioning system comprising a pair of air cycle refrigeration systems which provide chilled air to the cabin, airflow through the air cycle refrigeration systems being controllable by a pair of pressure regulating valves, each of the pressure regulating valves being disposed in a corresponding main airflow conduit and operated by a corresponding pneumatic valve actuator, the improvement is described by: one of the pneumatic valve actuators associated with one of the pressure regulating valves being operated by a controller comprising: a main servo conduit communicating with one of the main airflow conduits and the pneumatic valve actuator for channeling pneumatic pressure thereto from the main airflow; a first pressure regulator communicating with the main servo conduit for continuously adjusting pneumatic pressure therewithin in response to ram air temperature; a second pressure regulator communicating with the main servo conduit for providing step function adjustment in pneumatic pressure; and means communicating with the main servo conduit for overriding the second pressure regulator to effect partial closing of the one pressure regulating valve despite the deactivation of the air cycle system.

Goodman, R.B.

1988-04-05

104

Regulation in primary care.  

PubMed

Professional bodies have long overseen the maintenance of standards of training and practice within the different healthcare professions. Organisational regulation of healthcare in England comprises two main elements: regulation of the quality and safety of care offered by healthcare providers, currently undertaken by the Care Quality Commission (CQC); and regulation of the market in healthcare services, currently the responsibility of Monitor and the Department of Health. The eighth in the series, this article considers the expanding roles of newer bodies, particularly in relation to primary care. The cost-effectiveness of these new arrangements is unknown - and possibly unknowable. PMID:24762314

Gillam, Steve; Siriwardena, A Niroshan

2014-01-01

105

Subdivision Regulations for Boaz, Alabama.  

National Technical Information Service (NTIS)

Regulations contained herein revise the previously adopted land subdivision regulations for the city of Boaz and also extends the application of such regulations to include areas beyond the city's police jurisdiction and within its subdivision jurisdictio...

1968-01-01

106

Design for Pressure Regulating Components.  

National Technical Information Service (NTIS)

The design development for Pressure Regulating Components included a regulator component trade-off study with analog computer performance verification to arrive at a final optimized regulator configuration for the Space Storable Propulsion Module, under d...

H. Wichmann

1973-01-01

107

R2 REGULATED FACILITIES  

EPA Science Inventory

The Facility Registry System (FRS) is a centrally managed database that identifies facilities, sites or places subject to environmental regulations or of environmental interest. FRS creates high-quality, accurate, and authoritative facility identification records through rigorous...

108

Self-Regulated Learning  

NSDL National Science Digital Library

Self-regulated learning (SRL) encourages students to learn using metacognition, strategic action, and motivation. This nontraditional approach to education relies on the student's active role in learning and the instructor's facilitatory role in teaching.

Corsi, Gianluca

2010-10-01

109

From Regulations to Reality:  

Cancer.gov

Phase 0 Imaging Studies From Regulations to Reality: Obtaining and Holding an IND at Your Institution Karen A. Kurdziel, MD Virginia Commonwealth University, Richmond, VA National Cancer Institute, Bethesda, MD www.molecularimaging.vcu.edu Phase 0 “First-in

110

Metabolite turns master regulator  

PubMed Central

The phenomenon of catabolite repression enables microorganisms to use their favourite carbon source first. New work reveals ?-ketoacids as key effectors of this process, with their levels regulating gene expression.

Rabinowitz, Joshua D.; Silhavy, Thomas J.

2014-01-01

111

Subdivision Regulations, Brandon, Mississippi.  

National Technical Information Service (NTIS)

The subdivision Regulations are set forth to provide for properly designed development and to provide assurance to both the people and the county that proper design and criteria will be followed in all future development.

1972-01-01

112

Epigenetic Regulation in Drosophila  

Microsoft Academic Search

Epigenetic regulation of gene transcription relies on molecular marks like DNA methylation or histone modifications. Here\\u000a we review recent advances in our understanding of epigenetic regulation in the fruit fly Drosophila melanogaster. In the past, DNA methylation research has primarily utilized mammalian model systems. However, several recent landmark discoveries\\u000a have been made in other organisms. For example, the interaction between

F. Lyko; C. Beisel; J. Marhold; R. Paro

113

Emotion-regulation choice.  

PubMed

Despite centuries of speculation about how to manage negative emotions, little is actually known about which emotion-regulation strategies people choose to use when confronted with negative situations of varying intensity. On the basis of a new process conception of emotion regulation, we hypothesized that in low-intensity negative situations, people would show a relative preference to choose to regulate emotions by engagement reappraisal, which allows emotional processing. However, we expected people in high-intensity negative situations to show a relative preference to choose to regulate emotions by disengagement distraction, which blocks emotional processing at an early stage before it gathers force. In three experiments, we created emotional contexts that varied in intensity, using either emotional pictures (Experiments 1 and 2) or unpredictable electric stimulation (Experiment 3). In response to these emotional contexts, participants chose between using either reappraisal or distraction as an emotion-regulation strategy. Results in all experiments supported our hypothesis. This pattern in the choice of emotion-regulation strategies has important implications for the understanding of healthy adaptation. PMID:21960251

Sheppes, Gal; Scheibe, Susanne; Suri, Gaurav; Gross, James J

2011-11-01

114

Interpersonal emotion regulation.  

PubMed

Contemporary emotion regulation research emphasizes intrapersonal processes such as cognitive reappraisal and expressive suppression, but people experiencing affect commonly choose not to go it alone. Instead, individuals often turn to others for help in shaping their affective lives. How and under what circumstances does such interpersonal regulation modulate emotional experience? Although scientists have examined allied phenomena such as social sharing, empathy, social support, and prosocial behavior for decades, there have been surprisingly few attempts to integrate these data into a single conceptual framework of interpersonal regulation. Here we propose such a framework. We first map a "space" differentiating classes of interpersonal regulation according to whether an individual uses an interpersonal regulatory episode to alter their own or another person's emotion. We then identify 2 types of processes--response-dependent and response-independent--that could support interpersonal regulation. This framework classifies an array of processes through which interpersonal contact fulfills regulatory goals. More broadly, it organizes diffuse, heretofore independent data on "pieces" of interpersonal regulation, and identifies growth points for this young and exciting research domain. PMID:24098929

Zaki, Jamil; Williams, W Craig

2013-10-01

115

The Hippo pathway: regulators and regulations  

PubMed Central

Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions.

Yu, Fa-Xing; Guan, Kun-Liang

2013-01-01

116

Chloroplast translation regulation.  

PubMed

Chloroplast gene expression is primarily controlled during the translation of plastid mRNAs. Translation is regulated in response to a variety of biotic and abiotic factors, and requires a coordinate expression with the nuclear genome. The translational apparatus of chloroplasts is related to that of bacteria, but has adopted novel mechanisms in order to execute the specific roles that this organelle performs within a eukaryotic cell. Accordingly, plastid ribosomes contain a number of chloroplast-unique proteins and domains that may function in translational regulation. Chloroplast translation regulation involves cis-acting RNA elements (located in the mRNA 5' UTR) as well as a set of corresponding trans-acting protein factors. While regulation of chloroplast translation is primarily controlled at the initiation steps through these RNA-protein interactions, elongation steps are also targets for modulating chloroplast gene expression. Translation of chloroplast mRNAs is regulated in response to light, and the molecular mechanisms underlying this response involve changes in the redox state of key elements related to the photosynthetic electron chain, fluctuations of the ADP/ATP ratio and the generation of a proton gradient. Photosynthetic complexes also experience assembly-related autoinhibition of translation to coordinate the expression of different subunits of the same complex. Finally, the localization of all these molecular events among the different chloroplast subcompartments appear to be a crucial component of the regulatory mechanisms of chloroplast gene expression. PMID:17661159

Marín-Navarro, Julia; Manuell, Andrea L; Wu, Joann; P Mayfield, Stephen

2007-01-01

117

Endothelin-1 gene regulation  

PubMed Central

Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1). Studies conducted on a variety of cell types have identified key transcription factors that govern edn1 expression. With few exceptions, the cis-acting elements bound by these factors have been mapped in the edn1 regulatory region. Recent evidence has revealed new roles for some factors originally believed to regulate edn1 in a tissue or hormone-specific manner. In addition, other mechanisms involved in epigenetic regulation and mRNA stability have emerged as important processes for regulated edn1 expression. The goal of this review is to provide a comprehensive overview of the specific factors and signaling systems that govern edn1 activity at the molecular level.—Stow, L. R., Jacobs, M. E., Wingo, C. S., Cain, B. D. Endothelin-1 gene regulation.

Stow, Lisa R.; Jacobs, Mollie E.; Wingo, Charles S.; Cain, Brian D.

2011-01-01

118

Environmentally regulated aerospace coatings  

NASA Technical Reports Server (NTRS)

Aerospace coatings represent a complex technology which must meet stringent performance requirements in the protection of aerospace vehicles. Topcoats and primers are used, primarily, to protect the structural elements of the air vehicle from exposure to and subsequent degradation by environmental elements. There are also many coatings which perform special functions, i.e., chafing resistance, rain erosion resistance, radiation and electric effects, fuel tank coatings, maskants, wire and fastener coatings. The scheduled promulgation of federal environmental regulations for aerospace manufacture and rework materials and processes will regulate the emissions of photochemically reactive precursors to smog and air toxics. Aerospace organizations will be required to identify, qualify and implement less polluting materials. The elimination of ozone depleting chemicals (ODC's) and implementation of pollution prevention requirements are added constraints which must be addressed concurrently. The broad categories of operations affected are the manufacture, operation, maintenance, and repair of military, commercial, general aviation, and space vehicles. The federal aerospace regulations were developed around the precept that technology had to be available to support the reduction of organic and air toxic emissions, i.e., the regulations cannot be technology forcing. In many cases, the regulations which are currently in effect in the South Coast Air Quality Management District (SCAQMD), located in Southern California, were used as the baseline for the federal regulations. This paper addresses strategies used by Southern California aerospace organizations to cope with these regulatory impacts on aerospace productions programs. All of these regulatory changes are scheduled for implementation in 1993 and 1994, with varying compliance dates established.

Morris, Virginia L.

1995-01-01

119

Epigenetic regulation of pluripotency.  

PubMed

Epigenetic regulation refers to the mechanisms that alter gene expression patterns in the absence of changes in the nucleotide sequence of the DNA molecule. The best understood epigenetic marks include posttranslational modifications of the histone tails and DNA methylation. Both play central roles in normal development and in diseases. Pluripotent stem cells have great promise for regenerative medicine and recent efforts have focused on identifying molecular networks that govern pluripotency. This chapter provides an overview of epigenetic regulation in embryonic stem cells. We present a brief introduction into epigenetic mechanisms and focus on their role in pluripotent cells. PMID:21222197

Tomazou, Eleni M; Meissner, Alexander

2010-01-01

120

Regulation by Price Adjustment  

Microsoft Academic Search

The regulatory price-adjustment process originally proposed by Vogelsang and Finsinger has been shown to be vulnerable to strategic manipulation by the regulated firm. This article proposes several modifications to that scheme which improve its performance and broaden its applicability. Inclusion of a monopoly franchise market and the firm's past prices and earnings in the price-adjustment constraints are shown to ensure

James Hagerman

1990-01-01

121

Metabolic regulation of yeast  

NASA Astrophysics Data System (ADS)

Metabolic regulation which is based on endogeneous and exogeneous process variables which may act constantly or time dependently on the living cell is discussed. The observed phenomena of the regulation are the result of physical, chemical, and biological parameters. These parameters are identified. Ethanol is accumulated as an intermediate product and the synthesis of biomass is reduced. This regulatory effect of glucose is used for the aerobic production of ethanol. Very high production rates are thereby obtained. Understanding of the regulation mechanism of the glucose effect has improved. In addition to catabolite repression, several other mechanisms of enzyme regulation have been described, that are mostly governed by exogeneous factors. Glucose also affects the control of respiration in a third class of yeasts which are unable to make use of ethanol as a substrate for growth. This is due to the lack of any anaplerotic activity. As a consequence, diauxic growth behavior is reduced to a one-stage growth with a drastically reduced cell yield. The pulse chemostat technique, a systematic approach for medium design is developed and medium supplements that are essential for metabolic control are identified.

Fiechter, A.

1982-12-01

122

Federal Regulation of Education.  

ERIC Educational Resources Information Center

Fresh light might be shed on problems of federal education policy by treating them not only as problems of intergovernmental relations but of government regulation of enterprise, given that they involve the attempts of a central government to influence the conduct of enterprises that it does not own nor directly operate. Using well-established…

Shapiro, Martin

123

REGULATIONS AND SYLLABUSES 1967.  

ERIC Educational Resources Information Center

DESCRIBED IN THIS MANUAL ARE EXAMINATIONS USED IN 1967 IN AWARDING EDUCATIONAL CERTIFICATES TO STUDENTS IN ENGLISH SECONDARY SCHOOLS AND ESTABLISHMENTS FOR FURTHER EDUCATION. IT IS WRITTEN PRIMARILY FOR HEADS OF COLLEGES AND SCHOOLS AND DESCRIBES IN DETAIL THE PROCEDURES AND REGULATIONS FOR THE ADMINISTRATION OF EXAMINATIONS IN ALL SUBJECT AREAS.…

Associated Examining Board, Aldershot, Hampshire (England).

124

REGULATIONS AND SYLLABUSES, 1968.  

ERIC Educational Resources Information Center

EXAMINATIONS USED IN AWARDING EDUCATIONAL CERTIFICATES TO STUDENTS IN ENGLISH SECONDARY SCHOOLS IN 1968 ARE DESCRIBED IN THIS MANUAL. IT IS WRITTEN PRIMARILY FOR HEADS OF COLLEGES AND SCHOOLS AND DESCRIBES IN DETAIL THE PROCEDURES AND REGULATIONS FOR THE ADMINISTRATION OF EXAMINATIONS IN ALL SUBJECT AREAS. EXAMINATIONS MAY BE TAKEN AT THE ORDINARY…

Associated Examining Board, Aldershot, Hampshire (England).

125

Airport regulation and competition  

Microsoft Academic Search

In the airports industry, there is a trade off between imperfect (or monopolistic) competition and economic regulation (with the latter introducing separate economic distortions). The nature of the imperfectly competitive market in the supply of airport services is examined and it is suggested that market power is the consequence of the problems of gaining access to competing sites rather than

David Starkie

2002-01-01

126

On regulation under sampling  

Microsoft Academic Search

The paper deals with linear and nonlinear regulation under sampling. It is shown that digital solutions exist under assumptions which are closely related to the existence of robust solutions to the continuous problem. Approximated solutions are computed starting from the continuous ones

B. Castillo; S. Di Gennaro; S. Monaco; D. Normand-Cyrot

1997-01-01

127

Regulation and Behaviour  

NSDL National Science Digital Library

How can animals and plants exist in every biome on Earth: blazing hot or freezing cold, sopping wet or bone dry? How does homeostasis help organisms survive changes in their environment? How do animals, including humans, sense change in their environment, and how do they respond? Explore these questions and more in this collection of Regulation and Behavior resources.

2010-01-01

128

Regulating Railroad Innovation  

Microsoft Academic Search

Efforts to create and mould new technologies have been a central, recurrent feature of the American experience since at least the time of the Revolution. In Regulating Railroad Innovation, historian Steven Usselman brings this neglected aspect of American history to light. For nearly a century, railroad technology persistently posed novel challenges for Americans, prompting them to re-examine their most cherished

Steven W. Usselman

129

Nondissipative optimum charge regulator  

NASA Technical Reports Server (NTRS)

Optimum charge regulator provides constant level charge/discharge control of storage batteries. Basic power transfer and control is performed by solar panel coupled to battery through power switching circuit. Optimum controller senses battery current and modifies duty cycle of switching circuit to maximize current available to battery.

Rosen, R.; Vitebsky, J. N.

1970-01-01

130

Regulation of Chloroplast Translation  

Microsoft Academic Search

During the evolution of chloroplasts from cyanobacterial endosymbionts, many genes encoding components necessary for protein synthesis and photosynthesis have been transferred to the nucleus. Assembly of the machinery for both processes now relies on the concerted expression of genes in the nuclear and plastid genomes. Evidence accumulating in C. reinhardtii indicates that the expression and regulation of chloroplast genes probably

Charles R. Hauser; Nicholas W. Gillham; John E. Boynton

131

Migratory Bird Hunting Regulations  

NSDL National Science Digital Library

The US Fish and Wildlife Service has placed online this collection of documents (.pdf format) on the regulations associated with hunting of migratory birds. Several dozen documents are posted here, with new documents (e.g., Federal Register releases) added periodically.

132

Proprioceptive regulation of locomotion  

Microsoft Academic Search

Recent investigations of proprioreceptors in the walking systems of cats, insects and crustaceans have identified reflex pathways that regulate the timing of the transition from stance to swing, and control the magnitude of ongoing motoneuronal activity. An important finding in the cat is that during locomotor activity, the influence of feedback from the Golgi tendon organs in extensor muscles onto

Keir G Pearson

1995-01-01

133

Aboveground storage tank regulations  

SciTech Connect

There are critical differences between the potential for environmental impact of aboveground and underground oil storage. For example, while leaks from underground storage tanks (USTs) seep into soil or aquifers, the concern with aboveground storage tanks (ASTs) is that an overfill or tank rupture can cause product to escape into a navigable stream and immediately create an oil spill pollution incident. The US Environmental Protection Agency (EPA) has very distinct programs outlining regulation parameters for each type of storage, including source of authority, regulatory cutoffs and exclusions, definitions, prevention and response requirements, and penalties, etc. Engineers considering changing or recommending a change in type of storage, particularly from a UST to an AST, need to be aware of existing federal regulations. UST regulation, administered primarily by the states, falls under EPA Regulation 40 CFR 280. EPA's underground storage tank program, which began in 1988, and the individual state programs that have evolved since then, provide generally accepted benchmarks for safe, reliable underground storage of petroleum and hazardous liquid products.

Geyer, W. (Steel Tank Inst., Lake Zurich, IL (United States))

1993-09-01

134

Catecholamine regulated protein  

US Patent & Trademark Office Database

A novel mammalian catecholamine-regulated protein called CRP40 is identified. This protein, and nucleic acid encoding same, is useful in methods of diagnosing and treating hypodopaminergic neurological disease, such as Parkinson's disease, multisystem atrophy, lewy body dementia, schizophrenia, and bipolar disease.

2013-06-25

135

REGULATION OF GLUTATHIONE SYNTHESIS  

PubMed Central

Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor ? B (NF?B). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.

Lu, Shelly C.

2009-01-01

136

CODE OF FEDERAL REGULATIONS  

EPA Science Inventory

The Code of Federal Regulations (CFR) is an annually revised codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government. The CFR is divided into 50 titles which represent broad areas subje...

137

Self-regulated learning and college students' regulation of motivation  

Microsoft Academic Search

This study extends current models of self-regulated learning by addressing 3 research questions, including what strategies do students use to regulate their motivation? is the use of these strategies dependent on contextual factors? how is motivational regulation related to other aspects of self-regulated learning and achievement? Self-report data were collected from 115 college students by using an open-ended questionnaire and

Christopher A. Wolters

1998-01-01

138

DAILY PATTERNS OF CLOCK AND COGNITION-RELATED FACTORS ARE MODIFIED IN THE HIPPOCAMPUS OF VITAMIN A-DEFICIENT RATS  

PubMed Central

The circadian expression of clock and clock-controlled cognition-related genes in the hippocampus would be essential to achieve an optimal daily cognitive performance. There is some evidence that retinoid nuclear receptors (RARs and RXRs) can regulate circadian gene expression in different tissues. In this study, Holtzman male rats from control and vitamin A-deficient groups were sacrificed throughout a 24-h period and hippocampus samples were isolated every 4 or 5 h. RAR? and RXR? expression level was quantified and daily expression patterns of clock BMAL1, PER1, ROR? and REVERB genes, ROR? and REVERB proteins, as well as temporal expression of cognition-related RC3 and BDNF genes were determined in the hippocampus of the two groups of rats. Our results show significant daily variations of BMAL1, PER1, ROR? and REVERB genes, ROR? and REVERB proteins and, consequently, daily oscillating expression of RC3 and BDNF genes in the rat hippocampus. Vitamin A deficiency reduced RXR? mRNA level as well as the amplitude of PER1, REVERB gene and REVERB protein rhythms, and phase-shifted the daily peaks of BMAL1 and ROR? mRNA, ROR? protein and RC3 and BDNF mRNA levels. Thus, nutritional factors, such as vitamin A and its derivatives the retinoids, might modulate daily patterns of BDNF and RC3 expression in the hippocampus and they could be essential to maintain an optimal daily performance at molecular level in this learning-and-memory-related brain area.

Golini, Rebeca S.; Delgado, Silvia M.; Navigatore Fonzo, Lorena S.; Ponce, Ivana T.; Lacoste, Maria G.; Anzulovich, Ana C.

2012-01-01

139

Differential role of melatonin in restoration of age-induced alterations in daily rhythms of expression of various clock genes in suprachiasmatic nucleus of male Wistar rats.  

PubMed

Aging is associated with changes in several basic parameters of circadian rhythms in mammals leading to circadian dysfunction. The hypothalamic Suprachiasmatic nucleus (SCN) regulates neuronal, endocrine and behavioral rhythms through the expression of various clock genes and release of melatonin from pineal gland. In the present study, we investigated the effect of aging on daily rhythms of various clock genes such as rPer1, rPer2, rCry1, rCry2 and rBmal1 in the SCN of male Wistar rats. The m-RNA expression levels of these genes were studied by using quantitative Polymerase Chain Reaction (qPCR) in 3 age groups [3 (adult), 12 and 24 month (m)] at variable time points (Zeitgeber time (ZT)-0, 6, 12 and 18). The m-RNA expression for all genes studied was rhythmic in SCN of adult rats with maximum for rPer1 at ZT-6, rPer2, rCry1 and rCry2 at ZT-12 and rBmal1 at ZT-18. However in 12 and 24 m, the phases of expression of these genes were significantly altered with abolition of daily rhythms of rCry1, rCry2 and rBmal1 in 24 m. Melatonin, messenger of darkness, an endogenous synchronizer of rhythm, an antioxidant and an antiaging drug, declines with aging. We therefore studied the effects of melatonin administered subcutaneously at 1 h before the onset of darkness (ZT-11) for 11 days on age induced desynchronization in expression of these genes. We report here differential restoration of daily rhythm, phase, levels and stoichiometric interaction of m-RNA expression of these genes in various age groups in rat SCN with melatonin treatment. PMID:24619734

Mattam, Ushodaya; Jagota, Anita

2014-06-01

140

Machine learning helps identify CHRONO as a circadian clock component.  

PubMed

Over the last decades, researchers have characterized a set of "clock genes" that drive daily rhythms in physiology and behavior. This arduous work has yielded results with far-reaching consequences in metabolic, psychiatric, and neoplastic disorders. Recent attempts to expand our understanding of circadian regulation have moved beyond the mutagenesis screens that identified the first clock components, employing higher throughput genomic and proteomic techniques. In order to further accelerate clock gene discovery, we utilized a computer-assisted approach to identify and prioritize candidate clock components. We used a simple form of probabilistic machine learning to integrate biologically relevant, genome-scale data and ranked genes on their similarity to known clock components. We then used a secondary experimental screen to characterize the top candidates. We found that several physically interact with known clock components in a mammalian two-hybrid screen and modulate in vitro cellular rhythms in an immortalized mouse fibroblast line (NIH 3T3). One candidate, Gene Model 129, interacts with BMAL1 and functionally represses the key driver of molecular rhythms, the BMAL1/CLOCK transcriptional complex. Given these results, we have renamed the gene CHRONO (computationally highlighted repressor of the network oscillator). Bi-molecular fluorescence complementation and co-immunoprecipitation demonstrate that CHRONO represses by abrogating the binding of BMAL1 to its transcriptional co-activator CBP. Most importantly, CHRONO knockout mice display a prolonged free-running circadian period similar to, or more drastic than, six other clock components. We conclude that CHRONO is a functional clock component providing a new layer of control on circadian molecular dynamics. PMID:24737000

Anafi, Ron C; Lee, Yool; Sato, Trey K; Venkataraman, Anand; Ramanathan, Chidambaram; Kavakli, Ibrahim H; Hughes, Michael E; Baggs, Julie E; Growe, Jacqueline; Liu, Andrew C; Kim, Junhyong; Hogenesch, John B

2014-04-01

141

TEMPORAL PATTERNS OF LIPOPEROXIDATION AND ANTIOXIDANT ENZYMES ARE MODIFIED IN THE HIPPOCAMPUS OF VITAMIN A-DEFICIENT RATS  

PubMed Central

Animals can adapt their behavior to predictable temporal fluctuations in the environment through both, memory-and-learning processes and an endogenous time-keeping mechanism. Hippocampus plays a key role in memory and learning and is especially susceptible to oxidative stress. In compensation, antioxidant enzymes activity, such as Catalase (CAT) and Glutathione peroxidase (GPx), has been detected in this brain region. Daily rhythms of antioxidant enzymes activitiy, as well as of glutathione and lipid peroxides levels, have been described in brain. Here, we investigate day/night variations in lipoperoxidation, CAT and GPx expression and activity, as well as the temporal fluctuations of two key components of the endogenous clock, BMAL1 and PER1, in the rat hippocampus and evaluate to which extent vitamin A deficiency may affect their amplitude or phase. Holtzman male rats from control, vitamin A-deficient and vitamin A-refed groups were sacrificed throughout a 24-h period. Daily levels of clock proteins, lipoperoxidation, CAT and GPx mRNA, protein, and activity, were determined in the rat hippocampus obtained every 4 or 5 h. Gene expression of RAR? and RXR? was also quantified in the hippocampus of the three groups of rats. Our results show significant daily variations of BMAL1 and PER1 protein expression. Rhythmic lipoperoxidation, CAT, and GPx, expression and activity, were also observed in the rat hippocampus. Vitamin A deficiency reduced RXR? mRNA level, as well as the amplitude of BMAL1 and PER1 daily oscillation, phase-shifted the daily peak of lipoperoxidation, and had a differential effect on the oscillating CAT and GPx mRNA, protein, and activity. Learning how vitamin A deficiency affects the circadian gene expression in the hippocampus may have an impact on the neurobiology, nutritional and chronobiology fields, emphasizing for the first time the importance of nutritional factors, such as dietary micronutrients, in the regulation of circadian parameters in this brain memory-and-learning-related region.

Navigatore Fonzo, Lorena S.; Golini, Rebeca S.; Delgado, Silvia M.; Ponce, Ivana T.; Bonomi, Myrta R.; Rezza, Irma G.; Gimenez, Maria S.; Anzulovich, Ana C.

2011-01-01

142

State Licensing and Regulation Information  

MedlinePLUS

... Licensing and Regulation Information State Licensing and Regulation Information States are contacted at least twice per year to verify the accuracy of regulatory information. Click on state below to view state information. ...

143

White paper on occupational regulation.  

PubMed

There are many ways that occupations are regulated, with the degree of regulation usually depending on the amount of harm to the public that lack of regulation could bring. Strict regulations, such as mandatory licensure, are established through state law and maintained by a state board. Less strict regulations, such as voluntary credentialing, may be requirements by employers or third-party payers. This white paper reviews the possible approaches ASET could take toward regulation of the practice of electroneurodiagnostic technology: maintain position of neutrality, advocate for no statutory regulation of END, advocate for statutory regulation of END, or advocate for voluntary credentialing. The routes taken by other allied health fields are outlined, with exploration of the advantages and disadvantages of each option, as well as what would be required of ASET in terms of time and other resources to achieve each option. The appendix is a summary of entry requirements of several healthcare professions. PMID:15675734

Rops, Mickie S

2004-12-01

144

FDA 101: Regulating Biological Products  

MedlinePLUS

... mail Consumer Updates RSS Feed FDA 101: Regulating Biological Products Search the Consumer Updates Section Consumer Update ... friendly PDF (196 KB) On this page: What biological products does FDA regulate? How do biologics differ ...

145

Low-noise current regulator  

NASA Technical Reports Server (NTRS)

Modification of conventional regulator minimizes current drift. Current to be regulated flows through sensing resistor in series with load, producing voltage that is fed into operational amplifier. Other input into amplifier is reference voltage from Zener diode network.

Bunn, J.

1979-01-01

146

Regulation of Meiotic Recombination  

SciTech Connect

Meiotic recombination results in the heritable rearrangement of DNA, primarily through reciprocal exchange between homologous chromosome or gene conversion. In plants these events are critical for ensuring proper chromosome segregation, facilitating DNA repair and providing a basis for genetic diversity. Understanding this fundamental biological mechanism will directly facilitate trait mapping, conventional plant breeding, and development of genetic engineering techniques that will help support the responsible production and conversion of renewable resources for fuels, chemicals, and the conservation of energy (1-3). Substantial progress has been made in understanding the basal recombination machinery, much of which is conserved in organisms as diverse as yeast, plants and mammals (4, 5). Significantly less is known about the factors that regulate how often and where that basal machinery acts on higher eukaryotic chromosomes. One important mechanism for regulating the frequency and distribution of meiotic recombination is crossover interference - or the ability of one recombination event to influence nearby events. The MUS81 gene is thought to play an important role in regulating the influence of interference on crossing over. The immediate goals of this project are to use reverse genetics to identify mutants in two putative MUS81 homologs in the model plant Arabidopsis thaliana, characterize those mutants and initiate a novel forward genetic screen for additional regulators of meiotic recombination. The long-term goal of the project is to understand how meiotic recombination is regulated in higher eukaryotes with an emphasis on the molecular basis of crossover interference. The ability to monitor recombination in all four meiotic products (tetrad analysis) has been a powerful tool in the arsenal of yeast geneticists. Previously, the qrt mutant of Arabidopsis, which causes the four pollen products of male meiosis to remain attached, was developed as a facile system for assaying recombination using tetrad analysis in a higher eukaryotic system (6). This system enabled the measurement of the frequency and distribution of recombination events at a genome wide level in wild type Arabidopsis (7), construction of genetic linkage maps which include positions for each centromere (8), and modeling of the strength and pattern of interference (9). This proposal extends the use of tetrad analysis in Arabidopsis by using it as the basis for assessing the phenotypes of mutants in genes important for recombination and the regulation of crossover interference and performing a novel genetic screen. In addition to broadening our knowledge of a classic genetic problem - the regulation of recombination by crossover interference - this proposal also provides broader impact by: generating pedagogical tools for use in hands-on classroom experience with genetics, building interdisciplinary collegial partnerships, and creating a platform for participation by junior scientists from underrepresented groups. There are three specific aims: (1) Isolate mutants in Arabidopsis MUS81 homologs using T-DNA and TILLING (2) Characterize recombination levels and interference in mus81 mutants (3) Execute a novel genetic screen, based on tetrad analysis, for genes that regulate meiotic recombination

Gregory p. Copenhaver

2011-11-09

147

Ikaros regulates neutrophil differentiation.  

PubMed

The Ikaros gene encodes a zinc finger transcription factor that is selectively expressed by all hematopoietic cells. Although Ikaros is required for lymphocyte differentiation, its role in the myeloid lineage is unclear. We show here that Ikaros expression is temporally regulated during neutrophil differentiation: Ikaros is primarily expressed at immature stages and significantly less so in mature neutrophils. Furthermore Ik(L/L) mice, harboring a hypomorphic mutation at the Ikaros locus, exhibit several defects during neutrophil differentiation. (1) Ik(L/L) fetal livers contain high numbers of neutrophil lineage cells, and this increase is reflected in the number of GM-CSF-dependent progenitor cells. (2) The migratory potential and survival of neutrophil progenitors is altered in vitro. (3) Expression of the Gr-1 marker is delayed and repressed. In contrast, neutrophil function appears normal. These data demonstrate that Ikaros regulates early neutrophil differentiation but is dispensable in mature neutrophils. PMID:12406904

Dumortier, Alexis; Kirstetter, Peggy; Kastner, Philippe; Chan, Susan

2003-03-15

148

Autophagy regulates lipid metabolism  

PubMed Central

The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.

Singh, Rajat; Kaushik, Susmita; Wang, Yongjun; Xiang, Youqing; Novak, Inna; Komatsu, Masaaki; Tanaka, Keiji; Cuervo, Ana Maria; Czaja, Mark J.

2009-01-01

149

Regulation of inflammasome signaling  

PubMed Central

Innate immune responses have the ability to both combat infectious microbes and drive pathological inflammation. Inflammasome complexes are a central component of these processes through their regulation of interleukin 1? (IL-1?), IL-18 and pyroptosis. Inflammasomes recognize microbial products or endogenous molecules released from damaged or dying cells both through direct binding of ligands and indirect mechanisms. The potential of the IL-1 family of cytokines to cause tissue damage and chronic inflammation emphasizes the importance of regulating inflammasomes. Many regulatory mechanisms have been identified that act as checkpoints for attenuating inflammasome signaling at multiple steps. Here we discuss the various regulatory mechanisms that have evolved to keep inflammasome signaling in check to maintain immunological balance.

Rathinam, Vijay A K; Vanaja, Sivapriya Kailasan; Fitzgerald, Katherine A

2012-01-01

150

Regulations for insulating material  

SciTech Connect

The text of the California Administrative Code, Title 20, Chapter 2, Subchapter 4, Article 3, Standards for Insulating Material (parts 1551 through 1565), is presented. These regulations establish standards governing the quality of insulation material sold or installed within the state after June 4, 1979, including those properties which affect the safety and thermal performance of insulation material during application and in the use intended. (MCW)

Not Available

1978-01-01

151

Basic Sciences - Gene Regulation  

Cancer.gov

Currently, Dr. Levens's research is focusing on the transcriptional regulation of c-myc and the elucidation of the roles of conformation and topology-selective, sequence-specific DNA binding transcription factors. The c-myc gene employs multiple cis-elements, upstream and downstream of its promoters, P1 and P2. The goal is to illuminate the mechanisms through which the input of multiple factors sets the expression level of this critical proto-oncogene.

152

Regulation of Protein Translation  

NSDL National Science Digital Library

This Teaching Resource provides a summary and slides derived from a lecture on protein translation and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of the various components that perform the translation process and then proceeds to describe the initiation, scanning, and ribosomal entry processes. The lecture concludes with the signaling mechanisms underlying translation regulation.

Emmanuel M. Landau (Mount Sinai School;Departments of Psychiatry and Pharmacology and Biological Chemistry REV)

2006-03-07

153

Restructuring nuclear regulations.  

PubMed Central

Nuclear regulations are a subset of social regulations (laws to control activities that may negatively impact the environment, health, and safety) that concern control of ionizing radiation from radiation-producing equipment and from radioactive materials. The impressive safety record among nuclear technologies is due, in no small part, to the work of radiation safety professionals and to a protection system that has kept pace with the rapid technologic advancements in electric power generation, engineering, and medicine. The price of success, however, has led to a regulatory organization and philosophy characterized by complexity, confusion, public fear, and increasing economic costs. Over the past 20 years, regulatory costs in the nuclear sector have increased more than 250% in constant 1995 U.S. dollars. Costs of regulatory compliance can be reduced sharply, particularly when health and environmental benefits of risk reduction are questionable. Three key regulatory areas should be closely examined and modified to improve regulatory effectiveness and efficiency: a) radiation protection should be changed from a risk-based to dose-based system; b) the U.S. government should adopt the modern metric system (International System of Units), and radiation quantities and units should be simplified to facilitate international communication and public understanding; and c) a single, independent office is needed to coordinate nuclear regulations established by U.S. federal agencies and departments.

Mossman, Kenneth L

2003-01-01

154

Improving CS regulations.  

SciTech Connect

President Carter issued Executive Order 12044 (3/28/78) that required all Federal agencies to distinguish between significant and insignificant regulations, and to determine whether a regulation will result in major impacts. This study gathered information on the impact of the order and the guidelines on the Office of Conservation and Solar Energy (CS) regulatory practices, investigated problems encountered by the CS staff when implementing the order and guidelines, and recommended solutions to resolve these problems. Major tasks accomplished and discussed are: (1) legislation, Executive Orders, and DOE Memoranda concerning Federal administrative procedures relevant to the development and analysis of regulations within CS reviewed; (2) relevant DOE Orders and Memoranda analyzed and key DOE and CS staff interviewed in order to accurately describe the current CS regulatory process; (3) DOE staff from the Office of the General Counsel, the Office of Policy and Evaluation, the Office of the Environment, and the Office of the Secretary interviewed to explore issues and problems encountered with current CS regulatory practices; (4) the regulatory processes at five other Federal agencies reviewed in order to see how other agencies have approached the regulatory process, dealt with specific regulatory problems, and responded to the Executive Order; and (5) based on the results of the preceding four tasks, recommendations for potential solutions to the CS regulatory problems developed. (MCW)

Nesse, R.J.; Scheer, R.M.; Marasco, A.L.; Furey, R.

1980-10-01

155

[Chromatin and transcription regulation].  

PubMed

Recent years are marked by drastic increase of interest in the role of chromatin in regulation of gene activity. In the seventies of the last century many studies were undertaken in order to identify different forms of histones involved in regulation on transcription. The results of these studies were conflicting. Determination of primary structures of the main forms of histones demonstrated the extreme conservativity of these proteins. Once the nucleosomes were discovered and their organization was studied, it became clear that nucleosome as a basic unit of chromatin is also highly conservative. This conception gradually changed in recent years. Many variant forms of nucleosomal core histones encoded by separate genes were discovered. In addition it was demonstrated that both canonical and variant forms of histones may by modified post-translationally in different ways. As a result, a possibility to assemble a number of different nucleosomal particles became evident. Furthermore, a clear correlation between certain modification of histones and DNA packaging in either active or inactive chromatin was established. Similarly, a correlation between formation of active (inactive) chromatin and incorporation of particular histone variants into nucleosomes was observed. To integrate all the above findings into the existing model of chromatin organization and functioning, the hypothesis of "histone code" was proposed. In this review the present state of our knowledge about chromatin organization and the role of this organization in transcription regulation will be discussed. PMID:17685218

Razin, S V

2007-01-01

156

Regulation of biomedical products.  

PubMed

Two recent decisions, one from Australia and one from Canada, should cause us to examine the ethical issues surrounding the regulation of biomedical products. The protection of vulnerable consumers from variable quality and poorly prepared drugs with uncertain parameters of safety and efficacy is a priority for any community and should not have to be weighed against possible costs based on restrictions of trade. However, the possibility of an environment in which the multinational biomedical industry edges out any other players in the treatment of various illnesses has its own dangers. Not least is the apparent collusion between regulators and industry that ramps up the costs and intensity of licensing and risk management so that only an industry-type budget can sustain the costs of compliance. This has the untoward effect of delivering contemporary health care into the hands of those who make immense fortunes out of it. An approach to regulation that tempers bureaucratic mechanisms with a dose of common sense and realistic evidence-based risk assessment could go a long way in avoiding the Scylla and Charybdis awaiting the clinical world in these troubled waters. PMID:20552933

Gillett, Grant; Saville-Cook, Donald

2010-05-01

157

Aboveground storage tank regulations  

SciTech Connect

There are critical differences between the potential for environmental impact of aboveground and underground oil storage. For example, while leaks from underground storage tanks (USTs) seep into soil or aquifers, the concern with aboveground storage tanks (ASTs) is that an overfill or tank rupture can cause product to escape into a navigable stream and immediately create an oil spill pollution incident. The US Environmental Protection Agency (EPA) has very distinct programs outlining regulation parameters for each type of storage, including source of authority, regulatory cutoffs and exclusions, definitions, prevention and response requirements, and penalties, etc. Engineers considering changes or recommending a change in type of storage, particularly from a UST to an AST, need to be aware of existing federal regulations. Since the federal UST program began, remediation costs have skyrocketed as a result of the need to clean up leaking tank and piping sites, backfill and surrounding soil or groundwater. Compliance with federal and state UST regulations has not been cheap, and is expected to top $23 billion, according to some estimates. Partly as a result, market demand has shifted toward use of aboveground storage tanks, a trend that is expected to continue. Industry figures show a 100% increase in factory fabricated aboveground tank activity during the last four years.

Geyer, W. (Steel Tank Inst., Lake Zurich, IL (United States))

1993-01-01

158

Human telomerase activity regulation.  

PubMed

Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control but also other factors contributing to the enzyme phosphorylation status, assembling or complex subunits transport. Thus, we show that the telomerase expression targeting cannot be the only possibility to shorten telomeres and induce cell apoptosis. It is important especially since the transcription expression is not always correlated with the enzyme activity which might result in transcription modulation failure or a possibility for the gene therapy to be overcome. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms that take place after telomerase subunits coding genes transcription. Thus we show the possible mechanisms of telomerase activity regulation which might become attractive anticancer therapy targets. PMID:21086176

Wojtyla, Aneta; Gladych, Marta; Rubis, Blazej

2011-06-01

159

Flow compensating pressure regulator  

NASA Technical Reports Server (NTRS)

An apparatus for regulating pressure of treatment fluid during ophthalmic procedures is described. Flow sensing and pressure regulating diaphragms are used to modulate a flow control valve. The pressure regulating diaphragm is connected to the flow control valve to urge the valve to an open position due to pressure being applied to the diaphragm by bias means such as a spring. The flow sensing diaphragm is mechanically connected to the flow control valve and urges it to an opened position because of the differential pressure on the diaphragm generated by a flow of incoming treatment fluid through an orifice in the diaphragm. A bypass connection with a variable restriction is connected in parallel relationship to the orifice to provide for adjusting the sensitivity of the flow sensing diaphragm. A multiple lever linkage system is utilized between the center of the second diaphragm and the flow control valve to multiply the force applied to the valve by the other diaphragm and reverse the direction of the force.

Baehr, E. F. (inventor)

1978-01-01

160

The Theory of Economic Regulation  

Microsoft Academic Search

The potential uses of public resources and powers to improve the economic status of economic groups (such as industries and occupations) are analyzed to provide a scheme of the demand for regulation. The characteristics of the political process which allow relatively small groups to obtain such regulation is then sketched to provide elements of a theory of supply of regulation.

George J. Stigler

1971-01-01

161

Temperature controlled high voltage regulator  

DOEpatents

A temperature controlled high voltage regulator for automatically adjusting the high voltage applied to a radiation detector is described. The regulator is a solid state device that is independent of the attached radiation detector, enabling the regulator to be used by various models of radiation detectors, such as gas flow proportional radiation detectors.

Chiaro, Jr., Peter J. (Clinton, TN); Schulze, Gerald K. (Knoxville, TN) [Knoxville, TN

2004-04-20

162

Bidirectional Pressure-Regulator System  

NASA Technical Reports Server (NTRS)

A bidirectional pressure-regulator system has been devised for use in a regenerative fuel cell system. The bidirectional pressure-regulator acts as a back-pressure regulator as gas flows through the bidirectional pressure-regulator in one direction. Later, the flow of gas goes through the regulator in the opposite direction and the bidirectional pressure-regulator operates as a pressure- reducing pressure regulator. In the regenerative fuel cell system, there are two such bidirectional regulators, one for the hydrogen gas and another for the oxygen gas. The flow of gases goes from the regenerative fuel cell system to the gas storage tanks when energy is being stored, and reverses direction, flowing from the storage tanks to the regenerative fuel cell system when the stored energy is being withdrawn from the regenerative fuel cell system. Having a single bidirectional regulator replaces two unidirectional regulators, plumbing, and multiple valves needed to reverse the flow direction. The term "bidirectional" refers to both the bidirectional nature of the gas flows and capability of each pressure regulator to control the pressure on either its upstream or downstream side, regardless of the direction of flow.

Burke, Kenneth; Miller, John R.

2008-01-01

163

Emotion Regulation and Anxiety Disorders  

PubMed Central

A growing body of research suggests that the construct of emotion regulation is important for understanding the onset, maintenance, and treatment of anxiety disorders. In this review, we provide a selective overview of this emerging field and highlight the major sources of evidence. First, evidence suggests that the construct of emotion regulation can be differentiated from the construct of emotion. Second, there is a large and consistent body of research demonstrating that emotion regulation strategies can modulate emotional responding, and this finding is observed in both behavioral and neuroimaging studies. Third, measures of emotion regulation explain incremental variance in measures of anxiety disorder symptoms not accounted for by measures of negative affect. Although the research implicating emotion regulation in the anxiety disorders is promising, future research will be necessary to further clarify causal mechanisms explaining how emotion regulation confers vulnerability for anxiety disorders and to improve the clarity and consistency of definitions of emotion regulation.

Cisler, Josh M.; Olatunji, Bunmi O.

2013-01-01

164

Emotion regulation and anxiety disorders.  

PubMed

A growing body of research suggests that the construct of emotion regulation is important for understanding the onset, maintenance, and treatment of anxiety disorders. In this review, we provide a selective overview of this emerging field and highlight the major sources of evidence. First, evidence suggests that the construct of emotion regulation can be differentiated from the construct of emotion. Second, there is a large and consistent body of research demonstrating that emotion regulation strategies can modulate emotional responding, and this finding is observed in both behavioral and neuroimaging studies. Third, measures of emotion regulation explain incremental variance in measures of anxiety disorder symptoms not accounted for by measures of negative affect. Although the research implicating emotion regulation in the anxiety disorders is promising, future research will be necessary to further clarify causal mechanisms explaining how emotion regulation confers vulnerability for anxiety disorders and to improve the clarity and consistency of definitions of emotion regulation. PMID:22392595

Cisler, Josh M; Olatunji, Bunmi O

2012-06-01

165

Self-regulating valve  

DOEpatents

A variable, self-regulating valve having a hydraulic loss coefficient proportional to a positive exponential power of the flow rate. The device includes two objects in a flow channel and structure which assures that the distance between the two objects is an increasing function of the flow rate. The range of spacing between the objects is such that the hydraulic resistance of the valve is an increasing function of the distance between the two objects so that the desired hydraulic loss coefficient as a function of flow rate is obtained without variation in the flow area.

Humphreys, D.A.

1982-07-20

166

Gastrointestinal hormones regulating appetite  

PubMed Central

The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood–brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain–gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain–gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity.

Chaudhri, Owais; Small, Caroline; Bloom, Steve

2006-01-01

167

Regulations, 30 January 1987.  

PubMed

Regulations adopted by the All-Union Women's Committee give recently established women's councils greater scope to initiate legislation and provide that laws and statutory instruments affecting women's interests cannot be discussed without their participation. The Councils are also to play an active role in representing the interests of the female workforce at the enterprise level through participation in formulating and monitoring collective agreements, planning the allocation of resources on the social and day-to-day needs of the staff, and supervising the work of medical, pre-school and educational institutions, commercial and public catering enterprises, and day-to-day services. PMID:12346611

1987-01-01

168

[Regulation of terpene metabolism  

SciTech Connect

This report describes accomplishments over the past year on understanding of terpene synthesis in mint plants and sage. Specifically reported are the fractionation of 4-S-limonene synthetase, the enzyme responsible for the first committed step to monoterpene synthesis, along with isolation of the corresponding RNA and DNA cloning of its gene; the localization of the enzyme within the oil glands, regulation of transcription and translation of the synthetase, the pathway to camphor biosynthesis,a nd studies on the early stages and branch points of the isoprenoid pathway.

Croteau, R.

1992-01-01

169

Phospholipid - Driven gene regulation  

PubMed Central

Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters.

Musille, Paul M.; Kohn, Jeffrey A.; Ortlund, Eric A.

2013-01-01

170

43 CFR 1821.13 - What if the specific program regulations conflict with these regulations?  

Code of Federal Regulations, 2013 CFR

...What if the specific program regulations conflict with these regulations? 1821.13 Section...What if the specific program regulations conflict with these regulations? If there is a conflict, the specific program regulations will...

2013-10-01

171

Regulation of myoglobin expression  

PubMed Central

Myoglobin is a well-characterized, cytoplasmic hemoprotein that is expressed primarily in cardiomyocytes and oxidative skeletal muscle fibers. However, recent studies also suggest low-level myoglobin expression in various non-muscle tissues. Prior studies incorporating molecular, pharmacological, physiological and transgenic technologies have demonstrated that myoglobin is an essential oxygen-storage hemoprotein capable of facilitating oxygen transport and modulating nitric oxide homeostasis within cardiac and skeletal myocytes. Concomitant with these studies, scientific investigations into the transcriptional regulation of myoglobin expression have been undertaken. These studies have indicated that activation of key transcription factors (MEF2, NFAT and Sp1) and co-activators (PGC-1?) by locomotor activity, differential intracellular calcium fluxes and low intracellular oxygen tension collectively regulate myoglobin expression. Future studies focused on tissue-specific transcriptional regulatory pathways and post-translational modifications governing myoglobin expression will need to be undertaken. Finally, further studies investigating the modulation of myoglobin expression under various myopathic processes may identify myoglobin as a novel therapeutic target for the treatment of various cardiac and skeletal myopathies.

Kanatous, Shane B.; Mammen, Pradeep P. A.

2010-01-01

172

[Regulation of terpene metabolism  

SciTech Connect

During the last grant period, we have completed studies on the key pathways of monoterpene biosynthesis and catabolism in sage and peppermint, and have, by several lines of evidence, deciphered the rate-limiting step of each pathway. We have at least partially purified and characterized the relevant enzymes of each pathway. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation depends upon the balance between biosynthesis and catabolism, and provided supporting evidence that these processes are developmentally-regulated and very closely associated with senescence of the oil glands. Oil gland ontogeny has been characterized at the ultrastructural level. We have exploited foliar-applied bioregulators to delay gland senescence, and have developed tissue explant and cell culture systems to study several elusive aspects of catabolism. We have isolated pure gland cell clusters and localized monoterpene biosynthesis and catabolism within these structures, and have used these preparations as starting materials for the purification to homogeneity of target regulatory'' enzymes. We have thus developed the necessary background knowledge, based on a firm understanding of enzymology, as well as the necessary experimental tools for studying the regulation of monoterpene metabolism at the molecular level. Furthermore, we are now in a position to extend our systematic approach to other terpenoid classes (C[sub 15]-C[sub 30]) produced by oil glands.

Croteau, R.

1991-01-01

173

Solar heat regulator  

US Patent & Trademark Office Database

A solar heat regulating device selectively heats, with sunlight, the air in a building having a window therein and alternately shields and insulates the air in the building from the heat of sunlight. A frame is provided for mounting the solar heat regulating device inside the structure adjacent to the window. A plurality of hollow vanes each of which have a passageway therethrough. Each of the vanes has a heat absorptive surface on one side which allows solar radiation impinging thereon to heat the air in the passageways of the vanes. The vanes also have a heat reflective surface on another side. The heat reflective surface reflects the solar radiation impinging thereon and insulates the air inside the building from the heat of the sunlight. The vanes are rotatably mounted about vertical axes and spaced so that either the heat absorptive surfaces on the vanes or the heat reflective surfaces on the vanes may face the outside of the building. The device includes means for sealing the outside facing surfaces of the vanes from the inside of the building. Manifold means are also provided for conducting the cooler air from the inside of the building to the bottom of the passageways in the vanes and for conducting the heated air from the top of the passageways of the vanes to the inside of the building.

1987-04-07

174

Regulation of macronutrient transport.  

PubMed

In addition to light, water and CO(2), plants require a number of mineral nutrients, in particular the macronutrients nitrogen, sulphur, phosphorus, magnesium, calcium and potassium. After uptake from the soil by the root system they are either immediately assimilated into organic compounds or distributed within the plant for usage in different tissues. A good understanding of how the transport of macronutrients into and between plant cells is adjusted to different environmental conditions is essential to achieve an increase of nutrient usage efficiency and nutritional value in crops. Here, we review the current state of knowledge regarding the regulation of macronutrient transport, taking both a physiological and a mechanistic approach. We first describe how nutrient transport is linked to environmental and internal cues such as nutrient, carbon and water availability via hormonal, metabolic and physical signals. We then present information on the molecular mechanisms for regulation of transport proteins, including voltage gating, auto-inhibition, interaction with other proteins, oligomerization and trafficking. Combining of evidence for different nutrients, signals and regulatory levels creates an opportunity for making new connections within a large body of data, and thus contributes to an integrative understanding of nutrient transport. PMID:19076716

Amtmann, Anna; Blatt, Michael R

2009-01-01

175

Buck/boost regulator  

NASA Technical Reports Server (NTRS)

A voltage regulated DC to DC converter uses an inductor and a capacitor as storage elements. The inductor is composed of two windings having a common junction. A transformer with a center tap connected to the common junction of the two windings is connected at either end of its winding to ground through controlled switches. One winding of the inductor and either end of the transformer winding are connected by power diodes to the capacitor which supplies the output voltage to a load. The other winding of the inductor is connected to a fourth power diode as a clamping diode. Input voltage is supplied to the inductor through a third controlled switch. A pulse width modulator connected to the output of the converter alternately closes and opens the switches connected to either end of the transformer winding and also closes the switch supplying input voltage to the inductor each time either of the switches connected to the ends of the transformer winding are closed. The duty cycle of the closing and opening of the several switches is adjusted by the pulse modulator to regulate the output voltage.

Paulkovich, J.; Rodriguez, G. E. (inventors)

1981-01-01

176

Coping with gas turbine emissions regulations  

Microsoft Academic Search

The subject of emissions regulations is complex. Worldwide there are over 20 countries that regulate permissible emissions, each with its own regulations. Certain groups, such as the European Economic Community (EEC) have regulations for all of their members. In the United States, federal regulations fall under the Environmental Protection Agency (EPA), while there are separate regulations for each of the

Solt

1987-01-01

177

Regulating the regulators: serine/arginine-rich proteins under scrutiny.  

PubMed

Serine/arginine-rich (SR) proteins are among the most studied splicing regulators. They constitute a family of evolutionarily conserved proteins that, apart from their initially identified and deeply studied role in splicing regulation, have been implicated in genome stability, chromatin binding, transcription elongation, mRNA stability, mRNA export and mRNA translation. Remarkably, this list of SR protein activities seems far from complete, as unexpected functions keep being unraveled. An intriguing aspect that awaits further investigation is how the multiple tasks of SR proteins are concertedly regulated within mammalian cells. In this article, we first discuss recent findings regarding the regulation of SR protein expression, activity and accessibility. We dive into recent studies describing SR protein auto-regulatory feedback loops involving different molecular mechanisms such asunproductive splicing, microRNA-mediated regulation and translational repression. In addition, we take into account another step of regulation of SR proteins, presenting new findings about a variety of post-translational modifications by proteomics approaches and how some of these modifications can regulate SR protein sub-cellular localization or stability. Towards the end, we focus in two recently revealed functions of SR proteins beyond mRNA biogenesis and metabolism, the regulation of micro-RNA processing and the regulation of small ubiquitin-like modifier (SUMO) conjugation. PMID:22941908

Risso, Guillermo; Pelisch, Federico; Quaglino, Ana; Pozzi, Berta; Srebrow, Anabella

2012-10-01

178

ROS Stress Resets Circadian Clocks to Coordinate Pro-Survival Signals  

PubMed Central

Dysfunction of circadian clocks exacerbates various diseases, in part likely due to impaired stress resistance. It is unclear how circadian clock system responds toward critical stresses, to evoke life-protective adaptation. We identified a reactive oxygen species (ROS), H2O2 -responsive circadian pathway in mammals. Near-lethal doses of ROS-induced critical oxidative stress (cOS) at the branch point of life and death resets circadian clocks, synergistically evoking protective responses for cell survival. The cOS-triggered clock resetting and pro-survival responses are mediated by transcription factor, central clock-regulatory BMAL1 and heat shock stress-responsive (HSR) HSF1. Casein kinase II (CK2) –mediated phosphorylation regulates dimerization and function of BMAL1 and HSF1 to control the cOS-evoked responses. The core cOS-responsive transcriptome includes CK2-regulated crosstalk between the circadian, HSR, NF-kappa-B-mediated anti-apoptotic, and Nrf2-mediated anti-oxidant pathways. This novel circadian-adaptive signaling system likely plays fundamental protective roles in various ROS-inducible disorders, diseases, and death.

Tamaru, Teruya; Kawamura, Genki; Vares, Guillaume; Honda, Kousuke; Mishra, Durga Prasad; Wang, Bing; Benjamin, Ivor; Sassone-Corsi, Paolo; Ozawa, Takeaki; Takamatsu, Ken

2013-01-01

179

Shame regulation in personality pathology.  

PubMed

Drawing on extant work on shame and emotion regulation, this article proposes that three broad forms of maladaptive shame regulation strategies are fundamental in much of personality pathology: Prevention (e.g., dependence, fantasy), used preemptively, lessens potential for shame; Escape (e.g., social withdrawal, misdirection) reduces current or imminent shame; Aggression, used after shame begins, refocuses shame into anger directed at the self (e.g., physical self-harm) or others (e.g., verbal aggression). This article focuses on the contributions of shame regulation to the development and maintenance of personality pathology, highlighting how various maladaptive shame regulation strategies may lead to personality pathology symptoms, associated features, and dimensions. Consideration is also given to the possible shame-related constructs necessitating emotion regulation (e.g., shame aversion and proneness) and the points in the emotion process when regulation can occur. PMID:21895346

Schoenleber, Michelle; Berenbaum, Howard

2012-05-01

180

Transcriptional regulation during Drosophila spermatogenesis  

PubMed Central

Drosophila spermatogenesis has become a paradigmatic system for the study of mechanisms that regulate adult stem cell maintenance, proliferation and differentiation. The dramatic cellular differentiation process from germline stem cell (GSC) to mature sperm is accompanied by dynamic changes in gene expression, which are regulated at transcriptional, post-transcriptional (including translational) and post-translational levels. Post-transcriptional regulation has been proposed as a unique feature of germ cells. However, recent studies have provided new insights into transcriptional regulation during Drosophila spermatogenesis. Both signaling pathways and epigenetic mechanisms act to orchestrate the transcriptional regulation of distinct genes at different germ cell differentiation stages. Many of the regulatory pathways that control male gamete differentiation in Drosophila are conserved in mammals. Therefore, studies using Drosophila spermatogenesis will provide insight into the molecular mechanisms that regulate mammalian germ cell differentiation pathways.

Lim, Cindy; Tarayrah, Lama; Chen, Xin

2012-01-01

181

Strategic Automation of Emotion Regulation  

Microsoft Academic Search

As implementation intentions are a powerful self-regulation tool for thought and action (meta-analysis by P. M. Gollwitzer & P. Sheeran, 2006), the present studies were conducted to address their effectiveness in regulating emotional reactivity. Disgust- (Study 1) and fear- (Study 2) eliciting stimuli were viewed under 3 different self-regulation instructions: the goal intention to not get disgusted or frightened, respectively,

Inge Schweiger Gallo; Andreas Keil; Kathleen C. McCulloch; Brigitte Rockstroh; Peter M. Gollwitzer

2009-01-01

182

Common mechanisms of PIKK regulation  

PubMed Central

Kinases in the phosphoinositide 3-kinase related kinase (PIKK) family include ATM (ataxia-telangiectasia mutated), ATR (ATM and Rad3-related), DNA-PKcs (DNA-dependent protein kinase catalytic subunit, mTOR (mammalian target of rapamycin), and SMG1 (suppressor with morphological effect on genitalia family member). These atypical protein kinases regulate DNA damage responses, nutrient-dependent signaling, and nonsense-mediated mRNA decay. This review focuses on the mechanisms regulating the PIKK family with a strong emphasis on the DNA damage regulated kinases. We outline common regulatory themes and suggest how discoveries about the regulation of one PIKK can be informative for the other family members.

Lovejoy, Courtney A.; Cortez, David

2009-01-01

183

Power-MOSFET Voltage Regulator  

NASA Technical Reports Server (NTRS)

Ninety-six parallel MOSFET devices with two-stage feedback circuit form a high-current dc voltage regulator that also acts as fully-on solid-state switch when fuel-cell out-put falls below regulated voltage. Ripple voltage is less than 20 mV, transient recovery time is less than 50 ms. Parallel MOSFET's act as high-current dc regulator and switch. Regulator can be used wherever large direct currents must be controlled. Can be applied to inverters, industrial furnaces photovoltaic solar generators, dc motors, and electric autos.

Miller, W. N.; Gray, O. E.

1982-01-01

184

Regulation by mitophagy.  

PubMed

Eukaryotes employ elaborate mitochondrial quality control to maintain the function of the power-generating organelle. Mitochondrial quality control is particularly important for the maintenance of neural and muscular tissues. Mitophagy is specialized version of the autophagy pathway. Mitophagy delivers damaged mitochondria to lysosomes for degradation. Recently, a series of elegant studies have demonstrated that two Parkinson's disease-associated genes PINK1 and parkin are involved in the maintenance of healthy mitochondria as mitophagy. Parkin in co-operation with PINK1 specifically recognizes damaged mitochondria with reduced mitochondrial membrane potential (??m), rapidly isolates them from the mitochondrial network and eliminates them through the ubiquitin-proteasome and autophagy pathways. Here we introduce and review recent studies that contribute to understanding the molecular mechanisms of mitophagy such as PINK1 and Parkin-mediated mitochondrial regulation. We also discuss how defects in the PINK1-Parkin pathway may cause neurodegeneration in Parkinson's disease. PMID:24842103

Hattori, Nobutaka; Saiki, Shinji; Imai, Yuzuru

2014-08-01

185

TFEB regulates lysosomal proteostasis.  

PubMed

Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a ?-hexosaminidase mutant associated with the development of another LSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs. PMID:23393155

Song, Wensi; Wang, Fan; Savini, Marzia; Ake, Ashley; di Ronza, Alberto; Sardiello, Marco; Segatori, Laura

2013-05-15

186

Regulation of Organelle Acidity  

PubMed Central

Intracellular organelles have characteristic pH ranges that are set and maintained by a balance between ion pumps, leaks, and internal ionic equilibria. Previously, a thermodynamic study by Rybak et al. (Rybak, S., F. Lanni, and R. Murphy. 1997. Biophys. J. 73:674–687) identified the key elements involved in pH regulation; however, recent experiments show that cellular compartments are not in thermodynamic equilibrium. We present here a nonequilibrium model of lumenal acidification based on the interplay of ion pumps and channels, the physical properties of the lumenal matrix, and the organelle geometry. The model successfully predicts experimentally measured steady-state and transient pH values and membrane potentials. We conclude that morphological differences among organelles are insufficient to explain the wide range of pHs present in the cell. Using sensitivity analysis, we quantified the influence of pH regulatory elements on the dynamics of acidification. We found that V-ATPase proton pump and proton leak densities are the two parameters that most strongly influence resting pH. Additionally, we modeled the pH response of the Golgi complex to varying external solutions, and our findings suggest that the membrane is permeable to more than one dominant counter ion. From this data, we determined a Golgi complex proton permeability of 8.1 × 10?6 cm/s. Furthermore, we analyzed the early-to-late transition in the endosomal pathway where Na,K-ATPases have been shown to limit acidification by an entire pH unit. Our model supports the role of the Na,K-ATPase in regulating endosomal pH by affecting the membrane potential. However, experimental data can only be reproduced by (1) positing the existence of a hypothetical voltage-gated chloride channel or (2) that newly formed vesicles have especially high potassium concentrations and small chloride conductance.

Grabe, Michael; Oster, George

2001-01-01

187

[Regulation of terpene metabolism  

SciTech Connect

Terpenoid oils, resins, and waxes from plants are important renewable resources. The objective of this project is to understand the regulation of terpenoid metabolism using the monoterpenes (C[sub 10]) as a model. The pathways of monoterpene biosynthesis and catabolism have been established, and the relevant enzymes characterized. Developmental studies relating enzyme levels to terpene accumulation within the oil gland sites of synthesis, and work with bioregulators, indicate that monoterpene production is controlled by terpene cyclases, the enzymes catalyzing the first step of the monoterpene pathway. As the leaf oil glands mature, cyclase levels decline and monoterpene biosynthesis ceases. Yield then decreases as the monoterpenes undergo catabolism by a process involving conversion to a glycoside and transport from the leaf glands to the root. At this site, the terpenoid is oxidatively degraded to acetate that is recycled into other lipid metabolites. During the transition from terpene biosynthesis to catabolism, the oil glands undergo dramatic ultrastructural modification. Degradation of the producing cells results in mixing of previously compartmentized monoterpenes with the catabolic enzymes, ultimately leading to yield decline. This regulatory model is being applied to the formation of other terpenoid classes (C[sub 15] C[sub 20], C[sub 30], C[sub 40]) within the oil glands. Preliminary investigations on the formation of sesquiterpenes (C[sub 15]) suggest that the corresponding cyclases may play a lesser role in determining yield of these products, but that compartmentation effects are important. From these studies, a comprehensive scheme for the regulation of terpene metabolism is being constructed. Results from this project wail have important consequences for the yield and composition of terpenoid natural products that can be made available for industrial exploitation.

Croteau, R.

1989-11-09

188

Banking regulation’s impact on industry monopoly and risk  

Microsoft Academic Search

Suggests that banks are different due to plasticity of assets and high debt\\/equity ratios. For this reason banks need to be regulated. Discusses the most efficient method of regulating banks. Highlights that the move from unlimited liability banking to limited liability banking was inefficient as it led to a more unstable banking system. The unstable banking system required government monitoring

Charles Hickson; John Turner

1996-01-01

189

PLANT CHITINASES - REGULATION AND FUNCTION  

Microsoft Academic Search

The aim of this review is to present the current state of knowledge on plant chitinases and their regulation and function. Chitinases are up-regulated by a variety of stress conditions, both biotic and abiotic, and by such phytohormones as ethylene, jasmonic acid, and salicylic acid. Like other PR proteins, chitinases play a role in plant resistance against distinct pathogens. Moreover,

ANNA KASPRZEWSKA

2003-01-01

190

The effectiveness of Regulation FD  

Microsoft Academic Search

We examine whether Regulation Fair Disclosure (Reg FD) has reduced the informativeness of analysts’ information outputs. For a sample of financial analysts’ earnings forecasts and recommendations released in a 2-year window around Reg FD's effective date, we show that in the post-Regulation FD period the absolute price impact of information disseminated by financial analysts is lower by 28%. We also

Andreas Gintschel; Stanimir Markov

2004-01-01

191

Deceptive Business Practices: Federal Regulations.  

ERIC Educational Resources Information Center

Federal regulations to prevent deceptive advertising seek to balance the advertiser's freedom of speech with protection of the consumer. This paper discusses what the Federal Trade Commission (FTC) has done to regulate advertising and evaluates the adequacy of its controls. The commission uses cease-and-desist orders, affirmative disclosure,…

Rohrer, Daniel Morgan

192

Technological Change in Regulated Industries.  

ERIC Educational Resources Information Center

The articles in this volume discuss how well industries operating under government regulation respond to technical innovation: do the effects of regulations vary among industries, and if so, does this result from variations in the regulatory approach, the organization of the firms, or the nature of the technology? Industries considered include…

Capron, William M., Ed.

193

Gravity and body mass regulation  

NASA Technical Reports Server (NTRS)

The effects of altered gravity on body mass, food intake, energy expenditure, and body composition are examined. Metabolic adjustments are reviewed in maintenance of energy balance, neural regulation, and humoral regulation are discussed. Experiments with rats indicate that genetically obese rats respond differently to hypergravity than lean rats.

Warren, L. E.; Horwitz, B. A.; Fuller, C. A.

1997-01-01

194

Design for pressure regulating components  

NASA Technical Reports Server (NTRS)

The design development for Pressure Regulating Components included a regulator component trade-off study with analog computer performance verification to arrive at a final optimized regulator configuration for the Space Storable Propulsion Module, under development for a Jupiter Orbiter mission. This application requires the pressure regulator to be capable of long-term fluorine exposure. In addition, individual but basically identical (for purposes of commonality) units are required for separate oxidizer and fuel pressurization. The need for dual units requires improvement in the regulation accuracy over present designs. An advanced regulator concept was prepared featuring redundant bellows, all metallic/ceramic construction, friction-free guidance of moving parts, gas damping, and the elimination of coil springs normally used for reference forces. The activities included testing of actual size seat/poppet components to determine actual discharge coefficients and flow forces. The resulting data was inserted into the computer model of the regulator. Computer simulation of the propulsion module performance over two mission profiles indicated satisfactory minimization of propellant residual requirements imposed by regulator performance uncertainties.

Wichmann, H.

1973-01-01

195

Regulating Pornography: A Public Dilemma.  

ERIC Educational Resources Information Center

Examines attitudes toward sex and pornography by means of a telephone survey of Dane County, Wisconsin, adults. Describes survey questions about sexual attitudes, perceived effects of pornography, and pornography regulation. Concludes that adults who feel more strongly that pornography has negative effects are more opposed to its regulation. (SG)

Thompson, Margaret E.; And Others

1990-01-01

196

EPA REGULATIONS RELATED TO DIOXIN  

EPA Science Inventory

EPA currently has regulations relating to release of dioxin-like compounds from air sources and from pulp and paper mills into water bodies. Information on these regulations for dioxin-like compounds and other pollutants can be found at these sites. ...

197

Regulation and Preemptive Technology Adoption  

Microsoft Academic Search

Two rival firms must decide if and when to adopt a new technology, knowing how adoption costs decline over time and how profit flows vary with adoption patterns. In many cases, price and entry regulations beneficially slow technology adoption by making preemption strategies less attractive. In some cases, these regulations can so discourage a firm from preemption as to change

Michael H. Riordan

1992-01-01

198

Regulation of coronary blood flow  

PubMed Central

Coronary blood flow is dependent upon arterial pressure, diastolic time, and small vessel resistance. The system is regulated to achieve a low flow high oxygen extraction and low myocardial Po2. This setting is sensitive to change in oxygen needs. Regulation of blood flow occurs primarily through local intrinsic regulation, most likely through production of vasodilating metabolites in response to minimal degrees of ischaemia. Local regulation appears to dominate over remote regulation in most circumstances. Blood flow distribution to the myocardium is depth dependent as well as regional in variation. Both types of distribution of blood flow are profoundly disturbed in the presence of obstructive coronary atherosclerosis. This results in either concentric myocardial shells or patchy transmural zones of selective ischaemia with clear-cut but local abnormalities in metabolism and performance. Images

Gorlin, Richard

1971-01-01

199

Strategic automation of emotion regulation.  

PubMed

As implementation intentions are a powerful self-regulation tool for thought and action (meta-analysis by P. M. Gollwitzer & P. Sheeran, 2006), the present studies were conducted to address their effectiveness in regulating emotional reactivity. Disgust- (Study 1) and fear- (Study 2) eliciting stimuli were viewed under 3 different self-regulation instructions: the goal intention to not get disgusted or frightened, respectively, this goal intention furnished with an implementation intention (i.e., an if-then plan), and a no-self-regulation control group. Only implementation-intention participants succeeded in reducing their disgust and fear reactions as compared to goal-intention and control participants. In Study 3, electrocortical correlates (using dense-array electroencephalography) revealed differential early visual activity in response to spider slides in ignore implementation-intention participants, as reflected in a smaller P1. Theoretical and applied implications of the present findings for emotion regulation via implementation intentions are discussed. PMID:19210061

Gallo, Inge Schweiger; Keil, Andreas; McCulloch, Kathleen C; Rockstroh, Brigitte; Gollwitzer, Peter M

2009-01-01

200

Vehicle mounted voltage regulator  

SciTech Connect

In a roadway vehicle having a storage battery and an engine-driven alternator, the battery voltage is controlled by a voltage regulator which has a first voltage detector for detecting when the battery voltage reduces below a higher reference level at which the battery voltage is normally controlled, and a second voltage detector for detecting when the battery voltage reduces below a lower reference level. A third voltage detector detects when the alternator voltage rises above a predetermined level. A logic gate circuit responds to outputs from the second and third voltage detectors by generating a warning signal. A semiconductor switching element is coupled in series with the field coil of the alternator to supply thereto the alternator voltage in response to a switching control which is generated in response to an output signal from the first voltage detector to cause the switching element to operate the alternator in a high output state and in response to the logic gate circuit to operate the alternator in a low output state.

Akita, Y.; Maruyama, T.; Teshima, T.; Torii, K.

1984-05-29

201

[Ghrelin: beyond hunger regulation].  

PubMed

Man ingests food to mitigate hunger (mediated by physiological and biochemical signals), satisfy appetite (subjective sensation) and because of psychosocial reasons. Satiation biomarkers (stop feeding) are gastric distention and hormones (CCK, GLP-1) and satiety biomarkers (induce feeding) are food-induced thermogenesis, body temperature, glycaemia and also hormones (insulin, leptin and ghrelin). Oxidative metabolism/body composition, tryptophan/serotonin and proinflammatory cytokines are also implicated on hunger physiology. At the present time, ghrelin is the only known circulating orexigenic with potential on hunger/body weight regulation. It is a neuropeptide (endogenous ligand for the GH secretagogue) recently isolated from the oxyntic mucosa and synthesized mainly in the stomach. Its blood concentration depends on diet, hyperglucemia and adiposity/leptin. It is secreted 1-2 hours preprandially and its concentration decreases drastically during the postprandium. Ghrelin acts on the lateral hypothalamus and theoretically inhibits proinflammatory cytokine secretion and antagonizes leptin. Ghrelin physiologically increases food intake and stimulates adipogenesis, gastrointestinal motility and gastric acid secretion, and has other hormonal and cardiovascular functions. Ghrelin blood concentration is reduced in massive obesity, non-alcoholic steatohepatitis, polycystic ovary syndrome, acromegaly, hypogonadism, ageing, short bowel syndrome and rheumatoid arthritis; and increased in primary or secondary anorexia, starvation, chronic liver disease and celiac disease. Cerebral and peritoneal ghrelin administration (rats) and systemic administration (rats and healthy volunteers, cancer patients or patients on peritoneal dialysis) promotes food consumption and increases adiposity, of utmost importance in the treatment of patients with anorexia. PMID:17058987

Milke García, Maria del Pilar

2005-01-01

202

Redox regulation in cancer  

PubMed Central

Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and cell’s own antioxidant defenses. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Ultraviolet (UV) exposures, ?-radiation and other environmental carcinogens generate ROS in the cells, which can exert apoptosis in the tumors, thereby killing the malignant cells or induce the progression of the cancer growth by blocking cellular defense system. Cancer stem cells take the advantage of the aberrant redox system and spontaneously proliferate. Oxidative stress and gene-environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Prolonged lifetime exposure to estrogen is associated with several kinds of DNA damage. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. BRCA1, a tumor suppressor against hormone responsive cancers such as breast and prostate cancer, plays a significant role in inhibiting ROS and estrogen mediated DNA damage; thereby regulate the redox homeostasis of the cells. Several transcription factors and tumor suppressors are involved during stress response such as Nrf2, NF?B and BRCA1. A promising strategy for targeting redox status of the cells is to use readily available natural substances from vegetables, fruits, herbs and spices. Many of the phytochemicals have already been identified to have chemopreventive potential, capable of intervening in carcinogenesis.

Das, Ila; Chandhok, Des

2010-01-01

203

Assessing Academic Self-Regulated Learning  

Microsoft Academic Search

Abstract Self-regulated learning concerns the application of general models of regulation and self- regulation to issues of learning especially within academic contexts. Self-regulated learning is an active, constructive process whereby learners set goals for their learning and then attempt to monitor, regulate, and control their cognition, motivation, and behavior, guided and constrained

Christopher A. Wolters; Paul R. Pintrich; Stuart A. Karabenick

204

Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical Implications  

NSDL National Science Digital Library

Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations—including obesity, metabolic syndrome, and cardiovascular disease—by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.

Tomoshige Kino (NIH;Eunice Kennedy Shriver National Institute of Child Health and Human Development REV)

2012-10-02

205

Ontogeny of circadian oscillations in the heart and liver in chicken.  

PubMed

The circadian system drives postnatally rhythmic processes in the peripheral tissues. To extend information about embryonic stages, ontogeny of the circadian oscillations in chicken (Gallus gallus) heart and liver was analyzed. Nineteen day old embryos and 4-day old chicks were synchronized to a light:dark cycle and then the effects of light pulses applied during the dark and subjective light phases of the 24 h cycle were tested. Expression of Per2 and Bmal1 was measured by RT-PCR. The effects of light pulses on plasma glucose and melatonin levels were also analyzed. The expression of Per2 and Bmal1 was rhythmic in the heart and liver of 4-day old chicks, however, more pronounced rhythmic expression was observed in the liver. The light pulse induced a significant increase in Per2 expression in the liver. Plasma glucose was up- and melatonin down-regulated after the light pulse postnatally. Expression of Per2 did not show a rhythmic pattern and the light pulse did not cause changes in Per2 expression in the liver and heart of the embryos. The absence of the rhythmic expression of the clock genes in the embryonic heart and liver may reflect missing rhythmic cues since early after hatching peripheral oscillators function in a mature-like manner. PMID:19447189

Zeman, Michal; Szántóová, Kristína; Herichová, Iveta

2009-09-01

206

Real-time monitoring of circadian clock oscillations in primary cultures of mammalian cells using Tol2 transposon-mediated gene transfer strategy  

PubMed Central

Background The circadian rhythm in mammals is orchestrated by a central pacemaker in the brain, but most peripheral tissues contain their own intrinsic circadian oscillators. The circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as behavior, cardiovascular functions and energy metabolism. Thus, it is important to understand the correlation between circadian oscillator and physiological functions in peripheral tissues. However, it is still difficult to investigate the molecular oscillator in primary culture cells. Results In this study, we used a novel Tol2 transposon based Dbp promoter or Bmal1 promoter driven luciferase reporter vector system to detect and analyze the intrinsic molecular oscillator in primary culture cells (mouse embryonic fibroblasts, fetal bovine heart endothelial cells and rat astrocytes). The results showed circadian molecular oscillations in all examined primary culture cells. Moreover, the phase relationship between Dbp promoter driven and Bmal1 promoter driven molecular rhythms were almost anti-phase, which suggested that these reporters appropriately read-out the intrinsic cellular circadian clock. Conclusions Our results indicate that gene transfer strategy using the Tol2 transposon system of a useful and safe non-viral vector is a powerful tool for investigating circadian rhythms in peripheral tissues.

2010-01-01

207

Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical Implications  

PubMed Central

Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations—including obesity, metabolic syndrome, and cardiovascular disease—by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.

Kino, Tomoshige

2013-01-01

208

Post regulation circuit with energy storage  

DOEpatents

A charge regulation circuit provides regulation of an unregulated voltage supply and provides energy storage. The charge regulation circuit according to the present invention provides energy storage without unnecessary dissipation of energy through a resistor as in prior art approaches.

Ball, Don G. (Livermore, CA); Birx, Daniel L. (Oakley, CA); Cook, Edward G. (Livermore, CA)

1992-01-01

209

76 FR 35740 - North Korea Sanctions Regulations  

Federal Register 2010, 2011, 2012, 2013

...Foreign Assets Control 31 CFR Part 510 North Korea Sanctions Regulations AGENCY: Office of...OFAC'') is amending the North Korea Sanctions Regulations to implement Executive...Foreign Assets Control published the North Korea Sanctions Regulations, 31 CFR part...

2011-06-20

210

18 CFR 415.30 - Regulations generally.  

Code of Federal Regulations, 2013 CFR

...Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION ADMINISTRATIVE MANUAL BASIN REGULATIONS-FLOOD PLAIN REGULATIONS Standards § 415.30 Regulations generally. The uses of land within a flood hazard area shall be...

2013-04-01

211

Bolivar County, Mississippi: Subdivision Regulations.  

National Technical Information Service (NTIS)

The report creates and establishes suggested general rules and regulations for the subdivision of land in Bolivar County, MS. It sets forth transportation and thoroughfare design standards within subdivisions; and outlines administrative enforcement, pena...

1973-01-01

212

Regulation of Repressor Expression in ?*  

PubMed Central

A new gene in bacteriophage ? is described. The product of this gene cro prevents expression of immunity and regulates the expression of those genes to the left of the immunity region. cro- mutants have been isolated and characterized.

Eisen, H.; Brachet, P.; Silva, L. Pereira da; Jacob, F.

1970-01-01

213

Learned regulation of brain metabolism.  

PubMed

Self-regulation and voluntary control of circumscribed brain regions using real-time functional MRI (rt-fMRI) allows the establishment of a causal functional link between localized brain activity and behavior and cognition. A long tradition of research has clearly shown the brain's ability to learn volitional control of its own activity and effects on behavior. Yet, the underlying neural mechanism of self-regulation is still not fully understood. Here, we propose that self-regulation of brain activity is akin to skill learning and thus may depend on an intact subcortical motor system. We elaborate on the critical role of the basal ganglia in skill learning and neurofeedback, and clarify that brain-self-regulation need not be an explicit and conscious process as often mistakenly held. PMID:23664452

Birbaumer, Niels; Ruiz, Sergio; Sitaram, Ranganatha

2013-06-01

214

Cell Biology: Growth Regulation, Differentiation.  

National Technical Information Service (NTIS)

The scope of this Cancergram includes factors which have significant effects on growth and differentiation of normal and neoplastic cells in vivo and in vitro. The scope centers on the production, physical characteristics, and action of these growth regul...

1982-01-01

215

Cell Biology: Growth Regulation, Differentiation.  

National Technical Information Service (NTIS)

The scope of this Cancergram includes factors which have significant effects on growth and differentiation of normal and neoplastic cells in vivo and in vitro. The scope centers on the production, physical characteristics, and action of these growth regul...

1985-01-01

216

Cell Biology: Growth Regulation, Differentiation.  

National Technical Information Service (NTIS)

The scope of this Cancergram includes factors which have significant effects on growth and differentiation of normal and neoplastic cells in vivo and in vitro. The scope centers on the production, physical characteristics, and action of these growth regul...

1984-01-01

217

Flow-compensating pressure regulator  

NASA Technical Reports Server (NTRS)

Pressure regulator developed for use with cataract-surgery instrument controls intraocular pressure during substantial variations in flow rate of infusion fluid. Device may be applicable to variety of eye-surgery instruments.

Baehr, E. F.

1979-01-01

218

Vibrio Fischeri Symbiosis Gene Regulation.  

National Technical Information Service (NTIS)

The goals of this project were to investigate the molecular mechanisms controlling luminescence gene expression of the symbiotic bioluminescent bacterium Vibrio fischeri; and to identify and investigate the regulation of other symbiosis functions in this ...

P. V. Dunlap

1989-01-01

219

Cell Biology: Growth Regulation, Differentiation.  

National Technical Information Service (NTIS)

The scope of this Cancergram includes factors which have significant effects on growth and differentiation of normal and neoplastic cells in vivo and in vitro. The scope centers on the production, physical characteristics, and action of these growth regul...

1983-01-01

220

Subdivision Regulations, 1969, Erwin, Tennessee.  

National Technical Information Service (NTIS)

The study consists of subdivision regulations for the city of Erwin, Tennessee. Included in the study are standards for submitting and receiving preliminary and final approval for all subdivisions within the planning region. (Author)

1969-01-01

221

Wide Area Voltage Regulation & Protection  

Microsoft Academic Search

A very promising wide area voltage protection (V-WAP) solution to face EHV voltage stability and system security problems is presented. Its unique ability is mainly due to an effective co-ordination with a wide area voltage regulation (V-WAR) modern system where the secondary and tertiary voltage regulations (SVR and TVR respectively) operate according with their hierarchy. Evidence is given to the

S. Corsi

2009-01-01

222

Thyroid hormone regulation of metabolism.  

PubMed

Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, ? and ?, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets. PMID:24692351

Mullur, Rashmi; Liu, Yan-Yun; Brent, Gregory A

2014-04-01

223

A fast regulator with semi natural commutation  

Microsoft Academic Search

This paper presents an on load tap changing (OLTC) regulator used to maintain the output voltage between certain limits. This regulator uses the semi natural commutation in order to avoid the shortcircuit. The regulator is of the fast type, because is able to correct sags, swells, beside other voltage variations. I. INTRODUCTION OLTC regulators are widely used to improve voltage

Jose Alvarez; Rodolfo Echavarria; Armando Flores

2011-01-01

224

Air ambulance regulations: a model.  

PubMed

Prior attempts at establishing minimal federal air ambulance regulations and standards have been unsuccessful. However, reports of poor patient medical care during transport by some air ambulance services is now forcing many states to initiate air ambulance regulations. In 1984, the State of Utah Emergency Medical Services convened a special subcommittee to develop aeromedical regulations for the State of Utah. Using a three-level approach based upon the patient's requirements for basic, advanced, or specialized medical care and the urgency of transport, the subcommittee was able to derive medical categories necessary for the selection and utilization of air ambulance services. Minimum air ambulance regulations were then established for aircraft configuration, flight crew requirements, minimal equipment and medications, and the responsibilities of the medical director or designee for each of the three levels of medical care. We conclude that the application of a levels approach based upon the patient's medical requirements may be useful in assisting other states attempting to establish flexible but specific regulations directed at the safe transport of patients by aeromedical evacuation. PMID:3741293

Thomas, F; Gibbons, H; Clemmer, T P

1986-07-01

225

Regulation of Autophagy by Kinases  

PubMed Central

Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

2011-01-01

226

Bile Acids Regulate Cardiovascular Function  

PubMed Central

Research over the last decade has uncovered roles for bile acids (BAs) that extend beyond their traditional functions in regulating lipid digestion and cholesterol metabolism. BAs are now recognized as signaling molecules that interact with both plasma membrane and nuclear receptors. Emerging evidence indicates that by interacting with these receptors BAs regulate their own synthesis, glucose and energy homeostasis, and other important physiological events. Herein, we provide a comprehensive review of the actions of BAs on cardiovascular function. In the heart and the systemic circulation, BAs interact with plasma membrane G-protein coupled receptors, e.g. TGR5 and muscarinic receptors, and nuclear receptors, e.g. the farnesoid (FXR) and pregnane (PXR) xenobiotic receptors. BA receptors are expressed in cardiovascular tissue, however, the mechanisms underlying BA-mediated regulation of cardiovascular function remain poorly understood. BAs reduce heart rate by regulating channel conductance and calcium dynamics in sino-atrial and ventricular cardiomyocytes, and regulate vascular tone via both endothelium-dependent and -independent mechanisms. End-stage-liver disease, obstructive jaundice and intrahepatic cholestasis of pregnancy are prominent conditions in which elevated serum BAs alter vascular dynamics. This review focuses on BAs as newly-recognized signaling molecules that modulate cardiovascular function.

Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L.

2011-01-01

227

Law and regulation of benzene.  

PubMed Central

OSHA has created final benzene regulations after extensive rulemakings on two occasions, 1978 and 1987. These standards have been the subject of extensive litigation for nearly 20 years. This article examines in detail the conceptual underpinnings of the Benzene Case, (which was decided by the U.S. Supreme Court in 1980) in light of U.S. administrative law precedents that have set limits upon administrative discretion under the test for "substantial evidence" and the "hard look doctrine." This article also addresses recent developments in the wake of the Benzene Case and their implications for benzene regulations following the "significant risk" doctrine in that case. This article briefly describes other national, regional, and international laws governing the use of benzene. This article concludes that the revisions of the benzene regulation and subsequent rulemaking provide substantial evidence of scientific underpinnings for regulatory action and that laws from other nations reflect an international consensus that occupational exposure to benzene is a proper subject of regulation. Such regulations and policies are therefore likely to withstand scrutiny and remain enforceable as widely accepted norms.

Feitshans, I L

1989-01-01

228

Calcium regulation of keratinocyte differentiation  

PubMed Central

Calcium is the major regulator of keratinocyte differentiation in vivo and in vitro. A calcium gradient within the epidermis promotes the sequential differentiation of keratinocytes as they traverse the different layers of the epidermis to form the permeability barrier of the stratum corneum. Calcium promotes differentiation by both outside–in and inside–out signaling. A number of signaling pathways involved with differentiation are regulated by calcium, including the formation of desmosomes, adherens junctions and tight junctions, which maintain cell–cell adhesion and play an important intracellular signaling role through their activation of various kinases and phospholipases that produce second messengers that regulate intracellular free calcium and PKC activity, critical for the differentiation process. The calcium receptor plays a central role by initiating the intracellular signaling events that drive differentiation in response to extracellular calcium. This review will discuss these mechanisms.

Bikle, Daniel D; Xie, Zhongjian; Tu, Chia-Ling

2012-01-01

229

Energy regulation by the skeleton.  

PubMed

Bones of the skeleton are constantly remodeled through bone resorption by cells called osteoclasts and bone formation by cells called osteoblasts. Both cell types are under multi-hormone control. New research findings demonstrate that bone formation by osteoblasts is negatively regulated by the hormone leptin, which is secreted by adipocytes and acts through the leptin receptor in the central nervous system and ultimately through the sympathetic nervous system. Leptin deficiency leads to increased osteoblast activity and increased bone mass. Reciprocally, expression of the Esp gene, exclusive to osteoblasts, regulates glucose homeostasis and adiposity through controlling the osteoblastic secretion of the hormone-like substance osteocalcin. An undercarboxylated form of osteocalcin acts as a regulator of insulin in the pancreas and adiponectin in the adipocyte to modulate energy metabolism. Osteocalcin deficiency in knockout mice leads to decreased insulin and adiponectin secretion, insulin resistance, higher serum glucose levels and increased adiposity. PMID:18366536

Wolf, George

2008-04-01

230

Metabolic mechanisms of epigenetic regulation.  

PubMed

Chromatin modifications have been well-established to play a critical role in the regulation of genome function. Many of these modifications are introduced and removed by enzymes that utilize cofactors derived from primary metabolism. Recently, it has been shown that endogenous cofactors and metabolites can regulate the activity of chromatin-modifying enzymes, providing a direct link between the metabolic state of the cell and epigenetics. Here we review metabolic mechanisms of epigenetic regulation with an emphasis on their role in cancer. Focusing on three core mechanisms, we detail and draw parallels between metabolic and chemical strategies to modulate epigenetic signaling, and highlight opportunities for chemical biologists to help shape our knowledge of this emerging phenomenon. Continuing to integrate our understanding of metabolic and genomic regulatory mechanisms may help elucidate the role of nutrition in diseases such as cancer, while also providing a basis for new approaches to modulate epigenetic signaling for therapeutic benefit. PMID:24228614

Meier, Jordan L

2013-12-20

231

Upstream regulation of mycotoxin biosynthesis.  

PubMed

Mycotoxins are natural contaminants of food and feed products, posing a substantial health risk to humans and animals throughout the world. A plethora of filamentous fungi has been identified as mycotoxin producers and most of these fungal species belong to the genera Aspergillus, Fusarium, and Penicillium. A number of studies have been conducted to better understand the molecular mechanisms of biosynthesis of key mycotoxins and the regulatory cascades controlling toxigenesis. In many cases, the mycotoxin biosynthetic genes are clustered and regulated by one or more pathway-specific transcription factor(s). In addition, as biosynthesis of many secondary metabolites is coordinated with fungal growth and development, there are a number of upstream regulators affecting biosynthesis of mycotoxins in fungi. This review presents a concise summary of the regulation of mycotoxin biosynthesis, focusing on the roles of the upstream regulatory elements governing biosynthesis of aflatoxin and sterigmatocystin in Aspergillus. PMID:24377857

Yu, Jae-Hyuk; Alkhayyat, Fahad

2014-01-01

232

Positively regulated bacterial expression systems  

PubMed Central

Summary Regulated promoters are useful tools for many aspects related to recombinant gene expression in bacteria, including for high?level expression of heterologous proteins and for expression at physiological levels in metabolic engineering applications. In general, it is common to express the genes of interest from an inducible promoter controlled either by a positive regulator or by a repressor protein. In this review, we discuss established and potentially useful positively regulated bacterial promoter systems, with a particular emphasis on those that are controlled by the AraC?XylS family of transcriptional activators. The systems function in a wide range of microorganisms, including enterobacteria, soil bacteria, lactic bacteria and streptomycetes. The available systems that have been applied to express heterologous genes are regulated either by sugars (l?arabinose, l?rhamnose, xylose and sucrose), substituted benzenes, cyclohexanone?related compounds, ??caprolactam, propionate, thiostrepton, alkanes or peptides. It is of applied interest that some of the inducers require the presence of transport systems, some are more prone than others to become metabolized by the host and some have been applied mainly in one or a limited number of species. Based on bioinformatics analyses, the AraC?XylS family of regulators contains a large number of different members (currently over 300), but only a small fraction of these, the XylS/Pm, AraC/PBAD, RhaR?RhaS/rhaBAD, NitR/PnitA and ChnR/Pb regulator/promoter systems, have so far been explored for biotechnological applications.

Brautaset, Trygve; Lale, Rahmi; Valla, Svein

2009-01-01

233

Positively regulated bacterial expression systems.  

PubMed

Regulated promoters are useful tools for many aspects related to recombinant gene expression in bacteria, including for high-level expression of heterologous proteins and for expression at physiological levels in metabolic engineering applications. In general, it is common to express the genes of interest from an inducible promoter controlled either by a positive regulator or by a repressor protein. In this review, we discuss established and potentially useful positively regulated bacterial promoter systems, with a particular emphasis on those that are controlled by the AraC-XylS family of transcriptional activators. The systems function in a wide range of microorganisms, including enterobacteria, soil bacteria, lactic bacteria and streptomycetes. The available systems that have been applied to express heterologous genes are regulated either by sugars (L-arabinose, L-rhamnose, xylose and sucrose), substituted benzenes, cyclohexanone-related compounds, ?-caprolactam, propionate, thiostrepton, alkanes or peptides. It is of applied interest that some of the inducers require the presence of transport systems, some are more prone than others to become metabolized by the host and some have been applied mainly in one or a limited number of species. Based on bioinformatics analyses, the AraC-XylS family of regulators contains a large number of different members (currently over 300), but only a small fraction of these, the XylS/Pm, AraC/P(BAD), RhaR-RhaS/rhaBAD, NitR/PnitA and ChnR/Pb regulator/promoter systems, have so far been explored for biotechnological applications. PMID:21261879

Brautaset, Trygve; Lale, Rahmi; Valla, Svein

2009-01-01

234

Modulation of the TGF{beta}/Smad signaling pathway in mesangial cells by CTGF/CCN2  

SciTech Connect

Transforming growth factor-beta (TGF{beta}) drives fibrosis in diseases such as diabetic nephropathy (DN). Connective tissue growth factor (CTGF; CCN2) has also been implicated in this, but the molecular mechanism is unknown. We show that CTGF enhances the TGF{beta}/Smad signaling pathway by transcriptional suppression of Smad 7 following rapid and sustained induction of the transcription factor TIEG-1. Smad 7 is a known antagonist of TGF{beta} signaling and TIEG-1 is a known repressor of Smad 7 transcription. CTGF enhanced TGF{beta}-induced phosphorylation and nuclear translocation of Smad 2 and Smad 3 in mesangial cells. Antisense oligonucleotides directed against TIEG-1 prevented CTGF-induced downregulation of Smad 7. CTGF enhanced TGF{beta}-stimulated transcription of the SBE4-Luc reporter gene and this was markedly reduced by TIEG-1 antisense oligonucleotides. Expression of the TGF{beta}-responsive genes PAI-1 and Col III over 48 h was maximally stimulated by TGF{beta} + CTGF compared to TGF{beta} alone, while CTGF alone had no significant effect. TGF{beta}-stimulated expression of these genes was markedly reduced by both CTGF and TIEG-1 antisense oligonucleotides, consistent with the endogenous induction of CTGF by TGF{beta}. We propose that under pathological conditions, where CTGF expression is elevated, CTGF blocks the negative feedback loop provided by Smad 7, allowing continued activation of the TGF{beta} signaling pathway.

Abdel Wahab, Nadia [Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ (United Kingdom)]. E-mail: nadia.wahab@imperial.ac.uk; Weston, Benjamin S. [Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ (United Kingdom); Mason, Roger M. [Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ (United Kingdom)

2005-07-15

235

Mechanisms underlying regulated CFTR trafficking.  

PubMed

Stimulation of membrane capacitance and cell surface labeling of epitope-tagged CFTR provide evidence of cAMP-regulated CFTR trafficking. Co-expression of syntaxin 1A inhibits cAMP-stimulated current and capacitance changes in CFTR expressing cells and blocks cAMP-induced increases in cell surface CFTR. Inhibition of CFTR trafficking by syntaxin over-expression suggests a role for SNARE proteins in this process. CFTR phosphorylation may alter physical interactions with SNARE proteins to regulate plasma membrane CFTR density. PMID:10872420

Peters, K W; Qi, J; Watkins, S C; Frizzell, R A

2000-05-01

236

Regulation of Inflammation by Adenosine  

PubMed Central

Adenosine, a purine nucleoside generated by the dephosphorylation of adenine nucleotides, is a potent endogenous physiologic and pharmacologic regulator of many functions. Adenosine was first reported to inhibit the inflammatory actions of neutrophils nearly 30?years ago and since then the role of adenosine and its receptors as feedback regulators of inflammation has been well established. Here we review the effects of adenosine, acting at its receptors, on neutrophil and monocyte/macrophage function in inflammation. Moreover, we review the role of adenosine in mediating the anti-inflammatory effects of methotrexate, the anchor drug in the treatment of Rheumatoid Arthritis and other inflammatory disorders.

Hasko, Gyorgy; Cronstein, Bruce

2013-01-01

237

Redox regulation of Janus kinase  

PubMed Central

The redox regulation of Janus kinases (JAKs) is a complex subject. Due to other redox-sensitive kinases in the kinome, redox-sensitive phosphatases, and cellular antioxidant systems and reactive oxygen species (ROS) production systems, the net biological outcomes of oxidative stress on JAK-dependent signal transduction vary according to the specific biological system examined. This review begins with a discussion of the biochemical evidence for a cysteine-based redox switch in the catalytic domain of JAKs, proceeds to consider direct and indirect regulatory mechanisms involved in biological experiments, and ends with a discussion of the role(s) of redox regulation of JAKs in various diseases.

Duhe, Roy J

2013-01-01

238

Regulation of Francisella Tularensis Virulence  

PubMed Central

Francisella tularensis is one of the most virulent bacteria known and a Centers for Disease Control and Prevention Category A select agent. It is able to infect a variety of animals and insects and can persist in the environment, thus Francisella spp. must be able to survive in diverse environmental niches. However, F. tularensis has a surprising dearth of sensory and regulatory factors. Recent advancements in the field have identified new functions of encoded transcription factors and greatly expanded our understanding of virulence gene regulation. Here we review the current knowledge of environmental adaptation by F. tularensis, its transcriptional regulators and their relationship to animal virulence.

Dai, Shipan; Mohapatra, Nrusingh P.; Schlesinger, Larry S.; Gunn, John S.

2011-01-01

239

Regulation, efficiency, and Granger causality  

Microsoft Academic Search

This paper examines whether financial performance Granger causes productive efficiency. Improvements in current period financial performance provide firms with funds to initiate changes that can enhance future period efficiency and profits. Returns to equity and the rate base are used as measures of financial performance. Data Envelopment Analysis is used to compute regulated Farrell measures of cost, technical, and allocative

Gerald Granderson; Carl Linvill

2002-01-01

240

Endocrine Disorders of Sodium Regulation  

Microsoft Academic Search

Salt and water homoeostasis is tightly regulated by a variety of control mechanisms with the adrenal steroid hormone aldosterone playing a central role. Defects or disturbances in these systems lead to either salt loss, which is life threatening in the neonatal period, or sodium retention causing hypertension. Rapid and accurate diagnosis is required to avoid severe complications. During the last

Ursula Kuhnle; Sabina Lewicka; Peter J. Fuller

2004-01-01

241

Emotional regulation and emotional development  

Microsoft Academic Search

Current neofunctionalist views of emotion underscore the biologically adaptive and psychologically constructive contributions of emotion to organized behavior, but little is known of the development of the emotional regulatory processes by which this is fostered. Emotional regulation refers to the extrinsic and intrinsic processes responsible for monitoring, evaluating, and modifying emotional reactions. This review provides a developmental outline of emotional

Ross A. Thompson

1991-01-01

242

Redox Regulation of Cell Survival  

PubMed Central

Abstract Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play important roles in regulation of cell survival. In general, moderate levels of ROS/RNS may function as signals to promote cell proliferation and survival, whereas severe increase of ROS/RNS can induce cell death. Under physiologic conditions, the balance between generation and elimination of ROS/RNS maintains the proper function of redox-sensitive signaling proteins. Normally, the redox homeostasis ensures that the cells respond properly to endogenous and exogenous stimuli. However, when the redox homeostasis is disturbed, oxidative stress may lead to aberrant cell death and contribute to disease development. This review focuses on the roles of key transcription factors, signal-transduction pathways, and cell-death regulators in affecting cell survival, and how the redox systems regulate the functions of these molecules. The current understanding of how disturbance in redox homeostasis may affect cell death and contribute to the development of diseases such as cancer and degenerative disorders is reviewed. We also discuss how the basic knowledge on redox regulation of cell survival can be used to develop strategies for the treatment or prevention of those diseases. Antioxid. Redox Signal. 10, 1343–1374.

Trachootham, Dunyaporn; Lu, Weiqin; Ogasawara, Marcia A.; Valle, Nilsa Rivera-Del

2008-01-01

243

Cellular ADMA: Regulation and action  

Microsoft Academic Search

Asymmetric (NG,NG) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial

Tom Teerlink; Zaiming Luo; Fredrik Palm; Christopher S. Wilcox

2009-01-01

244

Angiostatic Regulators in Ovarian Cancer  

Microsoft Academic Search

Angiogenesis by either normal or neoplastic cells involves a delicate balance of both angiogenic and angiostatic regulators. In the ovary, normal physiological angiogenesis occurs around the developing follicle and corpus luteum in response to hormonal shifts. Interestingly, carcinomas arising from the ovary are usually highly vascularized and are commonly clinically observed to produce cyst fluids or ascites which contain both

Christina Diane Drenberg

2010-01-01

245

Amended Zoning Regulations, Surfside, Florida.  

National Technical Information Service (NTIS)

The draft contains recommendations for the content of zoning regulations designed to insure sound land use controls and a desirable character of development in the town of Surfside in accordance with a comprehensive plan. The draft has been developed by t...

1969-01-01

246

Phosphoprotein Regulation of Behavioral Reactivity.  

National Technical Information Service (NTIS)

The regulation of synaptic reactivity by protein kinase C and its substrates has been studied using the long-term potentation paradigm (LTP). We have studied the effects of protein kinase C activators and inhibitors on the durability of synaptic reactivit...

A. Routtenberg

1990-01-01

247

Regulating Railways in Logistics Chains  

Microsoft Academic Search

ailways contain natural monopoly components in their track infrastructure. Hence, like most infrastructure industries in Australia, they are subject to economic regulation to prevent abuses of monopoly power. Railways also form part of logistics chains and, as such, their ability to abuse market power depends upon the characteristics of those chains. Third party access regimes presently apply to the whole

Nick Wills-Johnson

2007-01-01

248

Temperature: Human Regulating, Ants Conforming  

ERIC Educational Resources Information Center

Biological processes speed up as temperature rises. Procedures for demonstrating this with ants traveling on trails, and data gathered by students on the Argentine ant ("Linepithema humile") are presented. The concepts of temperature regulation and conformity are detailed with a focus on the processes rather than on terms that label the organisms.

Clopton, Joe R.

2007-01-01

249

MORC proteins and epigenetic regulation  

PubMed Central

Two recent studies in Arabidopsis implicated MORC proteins, which contain a GHKL ATPase domain, in transcriptional gene silencing. Here, these studies are compared and contrasted to discuss the roles of MORC proteins in epigenetic regulation. Although MORC proteins are likely to catalyze changes in chromatin structure in response to epigenetic signals, their precise mode of action and target site-specificity still remain unclear.

Lorkovic, Zdravko J.

2012-01-01

250

HERBAL MEDICINES IN EUROPEAN REGULATION  

Microsoft Academic Search

Herbal medicines are assuming large use in the primary healthcare of individuals and communities consistently with the growing interest in traditional and alternative systems of medicine in many developed countries. Consumer surveys show a positive public attitude to complementary medicine.The regulation of herbal medicines is characterized by large differences depending on the ethnological, medical, and historical background of each country.

GIANNI BENZI; ADRIANA CECI

1997-01-01

251

Molecular regulation of vessel maturation  

Microsoft Academic Search

The maturation of nascent vasculature, formed by vasculogenesis or angiogenesis, requires recruitment of mural cells, generation of an extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function. In addition, the vascular network must be organized so that all the parenchymal cells receive adequate nutrients. All of these processes are orchestrated by physical forces

Rakesh K Jain

2003-01-01

252

International Harmonization of Economic Regulation  

Microsoft Academic Search

With the advancing globalization of the world economy, domestic economic regulations are becoming more and more subject to efforts at international harmonization. This book presents an analysis of this worldwide phenomenon from both a legal and a politico-economic perspective by focusing on (1) the backgrounds and objectives of international harmonization, (2) the negotiating processes involved, and (3) the impact of

Junji Nakagawa

253

The Regulation of Pubertal Growth  

Microsoft Academic Search

To understand the regulation of pubertal growth, it is important to understand the present concept of the control of the onset of puberty, the change in secretion of sex steroids during puberty, and the effects of these various factors upon the production and action of growth hormone (GH) and insulin-like growth factor (IGF). Nutrition plays a major role in this

Dennis M. Styne

2003-01-01

254

Regulated Childhood: Equivalence with Variation  

ERIC Educational Resources Information Center

The overriding aim of this article is to make a contribution to the discussion on individual development plans (IDPs) in Sweden as an expression of a regulated childhood and institutional practice. Individual development plans are seen as a phenomenon linked to the emergence of an auditing society. In sum, children are studied as subjects in…

Vallberg Roth, Ann-Christine; Mansson, Annika

2009-01-01

255

Hormonal regulation of apolipoprotein AI  

Microsoft Academic Search

Apolipoprotein AI (apo AI) is the major protein component of the serum high-density lipoprotein (HDL) particles. The antiatherogenic properties of apo AI alone or as part of HDL and their inverse correlation with the incidence of coronary heart disease underlie the clinical importance of the protein. A detailed understanding of the mech- anisms by which apo AI is regulated will

G M Hargrove; A Junco; N C W Wong

1999-01-01

256

Hormonal Regulation of Female Reproduction  

PubMed Central

Reproduction is an event that requires the coordination of peripheral organs with the nervous system to ensure that the internal and external environments are optimal for successful procreation of the species. This is accomplished by the hypothalamic-pituitary-gonadal axis that coordinates reproductive behavior with ovulation. The primary signal from the central nervous system is gonadotropin-releasing hormone (GnRH), which modulates the activity of anterior pituitary gonadotropes regulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) release. As ovarian follicles develop they release estradiol, which negatively regulates further release of GnRH and FSH. As estradiol concentrations peak they trigger the surge release of GnRH, which leads to LH release inducing ovulation. Release of GnRH within the central nervous system helps modulate reproductive behaviors providing a node at which control of reproduction is regulated. To address these issues, this review focuses on several critical questions. How is the HPG axis regulated in species with different reproductive strategies? What internal and external conditions modulate the synthesis and release of GnRH? How does GnRH modulate reproductive behavior within the hypothalamus? How does disease shift the activity of the HPG axis?

Christensen, A.; Bentley, G. E.; Cabrera, R.; Ortega, H. H.; Perfito, N.; Wu, T. J.; Micevych, P.

2013-01-01

257

Water regulation in aestivating snails  

Microsoft Academic Search

Aestivating snails form abundant lamellate vesicles in the cells of the mantle collar, an epithelium known to regulate the rate at which water is lost from its surface. Since lamellate vesicles are much reduced in hydrated mantle tissue of recently stimulated animals it is tentatively concluded that the vesicles, and their contents, form a barrier to water movement within these

P. F. Newell; J. Machin

1976-01-01

258

Regulating TransBoundary Trucking  

Microsoft Academic Search

Since the mid-eighties Austria has attempted to slow the growth in trans-boundary trucking. The number of trucking permits which is regulated in bilateral treaties (quotas) is increased only slowly, the permitted number of transit trips of trucks registered in Austria and in the EU was capped at the 1991 level in Austria's transit treaty with the EU. This change in

Wilfried Puwein

1994-01-01

259

78 FR 40651 - Regulated Navigation Area; Special Buzzards Bay Vessel Regulation, Buzzards Bay, MA  

Federal Register 2010, 2011, 2012, 2013

...USCG-2011-0322] RIN 1625-AA11 Regulated Navigation Area; Special Buzzards Bay Vessel Regulation...enhance environmental protections and navigation safety outlined in the Special Buzzards...Responsible Carrier Program RNA Regulated Navigation Area RA Technical Risk Assessment...

2013-07-08

260

Essential infrastructure: national nuclear regulation.  

PubMed

In order for nuclear power to expand to many countries that do not currently have it, it will be essential for these countries to have laws, regulations, guidance and organizations that can license or permit nuclear power plants and support nuclear facilities, ensure compliance by inspection, and enforce nuclear regulations. The viability of nuclear power worldwide depends on an extremely high level of safety everywhere, and compliance with a number of international treaties is required before supplier nations will provide the material, both hardware and software, to build and operate nuclear power plants. While infrastructure support can be obtained from the IAEA and other countries, an essential core of expertise must exist in the country seeking to establish domestic nuclear power generation. While some reliance can be placed on the safety reviews of standard reactor designs by the nuclear regulators in supplier nations, the certification of fuel design, the quality of instruments, and the matching of a new reactor to a proposed site in the importing nation will require site-specific reviews. National arrangements are also needed for emergency preparedness, environmental protection, fuel transportation and the storage, transportation and disposal of radioactive waste. If foreign contractors and consultants are engaged to perform much of the technical work for the regulatory body(s) that has to be performed by the importing nation, that nation must have a core cadre of technically knowledgeable regulators and an organization to provide management and oversight of the contractors and consultants. Consistency in national nuclear regulations, the deployment of standardized nuclear power plant designs and standardized supporting material infrastructure can promote the safe and secure worldwide growth in nuclear power. PMID:21399415

Paperiello, Carl J

2011-01-01

261

B7 family checkpoint regulators in immune regulation and disease.  

PubMed

Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target. PMID:23954143

Ceeraz, Sabrina; Nowak, Elizabeth C; Noelle, Randolph J

2013-11-01

262

Regulation of Drosophila metamorphosis by xenobiotic response regulators.  

PubMed

Mammalian Nrf2-Keap1 and the homologous Drosophila CncC-dKeap1 protein complexes regulate both transcriptional responses to xenobiotic compounds as well as native cellular and developmental processes. The relationships between the functions of these proteins in xenobiotic responses and in development were unknown. We investigated the genes regulated by CncC and dKeap1 during development and the signal transduction pathways that modulate their functions. CncC and dKeap1 were enriched within the nuclei in many tissues, in contrast to the reported cytoplasmic localization of Keap1 and Nrf2 in cultured mammalian cells. CncC and dKeap1 occupied ecdysone-regulated early puffs on polytene chromosomes. Depletion of either CncC or dKeap1 in salivary glands selectively reduced early puff gene transcription. CncC and dKeap1 depletion in the prothoracic gland as well as cncC(K6/K6) and dKeap1(EY5/EY5) loss of function mutations in embryos reduced ecdysone-biosynthetic gene transcription. In contrast, dKeap1 depletion and the dKeap1(EY5/EY5) loss of function mutation enhanced xenobiotic response gene transcription in larvae and embryos, respectively. Depletion of CncC or dKeap1 in the prothoracic gland delayed pupation by decreasing larval ecdysteroid levels. CncC depletion suppressed the premature pupation and developmental arrest caused by constitutive Ras signaling in the prothoracic gland; conversely, constitutive Ras signaling altered the loci occupied by CncC on polytene chromosomes and activated transcription of genes at these loci. The effects of CncC and dKeap1 on both ecdysone-biosynthetic and ecdysone-regulated gene transcription, and the roles of CncC in Ras signaling in the prothoracic gland, establish the functions of these proteins in the neuroendocrine axis that coordinates insect metamorphosis. PMID:23408904

Deng, Huai; Kerppola, Tom K

2013-01-01

263

Microtubule affinity-regulating kinase 4: structure, function, and regulation.  

PubMed

MAP/Microtubule affinity-regulating kinase 4 (MARK4) belongs to the family of serine/threonine kinases that phosphorylate the microtubule-associated proteins (MAP) causing their detachment from the microtubules thereby increasing microtubule dynamics and facilitating cell division, cell cycle control, cell polarity determination, cell shape alterations, etc. The MARK4 gene encodes two alternatively spliced isoforms, L and S that differ in their C-terminal region. These isoforms are differentially regulated in human tissues including central nervous system. MARK4L is a 752-residue-long polypeptide that is divided into three distinct domains: (1) protein kinase domain (59-314), (2) ubiquitin-associated domain (322-369), and (3) kinase-associated domain (703-752) plus 54 residues (649-703) involved in the proper folding and function of the enzyme. In addition, residues 65-73 are considered to be the ATP-binding domain and Lys88 is considered as ATP-binding site. Asp181 has been proposed to be the active site of MARK4 that is activated by phosphorylation of Thr214 side chain. The isoform MARK4S is highly expressed in the normal brain and is presumably involved in neuronal differentiation. On the other hand, the isoform MARK4L is upregulated in hepatocarcinoma cells and gliomas suggesting its involvement in cell cycle. Several biological functions are also associated with MARK4 including microtubule bundle formation, nervous system development, and positive regulation of programmed cell death. Therefore, MARK4 is considered as the most suitable target for structure-based rational drug design. Our sequence, structure- and function-based analysis should be helpful for better understanding of mechanisms of regulation of microtubule dynamics and MARK4 associated diseases. PMID:23471664

Naz, Farha; Anjum, Farah; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

2013-11-01

264

Cloning of circadian rhythmic pathway genes and perturbation of oscillation patterns in endocrine disrupting chemicals (EDCs)-exposed mangrove killifish Kryptolebias marmoratus.  

PubMed

To investigate the effect of endocrine disrupting chemicals (EDCs) on the circadian rhythm pathway, we cloned clock and circadian rhythmic pathway-associated genes (e.g. Per2, Cry1, Cry2, and BMAL1) in the self-fertilizing mangrove killifish Kryptolebias marmoratus. The promoter region of Km-clock had 1 aryl hydrocarbon receptor element (AhRE, GTGCGTGACA) and 8 estrogen receptor (ER) half-sites, indicating that the AhRE and ER half sites would likely be associated with regulation of clock protein activity during EDCs-induced cellular stress. The Km-clock protein domains (bHLH, PAS1, PAS2) were highly conserved in five additional fish species (zebrafish, Japanese medaka, Southern platyfish, Nile tilapia, and spotted green pufferfish), suggesting that the fish clock protein may play an important role in controlling endogenous circadian rhythms. The promoter regions of Km-BMAL1, -Cry1, -Cry2, and -Per2 were found to contain several xenobiotic response elements (XREs), indicating that EDCs may be able to alter the expression of these genes. To analyze the endogenous circadian rhythm in K. marmoratus, we measured expression of Km-clock and other circadian rhythmic genes (e.g. Per2, Cry1, Cry2, and BMAL1) in different tissues, and found ubiquitous expression, although there were different patterns of transcript amplification during different developmental stages. In an estrogen (E2)-exposed group, Km-clock expression was down-regulated, however, a hydroxytamoxifen (TMX, nonsteroid estrogen antagonist)-exposed group showed an upregulated pattern of Km-clock expression, suggesting that the expression of Km-clock is closely associated with exposure to EDCs. In response to the exposure of bisphenol A (BPA) and 4-tert-octyphenol (OP), Km-clock expression was down-regulated in the pituitary/brain, muscle, and skin in both gender types (hermaphrodite and secondary male). In juvenile K. marmoratus liver tissue, expression of Km-clock and other circadian rhythmic pathway-associated genes showed a regular oscillation pattern over a period of approximately 24h during a 12L:12D cycle. However, the circadian rhythm of BPA-exposed juvenile K. marmoratus liver tissue was perturbed over a 12L:12D period. This study will aid in our understanding of how EDCs perturb endogenous circadian rhythms, particularly in BPA-exposed fish liver tissue. PMID:24726801

Rhee, Jae-Sung; Kim, Bo-Mi; Lee, Bo-Young; Hwang, Un-Ki; Lee, Yong Sung; Lee, Jae-Seong

2014-08-01

265

Non-Circadian Expression Masking Clock-Driven Weak Transcription Rhythms in U2OS Cells  

PubMed Central

U2OS cells harbor a circadian clock but express only a few rhythmic genes in constant conditions. We identified 3040 binding sites of the circadian regulators BMAL1, CLOCK and CRY1 in the U2OS genome. Most binding sites even in promoters do not correlate with detectable rhythmic transcript levels. Luciferase fusions reveal that the circadian clock supports robust but low amplitude transcription rhythms of representative promoters. However, rhythmic transcription of these potentially clock-controlled genes is masked by non-circadian transcription that overwrites the weaker contribution of the clock in constant conditions. Our data suggest that U2OS cells harbor an intrinsically rather weak circadian oscillator. The oscillator has the potential to regulate a large number of genes. The contribution of circadian versus non-circadian transcription is dependent on the metabolic state of the cell and may determine the apparent complexity of the circadian transcriptome.

Hoffmann, Julia; Symul, Laura; Shostak, Anton; Fischer, Tamas; Naef, Felix; Brunner, Michael

2014-01-01

266

43 CFR 431.9 - Future regulations.  

Code of Federal Regulations, 2013 CFR

...INTERIOR GENERAL REGULATIONS FOR POWER GENERATION, OPERATION, MAINTENANCE, AND REPLACEMENT AT THE BOULDER CANYON PROJECT, ARIZONA/NEVADA § 431.9 Future regulations. (a) Reclamation may from time to time promulgate additional or...

2013-10-01

267

50 CFR 402.04 - Counterpart regulations.  

Code of Federal Regulations, 2013 CFR

...DEPARTMENT OF COMMERCE); ENDANGERED SPECIES COMMITTEE REGULATIONS SUBCHAPTER A INTERAGENCY COOPERATION-ENDANGERED SPECIES ACT OF 1973, AS AMENDED General § 402.04 Counterpart regulations. The consultation procedures...

2013-10-01

268

Current Regulator For Sodium-Vapor Lamps  

NASA Technical Reports Server (NTRS)

Regulating circuit maintains nearly-constant alternating current in sodium-vapor lamp. Regulator part of dc-to-ac inverter circuit used to supply power to street lamp from battery charged by solar-cell array.

Mclyman, W. T.

1989-01-01

269

77 FR 16784 - General Bridge Regulation; Amendment  

Federal Register 2010, 2011, 2012, 2013

...USCG-2008-1188] RIN 1625-AB36 General Bridge Regulation; Amendment AGENCY: Coast...rulemaking concerning amendments to the general bridge regulations. The rulemaking was initiated...clarify the statutory responsibilities of bridge owners to remove their bridges from...

2012-03-22

270

Subdivision Regulations, City of Anderson, South Carolina.  

National Technical Information Service (NTIS)

The regulations provide, in accordance with South Carolina law, for the regulation of the subdivision of land within the City of Anderson. Included therewith are procedures for preparing and approving plats; design standards for streets, alleys, or rights...

1968-01-01

271

15 CFR 922.185 - Emergency regulations.  

...COMMERCE OCEAN AND COASTAL RESOURCE MANAGEMENT NATIONAL MARINE SANCTUARY PROGRAM REGULATIONS Hawaiian Islands Humpback Whale National Marine Sanctuary § 922.185 Emergency regulations. Where necessary to prevent or minimize the destruction...

2014-01-01

272

15 CFR 922.185 - Emergency regulations.  

Code of Federal Regulations, 2011 CFR

...COMMERCE OCEAN AND COASTAL RESOURCE MANAGEMENT NATIONAL MARINE SANCTUARY PROGRAM REGULATIONS Hawaiian Islands Humpback Whale National Marine Sanctuary § 922.185 Emergency regulations. Where necessary to prevent or minimize the destruction...

2011-01-01

273

15 CFR 922.185 - Emergency regulations.  

Code of Federal Regulations, 2013 CFR

...COMMERCE OCEAN AND COASTAL RESOURCE MANAGEMENT NATIONAL MARINE SANCTUARY PROGRAM REGULATIONS Hawaiian Islands Humpback Whale National Marine Sanctuary § 922.185 Emergency regulations. Where necessary to prevent or minimize the destruction...

2013-01-01

274

15 CFR 922.185 - Emergency regulations.  

Code of Federal Regulations, 2010 CFR

...COMMERCE OCEAN AND COASTAL RESOURCE MANAGEMENT NATIONAL MARINE SANCTUARY PROGRAM REGULATIONS Hawaiian Islands Humpback Whale National Marine Sanctuary § 922.185 Emergency regulations. Where necessary to prevent or minimize the destruction...

2010-01-01

275

15 CFR 922.185 - Emergency regulations.  

Code of Federal Regulations, 2012 CFR

...COMMERCE OCEAN AND COASTAL RESOURCE MANAGEMENT NATIONAL MARINE SANCTUARY PROGRAM REGULATIONS Hawaiian Islands Humpback Whale National Marine Sanctuary § 922.185 Emergency regulations. Where necessary to prevent or minimize the destruction...

2012-01-01

276

78 FR 35195 - Acquisition Regulations: Export Control  

Federal Register 2010, 2011, 2012, 2013

...1991-AB99 Acquisition Regulations: Export Control AGENCY: Department of Energy...Acquisition Regulation (DEAR) to add export control requirements applicable to the...submit comments, identified by ``DEAR: Export Control and RIN 1991-AB99,'' by...

2013-06-12

277

Apoptotic regulation and transfer RNA  

PubMed Central

Apoptotic regulation is critical to organismal homeostasis and protection against many human disease processes such as cancer. Significant research efforts over the past several decades have illuminated many of the signaling molecules and effecter proteins responsible for this form of programmed cell death. Recent evidence suggests that transfer RNA (tRNA) regulates apoptotic sensitivity at the level of cytochrome c-mediated apoptosome formation. This finding unexpectedly places tRNA at the nexus of cellular biosynthesis and survival. Here we review the current understanding of both the apoptotic machinery and tRNA biology. We describe the evidence linking tRNA and cytochrome c in depth, and speculate on the implications of this link in cell biology.

Mei, Yide; Stonestrom, Aaron; Hou, Ya-Ming; Yang, Xiaolu

2010-01-01

278

Renewable energy and utility regulation  

SciTech Connect

This report summarizes the results of a joint project on renewable energy of the National Association of Regulatory Utility Commissioners (NARUC) and the US DOE. NARUC`S Task Force on Renewable Energy conducted a review of the current state of renewable energy technologies to evaluate their potential and extract key policy lessons from experience already gained in deployment of these technologies in numerous states. The main focus of this effort has been to clarify how utility regulators affect the development of renewable energy resources. The goal of the project was twofold: (1) identify the factors that have led to success or failure or renewable energy technologies in various energy markets, and (2) to develop an agenda on renewable energy and utility regulation for NARUC and the DOE. This report consists of three sections: renewable energy contributions, costs and potential; factors affecting development of renewable energy resources; and a renewable energy agenda for NARUC.

Not Available

1991-04-10

279

Renewable energy and utility regulation  

SciTech Connect

This report summarizes the results of a joint project on renewable energy of the National Association of Regulatory Utility Commissioners (NARUC) and the US DOE. NARUC'S Task Force on Renewable Energy conducted a review of the current state of renewable energy technologies to evaluate their potential and extract key policy lessons from experience already gained in deployment of these technologies in numerous states. The main focus of this effort has been to clarify how utility regulators affect the development of renewable energy resources. The goal of the project was twofold: (1) identify the factors that have led to success or failure or renewable energy technologies in various energy markets, and (2) to develop an agenda on renewable energy and utility regulation for NARUC and the DOE. This report consists of three sections: renewable energy contributions, costs and potential; factors affecting development of renewable energy resources; and a renewable energy agenda for NARUC.

Not Available

1991-04-10

280

Complex dynamics of transcription regulation.  

PubMed

Transcription is a tightly regulated cellular function which can be triggered by endogenous (intrinsic) or exogenous (extrinsic) signals. The development of novel techniques to examine the dynamic behavior of transcription factors and the analysis of transcriptional activity at the single cell level with increased temporal resolution has revealed unexpected elements of stochasticity and dynamics of this process. Emerging research reveals a complex picture, wherein a wide range of time scales and temporal transcription patterns overlap to generate transcriptional programs. The challenge now is to develop a perspective that can guide us to common underlying mechanisms, and consolidate these findings. Here we review the recent literature on temporal dynamics and stochastic gene regulation patterns governed by intrinsic or extrinsic signals, utilizing the glucocorticoid receptor (GR)-mediated transcriptional model to illustrate commonality of these emerging concepts. This article is part of a Special Issue entitled: Chromatin in time and space. PMID:22484099

Stavreva, Diana A; Varticovski, Lyuba; Hager, Gordon L

2012-07-01

281

Gene regulation by mechanical forces  

NASA Technical Reports Server (NTRS)

Endothelial cells are subjected to various mechanical forces in vivo from the flow of blood across the luminal surface of the blood vessel. The purpose of this review was to examine the data available on how these mechanical forces, in particular cyclic strain, affect the expression and regulation of endothelial cell function. Studies from various investigators using models of cyclic strain in vitro have shown that various vasoactive mediators such as nitric oxide and prostacyclin are induced by the effect of mechanical deformation, and that the expression of these mediators may be regulated at the transcription level by mechanical forces. There also seems to be emerging evidence that endothelial cells may also act as mechanotransducers, whereby the transmission of external forces induces various cytoskeletal changes and second messenger cascades. Furthermore, it seems these forces may act on specific response elements of promoter genes.

Oluwole, B. O.; Du, W.; Mills, I.; Sumpio, B. E.

1997-01-01

282

Regulating health: transcending disciplinary boundaries.  

PubMed

Health and health care problems can be addressed from multiple disciplinary perspectives. This raises challenges for how to do cross-disciplinary scholarship in ways that are still robust, rigorous and coherent. This paper sets out one particular approach to cross-cutting research--regulation--which has proved extremely fertile for scholars working in diverse fields, from coal mine safety to tax compliance. The first part of the paper considers how regulatory ideas might be applied to health and health care research in general. The second part goes on to sketch out how a regulation perspective on one specific area, illicit drug policy, can open up new directions for research. In conclusion, a future research agenda is outlined for regulatory scholarship on health and health care. PMID:23070460

Seddon, Toby

2013-03-01

283

The grammar of transcriptional regulation.  

PubMed

Eukaryotes employ combinatorial strategies to generate a variety of expression patterns from a relatively small set of regulatory DNA elements. As in any other language, deciphering the mapping between DNA and expression requires an understanding of the set of rules that govern basic principles in transcriptional regulation, the functional elements involved, and the ways in which they combine to orchestrate a transcriptional output. Here, we review the current understanding of various grammatical rules, including the effect on expression of the number of transcription factor binding sites, their location, orientation, affinity and activity; co-association with different factors; and intrinsic nucleosome organization. We review different methods that are used to study the grammar of transcription regulation, highlight gaps in current understanding, and discuss how recent technological advances may be utilized to bridge them. PMID:24390306

Weingarten-Gabbay, Shira; Segal, Eran

2014-06-01

284

Chromatin Organization and Transcriptional Regulation  

PubMed Central

Cell type specific transcriptional regulation must be adhered to in order to maintain cell identity throughout the lifetime of an organism, yet flexible enough to allow for responses to endogenous and exogenous stimuli. This regulation is mediated not only by molecular factors (e.g. cell type specific transcription factors, histone and DNA modifications), but also on the level of chromatin and genome organization. In this review we focus on recent findings that have contributed to our understanding of higher order chromatin structure and genome organization within the nucleus. We highlight new findings on the dynamic positioning of genes relative to each other, as well as to their chromosome territory and the nuclear lamina, and how the position of genes correlates with their transcriptional activity.

Hubner, Michael R.; Eckersley-Maslin, Melanie A.; Spector, David L.

2012-01-01

285

Regulated nucleocytoplasmic transport during gametogenesis.  

PubMed

Gametogenesis is the process by which sperm or ova are produced in the gonads. It is governed by a tightly controlled series of gene expression events, with some common and others distinct for males and females. Nucleocytoplasmic transport is of central importance to the fidelity of gene regulation that is required to achieve the precisely regulated germ cell differentiation essential for fertility. In this review we discuss the physiological importance for gamete formation of the molecules involved in classical nucleocytoplasmic protein transport, including importins/karyopherins, Ran and nucleoporins. To address what functions/factors are conserved or specialized for these developmental processes between species, we compare knowledge from mice, flies and worms. The present analysis provides evidence of the necessity for and specificity of each nuclear transport factor and for nucleoporins during germ cell differentiation. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing. PMID:22326858

Miyamoto, Yoichi; Boag, Peter R; Hime, Gary R; Loveland, Kate L

2012-06-01

286

Redox regulation of Ran GTPase  

SciTech Connect

Ran, a small Ras-like GTP-binding nuclear protein, plays a key role in modulation of various cellular signaling events including the cell cycle. This study shows that a cellular redox agent (nitrogen dioxide) facilitates Ran guanine nucleotide dissociation, and identifies a unique Ran redox architecture involved in that process. Sequence analysis suggests that Dexras1 and Rhes GTPases also possess the Ran redox architecture. As Ran releases an intact nucleotide, the redox regulation mechanism of Ran is likely to differ from the radical-based guanine nucleotide modification mechanism suggested for Ras and Rho GTPases. These results provide a mechanistic reason for the previously observed oxidative stress-induced perturbation of the Ran-mediated nuclear import, and suggest that oxidative stress could be a factor in the regulation of cell signal transduction pathways associated with Ran.

Heo, Jongyun [Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX 76019 (United States)], E-mail: jheo@uta.edu

2008-11-21

287

Acoustic saturation and output regulation.  

PubMed

Acoustic saturation pressures are predicted for ultrasonic beams of a range of frequencies and focal depths. Using reasonable approximations, saturation values for mechanical index (MI) and derated spatial-peak, time-average and pulse-average intensities are calculated. These are compared with thresholds set for regulatory purposes by the U. S. Food and Drug Administration (FDA), and by the International Electrotechnical Commission (IEC). It is concluded that there are many conditions for which acoustic saturation in water prevents the values of MI and regulated intensities from exceeding thresholds set by the FDA. These conditions are particularly associated with higher frequencies and deeper focal lengths. The thresholds for action set by IEC 61157 are sufficiently low that similar problems do not arise. It is concluded that present regulations are not fully effective in limiting the output from diagnostic ultrasound equipment, and that some conditions exist that are not subject to output control. PMID:10461731

Duck, F A

1999-07-01

288

Genetic Regulation of Mammalian Diversity  

PubMed Central

Mammals have evolved a variety of morphological adaptations that have allowed them to compete in their natural environments. The developmental genetic basis of this morphological diversity remains largely unknown. Bats are mammals that have the unique ability of powered flight. We have examined the molecular embryology of bats and investigated the developmental genetic basis for their highly derived limbs used for flight. Initially, we developed an embryo staging system for a model chiropteran, Carollia perspicillata, the short-tailed fruit bat that has subsequently been used for staging other bat species. Expression studies focusing on genes that regulate limb development indicate that there are similarities and differences between bats and mice. To determine the consequences of these expression differences, we have conducted an enhancer switch assay by gene targeting in mouse embryonic stem cells to create mice whose genes are regulated by bat sequences. Our studies indicate that cis-regulatory elements contribute to the morphological differences that have evolved among mammalian species.

Behringer, R.R.; Rasweiler, J.J.; Chen, C.-H.; Cretekos, C.J.

2014-01-01

289

Cardiac myofilaments: mechanics and regulation  

NASA Technical Reports Server (NTRS)

The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.

de Tombe, Pieter P.; Bers, D. M. (Principal Investigator)

2003-01-01

290

Complex Dynamics of Transcription Regulation  

PubMed Central

Transcription is a tightly regulated cellular function which can be triggered by endogenous (intrinsic) or exogenous (extrinsic) signals. The development of novel techniques to examine the dynamic behavior of transcription factors and the analysis of transcriptional activity at the single cell level with increased temporal resolution has revealed unexpected elements of stochasticity and dynamics of this process. Emerging research reveals a complex picture, wherein a wide range of time scales and temporal transcription patterns overlap to generate transcriptional programs. The challenge now is to develop a perspective that can guide us to common underlying mechanisms, and consolidate these findings. Here we review the recent literature on temporal dynamic and stochastic gene regulation patterns governed by intrinsic or extrinsic signals, utilizing the glucocorticoid receptor (GR)-mediated transcriptional model to illustrate commonality of these emerging concepts.

Stavreva, Diana A; Varticovski, Lyuba; Hager, Gordon L.

2012-01-01

291

Analog simulation of a gas pressure regulator.  

NASA Technical Reports Server (NTRS)

The behavior characteristics of direct-acting gas pressure regulators are discussed in terms of spring force, flow force, and friction force. The dynamics of the metering valve and bellows assembly are described by equating all forces on the valve to zero. Continuity equations for the regulator are derived. Simulations are carried out to determine effects of sensing orifice diameter, poppet stem friction, output volume, and supply pressure on regulator behavior. Several regulator configurations are studied.

Dustin, M. O.

1972-01-01

292

Microenvironmental regulation of cancer development  

PubMed Central

Numerous studies have demonstrated that the tumor microenvironment not only responds to and supports carcinogenesis, but actively contributes to tumor initiation, progression, and metastasis. During tumor progression all cells composing the tumor undergo phenotypic and epigenetic changes. Paracrine signaling between epithelial and stromal cells is important for the regulation of the proliferation, invasive, angiogenic, and metastatic behavior of cancer cells. Better understanding the molecular mechanisms by which stromal cells exert these effects may open up new venues for cancer therapeutic and preventative interventions.

Hu, Min; Polyak, Kornelia

2008-01-01

293

Frequency regulator for synchronous generators  

DOEpatents

The present invention is directed to a novel frequency regulator which controls a generator output frequency for variations in both the input power to the generator and the power supplied to an uncontrolled external load. The present invention further includes over current and current balance protection devices which are relatively inexpensive to manufacture, which may be encapsulated to provide protection from the operating environment and which respond more quickly than previously known electromechanical devices. 11 figs.

Karlicek, R.F.

1982-08-10

294

Signal regulation by family conspiracy  

Microsoft Academic Search

.   The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two\\u000a subgroups: SIRP? and SIRP?, containing more than ten members. SIRP? has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors.\\u000a This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which

C. A. Cant

2001-01-01

295

Redox circuitries driving SRC regulation.  

PubMed

Abstract Significance: Here, we review recent advances with regard to the role of Src kinase in the regulation of cytoskeleton organization, cell adhesion, and motility, focusing on redox circuitries engaging this kinase for anchorage and motility, control of cell survival to anoikis, as well as metabolic deregulation, all features belonging to the new hallmarks of cancer. Recent Advances: Several recent insights have reported that, alongside the well-known phosphorylation/dephosphorylation control, cysteine oxidation is a further mechanism of enzyme activation for both c-Src kinase and its oncogenic counterparts. Indeed, mounting evidence portrays redox regulation of Src kinase as a compulsory outcome in growth factors/cytokines signaling, integrin engagement, motility and invasiveness of tissues, receptor cross-talking at plasmamembrane, as well as during carcinogenesis and progression toward tumor malignancy or fibrotic disease. In addition, the kinase is an upstream regulator of NADPH oxidase-driven oxidants, a critical step for invadopodia formation and metastatic spread. Critical Issues: Not satisfactorily unraveled yet, the exact role of Src kinase in redox cancer biology needs to be implemented with studies that are aimed at clarifying (i) the exact hierarchy between oxidants sources, Src redox-dependent activation and the regulation of cell motility, and (ii) the actual susceptibility of invading cells to redox-based treatments, owing to the well-recognized ability of cancer cells to find new strategies to adapt to new environments. Future Directions: Once these critical issues are addressed, redox circuitries involving Src kinase should potentially be used as both biomarkers and targets for personalized therapies in the fight against cancer or fibrotic diseases. Antioxid. Redox Signal. 20, 2011-2025. PMID:23901911

Giannoni, Elisa; Chiarugi, Paola

2014-05-01

296

Dimensionally-regulated pentagon integrals  

Microsoft Academic Search

We present methods for evaluating the Feynman parameter integrals associated with the pentagon diagram in 4-2? dimensions, along with explicit results for the integrals with all masses vanishing or with one non-vanishing external mass. The scalar pentagon integral can be expressed as a linear combination of box integrals, up to O(?) corrections, a result which is the dimensionally-regulated version of

Zvi Bern; Lance Dixon; David A. Kosower

1994-01-01

297

MORC proteins and epigenetic regulation.  

PubMed

Two recent studies in Arabidopsis implicated MORC proteins, which contain a GHKL ATPase domain, in transcriptional gene silencing. Here, these studies are compared and contrasted to discuss the roles of MORC proteins in epigenetic regulation. Although MORC proteins are likely to catalyze changes in chromatin structure in response to epigenetic signals, their precise mode of action and target site-specificity still remain unclear. PMID:23072987

Lorkovi?, Zdravko J

2012-12-01

298

Frequency regulator for synchronous generators  

DOEpatents

The present invention is directed to a novel frequency regulator which controls a generator output frequency for variations in both the input power to the generator and the power supplied to an uncontrolled external load. The present invention further includes over current and current balance protection devices which are relatively inexpensive to manufacture, which may be encapsulated to provide protection from the operating environment and which respond more quickly than previously known electromechanical devices.

Karlicek, Robert F. (1920 Camino Centroloma, Fullerton, CA 92633)

1982-01-01

299

Redox regulation of transcriptional activators  

Microsoft Academic Search

Transcription factors\\/activators are a group of proteins that bind to specific consensus sequences (cis elements) in the promoter regions of downstream target\\/effector genes and transactivate or repress effector gene expression. The up-or downregulation of effector genes will ultimately lead to many biological changes such as proliferation, growth suppression, differentiation, or senescence. Transcription factors are subject to transcriptional and posttranslational regulation.

Yi Sun; Larry W. Oberley

1996-01-01

300

Blue light regulated shade avoidance.  

PubMed

Most plants grow in dense vegetation with the risk of being out-competed by neighboring plants. These neighbors can be detected not only through the depletion in light quantity that they cause, but also through the change in light quality, which plants perceive using specific photoreceptors. Both the reduction of the red:far-red ratio and the depletion of blue light are signals that induce a set of phenotypic traits, such as shoot elongation and leaf hyponasty, which increase the likelihood of light capture in dense plant stands. This set of phenotypic responses are part of the so called shade avoidance syndrome (SAS). This addendum discusses recent findings on the regulation of the SAS of Arabidopsis thaliana upon blue light depletion. Keller et al. and Keuskamp et al. show that the low blue light attenuation induced shade avoidance response of seedling and rosette-stage A. thaliana plants differ in their hormonal regulation. These studies also show there is a regulatory overlap with the R:FR-regulated SAS. PMID:22499181

Keuskamp, Diederik H; Keller, Mercedes M; Ballaré, Carlos L; Pierik, Ronald

2012-04-01

301

A closely regulated TWT converter.  

NASA Technical Reports Server (NTRS)

The design concept for the TWT amplifier converter for possible use in the Thermoelectric Outer Planet Spacecraft (TOPS) is presented. An unusual combination of semiconductors and magnetics was utilized to achieve very stable voltage regulation on a number of separate outputs to satisfy the requirements of a high-power TWT, and at the same time operate at an efficiency of better than 90% from a 30-V source. The circuitry consists of an output filter, an auxiliary Jensen oscillator driving a high-reactance transformer to provide current limiting to the heater, a variable time delay, a main Jensen oscillator driving the power transformer with a maximum step-up ratio of 120 to 1, and series transistorized post regulators to provide precise voltage adjustment and low output impedance. This paper discusses the design of the high-reactance transformer and the high step-up ratio transformer, as well as the high-voltage series regulators that are limited in range and operate at the top of the unregulated output voltage. Test data are presented, and details of current transients caused by charging the filter circuits, input current ripple, and output voltage ripples are considered.

Hopper, D. J.; Andryczyk, R. W.

1971-01-01

302

Rethinking regulations for disposal criticality  

SciTech Connect

This paper provides the basis for the position that the current U.S. Nuclear Regulatory Commission (NRC) criticality regulation is in need of revision to address problems in implementing it for the postclosure period in a geologic high-level waste repository. The authors believe that the applicant for such a facility should be able to demonstrate that postulated postclosure criticality events will not cause unacceptable risk of deleterious effects on public health and safety. In addition, the applicant should be expected to take practical and feasible measures to reduce the probability of a criticality occurring, even if (as expected) the consequences of such a criticality for repository performance and public health and safety would be negligible. This approach, while recognizing the probabilistic nature of analyses of events and conditions in the distant future, is also arguably consistent with the defense in depth concept that has been successfully applied to nuclear reactor regulation. The authors believe regulations for postclosure criticality control should support this dual approach, rather than require a deterministic prohibition of criticality as does the current rule. The existing rule seems appropriate for the preclosure period, as long as it is clearly specified to apply only to that period.

Scott, M. [Duke Engineering and Services, Inc., Las Vegas, NV (United States); Doering, T. [Framatome Cogema Fuels, Las Vegas, NV (United States)

1997-08-01

303

Negative regulators of cell proliferation  

NASA Technical Reports Server (NTRS)

Cell proliferation is governed by the influence of both mitogens and inhibitors. Although cell contact has long been thought to play a fundamental role in cell cycling regulation, and negative regulators have long been suspected to exist, their isolation and purification has been complicated by a variety of technical difficulties. Nevertheless, over recent years an ever-expanding list of putative negative regulators have emerged. In many cases, their biological inhibitory activities are consistent with density-dependent growth inhibition. Most likely their interactions with mitogenic agents, at an intracellular level, are responsible for either mitotic arrest or continued cell cycling. A review of naturally occurring cell growth inhibitors is presented with an emphasis on those factors shown to be residents of the cell surface membrane. Particular attention is focused on a cell surface sialoglycopeptide, isolated from intact bovine cerebral cortex cells, which has been shown to inhibit the proliferation of an unusually wide range of target cells. The glycopeptide arrest cells obtained from diverse species, both fibroblasts and epithelial cells, and a broad variety of transformed cells. Signal transduction events and a limited spectrum of cells that are refractory to the sialoglycopeptide have provided insight into the molecular events mediated by this cell surface inhibitor.

Johnson, T. C.; Spooner, B. S. (Principal Investigator)

1994-01-01

304

Transcriptional regulation of ?-cell differentiation.  

PubMed

The development of the endocrine pancreas and the differentiation of its five cell types, ?, ?, ?, ? and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of ?- and ?-cells are critical for blood glucose homeostasis. These processes are governed by multiple transcription factors and other signalling systems, and its dysregulation results in diabetes. The differentiation of ?-cells and the maintenance of ?-cell function can be influenced at several stages during development and in the maturing islet. Many transcription factors, such as neurogenin 3 (Ngn3), pancreatic duodenal homeobox 1 (Pdx1) and regulatory factor x6 (Rfx6), play a crucial role in the determination of the endocrine cell fate, while other transcription factors, such as aristaless-related homeobox (Arx) and forkhead box A2 (Foxa2), are implicated in the initial or terminal differentiation of ?-cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of ?-cell function, is regulated by several factors, including forkhead box A1 (Foxa1), paired box 6 (Pax6), brain4 (Brn4) and islet-1 (Isl-1). Detailed information about the regulation of normal and abnormal ?-cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of ?- to ?-cells for replacement therapy. PMID:21824252

Bramswig, N C; Kaestner, K H

2011-10-01

305

Regulation of Rad51 promoter.  

PubMed

The DNA double-strand break repair and homologous recombination protein Rad51 is overexpressed in the majority of human cancers. This correlates with therapy resistance and decreased patient survival. We previously showed that constructs containing Rad51 promoter fused to a reporter gene are, on average, 850-fold more active in cancer cells than in normal cells. It is not well understood what factors and sequences regulate the Rad51 promoter and cause its high activity in cancerous cells. Here we characterized regulatory regions and examined genetic requirements for oncogenic stimulation of the Rad51 promoter. We identified specific regions responsible for up- and downregulation of the Rad51 promoter in cancerous cells. Furthermore, we show that Rad51 expression is positively regulated by EGR1 transcription factor. We then modeled the malignant transformation process by expressing a set of oncoproteins in normal human fibroblasts. Expression of different combinations of SV40 large T antigen, oncogenic Ras and SV40 small T antigen resulted in step-wise increase in Rad51 promoter activity, with all the 3 oncoproteins together leading to a 47-fold increase in expression. Cumulatively, these results suggest that Rad51 promoter is regulated by multiple factors, and that its expression is gradually activated as cells progress toward malignancy. PMID:24781030

Hine, Christopher M; Li, Hongjie; Xie, Li; Mao, Zhiyong; Seluanov, Andrei; Gorbunova, Vera

2014-07-01

306

Regulation of Motivation: Contextual and Social Aspects  

ERIC Educational Resources Information Center

Background: Models of self-regulated learning have been used extensively as a way of understanding how students understand, monitor, and manage their own academic functioning. The regulation of motivation is a facet of self-regulated learning that describes students' efforts to control their own motivation or motivational processing. The…

Wolters, Christopher A.

2011-01-01

307

Emotional regulation goals and strategies of teachers  

Microsoft Academic Search

This study addresses two questions: what goals do teachers have for their own emotional regulation, and what strategies do teachers report they use to regulate their own emotions. Data were collected from middle school teachers in North East Ohio, USA through a semi-structured interview. All but one of the teachers reported regulating their emotions and there were no gender or

Rosemary E. Sutton

2004-01-01

308

Emotion Regulation and Depressive Symptoms in Preadolescence  

ERIC Educational Resources Information Center

This study examined associations among several measures of emotion regulation, and their links to depressive symptoms, in a sample of children ages 10-12 years old (N = 87). Both temporal features of emotion regulation and regulation processes involved in the evaluation, monitoring, and modification of emotion were assessed through parent and…

Siener, Shannon; Kerns, Kathryn A.

2012-01-01

309

Bureaucrats and Brainpower: Government Regulation of Universities.  

ERIC Educational Resources Information Center

The exploration of the growth and cost benefit effectiveness of governmental regulation of higher education is examined in this book. An introductory article by Robert Hatfield examines university regulation from a businessman's perspective. Hatfield concludes that business and higher education must work together to curb the stream of regulation.…

Seabury, Paul, Ed.

310

Regulation of commuter railways and spatial development  

Microsoft Academic Search

The Japanese commuter railway industry is unique in that many of the operators are engaged in a wide range of side businesses. Although they are subject to the rate-of-return regulation, the regulation is applied only to the railway division of a company. Using a simple spatial model of commuter railways, we examine the consequences of a regulation of this type.

Yoshitsugu Kanemoto; Kazuharu Kiyono

1995-01-01

311

Accessory Gene Regulator Locus of Staphylococcus intermedius  

Microsoft Academic Search

The accessory gene regulator (agr) locus, a candidate system for the regulation of the production of virulence factors in Staphylococcus intermedius, has been characterized. Using PCR-based genome walking, we have obtained the first complete sequence (3,436 bp) of the accessory gene regulator (agr) gene in this organism. Sequence analysis of the agr gene has identified five open reading frames (ORFs),

Julia M. L. Sung; Peter D. Chantler; David H. Lloyd

2006-01-01

312

The Truth About Regulation in America  

Microsoft Academic Search

The special interests leading the accelerating crusade against regulation have re-ignited a potent coalition of industry lobbyists, traditional conservatives, and grassroots Tea Party activists. The politicians speak in generic terms for public consumption: “the nation is broke,” “big government is bad,” “regulation costs trillions.” Behind the scenes, industry lobbyists target for repeal dozens of regulations that are designed to control

Rena I. Steinzor

2011-01-01

313

Private Regulation of Food Safety by Supermarkets  

Microsoft Academic Search

Food safety is a highly debated issue. Food industry organizations, retailers and national and transnational governments have been trying to find new ways to regulate food safety. Can private regulation of food safety meet the high expectations? A review of existing literature shows some conditions to be important for effectively protecting public interests by private regulation. In particular, retailers worldwide

TETTY HAVINGA

2006-01-01

314

Simple buck/boost voltage regulator  

NASA Technical Reports Server (NTRS)

Circuit corrects low or high supply voltage, produces regulated output voltage. Circuit has fewer components because inductory/transformer combination and pulse-width modulator serve double duty. Regulator handles input voltage variation from as low as one half output voltage to as high as input transistor rating. Solar arrays, fuel cells, and thermionic generators might use this regulator.

Paulkovich, J.; Rodriguez, G. E.

1980-01-01

315

Epigenetic Regulation of Tumor Necrosis Factor Alpha  

Microsoft Academic Search

Tumor necrosis factor alpha (TNF-) is a potent cytokine which regulates inflammation via the induction of adhesion molecules and chemokine expression. Its expression is known to be regulated in a complex manner with transcription, message turnover, message splicing, translation, and protein cleavage from the cell surface all being independently regulated. This study examined both cell lines and primary cells to

K. E. Sullivan; A. B. M. Reddy; K. Dietzmann; A. R. Suriano; V. P. Kocieda; M. Stewart; M. Bhatia

2007-01-01

316

The Goals for Regulating College Tuition  

ERIC Educational Resources Information Center

Regulation refers to governmental restrictions over enterprise in order to protect public interest. Research on governmental regulation in China primarily focuses on public utility, and inadequate attention has been paid to regulating college tuition. Currently, although the educational administrative agencies have successfully kept college…

Zeng, Xiaodong

2009-01-01

317

48 CFR 2001.104-2 - Arrangement of the regulations.  

Code of Federal Regulations, 2013 CFR

...regulations. 2001.104-2 Section 2001.104-2 Federal Acquisition Regulations System NUCLEAR REGULATORY COMMISSION GENERAL NUCLEAR REGULATORY COMMISSION ACQUISITION REGULATION SYSTEM Purpose, Authority, Issuance...

2013-10-01

318

Regulation of Motivation: Evaluating an Underemphasized Aspect of Self-Regulated Learning  

Microsoft Academic Search

Self-regulated learning is often described as a function of students' motivation, cognitive strat - egy use, and metacognition. The purpose of this article is to emphasize regulation of motivation as another important aspect of self-regulated learning. To achieve this goal, a specific concep - tual understanding of regulation of motivation is proposed and used to clarify theoretical dis - tinctions

Christopher A. Wolters

2003-01-01

319

Clarifying Metacognition, Self-Regulation, and Self-Regulated Learning: What's the Purpose?  

ERIC Educational Resources Information Center

In this commentary on the special issue, I join the authors in searching for a conceptual framework that would clarify the concepts of metacognition, self-regulation, and self-regulated learning. Building on the insights of the different articles, I suggest that metacognition, self-regulation, and self-regulated learning should be considered as…

Kaplan, Avi

2008-01-01

320

Removal of Regulations. Final Regulations. Federal Register, Department of Education, 34 CFR Part 345  

ERIC Educational Resources Information Center

The Secretary amends the Code of Federal Regulations (CFR) to remove obsolete regulations. As a result of the enactment of the Assistive Technology Act of 1998, these regulations are no longer needed. The Secretary therefore takes this action to remove the regulations. Part 345 is removed effective March 25, 2004.

National Archives and Records Administration, 2004

2004-01-01

321

Associations between lipid metabolism and fertility in the dairy cow.  

PubMed

Dairy cows mobilise body tissues to support milk production and, because glucose supplies are limited, lipids are used preferentially for energy production. Lipogenic activity is switched off and lipolytic mechanisms in adipose tissue increase through changes in the expression of several key enzymes. This results in a loss of body condition, together with high circulating concentrations of non-esterified fatty acids. Changes in the synthesis, secretion and signalling pathways of somatotrophic hormones (insulin, growth hormone, insulin-like growth factor 1) and adipokines (e.g. leptin) are central to the regulation of these processes. A high reliance on fatty acids as an energy source in the peripartum period causes oxidative damage to mitochondria in metabolically active tissues, including the liver and reproductive tract. The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway. Polymorphisms in TFAM and UCP2, two autosomal mitochondrial genes, have been associated with longevity in dairy cows. Polymorphisms in many other genes that affect lipid metabolism also show some associations with fertility traits. These include DGAT1, SCD1, DECR1, CRH, CBFA2T1, GH, LEP and NPY. Excess lipid accumulation in oocytes and the regenerating endometrium reduces fertility via reductions in embryo survival and increased inflammatory changes, respectively. PMID:23244828

Wathes, D Claire; Clempson, Andrew M; Pollott, Geoff E

2012-01-01

322

Global virulence regulation networks in phytopathogenic bacteria.  

PubMed

Phytopathogens coordinate multifaceted life histories and deploy stratified virulence determinants via complex, global regulation networks. We dissect the global regulation of four distantly related model phytopathogens to evaluate large-scale events and mechanisms that determine successful pathogenesis. Overarching themes include dependence on centralized cell-to-cell communication systems, pervasive two-component signal-transduction systems, post-transcriptional regulation systems, AraC-like regulators and sigma factors. Although these common regulatory systems control virulence, each functions in different capacities, and to differing ends, in the diverse species. Hence, the virulence regulation network of each species determines its survival and success in various life histories and niches. PMID:17627825

Mole, Beth M; Baltrus, David A; Dangl, Jeffery L; Grant, Sarah R

2007-08-01

323

Transfer regulations and cost-effectiveness analysis.  

PubMed

Recent scholarship on regulatory oversight has focused on cost-benefit analysis of prescriptive regulations--regulations that restrict behavior such as pollution--and their use to cure market failures, and has overlooked the vast number of transfer regulations. Transfer regulations are regulations that channel funds to beneficiaries. These regulations are authorized by statutes that establish entitlement programs like Medicare and Social Security, pay one-time distributions to victims of misfortunes such as natural disasters and the 9/11 terrorist attack, and fund pork barrel spending. Cost-benefit analysis cannot be used to evaluate transfer regulations because all transfer regulations fail cost-benefit analysis; cost-effectiveness analysis, however, can be used to evaluate transfer regulations. Although executive orders appear to require agencies to use cost-effectiveness analysis to evaluate transfer regulations that have a large economic impact, the agencies' record is dismal. Most agencies fail to perform cost-effectiveness analysis, and other agencies perform cost-effectiveness analysis incorrectly. More vigorous Office of Management and Budget and, possibly, judicial review could improve the quality of distributive regulations. PMID:15260020

Posner, Eric A

2003-12-01

324

Epigenetic regulation of polyomavirus JC  

PubMed Central

Background Polyomavirus JC (JCV) causes the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), which occurs almost exclusively in people with immune deficiencies, such as HIV-1/AIDS patients. JCV infection is very common and usually occurs early in life. After primary infection, virus is controlled by the immune system but, rarely when immune function is impaired, it can re-emerge and multiply in the astrocytes and oligodendrocytes in the brain and cause PML. Thus a central question in PML pathogenesis is the nature of the molecular mechanisms maintaining JCV in a latent state and then allowing reactivation. Methods Since transcription can be regulated by epigenetic mechanisms including DNA methylation and histone acetylation, we investigated their role in JCV regulation by employing inhibitors of epigenetic events. Results The histone deacetylase inhibitors trichostatin A (TSA) and sodium butyrate powerfully stimulated JCV early and late transcription while the DNA methylation inhibitor 5-azacytidine had no effect. Analysis of JCV mutants showed that this effect was mediated by the KB element of the JCV control region, which binds transcription factors NF-?B p65, NFAT4 and C/EBP? and mediates stimulation by TNF-?. Stimulation of transcription by p65 was additive with TSA as was cotransfection with transcriptional coactivators/acetyltransferase p300 whereas depletion of endogenous p65 by RNA interference inhibited the effect of TSA. EMSA with a KB oligonucleotide showed p65 expression, TNF-? stimulation or TSA treatment each caused a gel shift that was further shifted by antibody to p65. Conclusions We conclude that JCV is regulated epigenetically by protein acetylation events and that these involve the NF-?B p65 binding site in the JCV control region.

2013-01-01

325

Tonic regulation of vascular permeability  

PubMed Central

Our major theme is that the layered structure of the endothelial barrier requires continuous activation of signaling pathways regulated by S1P and intracellular cAMP. These pathways modulate the adherens junction, continuity of tight junction strands, and the balance of synthesis and degradation of glycocalyx components. We evaluate recent evidence that baseline permeability is maintained by constant activity of mechanisms involving the small GTPases Rap1 and Rac1. In the basal state, the barrier is compromised when activities of the small GTPases are reduced by low S1P supply or delivery. With inflammatory stimulus, increased permeability can be understood in part as the action of signaling to reduce Rap1 and Rac1 activation. With the hypothesis that microvessel permeability and selectivity under both normal and inflammatory conditions are regulated by mechanisms that are continuously active it follows that when S1P or intracellular cAMP are elevated at the time of inflammatory stimulus, they can buffer changes induced by inflammatory agents and maintain normal barrier stability. When endothelium is exposed to inflammatory conditions and subsequently exposed to elevated S1P or intracellular cAMP, the same processes restore the functional barrier by first reestablishing the adherens junction, then modulating tight junctions and glycocalyx. In more extreme inflammatory conditions, loss of the inhibitory actions of Rac1 dependent mechanisms may promote expression of more inflammatory endothelial phenotypes by contributing to the up-regulation of RhoA dependent contractile mechanisms and the sustained loss of surface glycocalyx allowing access of inflammatory cells to the endothelium.

Curry, Fitz-Roy E.; Adamson, Roger H.

2014-01-01

326

Regulation of airway mucosal hydration.  

PubMed

Ion channels control the hydration status of the airway epithelium through apical anion secretion and cation absorption, which is accompanied by osmotically obligated water. The key channels in this process are the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), which is principally responsible for Cl(-) secretion by airway epithelial cells, and the epithelial Na(+) channel (ENaC), which is responsible for the absorption of Na ions. In CF, defective CFTR-mediated Cl(-) secretion and an accompanying upregulation in ENaC-mediated Na absorption results in a reduction in airway surface liquid volume, leading to poorly hydrated mucus and impaired mucociliary clearance. Restoration of normal airway hydration by modulation of ion channel activity represents an important therapeutic strategy for CF. CFTR corrector and potentiator compounds are being developed with the aim of recovering normal Cl(-) secretion. Ca(2+)-activated Cl(-) channels (CaCCs) are expressed by the respiratory epithelia and are reported to be functionally upregulated in CF and offer a 'surrogate' pathway for Cl(-) secretion. TMEM16A has recently been described as a CaCC in the airway epithelium and, as such, represents an alternative target for restoring Cl(-) secretion in CF. An alternative therapeutic strategy for CF is to inhibit ENaC, thereby blocking excessive Na absorption. This can be achieved by direct blockade of ENaC or inhibition of the channel-activating proteases (CAPs), whose activity regulates ENaC function. This review will describe the regulation of airway mucosal hydration by ion channels and the efforts currently underway to restore normal mucosal hydration in disease patients by modulating the function of these channels. PMID:22111616

Paisley, Derek; Gosling, Martin; Danahay, Henry

2010-05-01

327

Cellular mechanisms regulating human melanogenesis.  

PubMed

The major differentiated function of melanocytes is the synthesis of melanin, a pigmented heteropolymer that is synthesized in specialized cellular organelles termed melanosomes. Mature melanosomes are transferred to neighboring keratinocytes and are arranged in a supranuclear cap, protecting the DNA against incident ultraviolet light (UV) irradiation. The synthesis and distribution of melanin in the epidermis involves several steps: transcription of melanogenic proteins, melanosome biogenesis, sorting of melanogenic proteins into the melanosomes, transport of melanosomes to the tips of melanocyte dendrites and finally transfer into keratinocytes. These events are tightly regulated by a variety of paracrine and autocrine factors in response to endogenous and exogenous stimuli, principally UV irradiation. PMID:19153661

Park, H Y; Kosmadaki, M; Yaar, M; Gilchrest, B A

2009-05-01

328

Regulation of Primary Response Genes  

PubMed Central

Primary response genes (PRGs) are a set of genes that are induced in response to both cell-extrinsic and cell-intrinsic signals and do not require de novo protein synthesis for their expression. These 'first responders' in the waves of transcription of signal responsive genes play pivotal roles in a wide rage of biological responses, including neuronal survival and plasticity, cardiac stress response, innate and adaptive immune responses, glucose metabolism and oncogeneic transformation. Here we bring together recent advances and our current understanding of the signal-induced transcriptional and epigenetic regulation of PRGs.

Fowler, Trent; Sen, Ranjan; Roy, Ananda L

2011-01-01

329

Regulation of xylem cell fate  

PubMed Central

The vascular system is organized throughout the plant body for transporting water, nutrients, and signaling molecules. During vascular development, xylem, phloem, and procambial/cambial cells are produced in a spatiotemporally organized manner. Several key regulators for xylem cell patterning and differentiation have been discovered, including auxin, cytokinin, CLE peptides, microRNAs, HD-ZIPIIIs, VNDs, and moving transcription factors SHR and AHLs. Recent studies are identifying functional interactions among these factors that ultimately determine xylem cell fate. This review focuses on regulatory networks underlying xylem cell fate determination in root vascular development.

Kondo, Yuki; Tamaki, Takayuki; Fukuda, Hiroo

2014-01-01

330

Modeling Auxin-regulated Development  

PubMed Central

The phytohormone auxin plays an essential role in many aspects of plant growth and development. Its patterning, intercellular transport, and means of signaling have been extensively studied both in experiments and computational models. Here, we present a review of models of auxin-regulated development in different plant tissues. This includes models of organ initiation in the shoot apical meristem, development of vascular strands in leafs and stems, and auxin-related functioning in roots. The examples show how mathematical modeling can help to examine expected and unexpected behavior of the system, challenge our knowledge and hypotheses, obtain quantitative results, or suggest new experiments and ways to approach a problem.

Krupinski, Pawel; Jonsson, Henrik

2010-01-01

331

QB1 - Stochastic Gene Regulation  

SciTech Connect

Summaries of this presentation are: (1) Stochastic fluctuations or 'noise' is present in the cell - Random motion and competition between reactants, Low copy, quantization of reactants, Upstream processes; (2) Fluctuations may be very important - Cell-to-cell variability, Cell fate decisions (switches), Signal amplification or damping, stochastic resonances; and (3) Some tools are available to mode these - Kinetic Monte Carlo simulations (SSA and variants), Moment approximation methods, Finite State Projection. We will see how modeling these reactions can tell us more about the underlying processes of gene regulation.

Munsky, Brian [Los Alamos National Laboratory

2012-07-23

332

Circadian regulation of adipose function  

PubMed Central

Adipose physiology shows prominent variation over the course of the day, responding to changing demands in energy metabolism. In the last years the tight interaction between the endogenous circadian timing system and metabolic function has been increasingly acknowledged. Recent work suggests that clock and adipose function go hand in hand, regulating each other to ensure optimal adaptation to environmental changes over the 24-h cycle. In this review we describe the current knowledge on the mechanistic basis of this interaction and summarize recent findings on the impact of clock dysfunction on adipose physiology and energy homeostasis.

Shostak, Anton; Husse, Jana; Oster, Henrik

2013-01-01

333

Cell Cycle Regulation & Interneuron Production  

PubMed Central

The regulation of progenitor proliferation in developing brain in has been extensively studied in the cerebral cortex, but relatively little is known about progenitor divisions in ventral germinal zones. Recent observations pertinent to interneuron genesis in the ventral forebrain, especially in the medial ganglionic eminence (MGE), indicate similarities to cerebral cortical neurogenesis and hint at some interesting differences between ventral and dorsal telencephalon progenitors. Proliferation within the ganglionic eminences (GE) is discussed from the vantage point of neural precursor cell cycles, especially G1-phase, and current models of neurogenic divisions in cortex that may apply to ventral forebrain as well.

Ross, M. Elizabeth

2011-01-01

334

Comment On The TANF Regulation  

NSDL National Science Digital Library

On August 22, 1996, President Clinton signed the "Personal Responsibility and Work Opportunity Reconciliation Act," which established the "Temporary Assistance for Needy Families (TANF) program," designed to replace the longstanding Aid to Families with Dependent Children (AFDC) program. Proposed regulations for the TANF program were issued in the Federal Register on November 20, 1997, and are posted at this site by the US Department of Health and Human Services. There is an open period for public comment from November 20, 1997 through February 18, 1997.

1997-01-01

335

Regulation: threat to converging technologies.  

PubMed

This article discusses two competing principles underlying efforts to regulate technological developments converging at the nanoscale that are intended to promote human health: the internalization of social cost by use of economic cost-benefit analysis and the precautionary principle by implementation of preventative safety standards. Overemphasis of the former may lead to potential unacceptable political and ethical effects while narrow focus on the latter may lead to potential retardation of innovation by deterring private risk capital investment. Suggestions are made for reconciling these principles through legislative initiatives. PMID:17312267

Ziegler, Alan S

2006-12-01

336

Epigenetic Regulation by Heritable RNA  

PubMed Central

Genomic concepts are based on the assumption that phenotypes arise from the expression of genetic variants. However, the presence of non-Mendelian inheritance patterns provides a direct challenge to this view and suggests an important role for alternative mechanisms of gene regulation and inheritance. Over the past few years, a highly complex and diverse network of noncoding RNAs has been discovered. Research in animal models has shown that RNAs can be inherited and that RNA methyltransferases can be important for the transmission and expression of modified phenotypes in the next generation. We discuss possible mechanisms of RNA-mediated inheritance and the role of these mechanisms for human health and disease.

Liebers, Reinhard; Rassoulzadegan, Minoo; Lyko, Frank

2014-01-01

337

Minimum criteria for DNA damage-induced phase advances in circadian rhythms.  

PubMed

Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle inhibitor kinase Wee1 (which is regulated by the heterodimeric circadian clock transcription factor, BMAL1/CLK), and possibly in conjunction with other cell cycle components that are known to be regulated by the circadian clock (i.e., c-Myc and cyclin D1). It has also been shown that DNA damage-induced activation of the cell cycle regulator, Chk2, leads to phosphorylation and destruction of a circadian clock component (i.e., PER1 in Mus or FRQ in Neurospora crassa). However, the molecular mechanism underlying how DNA damage causes predominantly phase advances in the circadian clock remains unknown. In order to address this question, we employ mathematical modeling to simulate different phase response curves (PRCs) from either dexamethasone (Dex) or IR treatment experiments. Dex is known to synchronize circadian rhythms in cell culture and may generate both phase advances and delays. We observe unique phase responses with minimum delays of the circadian clock upon DNA damage when two criteria are met: (1) existence of an autocatalytic positive feedback mechanism in addition to the time-delayed negative feedback loop in the clock system and (2) Chk2-dependent phosphorylation and degradation of PERs that are not bound to BMAL1/CLK. PMID:19424508

Hong, Christian I; Zámborszky, Judit; Csikász-Nagy, Attila

2009-05-01

338

Translational Regulation in Nutrigenomics12  

PubMed Central

The emergence of genome-wide analysis to interrogate cellular DNA, RNA, and protein content has revolutionized the study of the control network that mediates cellular homeostasis. Nutrigenomics addresses the effect of nutrients on gene expression, which provides a basis for understanding the biological activity of dietary components. Translation of mRNAs represents the last step of genetic flow and primarily defines the proteome. Translational regulation is thus critical for gene expression, in particular, under nutrient excess or deficiency. Until recently, it was unclear how the global effects of translational control are influenced by nutrient signaling. An emerging concept of translational reprogramming addresses how to maintain the expression of specific proteins during pathophysiological conditions by translation of selective mRNAs. Here we describe recent advances in our understanding of translational control, nutrient signaling, and their dysregulation in aging and cancer. The mechanistic understanding of translational regulation in response to different nutrient conditions may help identify potential dietary and therapeutic targets to improve human health.

Liu, Botao; Qian, Shu-Bing

2011-01-01

339

Stoichiometric regulation of phytoplankton toxins.  

PubMed

Ecological Stoichiometry theory predicts that the production, elemental structure and cellular content of biomolecules should depend on the relative availability of resources and the elemental composition of their producer organism. We review the extent to which carbon- and nitrogen-rich phytoplankton toxins are regulated by nutrient limitation and cellular stoichiometry. Consistent with theory, we show that nitrogen limitation causes a reduction in the cellular quota of nitrogen-rich toxins, while phosphorus limitation causes an increase in the most nitrogen-rich paralytic shellfish poisoning toxin. In addition, we show that the cellular content of nitrogen-rich toxins increases with increasing cellular N : P ratios. Also consistent with theory, limitation by either nitrogen or phosphorus promotes the C-rich toxin cell quota or toxicity of phytoplankton cells. These observed relationships may assist in predicting and managing toxin-producing phytoplankton blooms. Such a stoichiometric regulation of toxins is likely not restricted to phytoplankton, and may well apply to carbon- and nitrogen-rich secondary metabolites produced by bacteria, fungi and plants. PMID:24712512

Van de Waal, Dedmer B; Smith, Val H; Declerck, Steven A J; Stam, Eva C M; Elser, James J

2014-06-01

340

Melatonin regulation of biliary functions.  

PubMed

The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults. We first provide a general background on the general function of cholangiocytes including their anatomic characteristics, their innervation and vascularization as well the role of these cells on secretory and proliferation events. After a background on the synthesis and regulation of melatonin and its role on the maintenance of circadian rhythm, we will describe the specific effects of melatonin on biliary functions and liver damage. After a summary of the topics discussed, we provide a paragraph on the future perspectives related to melatonin and liver functions. PMID:24696836

Glaser, Shannon; Han, Yuyan; Francis, Heather; Alpini, Gianfranco

2014-02-01

341

Opening up on ELMO regulation  

PubMed Central

GTPases are central hubs for directing cytoskeletal reorganization and cell migration. The DOCK family enforces positive regulation of certain GTPases, leading to their activation in discrete areas of the cell. ELMO, a well-known DOCK180 binding partner, has been cast with the role of potentiating DOCK180-mediated Rac activation. Exactly how ELMO contributes to Rac signaling is only beginning to be understood. Here, we discuss our most recent research investigating ELMO regulation of the DOCK180/Rac pathway. Interestingly, we found that ELMO is autoinhibited via intramolecular contacts at basal levels and we explore the novel domains that we identified at the heart of the auto-regulatory switch. We propose that the closed ELMO molecule masks protein-protein interfaces or domains with novel uncharacterized function; cell stimulation and GTPase binding to ELMO is proposed to activate (open) the protein and/or target the ELMO/DOCK180 complex to the cell membrane. In this manner, promiscuous signaling/activity downstream of ELMO/DOCK180 can be controlled for both spatially and temporally. Additionally, we report new data highlighting that DOCK proteins can form heterodimers, and we discuss possible mechanisms that could be implicated in controlling the ELMO activation state.

Patel, Manishha; Pelletier, Ariane

2011-01-01

342

Regulation of inflammation by DAPK.  

PubMed

Death-associated protein kinase (DAPK) is a tumor suppressor and negatively regulates several activation signals. Consistent with its potential anti-inflammatory activity, DAPK promotes the formation of IFN-?-activated inhibitor of translation (GAIT) complex that suppresses the translation of selected inflammatory genes. DAPK has been found to inhibit tumor necrosis factor-? (TNF-?)- or lipopolysaccharides (LPS)-induced NF-?B activation and pro-inflammatory cytokine expression. Inflammation is always associated with T cell activation, while DAPK attenuates T cell activation by a selective suppression in T cell receptor-triggered NF-?B activation. Recent studies, however, also reveal a contribution of DAPK to pro-inflammatory processes. DAPK is shown to mediate pro-inflammatory signaling downstream of TNF-?, LPS, IL-17, or IL-32. In addition, DAPK is required for the full formation of NLRP3 inflammasome, essential for the generation of IL-1? and IL-18. These results suggest the complicated role of DAPK in the regulation of inflammation that is likely dependent on cell types and environmental cues. PMID:24185831

Lai, Ming-Zong; Chen, Ruey-Hwa

2014-02-01

343

Voltage regulates adrenergic receptor function.  

PubMed

The present study demonstrates that agonist-mediated activation of ?2A adrenergic receptors (?(2A)AR) is voltage-dependent. By resolving the kinetics of conformational changes of ?(2A)AR at defined membrane potentials, we show that negative membrane potentials in the physiological range promote agonist-mediated activation of ?(2A)AR. We discovered that the conformational change of ?(2A)AR by voltage is independent from receptor-G protein docking and regulates receptor signaling, including ?-arrestin binding, activation of G proteins, and G protein-activated inwardly rectifying K(+) currents. Comparison of the dynamics of voltage-dependence of clonidine- vs. norepinephrine-activated receptors uncovers interesting mechanistic insights. For norepinephrine, the time course of voltage-dependent deactivation reflected the deactivation kinetics of the receptor after agonist withdrawal and was strongly attenuated at saturating concentrations. In contrast, clonidine-activated ?(2A)AR were switched by voltage even under fully saturating concentrations, and the kinetics of this switch was notably faster than dissociation of clonidine from ?(2A)AR, indicating voltage-dependent regulation of the efficacy. We conclude that adrenergic receptors exhibit a unique, agonist-dependent mechanism of voltage-sensitivity that modulates downstream receptor signaling. PMID:23297214

Rinne, Andreas; Birk, Alexandra; Bünemann, Moritz

2013-01-22

344

Telomeres - Structure, Function, and Regulation  

PubMed Central

In mammals, maintenance of the linear chromosome ends (or telomeres) involves faithful replication of genetic materials and protection against DNA damage signals, to ensure genome stability and integrity. These tasks are carried out by the telomerase holoenzyme and a unique nucleoprotein structure in which an array of telomere-associated proteins bind to telomeric DNA to form special protein/DNA complexes. The telomerase complex, which is comprised of telomeric reverse transcriptase (TERT), telomeric RNA component (TERC), and other assistant factors, is responsible for adding telomeric repeats to the ends of chromosomes. Without proper telomere maintenance, telomere length will shorten with successive round of DNA replication due to the so-called end replication problem. Aberrant regulation of telomeric proteins and/or telomerase may lead to abnormalities that can result in diseases such as dyskeratosis congenita (DC) and cancers. Understanding the mechanisms that regulate telomere homeostasis and the factors that contribute to telomere dysfunction should aid us in developing diagnostic and therapeutic tools for these diseases.

Lu, Weisi; Zhang, Yi; Liu, Dan; Songyang, Zhou; Wan, Ma

2014-01-01

345

Informational requirements for transcriptional regulation.  

PubMed

Abstract Transcription factors (TFs) regulate transcription by binding to specific sites in promoter regions. Information theory provides a useful mathematical framework to analyze the binding motifs associated with TFs but imposes several assumptions that limit their applicability to specific regulatory scenarios. Explicit simulations of the co-evolution of TFs and their binding motifs allow the study of the evolution of regulatory networks with a high degree of realism. In this work we analyze the impact of differential regulatory demands on the information content of TF-binding motifs by means of evolutionary simulations. We generalize a predictive index based on information theory, and we validate its applicability to regulatory scenarios in which the TF binds significantly to the genomic background. Our results show a logarithmic dependence of the evolved information content on the occupancy of target sites and indicate that TFs may actively exploit pseudo-sites to modulate their occupancy of target sites. In regulatory networks with differentially regulated targets, we observe that information content in TF-binding motifs is dictated primarily by the fraction of total probability mass that the TF assigns to its target sites, and we provide a predictive index to estimate the amount of information associated with arbitrarily complex regulatory systems. We observe that complex regulatory patterns can exert additional demands on evolved information content, but, given a total occupancy for target sites, we do not find conclusive evidence that this effect is because of the range of required binding affinities. PMID:24689750

O'Neill, Patrick K; Forder, Robert; Erill, Ivan

2014-05-01

346

Connexin40 regulates platelet function.  

PubMed

The presence of multiple connexins was recently demonstrated in platelets, with notable expression of Cx37. Studies with Cx37-deficient mice and connexin inhibitors established roles for hemichannels and gap junctions in platelet function. It was uncertain, however, whether Cx37 functions alone or in collaboration with other family members through heteromeric interactions in regulation of platelet function. Here we report the presence and functions of an additional platelet connexin, Cx40. Inhibition of Cx40 in human platelets or its deletion in mice reduces platelet aggregation, fibrinogen binding, granule secretion and clot retraction. The effects of the Cx37 inhibitor (37,43)Gap27 on Cx40(-/-) mouse platelets and of the Cx40 inhibitor (40)Gap27 on Cx37(-/-) mouse platelets revealed that each connexin is able to function independently. Inhibition or deletion of Cx40 reduces haemostatic responses in mice, indicating the physiological importance of this protein in platelets. We conclude that multiple connexins are involved in regulating platelet function, thereby contributing to haemostasis and thrombosis. PMID:24096827

Vaiyapuri, Sakthivel; Moraes, Leonardo A; Sage, Tanya; Ali, Marfoua S; Lewis, Kirsty R; Mahaut-Smith, Martyn P; Oviedo-Orta, Ernesto; Simon, Alexander M; Gibbins, Jonathan M

2013-01-01

347

Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria  

PubMed Central

In the ancient anaerobic environment, ferrous iron (Fe2+) was one of the first metal cofactors. Oxygenation of the ancient world challenged bacteria to acquire the insoluble ferric iron (Fe3+) and later to defend against reactive oxygen species (ROS) generated by the Fenton chemistry. To acquire Fe3+, bacteria produce low-molecular weight compounds, known as siderophores, which have extremely high affinity for Fe3+. However, during infection the host restricts iron from pathogens by producing iron- and siderophore-chelating proteins, by exporting iron from intracellular pathogen-containing compartments, and by limiting absorption of dietary iron. Ferric Uptake Regulator (Fur) is a transcription factor which utilizes Fe2+ as a corepressor and represses siderophore synthesis in pathogens. Fur, directly or indirectly, controls expression of enzymes that protect against ROS damage. Thus, the challenges of iron homeostasis and defense against ROS are addressed via Fur. Although the role of Fur as a repressor is well-documented, emerging evidence demonstrates that Fur can function as an activator. Fur activation can occur through three distinct mechanisms (1) indirectly via small RNAs, (2) binding at cis regulatory elements that enhance recruitment of the RNA polymerase holoenzyme (RNAP), and (3) functioning as an antirepressor by removing or blocking DNA binding of a repressor of transcription. In addition, Fur homologs control defense against peroxide stress (PerR) and control uptake of other metals such as zinc (Zur) and manganese (Mur) in pathogenic bacteria. Fur family members are important for virulence within bacterial pathogens since mutants of fur, perR, or zur exhibit reduced virulence within numerous animal and plant models of infection. This review focuses on the breadth of Fur regulation in pathogenic bacteria.

Troxell, Bryan; Hassan, Hosni M.

2013-01-01

348

The effects of the heme precursor 5-aminolevulinic acid (ALA) on REV-ERB? activation  

PubMed Central

The nuclear receptor, REV-ERB?, has a key role in circadian rhythms and requires heme as its ligand. The present study determined whether the heme precursor, 5-aminolevulinic acid (ALA), affects REV-ERB? and its target genes. When exposed to ALA, the human lung diploid cell line, WI-38, exhibited activation of REV-ERB? and repression of the transcription of REV-ERB? target genes, including BMAL1, an essential component of the circadian oscillator. Moreover, co-incubation of sodium ferrous citrate (SFC) and ALA also activated REV-ERB? and repressed the transcription of REV-ERB? target genes. These results indicate that ALA regulates human circadian rhythms via REV-ERB?.

Yamashita, Kohei; Hagiya, Yuichiro; Nakajima, Motowo; Ishizuka, Masahiro; Tanaka, Tohru; Ogura, Shun-ichiro

2014-01-01

349

The effects of the heme precursor 5-aminolevulinic acid (ALA) on REV-ERB? activation.  

PubMed

The nuclear receptor, REV-ERB?, has a key role in circadian rhythms and requires heme as its ligand. The present study determined whether the heme precursor, 5-aminolevulinic acid (ALA), affects REV-ERB? and its target genes. When exposed to ALA, the human lung diploid cell line, WI-38, exhibited activation of REV-ERB? and repression of the transcription of REV-ERB? target genes, including BMAL1, an essential component of the circadian oscillator. Moreover, co-incubation of sodium ferrous citrate (SFC) and ALA also activated REV-ERB? and repressed the transcription of REV-ERB? target genes. These results indicate that ALA regulates human circadian rhythms via REV-ERB?. PMID:24918048

Yamashita, Kohei; Hagiya, Yuichiro; Nakajima, Motowo; Ishizuka, Masahiro; Tanaka, Tohru; Ogura, Shun-Ichiro

2014-01-01

350

Central Circadian Control of Female Reproductive Function  

PubMed Central

Over the past two decades, it has become clear just how much of our physiology is under the control of the suprachiasmatic nucleus (SCN) and the cell-intrinsic molecular clock that ticks with a periodicity of approximately 24?h. The SCN prepares our digestive system for meals, our adrenal axis for the stress of waking up in the morning, and the genes expressed in our muscles when we prepare to exercise. Long before molecular studies of genes such as Clock, Bmal1, and the Per homologs were possible, it was obvious that female reproductive function was under strict circadian control at every level of the hypothalamic-pituitary-gonadal axis, and in the establishment and successful maintenance of pregnancy. This review highlights our current understanding of the role that the SCN plays in regulating female reproductive physiology, with a special emphasis on the advances made possible through the use of circadian mutant mice.

Miller, Brooke H.; Takahashi, Joseph S.

2014-01-01

351

Circadian expressions of cardiac ion channel genes in mouse might be associated with the central clock in the SCN but not the peripheral clock in the heart  

PubMed Central

Significant circadian variations exist in the frequency of cardiac arrhythmia, but few studies have examined the relation between cardiac ion channels genes and biological clocks. We investigated this relation using suprachiasmatic nuclei lesion (SCNX) and pharmacological autonomic nervous system block (ANSB) mice. Significant 24-h variations were observed in the expression of clock genes Per2, Bmal1, and Dbp and ion channel genes KCNA5, KCND2, KCHIP2, and KCNK3 in the control mice hearts. In the SCNX mice, all genes examined lost circadian rhythm. In the ANSB mice, the expressions of the three clock genes were dampened significantly but still had circadian rhythm, whereas the four ion channel gene expressions lost rhythm. Heart rate also lost circadian rhythm in both the SCNX and ANSB mice. These results suggest that some ion channel gene expressions might be regulated by the central clock in the SCN through the ANS but not the peripheral clock in the heart.

Tong, Maoqing; Watanabe, Eiichi; Yamamoto, Naoki; Nagahata-Ishiguro, Misao; Maemura, Koji; Takeda, Norihiko; Nagai, Ryozo; Ozaki, Yukio

2012-01-01

352

Circadian rhythms and the effect of glucocorticoids on expression of the clock gene period1 in canine peripheral blood mononuclear cells.  

PubMed

Circadian rhythms have a periodicity of approximately 24h and, in mammals, are regulated by clock genes. In this study, expression profiles of clock genes (per1, per2, clock, bmal1 and cry1) were investigated over a single 24h period by real-time PCR in peripheral blood mononuclear cells (PBMCs) of healthy dogs and canine PBMCs treated in vitro and in vivo with glucocorticoids. Only per1 mRNA exhibited daily rhythms in canine PBMCs. Canine PBMCs cultured with dexamethasone in vitro had dose- and time-dependent increases in per1 mRNA expression. Intravenous injection of dexamethasone increased expression of per1 in canine PBMCs in vivo. Rhythmic expression of per1 in PBMCs could be used as a molecular marker for monitoring circadian rhythms and the effects of drugs on clock genes in dogs. PMID:23141960

Ohmori, Keitaro; Nishikawa, Sho; Oku, Keisuke; Oida, Kumiko; Amagai, Yosuke; Kajiwara, Naoki; Jung, Kyungsook; Matsuda, Akira; Tanaka, Akane; Matsuda, Hiroshi

2013-06-01

353

Cycles in spatial and temporal chromosomal organization driven by the circadian clock  

PubMed Central

Dynamic transitions in the epigenome have been associated with regulated patterns of nuclear organization. The accumulating evidence that chromatin remodeling is implicated in circadian function prompted us to explore whether the clock may control nuclear architecture. We applied the 3C-derived 4C technology (Chromosome Conformation Capture on Chip) in mouse embryonic fibroblasts (MEFs) to demonstrate the presence of circadian long-range interactions, using the clock-controlled Dbp gene as bait. The circadian genomic interactions with Dbp are highly specific and are absent in MEFs whose clock is disrupted by ablation of the Bmal1 gene. We establish that the Dbp circadian interactome contains a wide variety of genes and clock-related DNA elements. These findings reveal a previously unappreciated circadian and clock-dependent shaping of the nuclear landscape.

Aguilar-Arnal, Lorena; Hakim, Ofir; Patel, Vishal R.; Baldi, Pierre; Hager, Gordon L.; Sassone-Corsi, Paolo

2013-01-01

354

The regulation of organ size in Drosophila  

PubMed Central

The correct regulation of organ size is a fundamental developmental process, the failure of which can compromise organ function and organismal integrity. Consequently, the mechanisms that regulate organ size have been subject to intense research. This research has highlighted four classes of mechanism that are involved in organ size regulation: physiology, plasticity, patterning and physical force. Nevertheless, how these mechanisms are integrated and converge on the cellular process that regulate organ growth is unknown. One group of animals where this integration is beginning to be achieved is in the insects. Here, I review the different mechanisms that regulate organ size in insects, and describe our current understanding of how these mechanisms interact. The genes and hormones involved are remarkably conserved in all animals, so these studies in insects provide a precedent for future research on organ size regulation in mammals.

2010-01-01

355

Analysis of polymorphisms in the circadian-related genes and breast cancer risk in Norwegian nurses working night shifts  

PubMed Central

Introduction Some studies have suggested that night work may be associated with an increased risk of breast cancer in nurses. We aimed to explore the role of circadian gene polymorphisms in the susceptibility to night work-related breast cancer risk. Methods We conducted a nested case-control study of Norwegian nurses comprising 563 breast cancer cases and 619 controls within a cohort of 49,402 Norwegian nurses ages 35 to 74 years. We studied 60 single-nucleotide polymorphisms (SNPs) in 17 genes involved in the regulation of the circadian rhythm in cases and controls. The data were analyzed in relation to the two exposure variables "maximum number of consecutive night shifts ever worked" and "maximum number of consecutive night shifts worked for at least 5 years." The odds of breast cancer associated with each SNP was calculated in the main effects analysis and in relation to night shift work. The statistically significant odds ratios were tested for noteworthiness using two Bayesian tests: false positive report probability (FPRP) and Bayesian false discovery probability (BFDP). Results In the main effects analysis, CC carriers of rs4238989 and GG carriers of rs3760138 in the AANAT gene had increased risk of breast cancer, whereas TT carriers of BMAL1 rs2278749 and TT carriers of CLOCK rs3749474 had reduced risk. The associations were found to be noteworthy using both the FPRP and BFDP tests. With regard to the effect of polymorphisms and night work, several significant associations were observed. After applying FPRP and BFDP in women with at least four night shifts, an increased risk of breast cancer was associated with variant alleles of SNPs in the genes AANAT (rs3760138, rs4238989), BMAL1 (rs2290035, rs2278749, rs969485) and ROR-b (rs3750420). In women with three consecutive night shifts, a reduced risk of breast cancer was associated with carriage of variant alleles of SNPs in CLOCK (rs3749474), BMAL1 (rs2278749), BMAL2 (rs2306074), CSNK1E (rs5757037), NPAS2 (rs17024926), ROR-b (rs3903529, rs3750420), MTNR1A (rs131113549) and PER3 (rs1012477). Conclusions Significant and noteworthy associations between several polymorphisms in circadian genes, night work and breast cancer risk were found among nurses who had worked at least three consecutive night shifts.

2013-01-01

356

Phosphorylation Regulates SIRT1 Function  

PubMed Central

Background SIR2 is an NAD+-dependent deacetylase [1]–[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo [9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported. Methodology/Principal Findings We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD+-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13]. Conclusions/Significance Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]–[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify phosphorylation by cell cycle dependent kinases as a major mechanism controlling the level and function of this sirtuin and complement recent reports of factors that inhibit [17], [18] and activate [19] SIRT1 by protein-protein interactions.

Sasaki, Tsutomu; Maier, Bernhard; Koclega, Katarzyna D.; Chruszcz, Maksymilian; Gluba, Wendy; Stukenberg, P. Todd; Minor, Wladek; Scrable, Heidi

2008-01-01

357

Atypical transcriptional regulators and cofactors of PPAR?  

Microsoft Academic Search

Regulation of peroxisome proliferator-activated receptor gamma (PPAR?) activity is the result of several events. The first control level is the regulation of the expression of PPAR?. Examples of this regulation, during adipogenesis, is the transactivation of the PPAR? promoter by transcription factors of the classical pathway, such as C\\/EBPs or ADD1\\/SREBP1, but also newly identified factors, such as E2Fs. When

S Miard; L Fajas

2005-01-01

358

Focus Issue: Regulation of Lymphocyte Function  

NSDL National Science Digital Library

During the month of July, Science Signaling has highlighted mechanisms by which lymphocytes of the innate and adaptive immune responses are regulated to promote effective immunity and prevent inappropriate and damaging responses. Research Articles and Perspectives in this series and the Archives focus on the mechanisms by which the functions of T cells, B cells, and natural killer cells are regulated and the therapeutic implications of understanding the regulation of these cells.

Ernesto Andrianantoandro (American Association for the Advancement of Science;Science Signaling REV); John F. Foley (American Association for the Advancement of Science;Science Signaling REV)

2012-07-31

359

Regulated trafficking of the CFTR chloride channel  

Microsoft Academic Search

The cystic fibrosis transmembrane conductance regulator (CFTR), the ABC transporter encoded by the cystic fibrosis gene, is localized in the apical membrane of epithelial cells where it functions as a cyclic AMP-regulated chloride channel and as a regulator of other ion channels and transporters. Whereas a key role of cAMP-dependent phosphorylation in CFTR-channel gating has been firmly established, more recent

Bertrand Kleizen; Ineke Braakman; Hugo R. de Jonge

2000-01-01

360

Ultra-Low-Dropout Linear Regulator  

NASA Technical Reports Server (NTRS)

A radiation-tolerant, ultra-low-dropout linear regulator can operate between -150 and 150 C. Prototype components were demonstrated to be performing well after a total ionizing dose of 1 Mrad (Si). Unlike existing components, the linear regulator developed during this activity is unconditionally stable over all operating regimes without the need for an external compensation capacitor. The absence of an external capacitor reduces overall system mass/volume, increases reliability, and lowers cost. Linear regulators generate a precisely controlled voltage for electronic circuits regardless of fluctuations in the load current that the circuit draws from the regulator.

Thornton, Trevor; Lepkowski, William; Wilk, Seth

2011-01-01

361

Cognitive emotion regulation fails the stress test  

PubMed Central

Cognitive emotion regulation has been widely shown in the laboratory to be an effective way to alter the nature of emotional responses. Despite its success in experimental contexts, however, we often fail to use these strategies in everyday life where stress is pervasive. The successful execution of cognitive regulation relies on intact executive functioning and engagement of the prefrontal cortex, both of which are rapidly impaired by the deleterious effects of stress. Because it is specifically under stressful conditions that we may benefit most from such deliberate forms of emotion regulation, we tested the efficacy of cognitive regulation after stress exposure. Participants first underwent fear-conditioning, where they learned that one stimulus (CS+) predicted an aversive outcome but another predicted a neutral outcome (CS?). Cognitive regulation training directly followed where participants were taught to regulate fear responses to the aversive stimulus. The next day, participants underwent an acute stress induction or a control task before repeating the fear-conditioning task using these newly acquired regulation skills. Skin conductance served as an index of fear arousal, and salivary ?-amylase and cortisol concentrations were assayed as neuroendocrine markers of stress response. Although groups showed no differences in fear arousal during initial fear learning, nonstressed participants demonstrated robust fear reduction following regulation training, whereas stressed participants showed no such reduction. Our results suggest that stress markedly impairs the cognitive regulation of emotion and highlights critical limitations of this technique to control affective responses under stress.

Raio, Candace M.; Orederu, Temidayo A.; Palazzolo, Laura; Shurick, Ashley A.; Phelps, Elizabeth A.

2013-01-01

362

77 FR 66918 - Iranian Financial Sanctions Regulations  

Federal Register 2010, 2011, 2012, 2013

...Administrative practice and procedure, Banking, Banks, Brokers, Electronic funds transfers, Financial institutions, Foreign banking, Foreign trade, International...follows: PART 561--IRANIAN FINANCIAL SANCTIONS REGULATIONS 0 1....

2012-11-08

363

Endothelial Cell Regulation by Phospholipid Oxidation Products  

PubMed Central

Oxidized phospholipids accumulate in atherosclerotic lesions, on lipoproteins, in other states of chronic inflammation, on apoptotic cells, necrotic cells and cells exposed to oxidative stress. These lipids regulate the transcription of over 1000 gene, regulating many endothelial functions, by activating several different cell surface receptors and multiple signaling pathways. These lipids also have important effects not involving transcription that regulate cell junctions and leukocyte binding. Thus these lipids are potent regulators of endothelial cell function with broad effects comparable in extent but differing from those of cytokines.

Berliner, Judith A; Gharavi, Nima M

2010-01-01

364

Exporting licensing regulations affecting US geothermal firms  

SciTech Connect

This document presents a brief introduction and overview of the Department of Commerce's Export Administration Regulations which might affect potential US geothermal goods exporters. It is intended to make US geothermal firms officials aware of the existence of such regulations and to provide them with references, contacts and phone numbers where they can obtain specific and detailed information and assistance. It must be stressed however, that the ultimate responsibility for complying with the above mentioned regulations lies with the exporter who must consult the complete version of the regulations.

Not Available

1988-08-01

365

Shunt regulation electric power system  

NASA Technical Reports Server (NTRS)

A regulated electric power system having load and return bus lines is described. A plurality of solar cells interconnected in a power supplying relationship and having a power shunt tap point electrically spaced from the bus lines is provided. A power dissipator is connected to the shunt tap point and provides for a controllable dissipation of excess energy supplied by the solar cells. A dissipation driver is coupled to the power dissipator and controls its conductance and dissipation and is also connected to the solar cells in a power taping relationship to derive operating power therefrom. An error signal generator is coupled to the load bus and to a reference signal generator to provide an error output signal which is representative of the difference between the electric parameters existing at the load bus and the reference signal generator. An error amplifier is coupled to the error signal generator and the dissipation driver to provide the driver with controlling signals.

Wright, W. H.; Bless, J. J. (inventors)

1971-01-01

366

Metallochaperones regulate intracellular copper levels.  

PubMed

Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes. PMID:23349626

Pang, W Lee; Kaur, Amardeep; Ratushny, Alexander V; Cvetkovic, Aleksandar; Kumar, Sunil; Pan, Min; Arkin, Adam P; Aitchison, John D; Adams, Michael W W; Baliga, Nitin S

2013-01-01

367

Biomechanics of Fundamental Frequency Regulation  

PubMed Central

Accurate characterization of biomechanical characteristics of the vocal fold is critical for understanding the regulation of vocal fundamental frequency (F0), which depends on the active control of the intrinsic laryngeal muscles as well as the passive biomechanical response of the vocal fold lamina propria. Specifically, the tissue stress-strain response and viscoelastic properties under cyclic tensile deformation are relevant, when the vocal folds are subjected to length and tension changes due to posturing. This paper describes a constitutive modeling approach quantifying the relationship between vocal fold stress and strain (or stretch), and establishes predictions of F0 with the string model of phonation based on the constitutive parameters. Results indicated that transient and time-dependent changes in F0, including global declinations in declarative sentences, as well as local F0 overshoots and undershoots, can be partially attributed to the time-dependent viscoplastic response of the vocal fold cover.

Chan, Roger W.; Siegmund, Thomas; Zhang, Kai

2009-01-01

368

Homologous recombination and its regulation  

PubMed Central

Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements. Multiple regulatory mechanisms have evolved to ensure that HR takes place at the right time, place and manner. Several of these impinge on the control of Rad51 nucleofilaments that play a central role in HR. Some factors promote the formation of these structures while others lead to their disassembly or the use of alternative repair pathways. In this article, we review these mechanisms in both mitotic and meiotic environments and in different eukaryotic taxa, with an emphasis on yeast and mammal systems. Since mutations in several proteins that regulate Rad51 nucleofilaments are associated with cancer and cancer-prone syndromes, we discuss how understanding their functions can lead to the development of better tools for cancer diagnosis and therapy.

Krejci, Lumir; Altmannova, Veronika; Spirek, Mario; Zhao, Xiaolan

2012-01-01

369

Emotional mimicry as social regulation.  

PubMed

Emotional mimicry is the imitation of the emotional expressions of others. According to the classic view on emotional mimicry (the Matched Motor Hypothesis), people mimic the specific facial movements that comprise a discrete emotional expression. However, little evidence exists for the mimicry of discrete emotions; rather, the extant evidence supports only valence-based mimicry. We propose an alternative Emotion Mimicry in Context view according to which emotional mimicry is not based on mere perception but rather on the interpretation of signals as emotional intentions in a specific context. We present evidence for the idea that people mimic contextualized emotions rather than simply expressive muscle movements. Our model postulates that (implicit or explicit) contextual information is needed for emotional mimicry to take place. It takes into account the relationship between observer and expresser, and suggests that emotional mimicry depends on this relationship and functions as a social regulator. PMID:23348982

Hess, Ursula; Fischer, Agneta

2013-05-01

370

Metallochaperones Regulate Intracellular Copper Levels  

PubMed Central

Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes.

Pang, W. Lee; Kaur, Amardeep; Ratushny, Alexander V.; Cvetkovic, Aleksandar; Kumar, Sunil; Pan, Min; Arkin, Adam P.; Aitchison, John D.; Adams, Michael W. W.; Baliga, Nitin S.

2013-01-01

371

Social bonding: regulation by neuropeptides  

PubMed Central

Affiliative social relationships (e.g., among spouses, family members, and friends) play an essential role in human society. These relationships affect psychological, physiological, and behavioral functions. As positive and enduring bonds are critical for the overall well-being of humans, it is not surprising that considerable effort has been made to study the neurobiological mechanisms that underlie social bonding behaviors. The present review details the involvement of the nonapeptides, oxytocin (OT), and arginine vasopressin (AVP), in the regulation of social bonding in mammals including humans. In particular, we will discuss the role of OT and AVP in the formation of social bonds between partners of a mating pair as well as between parents and their offspring. Furthermore, the role of OT and AVP in the formation of interpersonal bonding involving trust is also discussed.

Lieberwirth, Claudia; Wang, Zuoxin

2014-01-01

372

Phosphatase regulation of intercellular junctions  

PubMed Central

Intercellular junctions represent the key contact points and sites of communication between neighboring cells. Assembly of these junctions is absolutely essential for the structural integrity of cell monolayers, tissues and organs. Disruption of junctions can have severe consequences such as diarrhea, edema and sepsis, and contribute to the development of chronic inflammatory diseases. Cell junctions are not static structures, but rather they represent highly dynamic micro-domains that respond to signals from the intracellular and extracellular environments to modify their composition and function. This review article will focus on the regulation of tight junctions and adherens junctions by phosphatase enzymes that play an essential role in preserving and modulating the properties of intercellular junction proteins.

McCole, Declan F

2013-01-01

373

Noncommutative geometry as a regulator  

SciTech Connect

We give a perturbative quantization of R{sup 4} space-time in the case where the commutators C{sup {mu}{nu}}=[X{sup {mu}},X{sup {nu}}] of the underlying algebra generators are not central. We argue that this kind of quantum space-time can be used as a regulator for quantum field theories. In particular we show, in the case of {phi}{sup 4} theory, that by choosing appropriately the commutators C{sup {mu}{nu}} we can remove all the infinities by reproducing all the counterterms. In other words, the renormalized action on R{sup 4} plus the counterterms can be rewritten as only a renormalized action on the quantum space-time QR{sup 4}. We conjecture therefore that the renormalization of quantum field theory is equivalent to the quantization of the underlying space-time R{sup 4}.

Ydri, Badis

2001-01-15

374

In Brief: Coal mining regulations  

NASA Astrophysics Data System (ADS)

The U.S. Department of the Interior (DOI) announced on 18 November measures to strengthen the oversight of state surface coal mining programs and to promulgate federal regulations to protect streams affected by surface coal mining operations. DOI's Office of Surface Mining Reclamation and Enforcement (OSM) is publishing an advance notice of a proposed rule about protecting streams from adverse impacts of surface coal mining operations. A rule issued by the Bush administration in December 2008 allows coal mine operators to place excess excavated materials into streams if they can show it is not reasonably possible to avoid doing so. “We are moving as quickly as possible under the law to gather public input for a new rule, based on sound science, that will govern how companies handle fill removed from mountaintop coal seams,” according to Wilma Lewis, assistant secretary for Land and Minerals Management at DOI.

Showstack, Randy

2009-12-01

375

Long noncoding RNAs regulate adipogenesis  

PubMed Central

The prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor ? (PPAR?) and CCAAT/enhancer-binding protein ? (CEBP?). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.

Sun, Lei; Goff, Loyal A.; Trapnell, Cole; Alexander, Ryan; Lo, Kinyui Alice; Hacisuleyman, Ezgi; Sauvageau, Martin; Tazon-Vega, Barbara; Kelley, David R.; Hendrickson, David G.; Yuan, Bingbing; Kellis, Manolis; Lodish, Harvey F.; Rinn, John L.

2013-01-01

376

Dynamics of bacterial gene regulation  

NASA Astrophysics Data System (ADS)

The phenomenon of diauxic growth is a classical problem of bacterial gene regulation. The most well studied example of this phenomenon is the glucose-lactose diauxie, which occurs because the expression of the lac operon is strongly repressed in the presence of glucose. This repression is often explained by appealing to molecular mechanisms such as cAMP activation and inducer exclusion. I will begin by analyzing data showing that these molecular mechanisms cannot explain the strong lac repression because they exert a relatively weak effect. I will then present a minimal model accounting only for enzyme induction and dilution, which yields strong repression despite the absence of catabolite repression and inducer exclusion. The model also explains the growth patterns observed in batch and continuous cultures of various bacterial strains and substrate mixtures. The talk will conclude with a discussion of the experimental evidence regarding positive feedback, the key component of the minimal model.

Narang, Atul

2009-03-01

377

Metabolic Regulation of T Lymphocytes  

PubMed Central

T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.

MacIver, Nancie J.; Michalek, Ryan D.; Rathmell, Jeffrey C.

2013-01-01

378

Implementing CITES regulations for timber.  

PubMed

Foresters are currently confronted with a new challenge. For the first time a commonly traded timber species has been listed on the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). At the 12th Conference of the Parties in November 2002, countries voted 68 to 30 to place the premier timber species of Latin America, big-leaf mahogany (Swietenia macrophylla King [Meliaceae]), on CITES Appendix II. Under Appendix II regulations, trade in mahogany requires that exporting countries verify that each shipment was legally obtained and that its harvest was non-detrimental to the survival of the species. Unfortunately, implementation has been weak, in part because countries have yet to develop a common, pragmatic, cost-effective system to make the legal and non-detriment findings. This paper recommends what such a system might include. PMID:17489241

Blundell, Arthur G

2007-03-01

379

Robustness in Glyoxylate Bypass Regulation  

PubMed Central

The glyoxylate bypass allows Escherichia coli to grow on carbon sources with only two carbons by bypassing the loss of carbons as CO2 in the tricarboxylic acid cycle. The flux toward this bypass is regulated by the phosphorylation of the enzyme isocitrate dehydrogenase (IDH) by a bifunctional kinase–phosphatase called IDHKP. In this system, IDH activity has been found to be remarkably robust with respect to wide variations in the total IDH protein concentration. Here, we examine possible mechanisms to explain this robustness. Explanations in which IDHKP works simultaneously as a first-order kinase and as a zero-order phosphatase with a single IDH binding site are found to be inconsistent with robustness. Instead, we suggest a robust mechanism where both substrates bind the bifunctional enzyme to form a ternary complex.

Shinar, Guy; Rabinowitz, Joshua D.; Alon, Uri

2009-01-01

380

Fibronectin regulates calvarial osteoblast differentiation  

NASA Technical Reports Server (NTRS)

The secretion of fibronectin by differentiating osteoblasts and its accumulation at sites of osteogenesis suggest that fibronectin participates in bone formation. To test this directly, we determined whether fibronectin-cell interactions regulate progressive differentiation of cultured fetal rat calvarial osteoblasts. Spatial distributions of alpha 5 integrin subunit, fibronectin, osteopontin (bone sialoprotein I) and osteocalcin (bone Gla-protein) were similar in fetal rat calvaria and mineralized, bone-like nodules formed by cultured osteoblasts. Addition of anti-fibronectin antibodies to cultures at confluence reduced subsequent formation of nodules to less than 10% of control values, showing that fibronectin is required for normal nodule morphogenesis. Anti-fibronectin antibodies selectively inhibited steady-state expression of mRNA for genes associated with osteoblast differentiation; mRNA levels for alkaline phosphatase and osteocalcin were suppressed, whereas fibronectin, type I collagen and osteopontin were unaffected. To identify functionally relevant domains of fibronectin, we treated cells with soluble fibronectin fragments and peptides. Cell-binding fibronectin fragments (type III repeats 6-10) containing the Arg-Gly-Asp (RGD) sequence blocked both nodule initiation and maturation, whether or not they contained a functional synergy site. In contrast, addition of the RGD-containing peptide GRGDSPK alone did not inhibit nodule initiation, although it did block nodule maturation. Thus, in addition to the RGD sequence, other features of the large cell-binding fragments contribute to the full osteogenic effects of fibronectin. Nodule formation and osteoblast differentiation resumed after anti-fibronectin antibodies or GRGDSPK peptides were omitted from the media, showing that the inhibition was reversible and the treatments were not cytotoxic. Outside the central cell-binding domain, peptides from the IIICS region and antibodies to the N terminus did not inhibit nodule formation. We conclude that osteoblasts interact with the central cell-binding domain of endogenously produced fibronectin during early stages of differentiation, and that these interactions regulate both normal morphogenesis and gene expression.

Moursi, A. M.; Damsky, C. H.; Lull, J.; Zimmerman, D.; Doty, S. B.; Aota, S.; Globus, R. K.

1996-01-01

381

CELLULAR ADMA: REGULATION AND ACTION  

PubMed Central

Asymmetric (NG,NG) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CAT) that supply intracellular NOS with its substrate, L-arginine from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5 ?mol · l?1 maybe below those required to inhibit NOS whose substrate, L-arginine, is present in concentrations manifold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by NG, NG-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate: inhibitor ratio (L-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of at least these three processes that regulate the intracellular levels of ADMA and arginine.

Teerlink, Tom; Luo, Zaiming; Palm, Fredrik; Wilcox, Christopher S.

2009-01-01

382

Air/fuel ratio regulator  

SciTech Connect

A description is given of an air/fuel ratio regulator for use with the fuel injection control system of an internal combustion engine of the spark ignition type having an air and exhaust gas (gas) induction passage open at one end to air at ambient pressure level and connected at its other end to the engine combustion chamber to be subject to manifold vacuum changes therein, a throttle valve rotatably mounted for movement across the passage to control the gas flow therethrough, exhaust gas recirculation (egr) passage means connecting engine exhaust gases to the induction passage above the closed position of the throttle valve, an egr flow control valve mounted in the egr passage means for movement between open and closed postions to control the volume of egr gas flow, an engine speed responsive positive displacement type fuel injection pump having a fuel flow output to the engine that varies in direct proportion to changes in engines speed to match fuel flow and mass airflow through the induction system of the engine over the entire speed and load range of the engine to maintain the intake mixture ratio of air to fuel constant, the pump having a fuel flow control lever movable to vary the fuel rate of flow, the regulator being characterized by engine manifold vacuum responsive first servo means operably connected to the fuel control lever for maintaining a constant air/fuel (A/F) ratio by changing fuel output as a function of changing manifold vacuum and air flow upon opening of the throttle valve, a fuel enrichment control lever operably connected to the pump control lever and movable to modify the position of the pump lever dictated by the first servo means to change the A/F ratio, and further means responsive to engine operating conditions for moving the fuel enrichment control lever to provide the changed A/F ratio.

Simko, A.

1980-07-22

383

Fetal Alcohol Exposure Disrupts Metabolic Signaling in Hypothalamic Proopiomelanocortin Neurons via a Circadian Mechanism in Male Mice.  

PubMed

Early-life ethanol feeding (ELAF) alters the metabolic function of proopiomelanocortin (POMC)-producing neurons and the circadian expression of clock regulatory genes in the hypothalamus. We investigated whether the circadian mechanisms control the action of ELAF on metabolic signaling genes in POMC neurons. Gene expression measurements of Pomc and a selected group of metabolic signaling genes, Stat3, Sirt1, Pgc1-?, and Asb4 in laser-captured microdissected POMC neurons in the hypothalamus of POMC-enhanced green fluorescent protein mice showed circadian oscillations under light/dark and constant darkness conditions. Ethanol programmed these neurons such that the adult expression of Pomc, Stat3, Sirt, and Asb4 gene transcripts became arrhythmic. In addition, ELAF dampened the circadian peak of gene expression of Bmal1, Per1, and Per2 in POMC neurons. We crossed Per2 mutant mice with transgenic POMC-enhanced green fluorescent protein mice to determine the role of circadian mechanism in ELAF-altered metabolic signaling in POMC neurons. We found that ELAF failed to alter arrhythmic expression of most circadian genes, with the exception of the Bmal1 gene and metabolic signaling regulating genes in Per2 mutant mice. Comparison of the ELAF effects on the circadian blood glucose in wild-type and Per2 mutant mice revealed that ELAF dampened the circadian peak of glucose, whereas the Per2 mutation shifted the circadian cycle and prevented the ELAF dampening of the glucose peak. These data suggest the possibility that the Per2 gene mutation may regulate the ethanol actions on Pomc and the metabolic signaling genes in POMC neurons in the hypothalamus by blocking circadian mechanisms. PMID:24797626

Agapito, Maria A; Zhang, Changqing; Murugan, Sengottuvelan; Sarkar, Dipak K

2014-07-01

384

Daily patterns and adaptation of the ghrelin, growth hormone and insulin-like growth factor-1 system under daytime food synchronisation in rats.  

PubMed

Daytime restricted feeding promotes the re-alignment of the food entrained oscillator (FEO). Endocrine cues which secretion is regulated by the transition of fasting and feeding cycles converge in the FEO. The present study aimed to investigate the ghrelin, growth hormone (GH) and insulin-like growth factor (IGF)-1 system because their release depends on rhythmic and nutritional factors, and the output from the system influences feeding and biochemical status. In a daily sampling approach, rats that were fed ad lib. were compared with rats on a reversed (daytime) and restricted feeding schedule by 3 weeks (dRF; food access for 2 h), also assessing the effect of acute fasting and refeeding. We undertook measurements of clock protein BMAL1 and performed somatometry of peripheral organs and determined the concentration of total, acylated and unacylated ghrelin, GH and IGF-1 in both serum and in its main synthesising organs. During dRF, BMAL1 expression was synchronised to mealtime in hypophysis and liver; rats exhibited acute hyperphagia, stomach distension with a slow emptying, a phase shift in liver mass towards the dark period and decrease in mass perigonadal white adipose tissue. Total ghrelin secretion during the 24-h period increased in the dRF group as a result of elevation of the unacylated form. By contrast, GH and IGF-1 serum concentration fell, with a modification of GH daily pattern after mealtime. In the dRF group, ghrelin content in the stomach and pituitary GH content decreased, whereas hepatic IGF-1 remained equal. The daily patterns and synthesis of these hormones had a rheostatic adaptation. The endocrine adaptive response elicited suggests that it may be associated with the regulation of metabolic, behavioural and physiological processes during the paradigm of daytime restricted feeding and associated FEO activity. PMID:24617825

Arellanes-Licea, E del C; Báez-Ruiz, A; Carranza, M E; Arámburo, C; Luna, M; Díaz-Muñoz, M

2014-05-01

385

Targeted Disruption of the mPer3 Gene: Subtle Effects on Circadian Clock Function  

PubMed Central

Neurons in the mammalian suprachiasmatic nucleus (SCN) contain a cell-autonomous circadian clock that is based on a transcriptional-translational feedback loop. The basic helix-loop-helix–PAS proteins CLOCK and BMAL1 are positive regulators and drive the expression of the negative regulators CRY1 and CRY2, as well as PER1, PER2, and PER3. To assess the role of mouse PER3 (mPER3) in the circadian timing system, we generated mice with a targeted disruption of the mPer3 gene. Western blot analysis confirmed the absence of mPER3-immunoreactive proteins in mice homozygous for the targeted allele. mPer1, mPer2, mCry1, and Bmal1 RNA rhythms in the SCN did not differ between mPER3-deficient and wild-type mice. Rhythmic expression of mPer1 and mPer2 RNAs in skeletal muscle also did not differ between mPER3-deficient and wild-type mice. mPer3 transcripts were rhythmically expressed in the SCN and skeletal muscle of mice homozygous for the targeted allele, but the level of expression of the mutant transcript was lower than that in wild-type controls. Locomotor activity rhythms in mPER3-deficient mice were grossly normal, but the circadian cycle length was significantly (0.5 h) shorter than that in controls. The results demonstrate that mPer3 is not necessary for circadian rhythms in mice.

Shearman, Lauren P.; Jin, Xiaowei; Lee, Choogon; Reppert, Steven M.; Weaver, David R.

2000-01-01

386

Erratic Black Hole Regulates Itself  

NASA Astrophysics Data System (ADS)

New results from NASA's Chandra X-ray Observatory have made a major advance in explaining how a special class of black holes may shut off the high-speed jets they produce. These results suggest that these black holes have a mechanism for regulating the rate at which they grow. Black holes come in many sizes: the supermassive ones, including those in quasars, which weigh in at millions to billions of times the mass of the Sun, and the much smaller stellar-mass black holes which have measured masses in the range of about 7 to 25 times the Sun's mass. Some stellar-mass black holes launch powerful jets of particles and radiation, like seen in quasars, and are called "micro-quasars". The new study looks at a famous micro-quasar in our own Galaxy, and regions close to its event horizon, or point of no return. This system, GRS 1915+105 (GRS 1915 for short), contains a black hole about 14 times the mass of the Sun that is feeding off material from a nearby companion star. As the material swirls toward the black hole, an accretion disk forms. This system shows remarkably unpredictable and complicated variability ranging from timescales of seconds to months, including 14 different patterns of variation. These variations are caused by a poorly understood connection between the disk and the radio jet seen in GRS 1915. Chandra, with its spectrograph, has observed GRS 1915 eleven times since its launch in 1999. These studies reveal that the jet in GRS 1915 may be periodically choked off when a hot wind, seen in X-rays, is driven off the accretion disk around the black hole. The wind is believed to shut down the jet by depriving it of matter that would have otherwise fueled it. Conversely, once the wind dies down, the jet can re-emerge. "We think the jet and wind around this black hole are in a sort of tug of war," said Joseph Neilsen, Harvard graduate student and lead author of the paper appearing in the journal Nature. "Sometimes one is winning and then, for reasons we don't entirely understand, the other one gets the upper hand." GRS 1915+105 Chandra X-ray Image of GRS 1915+105 The latest Chandra results also show that the wind and the jet carry about the same amount of matter away from the black hole. This is evidence that the black hole is somehow regulating its accretion rate, which may be related to the toggling between mass expulsion via either a jet or a wind from the accretion disk. Self-regulation is a common topic when discussing supermassive black holes, but this is the first clear evidence for it in stellar-mass black holes. "It is exciting that we may be on the track of explaining two mysteries at the same time: how black hole jets can be shut down and also how black holes regulate their growth," said co-author Julia Lee, assistant professor in the Astronomy department at the Harvard-Smithsonian Center for Astrophysics. "Maybe black holes can regulate themselves better than the financial markets!" Although micro-quasars and quasars differ in mass by factors of millions, they should show a similarity in behavior when their very different physical scales are taken into account. People Who Read This Also Read... Chandra Data Reveal Rapidly Whirling Black Holes Jet Power and Black Hole Assortment Revealed in New Chandra Image Celebrate the International Year of Astronomy Ghost Remains After Black Hole Eruption "If quasars and micro-quasars behave very differently, then we have a big problem to figure out why, because gravity treats them the same," said Neilsen. "So, our result is actually very reassuring, because it's one more link between these different types of black holes." The timescale for changes in behavior of a black hole should vary in proportion to the mass. For example, an hour-long timescale for changes in GRS 1915 would correspond to about 10,000 years for a supermassive black hole that weighs a billion times the mass of the Sun. "We cannot hope to explore at this level of detail in any single supermassive black hole system," said L

2009-03-01

387

Regulating emotion expression and regulating emotion experience: divergent associations with dimensions of attachment among older women  

Microsoft Academic Search

Adult attachment research does not systematically distinguish between experiential and expressive forms of regulation. Drawing insights from developmental-functionalism – a lifespan theory of emotion and emotion regulation – the current report examined the relations among attachment, trait emotion, and expressive emotion regulation in a large (N = 1204) sample of older women. Although both preoccupation and fearful-avoidance predicted more anxiety and anger,

Nathan S. Consedine; Katherine L. Fiori; Carol Magai

2012-01-01

388

Critical reflections on research approaches, accounting regulation and the regulation of accounting  

Microsoft Academic Search

The design and choice of research approaches, the nature of accounting regulation and the reactions to these regulations in organisations, involving, in effect, the regulation of accounting, are three themes of considerable importance in accounting research. They are the three themes that have dominated the research agenda of the author throughout his academic career. This paper explores the nature of

Richard Laughlin

2007-01-01

389

12 CFR 335.801 - Inapplicable SEC regulations; FDIC substituted regulations; additional information.  

Code of Federal Regulations, 2010 CFR

12 Banks and Banking 4...2009-01-01 false Inapplicable SEC regulations; FDIC substituted...335.801 Inapplicable SEC regulations; FDIC substituted...reference to regulations of the SEC issued under sections 10A(m), 12, 13, 14, and 16...

2009-01-01

390

12 CFR 335.801 - Inapplicable SEC regulations; FDIC substituted regulations; additional information.  

Code of Federal Regulations, 2010 CFR

12 Banks and Banking 4...2010-01-01 false Inapplicable SEC regulations; FDIC substituted...335.801 Inapplicable SEC regulations; FDIC substituted...reference to regulations of the SEC issued under sections 10A(m), 12, 13, 14, and 16...

2010-01-01

391

Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents  

Microsoft Academic Search

A B S T R AC T The cystic fibrosis transmembrane conductance regulator (CFTR) is a C1- channel that is regulated by cAMP-dependent phosphorylation and by intracel- lular ATP. Intracellular ATP also regulates a class of K + channels that have a distinct pharmacology: they are inhibited by sulfonylureas and activated by a novel class of drugs called K ÷

DAVID N. SHEPPARD; MICHAEL J. WEmH

1992-01-01

392

Input filter compensation for switching regulators  

NASA Technical Reports Server (NTRS)

Problems caused by input filter interaction and conventional input filter design techniques are discussed. The concept of feedforward control is modeled with an input filter and a buck regulator. Experimental measurement and comparison to the analytical predictions is carried out. Transient response and the use of a feedforward loop to stabilize the regulator system is described. Other possible applications for feedforward control are included.

Lee, F. C.

1984-01-01

393

Business roundtable calls for smarter regulation''  

Microsoft Academic Search

The Business Roundtable has decided that if industry can reengineer itself, the government can do the same to the regulatory process. Late last month, the Washington, D.C. based lobbying group issued a white paper calling for a more rational approach to government regulation of industry. The white paper, titled Toward Smarter Regulation'', was sparked by the increasing cost to companies

Storck

1994-01-01

394

Employment Effects of the Mandatory Deposit Regulation.  

National Technical Information Service (NTIS)

The report studies the effects on employment which would result from a deposit regulation on beverage containers in Illinois. The conclusion reached by the author was that such a regulation would increase employment by about 6,600 jobs, if there is a comp...

H. Folk

1972-01-01

395

36 CFR 34.5 - Applicable regulations.  

Code of Federal Regulations, 2010 CFR

...Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR EL PORTAL ADMINISTRATIVE SITE REGULATIONS § 34.5 Applicable regulations...c) and (f) Fishing. (4) 2.4Weapons, traps and nets. (5) 2.5Research specimens. (6) 2.10Camping...

2010-07-01

396

36 CFR 34.5 - Applicable regulations.  

Code of Federal Regulations, 2011 CFR

...Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR EL PORTAL ADMINISTRATIVE SITE REGULATIONS § 34.5 Applicable regulations...c) and (f) Fishing. (4) 2.4Weapons, traps and nets. (5) 2.5Research specimens. (6) 2.10Camping...

2011-07-01

397

36 CFR 34.5 - Applicable regulations.  

Code of Federal Regulations, 2012 CFR

...Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR EL PORTAL ADMINISTRATIVE SITE REGULATIONS § 34.5 Applicable regulations...c) and (f) Fishing. (4) 2.4Weapons, traps and nets. (5) 2.5Research specimens. (6) 2.10Camping...

2012-07-01

398

Amino acids as regulators of gene expression  

Microsoft Academic Search

The role of amino acids as substrates for protein synthesis is well documented. However, a function for amino acids in modulating the signal transduction pathways that regulate mRNA translation has only recently been described. Interesting, some of the signaling pathways regulated by amino acids overlap with those classically associated with the cellular response to hormones such as insulin and insulin-like

Scot R Kimball; Leonard S Jefferson

2004-01-01

399

Do Lax Environmental Regulations Attract Foreign Investment?  

Microsoft Academic Search

There has been considerable controversy over the empirical significance of the theoretically predicted pollution haven hypothesis. Generally, empirical papers have failed to find an effect on industrial location of weaker or stricter environmental regulations. In this paper we find strong confirmation of theoretical predictions. We present a statistical test of the impact of environmental regulations on the capital movement of

Charles D. Kolstad; Yuqing Xing

1998-01-01

400

Gender Differences in Self-Regulated Learning  

ERIC Educational Resources Information Center

Self-regulated learning is a relatively new construct in the domain of educational psychology but its theoretical relevance and important practical implications have already been well established. The study explored the extent to which the self-regulated learning strategies of metacognition, elaboration, critical thinking, organization, rehearsal,…

Bidjerano, Temi

2005-01-01

401

Focus on Preschool Aquatics: Child Care Regulations.  

ERIC Educational Resources Information Center

This paper proposes state regulations for the training of child care staff members in developmentally appropriate safe aquatic practices, outlines required features of any pools that children visit, and suggests safe practices for water-related activities at child care centers and swimming pools. The staff training regulation suggestions include…

Sayre, Nancy E.

402

Conserved Prefusion Protein Assembly in Regulated Exocytosis  

Microsoft Academic Search

The regulated release of hormones and neurotransmitters is a fundamental process throughout the animal kingdom. The short time scale for the calcium triggering of vesicle fusion in regulated secretion suggests that the calcium sensor synaptotagmin and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) membrane fusion machinery are well ordered before the calcium signal. To gain insight into the organization

Colin Rickman; JoseL Jimenez; Margaret E. Graham; Deborah A. Archer; Mikhail Soloviev; Robert D. Burgoyne; Bazbek Davletov

2006-01-01

403

MAPPING GASOLINE REQUIREMENTS, APPLICABLE REGULATIONS AND BANS  

EPA Science Inventory

Federal and State regulations play an important role in understanding gasoline composition around the United States. Multiple sources of information on these programs were used to develop reliable, up-to-date maps showing gasoline requirements imposed by various regulations. Th...

404

How FDA Evaluates Regulated Products: Cosmetics  

MedlinePLUS

... look at how FDA's Office of Cosmetics and Colors evaluates the safety of cosmetics. The Regulation of Cosmetics Under the ... to a cosmetic product? Does FDA approve the color additives used in cosmetics? If so, how does FDA ... FDA Evaluates Regulated Products: Cosmetics FDA Basics ...

405

Regulations and Universities: An Argument for Compliance.  

ERIC Educational Resources Information Center

The president of Towson State University (Maryland) encourages college administrators to comply with both the spirit and the letter of federal regulations, because (1) universities are similar to business corporations; (2) the university community has been an active supporter of many regulations; and (3) universities should model responsible…

Smith, Hoke L.

1992-01-01

406

Higher Education Regulations Study: Preliminary Findings  

ERIC Educational Resources Information Center

In the "Higher Education Opportunity Act" of 2008, Congress charged the Advisory Committee on Student Financial Assistance with conducting a review and analysis of regulations affecting higher education, to determine the extent to which regulations are overly burdensome and need to be streamlined, improved, or eliminated. Specifically, Congress…

Advisory Committee on Student Financial Assistance, 2011

2011-01-01

407

Markov process modelling of gene regulation  

Microsoft Academic Search

This paper discusses the mathematical modelling of gene regulation with emphasis on the bottom-up modelling of genetic componentry rather than the reverse-engineering of networks from gene expression data. Reflecting the stochastic nature of gene regulation, the chemical master equation is used as a tool to study Markovian models of networks of gene states between which probabilistic transitions occur. These states

Hilary S. Booth; Conrad J. Burden; Markus Hegland; Lucia Santoso

408

SOCS proteins, cytokine signalling and immune regulation  

Microsoft Academic Search

Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the

Tetsuji Naka; Masato Kubo; Akihiko Yoshimura

2007-01-01

409

Mechanisms regulating renal sodium excretion during development  

Microsoft Academic Search

The present review focuses on the ontogeny of mechanisms involved in renal sodium excretion during renal maturation. The effect of birth on renal excretion of sodium and the role played by the different tubular segments in the regulation of sodium excretion during maturation are discussed. The influence of circulating catecholamines and renal sympathetic innervation in regulating sodium excretion during renal

Jean E. Robillard; Francine G. Smith; Jeffrey L. Segar; Edward N. Guillery; Pedro A. Jose

1992-01-01

410

Administrative Regulations: Department of Desegregation Implementation.  

ERIC Educational Resources Information Center

Pursuant to the July 1979 Remedial Order of the Federal District Court, this document represents the Cleveland Board of Education Administrative Regulations for the desegregation of the Cleveland school system. Seventeen areas are covered by the regulations: transportation, student assignments, safety and security, community relations, student…

Fleming, Margaret, Ed.

411

Essays on electricity regulation and restructuring  

NASA Astrophysics Data System (ADS)

The study of the regulation of the electric power industry is important to understanding the role of the industry in the economic development of this country. These essays attempt to clarify the analysis and emphasize the salient features of regulation and the restructuring of the electric power industry and the organization of the firms that make up the industry.

Davis, Earl Hansford, III

412

Ways for regulators to use performance measures  

SciTech Connect

The core challenge for regulators is to determine what constitutes a well-performing utility. The question of what is considered acceptable performance needs to be addressed by regulators if they are to exploit fully the information contained in performance measures for regulatory actions such as prudence determination, further inquiry, and rate setting. (author)

Costello, Ken

2010-12-15

413

Higher Education Regulations Study: Final Report  

ERIC Educational Resources Information Center

In the "Higher Education Opportunity Act" of 2008, Congress charged the Advisory Committee on Student Financial Assistance with conducting a review and analysis of regulations affecting higher education to determine the extent to which regulations are overly burdensome and need to be streamlined, improved, or eliminated. Specifically, Congress…

Advisory Committee on Student Financial Assistance, 2011

2011-01-01

414

Benefits and costs of food safety regulation  

Microsoft Academic Search

This paper begins with a review of the concepts and methods that can be used to quantify the benefits and costs of food safety regulations. On the cost side, where research is only beginning to emerge, this paper also provides an analytical framework for measurement of the costs of statutory regulations in the form of design and performance standards. This

John M. Antle

1999-01-01

415

Self-Regulation and Academic Procrastination.  

ERIC Educational Resources Information Center

Assesses the role of autonomous self-regulation as a predictor of academic procrastination. Maintains that academic procrastination is often a motivational problem related to fear of failure. Reveals that students with intrinsic reasons for studying procrastinate less than those with less autonomous reasons (for example, external regulation). (MJP)

Senecal, Caroline; And Others

1995-01-01

416

Access regulation and strategic transfer pricing  

Microsoft Academic Search

Access price regulation is used in telecommunications to prevent a vertically integrated firm, which controls an essential input, from raising the rivals’ costs. When the authorities remove the access price as a strategic tool, it becomes optimal for the regulated firm to use the transfer price as an alternative strategic device. Ironically, the tools authorities use to implement access price

Kenneth Fjell; Øystein Foros

2008-01-01

417

Regulation of Pressure Groups and Lobbyists  

Microsoft Academic Search

Many states have lobbying laws which require the filing of registration, appearance and expense statements. However, these laws for the most part are restricted in cover age to direct communication with members of the Legislature and the Governor in influencing legislation. Although the in tention of the Federal Regulation of Lobbying Act of 1946 was to regulate both direct and

Belle Zeller

1958-01-01

418

The Regulation of Human Globin Gene Switching  

Microsoft Academic Search

This paper describes the mechanism of regulation of the human beta -globin on the basis of a number of natural mutations and experiments in transgenic mice. From these data we conclude that this multigene locus is regulated at a number of different levels involving specific interactions between the Locus Control Region (LCR) and the individual genes. Most important is the

Frank Grosveld; Mike Antoniou; Meera Berry; Ernie de Boer; Niall Dillon; James Ellis; Peter Fraser; Olivia Hanscombe; Jacky Hurst; Ali Imam; Mike Lindenbaum; Sjaak Philipsen; Sara Pruzina; John Strouboulis; Selina Raguz-Bolognesi; Dale Talbot

1993-01-01

419

Regulation of chromatin by histone modifications  

Microsoft Academic Search

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just

Andrew J Bannister; Tony Kouzarides

2011-01-01

420

Neuropilins in neoplasms: Expression, regulation, and function  

Microsoft Academic Search

Neuropilins (NRP) are membranous receptors capable of binding two disparate ligands, class 3 semaphorins (SEMA) and vascular endothelial growth factors (VEGF), and regulating two diverse systems, neuronal guidance and angiogenesis. The neuropilin genes, NRP1 and NRP2, share similar protein structure, but differ in their expression patterns, regulation, and ligand-binding specificities. NRPs vary in their expression patterns; for example, endothelial cells

Diane R. Bielenberg; Curtis A. Pettaway; Seiji Takashima; Michael Klagsbrun

2006-01-01

421

ENVIRONMENTAL REGULATIONS AND TECHNOLOGY - THE ELECTROPLATING INDUSTRY  

EPA Science Inventory

This 44-page Technology Transfer Environmental Regulations and Technology publication is an update of a 1980 EPA publication that has been revised to reflect changes in the EPA regulations, as well as in the pollution control technologies that affect the electroplating industry. ...

422

Gun Control after Heller: Litigating against Regulation  

Microsoft Academic Search

The “core right” established in D.C. vs. Heller (2008) is to keep an operable handgun in the home for self-defense purposes. If the Court extends this right to cover state and local jurisdictions, the result is likely to include the elimination of the most stringent existing regulations – such as Chicago’s handgun ban – and could also possibly ban regulations

Philip J. Cook; Jens Ludwig; Adam Samaha

2009-01-01

423

Transcriptional Regulation and its Misregulation in Disease  

PubMed Central

The gene expression programs that establish and maintain specific cell states in humans are controlled by thousands of transcription factors, cofactors and chromatin regulators. Misregulation of these gene expression programs can cause a broad range of diseases. Here we review recent advances in our understanding of transcriptional regulation and discuss how these have provided new insights into transcriptional misregulation in disease.

Lee, Tong Ihn; Young, Richard A.

2013-01-01

424

Cardiac Vagal Regulation and Early Peer Status  

ERIC Educational Resources Information Center

A sample of 341 5 1/2-year-old children participating in an ongoing longitudinal study was the focus of a study on the relation between cardiac vagal regulation and peer status. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (suppression) to 3 cognitively and emotionally challenging tasks…

Graziano, Paulo A.; Keane, Susan P.; Calkins, Susan D.

2007-01-01

425

Self-Regulation: Calm, Alert, and Learning  

ERIC Educational Resources Information Center

There is a growing awareness among developmental scientists that the better a child can self-regulate, the better she can rise to the challenge of mastering ever more complex skills and concepts. In the simplest terms, self-regulation can be defined as the ability to stay calmly focused and alert, which often involves--but cannot be reduced…

Shanker, Stuart

2010-01-01

426

Emotion Regulation and Childhood Aggression: Longitudinal Associations  

ERIC Educational Resources Information Center

Accumulating evidence suggests that emotion dysregulation is associated with psychopathology. This paper provides a review of recent longitudinal studies that investigate the relationship between emotion regulation and aggressive behavior in childhood age. While there is substantial evidence for assuming a close relation of emotion regulation and…

Roll, Judith; Koglin, Ute; Petermann, Franz

2012-01-01

427

California's new mandatory greenhouse gas reporting regulation  

Microsoft Academic Search

Beginning in early 2009, approximately 1000 California businesses will begin reporting their greenhouse gas (GHG) emissions based on the requirements of a new regulation adopted by the California Air Resources Board (CARB) in December 2007. California's mandatory GHG reporting regulation is the first rule adopted as a requirement of the Global Warming Solutions Act of 2006, passed by the California

Patrick Gaffney; Doug Thompson; Richard Bode

2008-01-01

428

Regulation of WASP/WAVE proteins  

PubMed Central

Despite their homology, the regulation of WASP and WAVE, activators of Arp2/3-dependent actin polymerization, has always been thought to be different. Several recent studies have revealed new aspects of their regulation, highlighting its complexity and the crucial role of post-translational modifications. New data also suggest additional functions for WASP family proteins, pushing us to reconsider existing models.

Bompard, Guillaume; Caron, Emmanuelle

2004-01-01

429

Regulation of the CFTR channel by phosphorylation  

Microsoft Academic Search

Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels are regulated tightly by protein kinases and phosphatases. The regulatory domain of CFTR has about 20 potential sites for phosphorylation by protein kinases A (PKA) and C (PKC). The reason for this large number of sites is not known, however their conservation from fish to humans implies that they play important roles

David Dahan; Alexandra Evagelidis; John W. Hanrahan; Deborah A. R. Hinkson; Yanlin Jia; Jiexin Luo; Tang Zhu

2001-01-01

430

Regulation of signalling by microRNAs  

PubMed Central

Stringent regulation of biochemical signalling pathways involves feedback and feedforward loops, which underlie robust cellular responses to external stimuli. Regulation occurs in all horizontal layers of signalling networks, primarily by proteins that mediate internalization of receptor–ligand complexes, dephosphorylation of kinases and their substrates, as well as transcriptional repression. Recent studies have unveiled the role of miRNAs (microRNAs), post-transcriptional regulators that control mRNA stability, as key modulators of signal propagation. By acting as genetic switches or fine-tuners, miRNAs can directly and multiply regulate cellular outcomes in response to diverse extracellular signals. Conversely, signalling networks temporally control stability, biogenesis and abundance of miRNAs, by regulating layers of the miRNA biogenesis pathway. In the present mini-review, we use a set of examples to illustrate the extensive interdependence between miRNAs and signalling networks.

Avraham, Roi; Yarden, Yosef

2013-01-01

431

Regulation of the aging process by autophagy.  

PubMed

Autophagy is involved in cellular protein and organelle degradation, which is mediated by the lysosomal pathway. Autophagocytosis has a key role in cellular housekeeping by removing damaged organelles. During aging, the efficiency of autophagic degradation declines and intracellular waste products accumulate. In Caenorhabditis elegans, there is clear evidence that lifespan is linked to the capacity to regulate autophagy. Recent studies have revealed that the same signaling factors regulate both aging and autophagocytosis, thus highlighting the role of autophagy in the regulation of aging and age-related degenerative diseases. Here, we examine in detail the interactions of the signaling network involving longevity factors SIRT1, mTOR, FoxO3, NF-kappaB and p53 in the regulation of autophagy. We discuss the possibility that these well-known stress resistance and longevity factors regulate the aging process via autophagy. PMID:19380253

Salminen, Antero; Kaarniranta, Kai

2009-05-01

432

[Central regulation of adenohypophyseal function].  

PubMed

The secretion of adenohypophyseal hormones is controlled by hypothalamic hypophysotropic hormones with stimulating (hormone releasing factors) or inhibitory (hormone release inhibiting factors) actions. The release of hypothalamic hormones is regulated by hierarchically higher nerve centres via neurons which liberate neurotransmitters at their endings. The secretion of growth hormone is controlled by hypothalamic hormones, somatotropin releasing factor and somatotropin release-inhibiting factor; of the neurotransmitters, the strongest effects have noradrenaline and dopamine. The release of ACTH is controlled by two stimulating hormones, the ACTH releasing factor and vasopressin, the effects of neurotransmitters are less marked, with the involvement of noradrenaline, serotonin, acetylcholine, gamma aminobutyric acid and other agents. Prolactin release is under the main inhibitory control of hypothalamic dopamine, no release-stimulating hypothalamic factor could be unequivocally demonstrated as yet; likely, several peptides are involved in this mechanism. The release of thyrotropic hormone is stimulated by thyrotropin releasing factor, whereas somatotropin release-inhibiting factor has an inhibitory action. Of the neurotransmitters, the inhibitory effect of dopamine is important; this agent however acts also at the hypophyseal level. External hypothalamic hormones and regulatory neurotransmitters are used in the diagnosis and treatment of neuroendocrine disorders. PMID:2567554

Vigas, M

1989-03-01

433

(Packaging regulations for chemical explosives)  

SciTech Connect

The purpose of the trip was to visit Nobel Chemicals in Sweden and to confer with the Department of Transportation personnel in Sweden and in England on the technical and regulatory problems in the bulk shipping of the high explosives RDX and HMX. It is customary in the United States (US) to add isopropyl alcohol to the bulk shipment of water-wet high explosives RDX and HMX. The explosives are packed in cloth bags which are placed in plastic-lined fiber drums. The addition of alcohol presumably prevents mildewing of cloth bags and freezing of the wet explosives in cold weather. In Europe, however, these explosives are shipped in polyethylene-lined fiber drums with not less than 15% water only, even in cold weather. Water-wet frozen explosives have not proved to be any more sensitive than its unfrozen counterpart and no mildew problem has been encountered. It looks promising that the US Department of Transportation regulations can be changed to permit the bulk shipment of these explosives in water only without the addition of isopropyl alcohol. This is expected to cut down the packaging cost considerably. In addition, the packaging procedure in the US can be modernized by introducing more mechanical and efficient handling as seen at Nobel Chemicals. 2 figs.

Pal, B.C.

1988-02-17

434

Proteasome regulators: activators and inhibitors  

PubMed Central

This mini review covers the drug discovery aspect of both proteasome activators and inhibitors. The proteasome is involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. Due to the importance of the proteasome in cellular functions, inhibition or activation of the proteasome could become a useful therapeutic strategy for a variety of diseases. Many proteasome inhibitors have been identified and can be classified into two groups according to their source: chemically synthesized small molecules and compounds derived from natural products. A successful case of developing a proteasome inhibitor as a clinically useful drug is that the peptide boronate, PS341 (Bortezomib), was approved for the treatment of multiple myeloma. In contrast to proteasome inhibitors, small molecules that can activate or enhance proteasome activity are rare and are not well studied. The fact that over-expression of the cellular proteasome activator PA28 exhibited beneficial effects on the Huntington’s disease neuronal model cells raised the prospect that small molecule proteasome activators could become useful therapeutics. The beneficial effect of oleuropein, a small molecule proteasome activator, on senescence of human fibroblasts also suggested that proteasome activators might have the potential to be developed into anti-aging agents.

Huang, Li; Chen, Chin Ho

2013-01-01

435

Autophagy regulates inflammation in adipocytes.  

PubMed

Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins. In insulin resistant adipocytes, various dysfunctional/damaged molecules, organelles, proteins, and end-products accumulate. However, the role of autophagy (in particular, whether autophagy is activated or not) is poorly understood. In this study we found that in adipose tissue of insulin resistant mice and hypertrophic 3T3-L1 adipocytes autophagy was suppressed. Also in hypertrophic adipocytes, autophagy-related gene expression, such as LAMP1, LAMP2, and Atg5 was reduced, whereas gene expression in the inflammatory-related genes, such as MCP-1, IL-6, and IL-1? was increased. To find out whether suppressed autophagy was linked to inflammation we used the autophagy inhibitor, 3-methyladenine, to inhibit autophagy. Our results suggest that such inhibition leads to an increase in inflammatory gene expression and causes endoplasmic reticulum (ER) stress (which can be attenuated by treatment with the ER stress inhibitor, Tauroursodeoxycholic Acid). Conversely, the levels of inflammatory gene expression were reduced by the activation of autophagy or by the inhibition of ER stress. The results indicate that the suppression of autophagy increases inflammatory responses via ER stress, and also defines a novel role of autophagy as an important regulator of adipocyte inflammation in systemic insulin resistance. PMID:22155234

Yoshizaki, Takeshi; Kusunoki, Chisato; Kondo, Motoyuki; Yasuda, Mako; Kume, Shinji; Morino, Katsutaro; Sekine, Osamu; Ugi, Satoshi; Uzu, Takashi; Nishio, Yoshihiko; Kashiwagi, Atsunori; Maegawa, Hiroshi

2012-01-01

436

Electronically Variable Pressure Regulator (EVPR)  

NASA Technical Reports Server (NTRS)

A new programmable electronically variable pressure regulator (EVPR) concept accurately controls the local outlet or remote system pressure. It uses an integral pulse width modulated rare earth permanent magnet motor operating in response to redundant pressure transducer feedback signals. The EVPR is a simple single stage device that does not use dynamic seals or pilot valving. Conversion of partial revolution motor torque to poppet lifting force is accomplished by pure flexure action to avoid using bearings. The flexure drive (called the ROTAX) has a variable lead to minimize motor weight and power consumption. Breadboard tests were completed successfully on two critical design elements of the EVPR: the ROTAX and the motor. The ROTAX cable system was tested for 250,000 cycles without failure. The breadboard motor met the basic design requirements including the design torque and power consumption. Prototype parts were fabricated, and testing of the prototype EVPR has started. It is PC computer controlled to facilitate programming, data acquisition and analysis. A lightweight dedicated microprocessor is planned for the flightweight EVPR.

Reinicke, R. H.; Nelson, R. O.; Hurlbert, E.

1989-01-01

437

Prion protein in ESC regulation  

PubMed Central

A large number of studies have analyzed the putative functions of the prion protein (PrPC) in mammals. Although its sequence conservation over a wide range of different animals may indicate that this protein could have a key role in prion diseases, an absolutely accepted involvement has not been found so far. We have recently reported that PrPC regulates Nanog mRNA expression, the first non-redundant function of PrPC in embryonic stem cells (ESC), which translates into control of pluripotency and early differentiation. Contrary to what is believed, the other two members of the prion protein family, Doppel and Shadoo, cannot replace the absence of PrPC, causing the appearance of a new embryoid body (EB) population in our in vitro culture. The similarities between EB and an early post-implantation embryo suggest that this might also occur in vivo, enhancing the importance of this finding. On the other hand, our data may support the hypothesis of a relationship between the loss of PrPC function and neuronal degeneration in prion diseases. A reduction in brain stem cells pluripotency after PrPC is misfolded into the pathological conformation (PrPSc) could lead to a delay or a disappearance of the normal brain damage recovery.

Pericuesta, Eva

2011-01-01

438

Type XIV Collagen Regulates Fibrillogenesis  

PubMed Central

Type XIV collagen is a fibril-associated collagen with an interrupted triple helix. This collagen interacts with the fibril surface and has been implicated as a regulator of fibrillogenesis; however, a specific role has not been elucidated. Functional roles for type XIV collagen were defined utilizing a new type XIV collagen-deficient mouse line. This line was produced using a conventional targeted knock-out approach. Col14a1(–/–) mice were devoid of type XIV collagen, whereas heterozygous mice had reduced synthesis. Both mutant Col14a1 genotypes were viable with a grossly normal phenotype; however, mature skin exhibited altered mechanical properties. Prior to evaluating tendon fibrillogenesis in type XIV collagen-deficient mice, the developmental expression patterns were analyzed in wild-type flexor digitorum longus (FDL) tendons. Analyses of mRNA and protein expression indicated tissue-specific temporal expression that was associated with the early stages in fibrillogenesis. Ultrastructural analyses of wild-type and null tendons demonstrated premature fibril growth and larger fibril diameters in tendons from null mice at postnatal day 4 (P4). However, fibril structure in mature tendons was normal. Biomechanical studies established a direct structure/function relationship with reduced strength in P7-null tendons. However, the biomechanical properties in P60 tendons were comparable in null and wild-type mice. Our results indicate a regulatory function for type XIV collagen in early stages of collagen fibrillogenesis with tissue differences.

Ansorge, Heather L.; Meng, Xianmin; Zhang, Guiyun; Veit, Guido; Sun, Mei; Klement, John F.; Beason, David P.; Soslowsky, Louis J.; Koch, Manuel; Birk, David E.

2009-01-01

439

Selection in regulated autocatalytic systems.  

PubMed

The paper deals with problems involved in the formation of stable structures in a system, in which processes typical of bimolecular autocatalytical reactions occur when the respective components are directly influenced from the outside. Such systems can arise in biochemical, biological and ecological sphere (see, e.g. Glansdorff and Prigogine 1971; Nicolis and Prigogine 1977; Haken 1977; 1980). It has been shown that a regions of so-called subcritical and supercritical regulation exist, manifested by the fact that the given system component would either persist or disappear. The selection of processes consists in the fact that generally only one solution can be realized from N alternatives as a stable state having the nature of a stable node, or a stable focus. When one of the components is supplied to the system from the exterior in a supercritical amount, the system can be "forced" to produce only that single substance. Thus, the system studied can be considered as a model of a biological filter. The results can also be applied in ecology and biotechnology. PMID:3803909

Krempaský, J; Kv?ton, R

1986-10-01

440

Regulation of intestinal cholesterol absorption.  

PubMed

The identification of defective structures in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in patients with sitosterolemia suggests that these two proteins are an apical sterol export pump promoting active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. The newly identified Niemann-Pick C1-like 1 (NPC1L1) protein is also expressed at the apical membrane of enterocytes and plays a crucial role in the ezetimibe-sensitive cholesterol absorption pathway. These findings indicate that cholesterol absorption is a multistep process that is regulated by multiple genes at the enterocyte level and that the efficiency of cholesterol absorption may be determined by the net effect between influx and efflux of intraluminal cholesterol molecules crossing the brush border membrane of the enterocyte. Combination therapy using cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) provides a powerful novel strategy for the prevention and treatment of hypercholesterolemia. PMID:17002594

Wang, David Q-H

2007-01-01

441

[Phosphocalcic metabolism: regulation and explorations].  

PubMed

Calcium and phosphate play a key role in bone mineralization but have also many other physiological functions. The control of serum phosphate concentration is mandatory to avoid the occurrence of severe metabolic disorders, but is less tightly regulated than serum ionized calcium concentration, which is maintained in a very limited range thanks to parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol. Any change in serum ionized calcium concentration is detected by the calcium sensing receptor (CaSR), a membranous protein located principally in the parathyroid glands and the kidney. A decrease in ionized calcium level inactivates the CaSR, thus stimulating PTH secretion. PTH in turn stimulates the release of calcium and phosphate from bone, renal calcium reabsorption and calcium and phosphate intestinal absorption by inducing renal calcitriol production. Moreover, PTH inhibits phosphate reabsorption in proximal tubular cells, thus contributing towards phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate by inhibiting renal phosphate reabsorption and calcitriol production and may have a great physiological role in phosphate homeostasis. Recently, vitamin D actions independent of calcium and phosphate homeostasis were discovered. Basal exploration of phosphocalcic metabolism abnormalities consists in measurement of serum calcium (ionized calcium if possible), phosphate, 25-hydroxy vitamine D and PTH and of 24 hours urinary calcium excretion as well as renal function. Hence, the understanding of physiopathological mechanisms has been improved by newly identified genetic disorders responsible for phophocalcic homeostasis disturbances. PMID:21273150

Courbebaisse, Marie; Souberbielle, Jean-Claude

2011-04-01

442

Regulating ISS— An interdisciplinary essay  

NASA Astrophysics Data System (ADS)

The International Space Station (ISS) is a multifaceted international project. Several space agencies from different countries work together in the Outer Space. This paper will illustrate the exciting questions arising from such a venture and therefore the challenge to incorporate a variety of issues into a legal order. The Paper is addressed to lawyers who need not necessarily be experts in space law, and also to space experts who have no legal background. It demonstrates the three layers of the ISS regime—from the "Intergovernmental Agreement" (IGA) as a "frame" with pillars and boundaries, over the "Memoranda of Understanding" (MOU) which rules in a more specific way, to the so-called "Implementing Arrangements" regulating the overall and single aspects of ISS in detail. The paper underlines questions of applicable jurisdiction, utilization rights and the rights on intellectual property onboard of the ISS. Furthermore the problem of liability in space flight is highlighted, also with a view to the different aspects of the liability issue, for example (internal) liability caused by programme delays (e.g. US Space Shuttle delays). In conclusion, the paper illustrates the situation of astronauts by the "Code of Conduct for the International Space Station Crew" and provides an example for the actual ISS Programme—an international cooperation in a highly demanding environment which will be a basis for future space ventures in many ways.

Brünner, Christian; Soucek, Alexander

2007-02-01

443

Microbial regulation of intestinal radiosensitivity  

PubMed Central

We describe a method for treating germ-free (GF) mice with ?-irradiation and transplanting them with normal or genetically manipulated bone marrow while maintaining their GF status. This approach revealed that GF mice are markedly resistant to lethal radiation enteritis. Furthermore, administering lethal doses of total body irradiation to GF mice produces markedly fewer apoptotic endothelial cells and lymphocytes in the mesenchymal cores of their small intestinal villi, compared with conventionally raised animals that have acquired a microbiota from birth. Analysis of GF and conventionally raised Rag1-/- mice disclosed that mature lymphocytes are not required for the development of lethal radiation enteritis or the microbiota-associated enhancement of endothelial radiosensitivity. Studies of gnotobiotic knockout mice that lack fasting-induced adipose factor (Fiaf), a fibrinogen/angiopoietin-like protein normally secreted from the small intestinal villus epithelium and suppressed by the microbiota, showed that Fiaf deficiency results in loss of resistance of villus endothelial and lymphocyte populations to radiation-induced apoptosis. Together, these findings provide insights about the cellular and molecular targets involved in microbial regulation of intestinal radiosensitivity.

Crawford, Peter A.; Gordon, Jeffrey I.

2005-01-01

444

Physiological regulation of lipoprotein lipase.  

PubMed

The enzyme lipoprotein lipase (LPL), originally identified as the clearing factor lipase, hydrolyzes triglycerides present in the triglyceride-rich lipoproteins VLDL and chylomicrons. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities such as the heart, skeletal muscle, brown adipose tissue and white adipose tissue. Upon production by the underlying parenchymal cells, LPL is transported and attached to the capillary endothelium by the protein GPIHBP1. Because LPL is rate limiting for plasma triglyceride clearance and tissue uptake of fatty acids, the activity of LPL is carefully controlled to adjust fatty acid uptake to the requirements of the underlying tissue via multiple mechanisms at the transcriptional and post-translational level. Although various stimuli influence LPL gene transcription, it is now evident that most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. These proteins can be divided into two main groups: the liver-derived apolipoproteins APOC1, APOC2, APOC3, APOA5, and APOE, and the angiopoietin-like proteins ANGPTL3, ANGPTL4 and ANGPTL8, which have a broader expression profile. This review will summarize the available literature on the regulation of LPL activity in various tissues, with an emphasis on the response to diverse physiological stimuli. PMID:24721265

Kersten, Sander

2014-07-01

445

The transcriptional regulation of pluripotency  

PubMed Central

The defining features of embryonic stem cells (ESCs) are their self-renewing and pluripotent capacities. Indeed, the ability to give rise into all cell types within the organism not only allows ESCs to function as an ideal in vitro tool to study embryonic development, but also offers great therapeutic potential within the field of regenerative medicine. However, it is also this same remarkable developmental plasticity that makes the efficient control of ESC differentiation into the desired cell type very difficult. Therefore, in order to harness ESCs for clinical applications, a detailed understanding of the molecular and cellular mechanisms controlling ESC pluripotency and lineage commitment is necessary. In this respect, through a variety of transcriptomic approaches, ESC pluripotency has been found to be regulated by a system of ESC-associated transcription factors; and the external signalling environment also acts as a key factor in modulating the ESC transcriptome. Here in this review, we summarize our current understanding of the transcriptional regulatory network in ESCs, discuss how the control of various signalling pathways could influence pluripotency, and provide a future outlook of ESC research.

Yeo, Jia-Chi; Ng, Huck-Hui

2013-01-01