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Sample records for cdt1-geminin complex regulates

  1. Cdt1 revisited: complex and tight regulation during the cell cycle and consequences of deregulation in mammalian cells

    Directory of Open Access Journals (Sweden)

    Fujita Masatoshi

    2006-10-01

    Full Text Available Abstract In eukaryotic cells, replication of genomic DNA initiates from multiple replication origins distributed on multiple chromosomes. To ensure that each origin is activated precisely only once during each S phase, a system has evolved which features periodic assembly and disassembly of essential pre-replication complexes (pre-RCs at replication origins. The pre-RC assembly reaction involves the loading of a presumptive replicative helicase, the MCM2-7 complexes, onto chromatin by the origin recognition complex (ORC and two essential factors, CDC6 and Cdt1. The eukaryotic cell cycle is driven by the periodic activation and inactivation of cyclin-dependent kinases (Cdks and assembly of pre-RCs can only occur during the low Cdk activity period from late mitosis through G1 phase, with inappropriate re-assembly suppressed during S, G2, and M phases. It was originally suggested that inhibition of Cdt1 function after S phase in vertebrate cells is due to geminin binding and that Cdt1 hyperfunction resulting from Cdt1-geminin imbalance induces re-replication. However, recent progress has revealed that Cdt1 activity is more strictly regulated by two other mechanisms in addition to geminin: (1 functional and SCFSkp2-mediated proteolytic regulation through phosphorylation by Cdks; and (2 replication-coupled proteolysis mediated by the Cullin4-DDB1Cdt2 ubiquitin ligase and PCNA, an eukaryotic sliding clamp stimulating replicative DNA polymerases. The tight regulation implies that Cdt1 control is especially critical for the regulation of DNA replication in mammalian cells. Indeed, Cdt1 overexpression evokes chromosomal damage even without re-replication. Furthermore, deregulated Cdt1 induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this could be a new molecular mechanism leading to carcinogenesis. In this review, recent insights into Cdt1 function and regulation in mammalian cells are discussed.

  2. Idas, a novel phylogenetically conserved geminin-related protein, binds to geminin and is required for cell cycle progression.

    Science.gov (United States)

    Pefani, Dafni-Eleutheria; Dimaki, Maria; Spella, Magda; Karantzelis, Nickolas; Mitsiki, Eirini; Kyrousi, Christina; Symeonidou, Ioanna-Eleni; Perrakis, Anastassis; Taraviras, Stavros; Lygerou, Zoi

    2011-07-01

    Development and homeostasis of multicellular organisms relies on an intricate balance between cell proliferation and differentiation. Geminin regulates the cell cycle by directly binding and inhibiting the DNA replication licensing factor Cdt1. Geminin also interacts with transcriptional regulators of differentiation and chromatin remodelling factors, and its balanced interactions are implicated in proliferation-differentiation decisions during development. Here, we describe Idas (Idas being a cousin of the Gemini in Ancient Greek Mythology), a previously uncharacterised coiled-coil protein related to Geminin. We show that human Idas localizes to the nucleus, forms a complex with Geminin both in cells and in vitro through coiled-coil mediated interactions, and can change Geminin subcellular localization. Idas does not associate with Cdt1 and prevents Geminin from binding to Cdt1 in vitro. Idas depletion from cells affects cell cycle progression; cells accumulate in S phase and are unable to efficiently progress to mitosis. Idas protein levels decrease in anaphase, whereas its overexpression causes mitotic defects. During development, we show that Idas exhibits high level expression in the choroid plexus and the cortical hem of the mouse telencephalon. Our data highlight Idas as a novel Geminin binding partner, implicated in cell cycle progression, and a putative regulator of proliferation-differentiation decisions during development. PMID:21543332

  3. Cellulose synthase complexes: structure and regulation

    Directory of Open Access Journals (Sweden)

    Lei eLei

    2012-04-01

    Full Text Available This review is to update the most recent progress on characterization of the composition, regulation, and trafficking of cellulose synthase complexes. We will highlight proteins that interact with cellulose synthases, e.g. cellulose synthase-interactive protein 1 (CSI1. The potential regulation mechanisms by which cellulose synthase interact with cortical microtubules in primary cell walls will be discussed.

  4. Noncommutative Biology: Sequential Regulation of Complex Networks

    Science.gov (United States)

    Letsou, William; Cai, Long

    2016-01-01

    Single-cell variability in gene expression is important for generating distinct cell types, but it is unclear how cells use the same set of regulatory molecules to specifically control similarly regulated genes. While combinatorial binding of transcription factors at promoters has been proposed as a solution for cell-type specific gene expression, we found that such models resulted in substantial information bottlenecks. We sought to understand the consequences of adopting sequential logic wherein the time-ordering of factors informs the final outcome. We showed that with noncommutative control, it is possible to independently control targets that would otherwise be activated simultaneously using combinatorial logic. Consequently, sequential logic overcomes the information bottleneck inherent in complex networks. We derived scaling laws for two noncommutative models of regulation, motivated by phosphorylation/neural networks and chromosome folding, respectively, and showed that they scale super-exponentially in the number of regulators. We also showed that specificity in control is robust to the loss of a regulator. Lastly, we connected these theoretical results to real biological networks that demonstrate specificity in the context of promiscuity. These results show that achieving a desired outcome often necessitates roundabout steps. PMID:27560383

  5. Complex regulation controls Neurogenin3 proteolysis

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    Ryan Roark

    2012-10-01

    The ubiquitin proteasome system (UPS is known to be responsible for the rapid turnover of many transcription factors, where half-life is held to be critical for regulation of transcriptional activity. However, the stability of key transcriptional regulators of development is often very poorly characterised. Neurogenin 3 (Ngn3 is a basic helix–loop–helix transcription factor that plays a central role in specification and differentiation of endocrine cells of the pancreas and gut, as well as spermatogonia and regions of the brain. Here we demonstrate that Ngn3 protein stability is regulated by the ubiquitin proteasome system and that Ngn3 can be ubiquitylated on lysines, the N-terminus and, highly unusually, on non-canonical residues including cysteines and serines/threonines. Rapid turnover of Ngn3 is regulated both by binding to its heterodimeric partner E protein and by the presence of cdk inhibitors. We show that protein half-life does appear to regulate the activity of Ngn3 in vivo, but, unlike the related transcription factor c-myc, ubiquitylation on canonical sites is not a requirement for transcriptional activity of Ngn3. Hence, we characterise an important new level of Ngn3 post-translational control, which may regulate its transcriptional activity.

  6. MLL1/WDR5 complex in leukemogenesis and epigenetic regulation

    Institute of Scientific and Technical Information of China (English)

    Min Wu; Hong-Bing Shu

    2011-01-01

    MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components. It plays important roles in developmental events, transcriptional regulation, and leukemogenesis. MLL1-fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia, which occurs in over 70% infant leukemia patients and often accompanies poor prognosis. Investigations in the past years on leukemogenesis and the MLL1-WDR5 histone H3Lys4 methyltransferase complex demonstrate that epigenetic regulation is one of the key steps in development and human diseases.

  7. COPI complex is a regulator of lipid homeostasis.

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    Mathias Beller

    2008-11-01

    Full Text Available Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.

  8. The altered complexity of cardiovascular regulation in depressed patients

    International Nuclear Information System (INIS)

    Major depressive disorders (MDD) are associated with an increased risk for cardiovascular morbidity and mortality. Even if it is known that MDD are accompanied by an autonomic dysbalance with increased sympathetic and/or reduced parasympathetic activity, to date only limited information is available about the degree and complexity of cardiovascular regulation. The aim of this study was to investigate the influence of MDD on the autonomous nervous system and cardiovascular complexity by means of linear and nonlinear indices from heart rate and blood pressure variability (HRV, BPV). From 57 non-medicated patients and 57 matched healthy controls with respect to age and gender HRV and BPV in time and frequency domain, symbolic dynamics, compression entropy, multiscale entropy, detrended fluctuation analysis, Poincaré plot analysis and baroreflex sensitivity were analysed from 30 min short-term recordings. Complexity indices from nonlinear dynamics demonstrated considerable changes in autonomous regulation due to MDD. For the first time we could show that non-medicated depressed patients who were matched with respect to age and gender reveal a significantly changed short-term as well as long-term complexity of cardiovascular regulation. These results suggest substantial changes in autonomic control probably due to a change of interactions between different physiological control loops in MDD

  9. Engineering complex riboswitch regulation by dual genetic selection.

    Science.gov (United States)

    Sharma, Vandana; Nomura, Yoko; Yokobayashi, Yohei

    2008-12-01

    The recent discovery of riboswitches in diverse species of bacteria and few eukaryotes added metabolite-responsive gene regulation to the growing list of RNA functions in biology. The natural riboswitches have inspired several designs of synthetic analogues capable of gene regulation in response to a small molecule trigger. In this work, we describe our efforts to engineer complex riboswitches capable of sensing and responding to two small molecules according to Boolean logics AND and NAND. Two aptamers that recognize theophylline and thiamine pyrophosphate were embedded in tandem in the 5' UTR of bacterial mRNA, and riboswitches that function as logic gates were isolated by dual genetic selection. The diverse phenotype of the engineered logic gates supports the versatility of RNA-based gene regulation which may have preceded the modern protein-based gene regulators. Additionally, our design strategy advances our ability to harness the versatile capacities of RNA to program complex behavior in bacteria without the use of engineered proteins. PMID:18998646

  10. A PLA1-2 Punch Regulates the Golgi Complex

    OpenAIRE

    Bechler, Marie E.; de Figueiredo, Paul; Brown, William J.

    2011-01-01

    The mammalian Golgi complex, trans Golgi network (TGN) and ER-Golgi intermediate compartment (ERGIC) are comprised of membrane cisternae, coated vesicles and membrane tubules, all of which contribute to membrane trafficking and maintenance of their unique architectures. Recently, a new cast of players was discovered to regulate the Golgi and ERGIC: four unrelated cytoplasmic phospholipase A (PLA) enzymes, cPLA(2)α (GIVA cPLA(2)), PAFAH Ib (GVIII PLA(2)), iPLA(2)-β (GVIA-2 iPLA(2)) and iPLA(1)...

  11. Postprandial transduodenal bolus transport is regulated by complex peristaltic sequence

    Institute of Scientific and Technical Information of China (English)

    Huan Nam Nguyen; Ron Winograd; Gerson Ricardo Souza Domingues; Frank Lammert

    2006-01-01

    AIM: To study the relationship between the patterns of postprandial peristalsis and transduodenal bolus transport in healthy subjects.METHODS: Synchronous recording of chyme transport and peristaltic activity was performed during the fasting state and after administration of a test meal using a special catheter device with cascade configuration of impedance electrodes and solid-state pressure transducers. The catheter was placed into the duodenum,where the first channel was located in the first part of the duodenum and the last channel at the duodenojejunal junction. After identification of previously defined chyme transport patterns the associated peristaltic patterns were analyzed.RESULTS: The interdigestive phase 3 complex was reliably recorded with both techniques. Of 497 analyzed impedance bolus transport events, 110 (22%) were short-spanned propulsive, 307 (62%) long-spanned propulsive, 70 (14%)complex propulsive, and 10 (2%) retrograde transport.Short-spanned chyme transports were predominantly associated with stationary or propagated contractions propagated over short distance. Long-spanned and complex chyme transports were predominantly associated with propulsive peristaltic patterns, which were frequently complex and comprised multiple contractions. Propagated double wave contraction, propagated contraction with a clustered contraction, and propagated cluster of contractions have been identified to be an integralted part of a peristaltic sequence in human duodenum.CONCLUSION: Combined impedancometry andmanometry improves the analysis of the peristaltic patterns that are associated with postprandial transduodenal chyme transport. Postprandial transduodenal bolus transport is regulated by propulsive peristaltic patterns, which are frequently complex but well organized. This finding should be taken into consideration in the analysis of intestinal motility studies.

  12. POPX2 phosphatase regulates the KIF3 kinesin motor complex.

    Science.gov (United States)

    Phang, Hui-Qun; Hoon, Jing-Ling; Lai, Soak-Kuan; Zeng, Yukai; Chiam, Keng-Hwee; Li, Hoi-Yeung; Koh, Cheng-Gee

    2014-02-15

    The kinesin motors are important in the regulation of cellular functions such as protein trafficking, spindle organization and centrosome separation. In this study, we have identified POPX2, a serine-threonine phosphatase, as an interacting partner of the KAP3 subunit of the kinesin-2 motor. The kinesin-2 motor is a heterotrimeric complex composed of KIF3A, KIF3B motor subunits and KAP3, the non-motor subunit, which binds the cargo. Here we report that the phosphatase POPX2 is a negative regulator of the trafficking of N-cadherin and other cargoes; consequently, it markedly influences cell-cell adhesion. POPX2 affects trafficking by determining the phosphorylation status of KIF3A at serine 690. This is consistent with the observation that the KIF3A-S690A mutant is defective in cargo trafficking. Our studies also implicate CaMKII as the kinase that phosphorylates KIF3A at serine 690. These results strongly suggest that POPX2 and CaMKII are a phosphatase-kinase pair that regulates kinesin-mediated transport and cell-cell adhesion. PMID:24338362

  13. Number and regulation of protozoan aquaporins reflect environmental complexity.

    Science.gov (United States)

    Von Bülow, Julia; Beitz, Eric

    2015-08-01

    Protozoa are a diverse group of unicellular eukaryotes. Evidence has accumulated that protozoan aquaporin water and solute channels (AQP) contribute to adaptation in changing environments. Intracellular protozoan parasites live a well-sheltered life. Plasmodium spp. express a single AQP, Toxoplasma gondii two, while Trypanosoma cruzi and Leishamnia spp. encode up to five AQPs. Their AQPs are thought to import metabolic precursors and simultaneously to dispose of waste and to help parasites survive osmotic stress during transmission to and from the insect vector or during kidney passages. Trypanosoma brucei is a protozoan parasite that swims freely in the human blood. Expression and intracellular localization of the three T. brucei AQPs depend on the stage of differentiation during the life cycle, suggesting distinct roles in energy generation, metabolism, and cell motility. Free-living amoebae are in direct contact with the environment, encountering severe and sudden changes in the availability of nutrition, and in the osmotic conditions due to rainfall or drought. Amoeba proteus expresses a single AQP that is present in the contractile vacuole complex required for osmoregulation, whereas Dictyostelium discoideum expresses four AQPs, of which two are present in the single-celled amoeboidal stage and two more in the later multicellular stages preceding spore formation. The number and regulation of protozoan aquaporins may reflect environmental complexity. We highlight the gated AqpB from D. discoideum as an example of how life in the wild is challenged by a complex AQP structure-function relationship. PMID:26338868

  14. Expression, purification and spectroscopic characterization of the Regulator complex

    Energy Technology Data Exchange (ETDEWEB)

    Nogueira, M.L.C.; Silva, A.L.S.; Camilotti, D.; Silva, C.A.; Sforca, M.L.; Smetana, J.H.C.; Zeri, A.C. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil); Ospina-Bedoya, M. [Universidad de Antioquia, Medellin (Colombia)

    2012-07-01

    Full text: The mammalian target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals, serves as a central regulator of cell metabolism in humans and its deregulation is linked to diseases like cancer and diabetes. The small GTPases Rag are mediators of signaling by amino acid (leucine). These GT-Pases are anchored on the surface of the lysosome through an interaction with a complex of three proteins, p18, MP1 and p14, called Ragulator. The p18 protein is responsible for interaction with the lysosomal membrane through its N terminal post translational modification. The objective of this project is to study the interaction of p18 and other components of the Ragulator complex. The p18 protein was expressed in inclusion bodies, which were isolated and solubilized in urea. p18 was renatured with its partners MP1/p14 and this complex, the Ragulator, was subjected to spectroscopic characterization using circular dichroism and dynamic light scattering. (author)

  15. Expression, purification and spectroscopic characterization of the Regulator complex

    International Nuclear Information System (INIS)

    Full text: The mammalian target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals, serves as a central regulator of cell metabolism in humans and its deregulation is linked to diseases like cancer and diabetes. The small GTPases Rag are mediators of signaling by amino acid (leucine). These GT-Pases are anchored on the surface of the lysosome through an interaction with a complex of three proteins, p18, MP1 and p14, called Ragulator. The p18 protein is responsible for interaction with the lysosomal membrane through its N terminal post translational modification. The objective of this project is to study the interaction of p18 and other components of the Ragulator complex. The p18 protein was expressed in inclusion bodies, which were isolated and solubilized in urea. p18 was renatured with its partners MP1/p14 and this complex, the Ragulator, was subjected to spectroscopic characterization using circular dichroism and dynamic light scattering. (author)

  16. LATS2 Positively Regulates Polycomb Repressive Complex 2

    Science.gov (United States)

    Torigata, Kosuke; Daisuke, Okuzaki; Mukai, Satomi; Hatanaka, Akira; Ohka, Fumiharu; Motooka, Daisuke; Nakamura, Shota; Ohkawa, Yasuyuki; Yabuta, Norikazu; Kondo, Yutaka; Nojima, Hiroshi

    2016-01-01

    LATS2, a pivotal Ser/Thr kinase of the Hippo pathway, plays important roles in many biological processes. LATS2 also function in Hippo-independent pathway, including mitosis, DNA damage response and epithelial to mesenchymal transition. However, the physiological relevance and molecular basis of these LATS2 functions remain obscure. To understand novel functions of LATS2, we constructed a LATS2 knockout HeLa-S3 cell line using TAL-effector nuclease (TALEN). Integrated omics profiling of this cell line revealed that LATS2 knockout caused genome-wide downregulation of Polycomb repressive complex 2 (PRC2) and H3K27me3. Cell-cycle analysis revealed that downregulation of PRC2 was not due to cell cycle aberrations caused by LATS2 knockout. Not LATS1, a homolog of LATS2, but LATS2 bound PRC2 on chromatin and phosphorylated it. LATS2 positively regulates histone methyltransferase activity of PRC2 and their expression at both the mRNA and protein levels. Our findings reveal a novel signal upstream of PRC2, and provide insight into the crucial role of LATS2 in coordinating the epigenome through regulation of PRC2. PMID:27434182

  17. Precise regulation of gene expression dynamics favors complex promoter architectures.

    Directory of Open Access Journals (Sweden)

    Dirk Müller

    2009-01-01

    Full Text Available Promoters process signals through recruitment of transcription factors and RNA polymerase, and dynamic changes in promoter activity constitute a major noise source in gene expression. However, it is barely understood how complex promoter architectures determine key features of promoter dynamics. Here, we employ prototypical promoters of yeast ribosomal protein genes as well as simplified versions thereof to analyze the relations among promoter design, complexity, and function. These promoters combine the action of a general regulatory factor with that of specific transcription factors, a common motif of many eukaryotic promoters. By comprehensively analyzing stationary and dynamic promoter properties, this model-based approach enables us to pinpoint the structural characteristics underlying the observed behavior. Functional tradeoffs impose constraints on the promoter architecture of ribosomal protein genes. We find that a stable scaffold in the natural design results in low transcriptional noise and strong co-regulation of target genes in the presence of gene silencing. This configuration also exhibits superior shut-off properties, and it can serve as a tunable switch in living cells. Model validation with independent experimental data suggests that the models are sufficiently realistic. When combined, our results offer a mechanistic explanation for why specific factors are associated with low protein noise in vivo. Many of these findings hold for a broad range of model parameters and likely apply to other eukaryotic promoters of similar structure.

  18. Complex structure and regulation of the ABP/SHBG gene.

    Science.gov (United States)

    Joseph, D R; Sullivan, P M; Wang, Y M; Millhorn, D E; Bayliss, D M

    1991-01-01

    Extracellular androgen-binding proteins (ABPs) are thought to modulate the regulatory functions of androgens and the trans-acting nuclear androgen receptor. Testicular ABP and plasma sex hormone-binding globulin (SHBG), which is produced in the liver, are encoded by the same gene. We report here that the ABP/SHBG gene is also expressed in fetal rat liver and adult brain. Immunoreactive ABP was localized in the brain and fetal liver and mRNAs were identified in both tissues by northern blot hybridization. Analysis of brain and fetal liver cDNA clones revealed alternatively processed RNAs with sequence characteristics suggesting the encoded proteins could act as competitors of ABP/SHBG binding to cell surface receptors. One cDNA represented a fused transcript of the ABP/SHBG gene and the histidine decarboxylase gene that was apparently formed by a trans-splicing process. Gene sequencing experiments indicate that tissue-specific ABP/SHBG gene promoter-enhancer elements are utilized in testis, brain and fetal liver. These data demonstrate that the structure, RNA transcript processing and likely regulation of the ABP/SHBG gene are very complex. PMID:1958575

  19. WASH complex regulates Arp2/3 complex for actin-based polar body extrusion in mouse oocytes

    OpenAIRE

    Wang, Fei; Zhang, Liang; Zhang, Guang-Li; Wang, Zhen-Bo; CUI, Xiang-Shun; Kim, Nam-Hyung; Sun, Shao-Chen

    2014-01-01

    Prior to their fertilization, oocytes undergo asymmetric division, which is regulated by actin filaments. Recently, WASH complex were identified as actin nucleation promoting factors (NPF) that activated Arp2/3 complex. However, the roles of WASH complex remain uncertain, particularly for oocyte polarization and asymmetric division. Here, we examined the functions of two important subunits of a WASH complex, WASH1 and Strumpellin, during mouse oocyte meiosis. Depleting WASH1 or disrupting Str...

  20. Biogenesis of photosystem II complexes: transcriptional, translational, and posttranslational regulation

    International Nuclear Information System (INIS)

    The integral membrane proteins of photosystem II (PS II) reaction center complexes are encoded by chloroplast genomes. These proteins are absent from thylakoids of PS II mutants of algae and vascular plants as a result of either chloroplast or nuclear gene mutations. To resolve the molecular basis and the concurrent absence of the PS II polypeptides, protein synthesis rates and mRNA levels were measured in mutants of Chlamydomonas reinhardtii that lack PS II. The analyses show that one nuclear gene product regulates the levels of transcripts from the chloroplast gene encoding the 51-kD chlorophyll α-binding polypeptide (polypeptide 5) but is not involved in the synthesis of other chloroplast mRNAs. The other nuclear product is specifically required for translation of mRNA encoding the 32-34-kD polypeptide, D1. The absence of either D1 or polypeptide 5 does not eliminate the synthesis and thylakoid insertion of two other integral membrane proteins of PS II, the chlorophyll α-binding polypeptide of 46 kD (polypeptide 6) and the 30-kD D1-like protein, D2. However, these two unassembled subunits cannot be properly processed and/or are degraded in the mutants even though they reside in the membrane. In addition, pulse labeling of the nuclear mutants and a chloroplast mutant that does not synthesize D1 mRNA indicates that synthesis of polypeptide 5 and D1 is coordinated at the translational level. A model is presented to explain how absence of one of the two proteins could lead to translational arrest of the other

  1. Ambition, Regulation and Reality. Complex use of land and water resources in Luwu, South Sulawesi, Indonesia

    NARCIS (Netherlands)

    Roth, D.

    2003-01-01

    In this book I present three case studies of the complex regulation of use of land and water resources in Luwu. Attention to the role of legalcomplexity -the existence of different sources and definitions of normative-legal regulation in

  2. Rac1 regulates neuronal polarization through the WAVE complex

    DEFF Research Database (Denmark)

    Tahirovic, Sabina; Hellal, Farida; Neukirchen, Dorothee;

    2010-01-01

    physiological function of Rac1 in neuronal development, we have generated a conditional knock-out mouse, in which Rac1 is ablated in the whole brain. Rac1-deficient cerebellar granule neurons, which do not express other Rac isoforms, showed impaired neuronal migration and axon formation both in vivo and in...... vitro. In addition, Rac1 ablation disrupts lamellipodia formation in growth cones. The analysis of Rac1 effectors revealed the absence of the Wiskott-Aldrich syndrome protein (WASP) family verprolin-homologous protein (WAVE) complex from the plasma membrane of knock-out growth cones. Loss of WAVE...... function inhibited axon growth, whereas overexpression of a membrane-tethered WAVE mutant partially rescued axon growth in Rac1-knock-out neurons. In addition, pharmacological inhibition of the WAVE complex effector Arp2/3 also reduced axon growth. We propose that Rac1 recruits the WAVE complex to the...

  3. Complexity in regulation of tryptophan biosynthesis in Bacillus subtilis.

    Science.gov (United States)

    Gollnick, Paul; Babitzke, Paul; Antson, Alfred; Yanofsky, Charles

    2005-01-01

    Bacillus subtilis uses novel regulatory mechanisms in controlling expression of its genes of tryptophan synthesis and transport. These mechanisms respond to changes in the intracellular concentrations of free tryptophan and uncharged tRNA(Trp). The major B. subtilis protein that regulates tryptophan biosynthesis is the tryptophan-activated RNA-binding attenuation protein, TRAP. TRAP is a ring-shaped molecule composed of 11 identical subunits. Active TRAP binds to unique RNA segments containing multiple trinucleotide (NAG) repeats. Binding regulates both transcription termination and translation in the trp operon, and translation of other coding regions relevant to tryptophan metabolism. When there is a deficiency of charged tRNA(Trp), B. subtilis forms an anti-TRAP protein, AT. AT antagonizes TRAP function, thereby increasing expression of all the genes regulated by TRAP. Thus B. subtilis and Escherichia coli respond to identical regulatory signals, tryptophan and uncharged tRNA(Trp), yet they employ different mechanisms in regulating trp gene expression. PMID:16285852

  4. Complex regulation of sister kinetochore orientation in meiosis-I

    Indian Academy of Sciences (India)

    Amit Bardhan

    2010-09-01

    Kinetochores mediate chromosome movement during cell division by interacting with the spindle microtubules. Sexual reproduction necessitates the daunting task of reducing ploidy (number of chromosome sets) in the gametes, which depends upon the specialized properties of meiosis. Kinetochores have a central role in the reduction process. In this review, we discuss the complexity of this role of kinetochores in meiosis-I.

  5. Translational regulation shapes the molecular landscape of complex disease phenotypes

    Czech Academy of Sciences Publication Activity Database

    Schafer, S.; Adami, E.; Heinig, M.; Rodrigues, K. E. C.; Kreuchwig, F.; Šilhavý, Jan; van Heesch, S.; Simaite, D.; Rajewsky, N.; Cuppen, E.; Pravenec, Michal; Vingron, M.; Cook, S. A.; Hubner, N.

    2015-01-01

    Roč. 6, May 2015 (2015), s. 7200. ISSN 2041-1723 R&D Projects: GA ČR(CZ) GB14-36804G; GA MŠk(CZ) LL1204; GA MŠk(CZ) 7E10067 Institutional support: RVO:67985823 Keywords : translational regulation * RNA sequencing * ribosome profiling * rat Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 11.470, year: 2014

  6. Complex Regulation of Arsenite Oxidation in Agrobacterium tumefaciens

    OpenAIRE

    Kashyap, Des R.; Botero, Lina M.; Franck, William L.; Daniel J Hassett; McDermott, Timothy R.

    2006-01-01

    Seminal regulatory controls of microbial arsenite [As(III)] oxidation are described in this study. Transposon mutagenesis of Agrobacterium tumefaciens identified genes essential for As(III) oxidation, including those coding for a two-component signal transduction pair. The transposon interrupted a response regulator gene (referred to as aoxR), which encodes an ntrC-like protein and is immediately downstream of a gene (aoxS) encoding a protein with primary structural features found in sensor h...

  7. The GIT–PIX complexes regulate the chemotactic response of rat basophilic leukaemia cells

    OpenAIRE

    Gavina, Manuela; Za, Lorena; Molteni, Raffaella; Pardi, Ruggero; Curtis, Ivan de

    2010-01-01

    Background information. Cell motility entails the reorganization of the cytoskeleton and membrane trafficking for effective protrusion. The GIT–PIX protein complexes are involved in the regulation of cell motility and adhesion and in the endocytic traffic of members of the family of G-protein-coupled receptors. We have investigated the function of the endogenous GIT complexes in the regulation of cell motility stimulated by fMLP (formyl-Met-Leu-Phe) peptide, in a rat basophilic leukaemia RBL-...

  8. Unraveling the complexities of SIRT1-mediated mitochondrial regulation in skeletal muscle

    OpenAIRE

    Philp, Andrew; Schenk, Simon

    2013-01-01

    SIRT1 is a purported central regulator of skeletal muscle mitochondrial biogenesis. Herein we discuss our recent work utilizing conditional mouse models, which highlight the complexities of SIRT1 biology in vivo, and question its role in regulating mitochondrial function and mitochondrial adaptions to endurance exercise. Further, we discuss the possible contribution of proposed SIRT1 substrates to muscle mitochondrial biogenesis.

  9. Detecting coordinated regulation of multi-protein complexes using logic analysis of gene expression

    Directory of Open Access Journals (Sweden)

    Yeates Todd O

    2009-12-01

    Full Text Available Abstract Background Many of the functional units in cells are multi-protein complexes such as RNA polymerase, the ribosome, and the proteasome. For such units to work together, one might expect a high level of regulation to enable co-appearance or repression of sets of complexes at the required time. However, this type of coordinated regulation between whole complexes is difficult to detect by existing methods for analyzing mRNA co-expression. We propose a new methodology that is able to detect such higher order relationships. Results We detect coordinated regulation of multiple protein complexes using logic analysis of gene expression data. Specifically, we identify gene triplets composed of genes whose expression profiles are found to be related by various types of logic functions. In order to focus on complexes, we associate the members of a gene triplet with the distinct protein complexes to which they belong. In this way, we identify complexes related by specific kinds of regulatory relationships. For example, we may find that the transcription of complex C is increased only if the transcription of both complex A AND complex B is repressed. We identify hundreds of examples of coordinated regulation among complexes under various stress conditions. Many of these examples involve the ribosome. Some of our examples have been previously identified in the literature, while others are novel. One notable example is the relationship between the transcription of the ribosome, RNA polymerase and mannosyltransferase II, which is involved in N-linked glycan processing in the Golgi. Conclusions The analysis proposed here focuses on relationships among triplets of genes that are not evident when genes are examined in a pairwise fashion as in typical clustering methods. By grouping gene triplets, we are able to decipher coordinated regulation among sets of three complexes. Moreover, using all triplets that involve coordinated regulation with the ribosome

  10. Regulation of mRNA Trafficking by Nuclear Pore Complexes

    Directory of Open Access Journals (Sweden)

    Amandine Bonnet

    2014-09-01

    Full Text Available Over the last two decades, multiple studies have explored the mechanisms governing mRNA export out of the nucleus, a crucial step in eukaryotic gene expression. During transcription and processing, mRNAs are assembled into messenger ribonucleoparticles (mRNPs. mRNPs are then exported through nuclear pore complexes (NPCs, which are large multiprotein assemblies made of several copies of a limited number of nucleoporins. A considerable effort has been put into the dissection of mRNA export through NPCs at both cellular and molecular levels, revealing the conserved contributions of a subset of nucleoporins in this process, from yeast to vertebrates. Several reports have also demonstrated the ability of NPCs to sort out properly-processed mRNPs for entry into the nuclear export pathway. Importantly, changes in mRNA export have been associated with post-translational modifications of nucleoporins or changes in NPC composition, depending on cell cycle progression, development or exposure to stress. How NPC modifications also impact on cellular mRNA export in disease situations, notably upon viral infection, is discussed.

  11. An asymmetric heterodomain interface stabilizes a response regulator-DNA complex

    Energy Technology Data Exchange (ETDEWEB)

    Narayanan, Anoop; Kumar, Shivesh; Evrard, Amanda N.; Paul, Lake N.; Yernool, Dinesh A. [Purdue; (Duke-MED)

    2014-02-14

    Two-component signal transduction systems consist of pairs of histidine kinases and response regulators, which mediate adaptive responses to environmental cues. Most activated response regulators regulate transcription by binding tightly to promoter DNA via a phosphorylation-triggered inactive-to-active transition. The molecular basis for formation of stable response regulator–DNA complexes that precede the assembly of RNA polymerases is unclear. Here, we present structures of DNA complexed with the response regulator KdpE, a member of the OmpR/PhoB family. The distinctively asymmetric complex in an active-like conformation reveals a unique intramolecular interface between the receiver domain (RD) and the DNA-binding domain (DBD) of only one of the two response regulators in the complex. Structure–function studies show that this RD–DBD interface is necessary to form stable complexes that support gene expression. The conservation of sequence and structure suggests that these findings extend to a large group of response regulators that act as transcription factors.

  12. Dynamic and Stable Cohesins Regulate Synaptonemal Complex Assembly and Chromosome Segregation.

    Science.gov (United States)

    Gyuricza, Mercedes R; Manheimer, Kathryn B; Apte, Vandana; Krishnan, Badri; Joyce, Eric F; McKee, Bruce D; McKim, Kim S

    2016-07-11

    Assembly of the synaptonemal complex (SC) in Drosophila depends on two independent pathways defined by the chromosome axis proteins C(2)M and ORD. Because C(2)M encodes a Kleisin-like protein and ORD is required for sister-chromatid cohesion, we tested the hypothesis that these two SC assembly pathways depend on two cohesin complexes. Through single- and double-mutant analysis to study the mitotic cohesion proteins Stromalin (SA) and Nipped-B (SCC2) in meiosis, we provide evidence that there are at least two meiosis-specific cohesin complexes. One complex depends on C(2)M, SA, and Nipped-B. Despite the presence of mitotic cohesins SA and Nipped-B, this pathway has only a minor role in meiotic sister-centromere cohesion and is primarily required for homolog interactions. C(2)M is continuously incorporated into pachytene chromosomes even though SC assembly is complete. In contrast, the second complex, which depends on meiosis-specific proteins SOLO, SUNN, and ORD is required for sister-chromatid cohesion, localizes to the centromeres and is not incorporated during prophase. Our results show that the two cohesin complexes have unique functions and are regulated differently. Multiple cohesin complexes may provide the diversity of activities required by the meiotic cell. For example, a dynamic complex may allow the chromosomes to regulate meiotic recombination, and a stable complex may be required for sister-chromatid cohesion. PMID:27291057

  13. The regulation of smart grids. Towards smarter, more functional or in particular more complex regulations?

    International Nuclear Information System (INIS)

    In current energy regulation, legal aspects of smart grids and smart meters seemed to be limited to the protection of the privacy of the energy users in the mandatory rollout of the smart meter. The current status of the implementation is that the small-scale rollout will start on 1 January 2012. According to the author, the current regulatory framework is insufficient for actual implementation of a smart grid. According to him it is possible to mark a testing ground smart grid as a closed distribution system as is to be implemented according to the Electricity Directive 2009/72.

  14. Mediator Complex Regulates Alternative mRNA Processing via the Med23 Subunit

    OpenAIRE

    Yan HUANG; Li, Wencheng; Yao, Xiao; Lin, Qi-jiang; Yin, Jing-wen; Liang, Yan; Heiner, Monika; Tian, Bin; HUI, JINGYI; Wang, Gang

    2012-01-01

    Mediator complex is an integrative hub for transcriptional regulation. Here we show that Mediator regulates alternative mRNA processing via its Med23 subunit. Combining tandem affinity purification and mass spectrometry, we identified a number of mRNA processing factors that bind to a soluble recombinant Mediator subunit MED23 but not to several other Mediator components. One of these factors, hnRNP L, specifically interacts with MED23 in vitro and in vivo. Consistently, Mediator partially co...

  15. Importin β Negatively Regulates Nuclear Membrane Fusion and Nuclear Pore Complex Assembly

    OpenAIRE

    Harel, Amnon; Chan, Rene C.; Lachish-Zalait, Aurelie; Zimmerman, Ella; Elbaum, Michael; Forbes, Douglass J.

    2003-01-01

    Assembly of a eukaryotic nucleus involves three distinct events: membrane recruitment, fusion to form a double nuclear membrane, and nuclear pore complex (NPC) assembly. We report that importin β negatively regulates two of these events, membrane fusion and NPC assembly. When excess importin β is added to a full Xenopus nuclear reconstitution reaction, vesicles are recruited to chromatin but their fusion is blocked. The importin β down-regulation of membrane fusion is Ran-GTP reversible. Inde...

  16. Role for the actomyosin complex in regulated exocytosis revealed by intravital microscopy

    OpenAIRE

    Masedunskas, Andrius; Sramkova, Monika; Parente, Laura; Sales, Katiuchia Uzzun; Amornphimoltham, Panomwat; Thomas H Bugge; Weigert, Roberto

    2011-01-01

    The regulation and the dynamics of membrane trafficking events have been studied primarily in in vitro models that often do not fully reflect the functional complexity found in a living multicellular organism. Here we used intravital microscopy in the salivary glands of live rodents to investigate regulated exocytosis, a fundamental process in all of the secretory organs. We found that β-adrenergic stimulation elicits exocytosis of large secretory granules, which gradually collapse with the a...

  17. Interplay of Prior Knowledge, Self-Regulation and Motivation in Complex Multimedia Learning Environments

    Science.gov (United States)

    Song, H. S.; Kalet, A. L.; Plass, J. L.

    2016-01-01

    This study examined the direct and indirect effects of medical clerkship students' prior knowledge, self-regulation and motivation on learning performance in complex multimedia learning environments. The data from 386 medical clerkship students from six medical schools were analysed using structural equation modeling. The structural model revealed…

  18. Identification of chromatin-associated regulators of MSL complex targeting in Drosophila dosage compensation.

    Directory of Open Access Journals (Sweden)

    Erica Larschan

    Full Text Available Sex chromosome dosage compensation in Drosophila provides a model for understanding how chromatin organization can modulate coordinate gene regulation. Male Drosophila increase the transcript levels of genes on the single male X approximately two-fold to equal the gene expression in females, which have two X-chromosomes. Dosage compensation is mediated by the Male-Specific Lethal (MSL histone acetyltransferase complex. Five core components of the MSL complex were identified by genetic screens for genes that are specifically required for male viability and are dispensable for females. However, because dosage compensation must interface with the general transcriptional machinery, it is likely that identifying additional regulators that are not strictly male-specific will be key to understanding the process at a mechanistic level. Such regulators would not have been recovered from previous male-specific lethal screening strategies. Therefore, we have performed a cell culture-based, genome-wide RNAi screen to search for factors required for MSL targeting or function. Here we focus on the discovery of proteins that function to promote MSL complex recruitment to "chromatin entry sites," which are proposed to be the initial sites of MSL targeting. We find that components of the NSL (Non-specific lethal complex, and a previously unstudied zinc-finger protein, facilitate MSL targeting and display a striking enrichment at MSL entry sites. Identification of these factors provides new insight into how MSL complex establishes the specialized hyperactive chromatin required for dosage compensation in Drosophila.

  19. The Secret Life of Tethers: The Role of Tethering Factors in SNARE Complex Regulation.

    Science.gov (United States)

    Dubuke, Michelle L; Munson, Mary

    2016-01-01

    Trafficking in eukaryotic cells is a tightly regulated process to ensure correct cargo delivery to the proper destination organelle or plasma membrane. In this review, we focus on how the vesicle fusion machinery, the SNARE complex, is regulated by the interplay of the multisubunit tethering complexes (MTC) with the SNAREs and Sec1/Munc18 (SM) proteins. Although these factors are used in different stages of membrane trafficking, e.g., Golgi to plasma membrane transport vs. vacuolar fusion, and in a variety of diverse eukaryotic cell types, many commonalities between their functions are being revealed. We explore the various protein-protein interactions and findings from functional reconstitution studies in order to highlight both their common features and the differences in their modes of regulation. These studies serve as a starting point for mechanistic explorations in other systems. PMID:27243006

  20. Economic valuation of gas regulation as a Service by rice-duck-fish complex ecosystem

    Institute of Scientific and Technical Information of China (English)

    Yuan Weiling; Cao Cougui; Wang Jinping

    2008-01-01

    Valuating the function of ecosystem services is crucial for accounting green GDP, making a conserva-tion policy of ecological environment and the decision of regional development as well as sustainable development strategy. Rice-duck-fish symbiosis has been promoted in several developing countries as a way of&creasing incomes for rice farmers, but investigations of its value have mainly focused on direct economic benefits, such as food and raw material production. Few studies have been conducted on the estimation of indirect services provided by rice-duck-fish complex ecosystem. The gas regulation service and its economic values provided by rice-duck-fish complex ecosystem were studied in Wuhan, China. The major components of gas regulation are O2 emission and greenhouse, gases (GHGs, CO2) regulation. The results show that O2 emission from different treatments (including rice-duck (RD) rice-fish (RF), rice-duck-fish (RDF) and rice (CK)) ranged from 26,370 kg/ha to 33,910 kg/ha per year, with an eco- nomic value of 10,050-12,920 yuan/ha per year (Chinese currency: I euro=10.2475 yuan, August 28, 2007). The net GHGs exchange varied from 1,200 to 3,320 kg/ha per year, and its economic value ranged.from 1,040 yuan/ha to 2, 900 yuan/ha per year Consequently, the total economic value of gas regulation provided by symbiosis complex ecosystems ranged from 11,090 yuan/ha to 15,820 yuan/ha per year, and the maximum overall economic value of gas regulation was provided by RDF complex ecosystem. The work will be useful for further understanding of the func tions of rice-duek-fish complex ecosystem services and supplying the theoretical references to agricultural policy.

  1. Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate

    International Nuclear Information System (INIS)

    Oriented cell division is a key regulator of tissue architecture and crucial for morphogenesis and homeostasis. Balanced regulation of proliferation and differentiation is an essential property of tissues not only to drive morphogenesis but also to maintain and restore homeostasis. In many tissues orientation of cell division is coupled to the regulation of differentiation producing daughters with similar (symmetric cell division, SCD) or differential fate (asymmetric cell division, ACD). This allows the organism to generate cell lineage diversity from a small pool of stem and progenitor cells. Division orientation and/or the ratio of ACD/SCD need to be tightly controlled. Loss of orientation or an altered ratio can promote overgrowth, alter tissue architecture and induce aberrant differentiation, and have been linked to morphogenetic diseases, cancer and aging. A key requirement for oriented division is the presence of a polarity axis, which can be established through cell intrinsic and/or extrinsic signals. Polarity proteins translate such internal and external cues to drive polarization. In this review we will focus on the role of the polarity complex aPKC/Par3/Par6 in the regulation of division orientation and cell fate in different mammalian epithelia. We will compare the conserved function of this complex in mitotic spindle orientation and distribution of cell fate determinants and highlight common and differential mechanisms in which this complex is used by tissues to adapt division orientation and cell fate to the specific properties of the epithelium

  2. Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate

    Energy Technology Data Exchange (ETDEWEB)

    Vorhagen, Susanne; Niessen, Carien M., E-mail: carien.niessen@uni-koeln.de

    2014-11-01

    Oriented cell division is a key regulator of tissue architecture and crucial for morphogenesis and homeostasis. Balanced regulation of proliferation and differentiation is an essential property of tissues not only to drive morphogenesis but also to maintain and restore homeostasis. In many tissues orientation of cell division is coupled to the regulation of differentiation producing daughters with similar (symmetric cell division, SCD) or differential fate (asymmetric cell division, ACD). This allows the organism to generate cell lineage diversity from a small pool of stem and progenitor cells. Division orientation and/or the ratio of ACD/SCD need to be tightly controlled. Loss of orientation or an altered ratio can promote overgrowth, alter tissue architecture and induce aberrant differentiation, and have been linked to morphogenetic diseases, cancer and aging. A key requirement for oriented division is the presence of a polarity axis, which can be established through cell intrinsic and/or extrinsic signals. Polarity proteins translate such internal and external cues to drive polarization. In this review we will focus on the role of the polarity complex aPKC/Par3/Par6 in the regulation of division orientation and cell fate in different mammalian epithelia. We will compare the conserved function of this complex in mitotic spindle orientation and distribution of cell fate determinants and highlight common and differential mechanisms in which this complex is used by tissues to adapt division orientation and cell fate to the specific properties of the epithelium.

  3. Biological and nonbiological complex drugs for multiple sclerosis in Latin America: regulations and risk management.

    Science.gov (United States)

    Carrá, Adriana; Macías Islas, Miguel Angel; Tarulla, Adriana; Bichuetti, Denis Bernardi; Finkelsztejn, Alessandro; Fragoso, Yara Dadalti; Árcega-Revilla, Raul; Cárcamo Rodríguez, Claudia; Durán, Juan Carlos; Bonitto, Juan García; León, Rosalba; Oehninger Gatti, Carlos; Orozco, Geraldine; Vizcarra Escobar, Darwin

    2015-06-01

    Biological drugs and nonbiological complex drugs with expired patents are followed by biosimilars and follow-on drugs that are supposedly similar and comparable with the reference product in terms of quality, safety and efficacy. Unlike simple molecules that can be copied and reproduced, biosimilars and follow-on complex drugs are heterogeneous and need specific regulations from health and pharmacovigilance agencies. A panel of 14 Latin American experts on multiple sclerosis from nine different countries met to discuss the recommendations regarding biosimilars and follow-on complex drugs for treating multiple sclerosis. Specific measures relating to manufacturing, therapeutic equivalence assessment and pharmacovigilance reports need to be implemented before commercialization. Physical, chemical, biological and immunogenic characterizations of the new product need to be available before clinical trials start. The new product must maintain the same immunogenicity as the original. Automatic substitution of biological and complex drugs poses unacceptable risks to the patient. PMID:25924772

  4. Ambition, Regulation and Reality. Complex use of land and water resources in Luwu, South Sulawesi, Indonesia

    OpenAIRE

    Roth, D.

    2003-01-01

    In this book I present three case studies of the complex regulation of use of land and water resources in Luwu. Attention to the role of legalcomplexity -the existence of different sources and definitions of normative-legal regulation in the same socio-political space - is an important conceptual point of departure of this study. Each of the three case study sections contains specific conclusions pertaining to the issues involved. The last chapter of the book (chapter 11) is primarily a refle...

  5. The Hsp90 Chaperone Complex Regulates GDI-dependent Rab Recycling

    OpenAIRE

    Chen, Christine Y.; Balch, William E.

    2006-01-01

    Rab GTPase regulated hubs provide a framework for an integrated coding system, the membrome network, that controls the dynamics of the specialized exocytic and endocytic membrane architectures found in eukaryotic cells. Herein, we report that Rab recycling in the early exocytic pathways involves the heat-shock protein (Hsp)90 chaperone system. We find that Hsp90 forms a complex with guanine nucleotide dissociation inhibitor (GDI) to direct recycling of the client substrate Rab1 required for e...

  6. Evidence for a cysteine-mediated mechanism of excitation energy regulation in a photosynthetic antenna complex.

    Science.gov (United States)

    Orf, Gregory S; Saer, Rafael G; Niedzwiedzki, Dariusz M; Zhang, Hao; McIntosh, Chelsea L; Schultz, Jason W; Mirica, Liviu M; Blankenship, Robert E

    2016-08-01

    Light-harvesting antenna complexes not only aid in the capture of solar energy for photosynthesis, but regulate the quantity of transferred energy as well. Light-harvesting regulation is important for protecting reaction center complexes from overexcitation, generation of reactive oxygen species, and metabolic overload. Usually, this regulation is controlled by the association of light-harvesting antennas with accessory quenchers such as carotenoids. One antenna complex, the Fenna-Matthews-Olson (FMO) antenna protein from green sulfur bacteria, completely lacks carotenoids and other known accessory quenchers. Nonetheless, the FMO protein is able to quench energy transfer in aerobic conditions effectively, indicating a previously unidentified type of regulatory mechanism. Through de novo sequencing MS, chemical modification, and mutagenesis, we have pinpointed the source of the quenching action to cysteine residues (Cys49 and Cys353) situated near two low-energy bacteriochlorophylls in the FMO protein from Chlorobaculum tepidum Removal of these cysteines (particularly removal of the completely conserved Cys353) through N-ethylmaleimide modification or mutagenesis to alanine abolishes the aerobic quenching effect. Electrochemical analysis and electron paramagnetic resonance spectra suggest that in aerobic conditions the cysteine thiols are converted to thiyl radicals which then are capable of quenching bacteriochlorophyll excited states through electron transfer photochemistry. This simple mechanism has implications for the design of bio-inspired light-harvesting antennas and the redesign of natural photosynthetic systems. PMID:27335466

  7. Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 "Signalosome"

    DEFF Research Database (Denmark)

    Owczarek, Sylwia; Bang, Marie Louise; Berezin, Vladimir

    2015-01-01

    -attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of the NX1 and NX3 genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1β can regulate the expression of DISC1 and induce signaling...... downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better...

  8. The Slx5-Slx8 complex affects sumoylation of DNA repair proteins and negatively regulates recombination

    DEFF Research Database (Denmark)

    Burgess, Rebecca C; Rahman, Sadia; Lisby, Michael;

    2007-01-01

    Recombination is important for repairing DNA lesions, yet it can also lead to genomic rearrangements. This process must be regulated, and recently, sumoylation-mediated mechanisms were found to inhibit Rad51-dependent recombination. Here, we report that the absence of the Slx5-Slx8 complex, a newly...... propose that, during replication, the Slx5-Slx8 complex helps prevent DNA lesions that are acted upon by recombination. In addition, the complex inhibits Rad51-independent recombination via modulating the sumoylation of DNA repair proteins....... identified player in the SUMO (small ubiquitin-like modifier) pathway, led to increased Rad51-dependent and Rad51-independent recombination. The increases were most striking during S phase, suggesting an accumulation of DNA lesions during replication. Consistent with this view, Slx8 protein localized to...

  9. Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development.

    Science.gov (United States)

    Nguyen, Huong; Sokpor, Godwin; Pham, Linh; Rosenbusch, Joachim; Stoykova, Anastassia; Staiger, Jochen F; Tuoc, Tran

    2016-05-18

    The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development. PMID:26986003

  10. Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis.

    Directory of Open Access Journals (Sweden)

    Orion D Weiner

    2006-02-01

    Full Text Available Migrating cells need to make different actin assemblies at the cell's leading and trailing edges and to maintain physical separation of signals for these assemblies. This asymmetric control of activities represents one important form of cell polarity. There are significant gaps in our understanding of the components involved in generating and maintaining polarity during chemotaxis. Here we characterize a family of complexes (which we term leading edge complexes, scaffolded by hematopoietic protein 1 (Hem-1, that organize the neutrophil's leading edge. The Wiskott-Aldrich syndrome protein family Verprolin-homologous protein (WAVE2 complex, which mediates activation of actin polymerization by Rac, is only one member of this family. A subset of these leading edge complexes are biochemically separable from the WAVE2 complex and contain a diverse set of potential polarity-regulating proteins. RNA interference-mediated knockdown of Hem-1-containing complexes in neutrophil-like cells: (a dramatically impairs attractant-induced actin polymerization, polarity, and chemotaxis; (b substantially weakens Rac activation and phosphatidylinositol-(3,4,5-tris-phosphate production, disrupting the (phosphatidylinositol-(3,4,5-tris-phosphate/Rac/F-actin-mediated feedback circuit that organizes the leading edge; and (c prevents exclusion of activated myosin from the leading edge, perhaps by misregulating leading edge complexes that contain inhibitors of the Rho-actomyosin pathway. Taken together, these observations show that versatile Hem-1-containing complexes coordinate diverse regulatory signals at the leading edge of polarized neutrophils, including but not confined to those involving WAVE2-dependent actin polymerization.

  11. Role of Histone-Modifying Enzymes and Their Complexes in Regulation of Chromatin Biology.

    Science.gov (United States)

    DesJarlais, Renee; Tummino, Peter J

    2016-03-22

    In 1964, Alfrey and colleagues proposed that acetylation and methylation of histones may regulate RNA synthesis and described "the possibility that relatively minor modifications of histone structure, taking place on the intact protein molecule, offer a means of switching-on or off RNA synthesis at different loci along the chromosome" [Allfrey, V., Faulkner, R., and Mirsky, A. (1964) Proc. Natl. Acad. Sci. U.S.A. 51, 786]. Fifty years later, this prescient description provides a simple but conceptually accurate model for the biological role of histone post-translational modifications (PTMs). The basic unit of chromosomes is the nucleosome, with double-stranded DNA wrapped around a histone protein oligomer. The "tails" of histone proteins are post-translationally modified, which alters the physical properties of nucleosomes in a manner that impacts gene accessibility for transcription and replication. Enzymes that catalyze the addition and removal of histone PTMs, histone-modifying enzymes (HMEs), are present in large protein complexes, with DNA-binding proteins, ATP-dependent chromatin remodeling enzymes, and epigenetic reader proteins that bind to post-translationally modified histone residues [Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., and Schapira, M. (2012) Nat. Rev. Drug Discovery 11, 384-400]. The activity of HME complexes is coordinated with that of other chromatin-associated complexes that, together, regulate gene transcription, DNA repair, and DNA replication. In this context, the enzymes that catalyze addition and removal of histone PTMs are an essential component of the highly regulated mechanism for accessing compacted DNA. To fully understand the function of HMEs, the structure of nucleosomes, their natural substrate, will be described. Each major class of HMEs subsequently will be discussed with regard to its biochemistry, enzymatic mechanism, and biological function in the context of a prototypical HME complex. PMID:26745824

  12. RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma.

    Science.gov (United States)

    Das, Arabinda; McDonald, Daniel G; Dixon-Mah, Yaenette N; Jacqmin, Dustin J; Samant, Vikram N; Vandergrift, William A; Lindhorst, Scott M; Cachia, David; Varma, Abhay K; Vanek, Kenneth N; Banik, Naren L; Jenrette, Joseph M; Raizer, Jeffery J; Giglio, Pierre; Patel, Sunil J

    2016-06-01

    Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma. PMID:26684801

  13. Structural analysis of DNA–protein complexes regulating the restriction–modification system Esp1396I

    International Nuclear Information System (INIS)

    Comparison of bound and unbound DNA in protein–DNA co-crystal complexes reveals insights into controller-protein binding and DNA distortion in transcriptional regulation. The controller protein of the type II restriction–modification (RM) system Esp1396I binds to three distinct DNA operator sequences upstream of the methyltransferase and endonuclease genes in order to regulate their expression. Previous biophysical and crystallographic studies have shown molecular details of how the controller protein binds to the operator sites with very different affinities. Here, two protein–DNA co-crystal structures containing portions of unbound DNA from native operator sites are reported. The DNA in both complexes shows significant distortion in the region between the conserved symmetric sequences, similar to that of a DNA duplex when bound by the controller protein (C-protein), indicating that the naked DNA has an intrinsic tendency to bend when not bound to the C-protein. Moreover, the width of the major groove of the DNA adjacent to a bound C-protein dimer is observed to be significantly increased, supporting the idea that this DNA distortion contributes to the substantial cooperativity found when a second C-protein dimer binds to the operator to form the tetrameric repression complex

  14. A ubiquitin ligase complex regulates caspase activation during sperm differentiation in Drosophila.

    Directory of Open Access Journals (Sweden)

    Eli Arama

    2007-10-01

    Full Text Available In both insects and mammals, spermatids eliminate their bulk cytoplasm as they undergo terminal differentiation. In Drosophila, this process of dramatic cellular remodeling requires apoptotic proteins, including caspases. To gain further insight into the regulation of caspases, we screened a large collection of sterile male flies for mutants that block effector caspase activation at the onset of spermatid individualization. Here, we describe the identification and characterization of a testis-specific, Cullin-3-dependent ubiquitin ligase complex that is required for caspase activation in spermatids. Mutations in either a testis-specific isoform of Cullin-3 (Cul3(Testis, the small RING protein Roc1b, or a Drosophila orthologue of the mammalian BTB-Kelch protein Klhl10 all reduce or eliminate effector caspase activation in spermatids. Importantly, all three genes encode proteins that can physically interact to form a ubiquitin ligase complex. Roc1b binds to the catalytic core of Cullin-3, and Klhl10 binds specifically to a unique testis-specific N-terminal Cullin-3 (TeNC domain of Cul3(Testis that is required for activation of effector caspase in spermatids. Finally, the BIR domain region of the giant inhibitor of apoptosis-like protein dBruce is sufficient to bind to Klhl10, which is consistent with the idea that dBruce is a substrate for the Cullin-3-based E3-ligase complex. These findings reveal a novel role of Cullin-based ubiquitin ligases in caspase regulation.

  15. Membrane anchoring subunits specify selective regulation of RGS9·Gβ5 GAP complex in photoreceptor neurons

    OpenAIRE

    Cao, Yan; Kolesnikov, Alexander V.; Masuho, Ikuo; Kefalov, Vladimir J.; Martemyanov, Kirill A.

    2010-01-01

    The RGS9·Gβ5 complex is the key regulator of neuronal G protein signaling that shows remarkable selectivity of subunit composition. In retinal photoreceptors, RGS9·Gβ5 is bound to the membrane anchor R9AP and the complex regulates visual signaling. In the basal ganglia neurons, RGS9·Gβ5 is instead associated with a homologous protein, R7BP, and regulates reward circuit. Switching this selective subunit composition of the complex in rod photoreceptors allowed us to study the molecular underpin...

  16. Golgi-localized STELLO proteins regulate the assembly and trafficking of cellulose synthase complexes in Arabidopsis.

    Science.gov (United States)

    Zhang, Yi; Nikolovski, Nino; Sorieul, Mathias; Vellosillo, Tamara; McFarlane, Heather E; Dupree, Ray; Kesten, Christopher; Schneider, René; Driemeier, Carlos; Lathe, Rahul; Lampugnani, Edwin; Yu, Xiaolan; Ivakov, Alexander; Doblin, Monika S; Mortimer, Jenny C; Brown, Steven P; Persson, Staffan; Dupree, Paul

    2016-01-01

    As the most abundant biopolymer on Earth, cellulose is a key structural component of the plant cell wall. Cellulose is produced at the plasma membrane by cellulose synthase (CesA) complexes (CSCs), which are assembled in the endomembrane system and trafficked to the plasma membrane. While several proteins that affect CesA activity have been identified, components that regulate CSC assembly and trafficking remain unknown. Here we show that STELLO1 and 2 are Golgi-localized proteins that can interact with CesAs and control cellulose quantity. In the absence of STELLO function, the spatial distribution within the Golgi, secretion and activity of the CSCs are impaired indicating a central role of the STELLO proteins in CSC assembly. Point mutations in the predicted catalytic domains of the STELLO proteins indicate that they are glycosyltransferases facing the Golgi lumen. Hence, we have uncovered proteins that regulate CSC assembly in the plant Golgi apparatus. PMID:27277162

  17. Golgi-localized STELLO proteins regulate the assembly and trafficking of cellulose synthase complexes in Arabidopsis

    Science.gov (United States)

    Zhang, Yi; Nikolovski, Nino; Sorieul, Mathias; Vellosillo, Tamara; McFarlane, Heather E.; Dupree, Ray; Kesten, Christopher; Schneider, René; Driemeier, Carlos; Lathe, Rahul; Lampugnani, Edwin; Yu, Xiaolan; Ivakov, Alexander; Doblin, Monika S.; Mortimer, Jenny C.; Brown, Steven P.; Persson, Staffan; Dupree, Paul

    2016-01-01

    As the most abundant biopolymer on Earth, cellulose is a key structural component of the plant cell wall. Cellulose is produced at the plasma membrane by cellulose synthase (CesA) complexes (CSCs), which are assembled in the endomembrane system and trafficked to the plasma membrane. While several proteins that affect CesA activity have been identified, components that regulate CSC assembly and trafficking remain unknown. Here we show that STELLO1 and 2 are Golgi-localized proteins that can interact with CesAs and control cellulose quantity. In the absence of STELLO function, the spatial distribution within the Golgi, secretion and activity of the CSCs are impaired indicating a central role of the STELLO proteins in CSC assembly. Point mutations in the predicted catalytic domains of the STELLO proteins indicate that they are glycosyltransferases facing the Golgi lumen. Hence, we have uncovered proteins that regulate CSC assembly in the plant Golgi apparatus. PMID:27277162

  18. The SOCS2 Ubiquitin Ligase Complex Regulates Growth Hormone Receptor Levels

    DEFF Research Database (Denmark)

    Vesterlund, Mattias; Zadjali, Fahad; Persson, Torbjörn;

    2011-01-01

    to GH is under regulatory control to avoid excessive and off-target effects upon GHR activation. The suppressor of cytokine signalling 2 (SOCS) is a key regulator of GHR sensitivity. This is clearly shown in mice where the SOCS2 gene has been inactivated, which show 30-40% increase in body length, a...... phenotype that is dependent on endogenous GH secretion. SOCS2 is a GH-stimulated, STAT5b-regulated gene that acts in a negative feedback loop to downregulate GHR signalling. Since the biochemical basis for these actions is poorly understood, we studied the molecular function of SOCS2. We demonstrated that...... SOCS2 is part of a multimeric complex with intrinsic ubiquitin ligase activity. Mutational analysis shows that the interaction with Elongin B/C controls SOCS2 protein turnover and affects its molecular activity. Increased GHR levels were observed in livers from SOCS2(-/-) mice and in the absence of...

  19. Lysine acetylation targets protein complexes and co-regulates major cellular functions

    DEFF Research Database (Denmark)

    Choudhary, Chuna Ram; Kumar, Chanchal; Gnad, Florian; Nielsen, Michael L; Rehman, Michael; Walther, Tobias C; Olsen, Jesper V; Mann, Matthias

    2009-01-01

    Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600...... lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling......, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other...

  20. The E2F-DP1 Transcription Factor Complex Regulates Centriole Duplication in Caenorhabditis elegans.

    Science.gov (United States)

    Miller, Jacqueline G; Liu, Yan; Williams, Christopher W; Smith, Harold E; O'Connell, Kevin F

    2016-01-01

    Centrioles play critical roles in the organization of microtubule-based structures, from the mitotic spindle to cilia and flagella. In order to properly execute their various functions, centrioles are subjected to stringent copy number control. Central to this control mechanism is a precise duplication event that takes place during S phase of the cell cycle and involves the assembly of a single daughter centriole in association with each mother centriole . Recent studies have revealed that posttranslational control of the master regulator Plk4/ZYG-1 kinase and its downstream effector SAS-6 is key to ensuring production of a single daughter centriole. In contrast, relatively little is known about how centriole duplication is regulated at a transcriptional level. Here we show that the transcription factor complex EFL-1-DPL-1 both positively and negatively controls centriole duplication in the Caenorhabditis elegans embryo. Specifically, we find that down regulation of EFL-1-DPL-1 can restore centriole duplication in a zyg-1 hypomorphic mutant and that suppression of the zyg-1 mutant phenotype is accompanied by an increase in SAS-6 protein levels. Further, we find evidence that EFL-1-DPL-1 promotes the transcription of zyg-1 and other centriole duplication genes. Our results provide evidence that in a single tissue type, EFL-1-DPL-1 sets the balance between positive and negative regulators of centriole assembly and thus may be part of a homeostatic mechanism that governs centriole assembly. PMID:26772748

  1. The E2F-DP1 Transcription Factor Complex Regulates Centriole Duplication in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Jacqueline G. Miller

    2016-03-01

    Full Text Available Centrioles play critical roles in the organization of microtubule-based structures, from the mitotic spindle to cilia and flagella. In order to properly execute their various functions, centrioles are subjected to stringent copy number control. Central to this control mechanism is a precise duplication event that takes place during S phase of the cell cycle and involves the assembly of a single daughter centriole in association with each mother centriole . Recent studies have revealed that posttranslational control of the master regulator Plk4/ZYG-1 kinase and its downstream effector SAS-6 is key to ensuring production of a single daughter centriole. In contrast, relatively little is known about how centriole duplication is regulated at a transcriptional level. Here we show that the transcription factor complex EFL-1-DPL-1 both positively and negatively controls centriole duplication in the Caenorhabditis elegans embryo. Specifically, we find that down regulation of EFL-1-DPL-1 can restore centriole duplication in a zyg-1 hypomorphic mutant and that suppression of the zyg-1 mutant phenotype is accompanied by an increase in SAS-6 protein levels. Further, we find evidence that EFL-1-DPL-1 promotes the transcription of zyg-1 and other centriole duplication genes. Our results provide evidence that in a single tissue type, EFL-1-DPL-1 sets the balance between positive and negative regulators of centriole assembly and thus may be part of a homeostatic mechanism that governs centriole assembly.

  2. A FAM21-Containing WASH Complex Regulates Retromer-Dependent Sorting

    OpenAIRE

    Gomez, Timothy S.; BILLADEAU, DANIEL D.

    2009-01-01

    The Arp2/3 complex regulates endocytosis, sorting and trafficking, yet the Arp2/3-stimulating factors orchestrating these distinct events remain ill-defined. WASH (Wiskott-Aldrich Syndrome Protein and SCAR Homolog) is an Arp2/3 activator with unknown function that was duplicated during primate evolution. We demonstrate that WASH associates with tubulin and localizes to early endosomal subdomains, which are enriched in Arp2/3, F-actin, and retromer components. While WASH localized with activat...

  3. A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses

    Directory of Open Access Journals (Sweden)

    Hui Zheng

    2013-10-01

    Full Text Available Lysine63-linked ubiquitin (K63-Ub chains represent a particular ubiquitin topology that mediates proteasome-independent signaling events. The deubiquitinating enzyme (DUB BRCC36 segregates into distinct nuclear and cytoplasmic complexes that are specific for K63-Ub hydrolysis. RAP80 targets the five-member nuclear BRCC36 complex to K63-Ub chains at DNA double-strand breaks. The alternative four-member BRCC36 containing complex (BRISC lacks a known targeting moiety. Here, we identify serine hydroxymethyltransferase (SHMT as a previously unappreciated component that fulfills this function. SHMT directs BRISC activity at K63-Ub chains conjugated to the type 1 interferon (IFN receptor chain 1 (IFNAR1. BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, thus limiting its K63-Ub-mediated internalization and lysosomal degradation. BRISC-deficient cells and mice exhibit attenuated responses to IFN and are protected from IFN-associated immunopathology. These studies reveal a mechanism of DUB regulation and suggest a therapeutic use of BRISC inhibitors for treating pathophysiological processes driven by elevated IFN responses.

  4. Structural Basis for Conserved Regulation and Adaptation of the Signal Recognition Particle Targeting Complex.

    Science.gov (United States)

    Wild, Klemens; Bange, Gert; Motiejunas, Domantas; Kribelbauer, Judith; Hendricks, Astrid; Segnitz, Bernd; Wade, Rebecca C; Sinning, Irmgard

    2016-07-17

    The signal recognition particle (SRP) is a ribonucleoprotein complex with a key role in targeting and insertion of membrane proteins. The two SRP GTPases, SRP54 (Ffh in bacteria) and FtsY (SRα in eukaryotes), form the core of the targeting complex (TC) regulating the SRP cycle. The architecture of the TC and its stimulation by RNA has been described for the bacterial SRP system while this information is lacking for other domains of life. Here, we present the crystal structures of the GTPase heterodimers of archaeal (Sulfolobus solfataricus), eukaryotic (Homo sapiens), and chloroplast (Arabidopsis thaliana) SRP systems. The comprehensive structural comparison combined with Brownian dynamics simulations of TC formation allows for the description of the general blueprint and of specific adaptations of the quasi-symmetric heterodimer. Our work defines conserved external nucleotide-binding sites for SRP GTPase activation by RNA. Structural analyses of the GDP-bound, post-hydrolysis states reveal a conserved, magnesium-sensitive switch within the I-box. Overall, we provide a general model for SRP cycle regulation by RNA. PMID:27241309

  5. Regulation of Fatty Acid Oxidation in Mouse Cumulus-Oocyte Complexes during Maturation and Modulation by PPAR Agonists

    OpenAIRE

    Dunning, Kylie R.; Anastasi, Marie R.; Zhang, Voueleng J.; Russell, Darryl L.; Robker, Rebecca L.

    2014-01-01

    Fatty acid oxidation is an important energy source for the oocyte; however, little is known about how this metabolic pathway is regulated in cumulus-oocyte complexes. Analysis of genes involved in fatty acid oxidation showed that many are regulated by the luteinizing hormone surge during in vivo maturation, including acyl-CoA synthetases, carnitine transporters, acyl-CoA dehydrogenases and acetyl-CoA transferase, but that many are dysregulated when cumulus-oocyte complexes are matured under i...

  6. Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi

    Science.gov (United States)

    Bromley, Mike; Johns, Anna; Davies, Emma; Fraczek, Marcin; Mabey Gilsenan, Jane; Kurbatova, Natalya; Keays, Maria; Kapushesky, Misha; Gut, Marta; Gut, Ivo; Denning, David W.; Bowyer, Paul

    2016-01-01

    Recent estimates of the global burden of fungal disease suggest that that their incidence has been drastically underestimated and that mortality may rival that of malaria or tuberculosis. Azoles are the principal class of antifungal drug and the only available oral treatment for fungal disease. Recent occurrence and increase in azole resistance is a major concern worldwide. Known azole resistance mechanisms include over—expression of efflux pumps and mutation of the gene encoding the target protein cyp51a, however, for one of the most important fungal pathogens of humans, Aspergillus fumigatus, much of the observed azole resistance does not appear to involve such mechanisms. Here we present evidence that azole resistance in A. fumigatus can arise through mutation of components of mitochondrial complex I. Gene deletions of the 29.9KD subunit of this complex are azole resistant, less virulent and exhibit dysregulation of secondary metabolite gene clusters in a manner analogous to deletion mutants of the secondary metabolism regulator, LaeA. Additionally we observe that a mutation leading to an E180D amino acid change in the 29.9 KD subunit is strongly associated with clinical azole resistant A. fumigatus isolates. Evidence presented in this paper suggests that complex I may play a role in the hypoxic response and that one possible mechanism for cell death during azole treatment is a dysfunctional hypoxic response that may be restored by dysregulation of complex I. Both deletion of the 29.9 KD subunit of complex I and azole treatment alone profoundly change expression of gene clusters involved in secondary metabolism and immunotoxin production raising potential concerns about long term azole therapy. PMID:27438017

  7. The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation

    Directory of Open Access Journals (Sweden)

    Sonia eDuchemin

    2012-08-01

    Full Text Available Following the discovery of the vasorelaxant properties of nitric oxide (NO by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow. Anatomically, axons, dendrites or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting cerebral blood flow as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e. neuronal, glial and vascular cells also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.

  8. Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 "Signalosome".

    Science.gov (United States)

    Owczarek, Sylwia; Bang, Marie Louise; Berezin, Vladimir

    2015-01-01

    Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of the NX1 and NX3 genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1β can regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia. PMID:26078884

  9. Magnetically Regulated Star Formation in Three Dimensions: The Case of the Taurus Molecular Cloud Complex

    Science.gov (United States)

    Nakamura, Fumitaka; Li, Zhi-Yun

    2008-11-01

    We carry out three-dimensional MHD simulations of star formation in turbulent, magnetized clouds, including ambipolar diffusion and feedback from protostellar outflows. The calculations focus on relatively diffuse clouds threaded by a strong magnetic field capable of resisting severe tangling by turbulent motions and retarding global gravitational contraction in the cross field direction. They are motivated by observations of the Taurus molecular cloud complex (and, to a lesser extent, Pipe Nebula), which shows an ordered large-scale magnetic field, as well as elongated condensations that are generally perpendicular to the large-scale field. We find that stars form in earnest in such clouds when enough material has settled gravitationally along the field lines that the mass-to-flux ratios of the condensations approach the critical value. Only a small fraction (of order 1% or less) of the nearly magnetically critical, condensed material is turned into stars per local free-fall time, however. The slow star formation takes place in condensations that are moderately supersonic; it is regulated primarily by magnetic fields, rather than turbulence. The quiescent condensations are surrounded by diffuse halos that are much more turbulent, as observed in the Taurus complex. Strong support for magnetic regulation of star formation in this complex comes from the extremely slow conversion of the already condensed, relatively quiescent C18O gas into stars, at a rate 2 orders of magnitude below the maximum, free-fall value. We analyze the properties of dense cores, including their mass spectrum, which resembles the stellar initial mass function.

  10. The Monopolin Complex Crosslinks Kinetochore Components to Regulate Chromosome-Microtubule Attachments

    Energy Technology Data Exchange (ETDEWEB)

    Corbett, Kevin D.; Yip, Calvin K.; Ee, Ly-Sha; Walz, Thomas; Amon, Angelika; Harrison, Stephen C. (Harvard-Med); (MIT)

    2010-09-27

    The monopolin complex regulates different types of kinetochore-microtubule attachments in fungi, ensuring sister chromatid co-orientation in Saccharomyces cerevisiae meiosis I and inhibiting merotelic attachment in Schizosaccharomyces pombe mitosis. In addition, the monopolin complex maintains the integrity and silencing of ribosomal DNA (rDNA) repeats in the nucleolus. We show here that the S. cerevisiae Csm1/Lrs4 monopolin subcomplex has a distinctive V-shaped structure, with two pairs of protein-protein interaction domains positioned {approx}10 nm apart. Csm1 presents a conserved hydrophobic surface patch that binds two kinetochore proteins: Dsn1, a subunit of the outer-kinetochore MIND/Mis12 complex, and Mif2/CENP-C. Csm1 point-mutations that disrupt kinetochore-subunit binding also disrupt sister chromatid co-orientation in S. cerevisiae meiosis I. We further show that the same Csm1 point-mutations affect rDNA silencing, probably by disrupting binding to the rDNA-associated protein Tof2. We propose that Csm1/Lrs4 functions as a molecular clamp, crosslinking kinetochore components to enforce sister chromatid co-orientation in S. cerevisiae meiosis I and to suppress merotelic attachment in S. pombe mitosis, and crosslinking rDNA repeats to aid rDNA silencing.

  11. γ-SNAP stimulates disassembly of endosomal SNARE complexes and regulates endocytic trafficking pathways.

    Science.gov (United States)

    Inoue, Hiroki; Matsuzaki, Yuka; Tanaka, Ayaka; Hosoi, Kaori; Ichimura, Kaoru; Arasaki, Kohei; Wakana, Yuichi; Asano, Kenichi; Tanaka, Masato; Okuzaki, Daisuke; Yamamoto, Akitsugu; Tani, Katsuko; Tagaya, Mitsuo

    2015-08-01

    Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) that reside in the target membranes and transport vesicles assemble into specific SNARE complexes to drive membrane fusion. N-ethylmaleimide-sensitive factor (NSF) and its attachment protein, α-SNAP (encoded by NAPA), catalyze disassembly of the SNARE complexes in the secretory and endocytic pathways to recycle them for the next round of fusion events. γ-SNAP (encoded by NAPG) is a SNAP isoform, but its function in SNARE-mediated membrane trafficking remains unknown. Here, we show that γ-SNAP regulates the endosomal trafficking of epidermal growth factor (EGF) receptor (EGFR) and transferrin. Immunoprecipitation and mass spectrometry analyses revealed that γ-SNAP interacts with a limited range of SNAREs, including endosomal ones. γ-SNAP, as well as α-SNAP, mediated the disassembly of endosomal syntaxin-7-containing SNARE complexes. Overexpression and small interfering (si)RNA-mediated depletion of γ-SNAP changed the morphologies and intracellular distributions of endosomes. Moreover, the depletion partially suppressed the exit of EGFR and transferrin from EEA1-positive early endosomes to delay their degradation and uptake. Taken together, our findings suggest that γ-SNAP is a unique SNAP that functions in a limited range of organelles - including endosomes - and their trafficking pathways. PMID:26101353

  12. Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex.

    Directory of Open Access Journals (Sweden)

    Tomoko M Tabuchi

    2011-05-01

    Full Text Available DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in development and cancer. Here we describe new aspects of DRM binding and function revealed through genome-wide analyses of the Caenorhabditis elegans DRM subunit LIN-54. We show that LIN-54 DNA-binding activity recruits DRM to promoters enriched for adjacent putative E2F/DP and LIN-54 binding sites, suggesting that these two DNA-binding moieties together direct DRM to its target genes. Chromatin immunoprecipitation and gene expression profiling reveals conserved roles for DRM in regulating genes involved in cell division, development, and reproduction. We find that LIN-54 promotes expression of reproduction genes in the germline, but prevents ectopic activation of germline-specific genes in embryonic soma. Strikingly, C. elegans DRM does not act uniformly throughout the genome: the DRM recruitment motif, DRM binding, and DRM-regulated embryonic genes are all under-represented on the X chromosome. However, germline genes down-regulated in lin-54 mutants are over-represented on the X chromosome. We discuss models for how loss of autosome-bound DRM may enhance germline X chromosome silencing. We propose that autosome-enriched binding of DRM arose in C. elegans as a consequence of germline X chromosome silencing and the evolutionary redistribution of germline-expressed and essential target genes to autosomes. Sex chromosome gene regulation may thus have profound evolutionary effects on genome organization and transcriptional regulatory networks.

  13. The afferent signaling complex: Regulation of type I spiral ganglion neuron responses in the auditory periphery.

    Science.gov (United States)

    Reijntjes, Daniël O J; Pyott, Sonja J

    2016-06-01

    The spiral ganglion neurons (SGNs) are the first action potential generating neurons in the auditory pathway. The type I SGNs contact the sensory inner hair cells via their peripheral dendrites and relay auditory information to the brainstem via their central axon fibers. Individual afferent fibers show differences in response properties that are essential for normal hearing. The mechanisms that give rise to the heterogeneity of afferent responses are very poorly understood but are likely already in place at the peripheral dendrites where synapses are formed and action potentials are generated. To identify these molecular mechanisms, this review synthesizes a variety of literature and comprehensively outlines the cellular and molecular components positioned to regulate SGN afferent dendrite excitability, especially following glutamate release. These components include 1) proteins of the SGN postsynapses and neighboring supporting cells that together shape glutamatergic signaling, 2) the ion channels and transporters that determine the intrinsic excitability of the SGN afferent dendrites, and 3) the neurotransmitter receptors that extrinsically modify this excitability via synaptic input from the lateral olivocochlear efferents. This cellular and molecular machinery, together with presynaptic specializations of the inner hair cells, can be collectively referred to as the type I afferent signaling complex. As this review underscores, interactions of this signaling complex determine excitability of the SGN afferent dendrites and the afferent fiber responses. Moreover, this complex establishes the environmental milieu critical for the development and maintenance of the SGN afferent dendrites and synapses. Motivated by these important functions, this review also indicates areas of future research to elucidate the contributions of the afferent signaling complex to both normal hearing and also hearing loss. PMID:27018296

  14. The Atg17-Atg31-Atg29 complex and Atg11 regulate autophagosome-vacuole fusion.

    Science.gov (United States)

    Liu, Xu; Klionsky, Daniel J

    2016-05-01

    The macroautophagy (hereafter autophagy) process involves de novo formation of double-membrane autophagosomes; after sequestering cytoplasm these transient organelles fuse with the vacuole/lysosome. Genetic studies in yeasts have characterized more than 40 autophagy-related (Atg) proteins required for autophagy, and the majority of these proteins play roles in autophagosome formation. The fusion of autophagosomes with the vacuole is mediated by the Rab GTPase Ypt7, its guanine nucleotide exchange factor Mon1-Ccz1, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. However, these factors are not autophagosome-vacuole fusion specific. We recently showed that 2 autophagy scaffold proteins, the Atg17-Atg31-Atg29 complex and Atg11, regulate autophagosome-vacuole fusion by recruiting the vacuolar SNARE Vam7 to the phagophore assembly site (PAS), where an autophagosome forms in yeast. PMID:26986547

  15. The Ccr4-Not complex is a key regulator of eukaryotic gene expression.

    Science.gov (United States)

    Collart, Martine A

    2016-07-01

    The Ccr4-Not complex is a multisubunit complex present in all eukaryotes that contributes to regulate gene expression at all steps, from production of messenger RNAs (mRNAs) in the nucleus to their degradation in the cytoplasm. In the nucleus it influences the post-translational modifications of the chromatin template that has to be remodeled for transcription, it is present at sites of transcription and associates with transcription factors as well as with the elongating polymerase, it interacts with the factors that prepare the new transcript for export to the cytoplasm and finally is important for nuclear quality control and influences mRNA export. In the cytoplasm it is present in polysomes where mRNAs are translated and in RNA granules where mRNAs will be redirected upon inhibition of translation. It influences mRNA translatability, and is needed during translation, on one hand for co-translational protein interactions and on the other hand to preserve translation that stalls. It is one of the relevant players during co-translational quality control. It also interacts with factors that will repress translation or induce mRNA decapping when recruited to the translating template. Finally, Ccr4-Not carries deadenylating enzymes and is a key player in mRNA decay, generic mRNA decay that follows normal translation termination, co-translational mRNA decay of transcripts on which the ribosomes stall durably or which carry a non-sense mutation and finally mRNA decay that is induced by external signaling for a change in genetic programming. Ccr4-Not is a master regulator of eukaryotic gene expression. WIREs RNA 2016, 7:438-454. doi: 10.1002/wrna.1332 For further resources related to this article, please visit the WIREs website. PMID:26821858

  16. DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites.

    Science.gov (United States)

    Norkett, Rosalind; Modi, Souvik; Birsa, Nicol; Atkin, Talia A; Ivankovic, Davor; Pathania, Manav; Trossbach, Svenja V; Korth, Carsten; Hirst, Warren D; Kittler, Josef T

    2016-01-01

    The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development. PMID:26553875

  17. DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites*

    Science.gov (United States)

    Norkett, Rosalind; Modi, Souvik; Birsa, Nicol; Atkin, Talia A.; Ivankovic, Davor; Pathania, Manav; Trossbach, Svenja V.; Korth, Carsten; Hirst, Warren D.; Kittler, Josef T.

    2016-01-01

    The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development. PMID:26553875

  18. The evolution and regulation of the mucosal immune complexity in the basal chordate amphioxus.

    Science.gov (United States)

    Huang, Shengfeng; Wang, Xin; Yan, Qingyu; Guo, Lei; Yuan, Shaochun; Huang, Guangrui; Huang, Huiqing; Li, Jun; Dong, Meiling; Chen, Shangwu; Xu, Anlong

    2011-02-15

    Both amphioxus and the sea urchin encode a complex innate immune gene repertoire in their genomes, but the composition and mechanisms of their innate immune systems, as well as the fundamental differences between two systems, remain largely unexplored. In this study, we dissect the mucosal immune complexity of amphioxus into different evolutionary-functional modes and regulatory patterns by integrating information from phylogenetic inferences, genome-wide digital expression profiles, time course expression dynamics, and functional analyses. With these rich data, we reconstruct several major immune subsystems in amphioxus and analyze their regulation during mucosal infection. These include the TNF/IL-1R network, TLR and NLR networks, complement system, apoptosis network, oxidative pathways, and other effector genes (e.g., peptidoglycan recognition proteins, Gram-negative binding proteins, and chitin-binding proteins). We show that beneath the superficial similarity to that of the sea urchin, the amphioxus innate system, despite preserving critical invertebrate components, is more similar to that of the vertebrates in terms of composition, expression regulation, and functional strategies. For example, major effectors in amphioxus gut mucous tissue are the well-developed complement and oxidative-burst systems, and the signaling network in amphioxus seems to emphasize signal transduction/modulation more than initiation. In conclusion, we suggest that the innate immune systems of amphioxus and the sea urchin are strategically different, possibly representing two successful cases among many expanded immune systems that arose at the age of the Cambrian explosion. We further suggest that the vertebrate innate immune system should be derived from one of these expanded systems, most likely from the same one that was shared by amphioxus. PMID:21248255

  19. RBFox2 Binds Nascent RNA to Globally Regulate Polycomb Complex 2 Targeting in Mammalian Genomes.

    Science.gov (United States)

    Wei, Chaoliang; Xiao, Rui; Chen, Liang; Cui, Hanwei; Zhou, Yu; Xue, Yuanchao; Hu, Jing; Zhou, Bing; Tsutsui, Taiki; Qiu, Jinsong; Li, Hairi; Tang, Liling; Fu, Xiang-Dong

    2016-06-16

    Increasing evidence suggests that diverse RNA binding proteins (RBPs) interact with regulatory RNAs to regulate transcription. RBFox2 is a well-characterized pre-mRNA splicing regulator, but we now encounter an unexpected paradigm where depletion of this RBP induces widespread increase in nascent RNA production in diverse cell types. Chromatin immunoprecipitation sequencing (ChIP-seq) reveals extensive interaction of RBFox2 with chromatin in a nascent RNA-dependent manner. Bayesian network analysis connects RBFox2 to Polycomb complex 2 (PRC2) and H3K27me3, and biochemical experiments demonstrate the ability of RBFox2 to directly interact with PRC2. Strikingly, RBFox2 inactivation eradicates PRC2 targeting on the majority of bivalent gene promoters and leads to transcriptional de-repression. Together, these findings uncover a mechanism underlying the enigmatic association of PRC2 with numerous active genes, highlight the importance of gene body sequences to gauge transcriptional output, and suggest nascent RNAs as critical signals for transcriptional feedback control to maintain homeostatic gene expression in mammalian genomes. PMID:27211866

  20. Epidermal Differentiation Complex: A Review on Its Epigenetic Regulation and Potential Drug Targets

    Directory of Open Access Journals (Sweden)

    Sinha Abhishek

    2016-04-01

    Full Text Available The primary feature of the mammalian skin includes the hair follicle, inter-follicular epidermis and the sebaceous glands, all of which form pilo-sebaceous units. The epidermal protective layer undergoes an ordered/programmed process of proliferation and differentiation, ultimately culminating in the formation of a cornified envelope consisting of enucleated corneocytes. These terminally differentiated cells slough off in a cyclic manner and this process is regulated via induction or repression of epidermal differentiation complex (EDC genes. These genes, spanning 2 Mb region of human chromosome 1q21, play a crucial role in epidermal development, through various mechanisms. Each of these mechanisms employs a unique chromatin re-modelling factor or an epigenetic modifier. These factors act to regulate epidermal differentiation singly and/or in combination. Diseases like psoriasis and cancer exhibit aberrations in proliferation and differentiation through, in part, dysregulation in these epigenetic mechanisms. Knowledge of the existing mechanisms in the physiological and the aforesaid pathological contexts may not only facilitate drug development, it also can make refinements to the existing drug delivery systems.

  1. Epidermal Differentiation Complex: A Review on Its Epigenetic Regulation and Potential Drug Targets.

    Science.gov (United States)

    Abhishek, Sinha; Palamadai Krishnan, Suresh

    2016-01-01

    The primary feature of the mammalian skin includes the hair follicle, inter-follicular epidermis and the sebaceous glands, all of which form pilo-sebaceous units. The epidermal protective layer undergoes an ordered/programmed process of proliferation and differentiation, ultimately culminating in the formation of a cornified envelope consisting of enucleated corneocytes. These terminally differentiated cells slough off in a cyclic manner and this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes. These genes, spanning 2 Mb region of human chromosome 1q21, play a crucial role in epidermal development, through various mechanisms. Each of these mechanisms employs a unique chromatin re-modelling factor or an epigenetic modifier. These factors act to regulate epidermal differentiation singly and/or in combination. Diseases like psoriasis and cancer exhibit aberrations in proliferation and differentiation through, in part, dysregulation in these epigenetic mechanisms. Knowledge of the existing mechanisms in the physiological and the aforesaid pathological contexts may not only facilitate drug development, it also can make refinements to the existing drug delivery systems. PMID:27054112

  2. TNL-mediated immunity in Arabidopsis requires complex regulation of the redundant ADR1 gene family.

    Science.gov (United States)

    Dong, Oliver Xiaoou; Tong, Meixuezi; Bonardi, Vera; El Kasmi, Farid; Woloshen, Virginia; Wünsch, Lisa K; Dangl, Jeffery L; Li, Xin

    2016-05-01

    Nucleotide-binding leucine-rich repeat proteins (NLRs) serve as intracellular immune receptors in animals and plants. Sensor NLRs perceive pathogen-derived effector molecules and trigger robust host defense. Recent studies revealed the role of three coiled-coil-type NLRs (CNLs) of the ADR1 family - ADR1, ADR1-L1 and ADR1-L2 - as redundant helper NLRs, whose function is required for defense mediated by multiple sensor NLRs. From a mutant snc1-enhancing (MUSE) forward genetic screen in Arabidopsis targeted to identify negative regulators of snc1 that encodes a TIR-type NLR (TNL), we isolated two alleles of muse15, both carrying mutations in ADR1-L1. Interestingly, loss of ADR1-L1 also enhances immunity-related phenotypes in other autoimmune mutants including cpr1, bal and lsd1. This immunity-enhancing effect is not mediated by increased SNC1 protein stability, nor is it fully dependent on the accumulation of the defense hormone salicylic acid (SA). Transcriptional analysis revealed an upregulation of ADR1 and ADR1-L2 in the adr1-L1 background, which may overcompensate the loss of ADR1-L1, resulting in enhanced immunity. Interestingly, autoimmunity of snc1 and chs2, which encode typical TNLs, is fully suppressed by the adr1 triple mutant, suggesting that the ADRs are required for TNL downstream signaling. This study extends our knowledge on the interplay among ADRs and reveals their complexity in defense regulation. PMID:27074399

  3. A simple strategy guides the complex metabolic regulation in Escherichia coli

    Science.gov (United States)

    Facchetti, Giuseppe

    2016-06-01

    A way to decipher the complexity of the cellular metabolism is to study the effect of different external perturbations. Through an analysis over a sufficiently large set of gene knockouts and growing conditions, one aims to find a unifying principle that governs the metabolic regulation. For instance, it is known that the cessation of the microorganism proliferation after a gene deletion is only transient. However, we do not know the guiding principle that determines the partial or complete recovery of the growth rate, the corresponding redistribution of the metabolic fluxes and the possible different phenotypes. In spite of this large variety in the observed metabolic adjustments, we show that responses of E. coli to several different perturbations can always be derived from a sequence of greedy and myopic resilencings. This simple mechanism provides a detailed explanation for the experimental dynamics both at cellular (proliferation rate) and molecular level (13C-determined fluxes), also in case of appearance of multiple phenotypes. As additional support, we identified an example of a simple network motif that is capable of implementing this myopic greediness in the regulation of the metabolism.

  4. Complex regulation of CREB-binding protein by homeodomain-interacting protein kinase 2

    KAUST Repository

    Kovács, Krisztián A.

    2015-11-01

    CREB-binding protein (CBP) and p300 are transcriptional coactivators involved in numerous biological processes that affect cell growth, transformation, differentiation, and development. In this study, we provide evidence of the involvement of homeodomain-interacting protein kinase 2 (HIPK2) in the regulation of CBP activity. We show that HIPK2 interacts with and phosphorylates several regions of CBP. We demonstrate that serines 2361, 2363, 2371, 2376, and 2381 are responsible for the HIPK2-induced mobility shift of CBP C-terminal activation domain. Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CBP. However, our data suggest that HIPK2 activates CBP mainly by counteracting the repressive action of cell cycle regulatory domain 1 (CRD1), located between amino acids 977 and 1076, independently of CBP phosphorylation. Our findings thus highlight a complex regulation of CBP activity by HIPK2, which might be relevant for the control of specific sets of target genes involved in cellular proliferation, differentiation and apoptosis. © 2015 Elsevier Inc.

  5. Novel Inhibitors Complexed with Glutamate Dehydrogenase: ALLOSTERIC REGULATION BY CONTROL OF PROTEIN DYNAMICS

    Energy Technology Data Exchange (ETDEWEB)

    Li, Ming; Smith, Christopher J.; Walker, Matthew T.; Smith, Thomas J.; (Danforth)

    2009-12-01

    Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of L-glutamate to 2-oxoglutarate using NAD(P){sup +} as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH.

  6. The Caenorhabditis elegans Elongator complex regulates neuronal alpha-tubulin acetylation.

    Directory of Open Access Journals (Sweden)

    Jachen A Solinger

    2010-01-01

    Full Text Available Although acetylated alpha-tubulin is known to be a marker of stable microtubules in neurons, precise factors that regulate alpha-tubulin acetylation are, to date, largely unknown. Therefore, a genetic screen was employed in the nematode Caenorhabditis elegans that identified the Elongator complex as a possible regulator of alpha-tubulin acetylation. Detailed characterization of mutant animals revealed that the acetyltransferase activity of the Elongator is indeed required for correct acetylation of microtubules and for neuronal development. Moreover, the velocity of vesicles on microtubules was affected by mutations in Elongator. Elongator mutants also displayed defects in neurotransmitter levels. Furthermore, acetylation of alpha-tubulin was shown to act as a novel signal for the fine-tuning of microtubules dynamics by modulating alpha-tubulin turnover, which in turn affected neuronal shape. Given that mutations in the acetyltransferase subunit of the Elongator (Elp3 and in a scaffold subunit (Elp1 have previously been linked to human neurodegenerative diseases, namely Amyotrophic Lateral Sclerosis and Familial Dysautonomia respectively highlights the importance of this work and offers new insights to understand their etiology.

  7. JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships.

    Science.gov (United States)

    Zeke, András; Misheva, Mariya; Reményi, Attila; Bogoyevitch, Marie A

    2016-09-01

    The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states. PMID:27466283

  8. β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology

    Institute of Scientific and Technical Information of China (English)

    Xiaosong Liu; Xiaohui Zhao; Xianglu Zeng; Koen Bossers; Dick F Swaab; Jian Zhao; Gang Pei

    2013-01-01

    Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the γ-secretasemediated amyloid-β (Aβ) pathology plays an important role.We found that a multifunctional protein,β-arrestin1,facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature γ-secretase complex through its functional interaction with APH-1.Deficiency of β-arrestin1 or inhibition of binding of β-arrestin1 with APH-1 by small peptides reduced Aβ production without affecting Notch processing.Genetic ablation of β-arrestin1 diminished Aβ pathology and behavioral deficits in transgenic AD mice.Moreover,in brains of sporadic AD patients and transgenic AD mice,the expression of β-arrestin1 was upregulated and correlated well with neuropathological severity and senile Aβ plaques.Thus,our study identifies a regulatory mechanism underlying both γ-secretase assembly and AD pathogenesis,and indicates that specific reduction of Aβ pathology can be achieved by regulation of the γ-secretase assembly.

  9. StuAp is a sequence-specific transcription factor that regulates developmental complexity in Aspergillus nidulans.

    OpenAIRE

    J.R. Dutton; Johns, S.; Miller, B.L.

    1997-01-01

    The Aspergillus nidulans Stunted protein (StuAp) regulates multicellular complexity during asexual reproduction by moderating the core developmental program that directs differentiation of uninucleate, terminally differentiated spores from multinucleate, vegetative hyphae. StuAp is also required for ascosporogenesis and multicellular development during sexual reproduction. StuAp is a member of a family of fungal transcription factors that regulate development or cell cycle progression. Furthe...

  10. Identification of a BET family Bromodomain / Casein Kinase II / TAF-containing complex as a regulator of mitotic condensin function

    OpenAIRE

    Kim, Hyun-Soo; Mukhopadhyay, Rituparna; Rothbart, Scott B.; Silva, Andrea C.; Vanoosthuyse, Vincent; Radovani, Ernest; Kislinger, Thomas; Roguev, Assen; Ryan, Colm J.; Xu, Jiewei; Jahari, Harlizawati; Hardwick, Kevin G.; Greenblatt, Jack F.; Krogan, Nevan J.; Fillingham, Jeffrey S.

    2014-01-01

    Condensin is a central regulator of mitotic genome structure, with mutants showing poorly condensed chromosomes and profound segregation defects. Here we identify NCT complex, comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), Casein Kinase II (CKII) and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions, but only briefly co-localize during the periods of chromosome condensation and decondensation. This pattern ...

  11. Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

    Science.gov (United States)

    Mabb, Angela M.; Simon, Jeremy M.; King, Ian F.; Lee, Hyeong-Min; An, Lin-Kun; Philpot, Benjamin D.; Zylka, Mark J.

    2016-01-01

    Topoisomerase 1 (TOP1) inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc’s) that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb) genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR-Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc’s, and a TOP1 mutation (T718A) that stabilizes TOP1cc’s. We found that topotecan treatment significantly alters the expression of many more genes, including long neuronal genes, immediate early genes, and paternal Ube3a, when compared to Top1 deletion. Our data show that topotecan has a stronger effect on neuronal transcription than Top1 deletion, and identifies TOP1cc-dependent and -independent contributions to gene expression. PMID:27231886

  12. Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms.

    Directory of Open Access Journals (Sweden)

    Angela M Mabb

    Full Text Available Topoisomerase 1 (TOP1 inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc's that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR-Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc's, and a TOP1 mutation (T718A that stabilizes TOP1cc's. We found that topotecan treatment significantly alters the expression of many more genes, including long neuronal genes, immediate early genes, and paternal Ube3a, when compared to Top1 deletion. Our data show that topotecan has a stronger effect on neuronal transcription than Top1 deletion, and identifies TOP1cc-dependent and -independent contributions to gene expression.

  13. TOR Complex 2-Ypk1 Signaling Maintains Sphingolipid Homeostasis by Sensing and Regulating ROS Accumulation

    Directory of Open Access Journals (Sweden)

    Brad J. Niles

    2014-02-01

    Full Text Available Reactive oxygen species (ROS are produced during normal metabolism and can function as signaling molecules. However, ROS at elevated levels can damage cells. Here, we identify the conserved target of rapamycin complex 2 (TORC2/Ypk1 signaling module as an important regulator of ROS in the model eukaryotic organism, S. cerevisiae. We show that TORC2/Ypk1 suppresses ROS produced both by mitochondria as well as by nonmitochondrial sources, including changes in acidification of the vacuole. Furthermore, we link vacuole-related ROS to sphingolipids, essential components of cellular membranes, whose synthesis is also controlled by TORC2/Ypk1 signaling. In total, our data reveal that TORC2/Ypk1 act within a homeostatic feedback loop to maintain sphingolipid levels and that ROS are a critical regulatory signal within this system. Thus, ROS sensing and signaling by TORC2/Ypk1 play a central physiological role in sphingolipid biosynthesis and in the maintenance of cell growth and viability.

  14. Direct regulation of Arp2/3 complex activity and function by the actin binding protein coronin

    OpenAIRE

    Humphries, Christine L.; Balcer, Heath I.; D'Agostino, Jessica L.; Winsor, Barbara; Drubin, David G.; Barnes, Georjana; Andrews, Brenda J.; Goode, Bruce L.

    2002-01-01

    Mechanisms for activating the actin-related protein 2/3 (Arp2/3) complex have been the focus of many recent studies. Here, we identify a novel mode of Arp2/3 complex regulation mediated by the highly conserved actin binding protein coronin. Yeast coronin (Crn1) physically associates with the Arp2/3 complex and inhibits WA- and Abp1-activated actin nucleation in vitro. The inhibition occurs specifically in the absence of preformed actin filaments, suggesting that Crn1 may restrict Arp2/3 compl...

  15. Genome-wide Screening of Regulators of Catalase Expression: ROLE OF A TRANSCRIPTION COMPLEX AND HISTONE AND tRNA MODIFICATION COMPLEXES ON ADAPTATION TO STRESS.

    Science.gov (United States)

    García, Patricia; Encinar Del Dedo, Javier; Ayté, José; Hidalgo, Elena

    2016-01-01

    In response to environmental cues, the mitogen-activated protein kinase Sty1-driven signaling cascade activates hundreds of genes to induce a robust anti-stress cellular response in fission yeast. Thus, upon stress imposition Sty1 transiently accumulates in the nucleus where it up-regulates transcription through the Atf1 transcription factor. Several regulators of transcription and translation have been identified as important to mount an integral response to oxidative stress, such as the Spt-Ada-Gcn5-acetyl transferase or Elongator complexes, respectively. With the aim of identifying new regulators of this massive gene expression program, we have used a GFP-based protein reporter and screened a fission yeast deletion collection using flow cytometry. We find that the levels of catalase fused to GFP, both before and after a threat of peroxides, are altered in hundreds of strains lacking components of chromatin modifiers, transcription complexes, and modulators of translation. Thus, the transcription elongation complex Paf1, the histone methylase Set1-COMPASS, and the translation-related Trm112 dimers are all involved in full expression of Ctt1-GFP and in wild-type tolerance to peroxides. PMID:26567340

  16. The salience and complexity of building, regulating, and governing the smart grid: Lessons from a statewide public–private partnership

    International Nuclear Information System (INIS)

    Smart grid deployment unfolds within a diverse array of multi-institutional arrangements that may be too fragmented and decentralized to allow for the kind of large-scale and coordinated investments needed to properly deploy the smart grid. This case study provides an account of how one state arranged for and eventually deployed smart grid technology to over 85 percent of its resident. The study asks: does the deployment of the smart grid introduce new socio-political variables into the electricity distribution industry? To make sense of the socio-political variables shaping the industry and regulators, the Salience–Complexity Model is used to assess whether the smart grid raises or lowers the level of public scrutiny caste upon the industry (issue salience) and the level of technical capacity needed to execute and utilize the smart grid (technical complexity). The conclusions to be drawn from this study include: smart grid technology heightens the issue salience and the technical complexity of electricity distribution, but that the smart grid will likely not have a significant impact on the restructuring of electricity regulation. - Highlights: • Smart grid introduces new socio-political variables into the electricity distribution industry. • Smart grid technology engenders high degrees of issue salience and technical complexity. • Smart grid deployment requires extensive industry-regulator collaboration. • Smart grid will likely not have a significant impact on the restructuring of electricity regulation

  17. Multi-functional regulation of 4E-BP gene expression by the Ccr4-Not complex.

    Directory of Open Access Journals (Sweden)

    Hirokazu Okada

    Full Text Available The mechanistic target of rapamycin (mTOR signaling pathway is highly conserved from yeast to humans. It senses various environmental cues to regulate cellular growth and homeostasis. Deregulation of the pathway has been implicated in many pathological conditions including cancer. Phosphorylation cascades through the pathway have been extensively studied but not much is known about the regulation of gene expression of the pathway components. Here, we report that the mRNA level of eukaryotic translation initiation factor (eIF subunit 4E-binding protein (4E-BP gene, one of the key mTOR signaling components, is regulated by the highly conserved Ccr4-Not complex. RNAi knockdown of Not1, a putative scaffold protein of this protein complex, increases the mRNA level of 4E-BP in Drosophila Kc cells. Examination of the gene expression mechanism using reporter swap constructs reveals that Not1 depletion increases reporter mRNAs with the 3'UTR of 4E-BP gene, but decreases the ones with the 4E-BP promoter region, suggesting that Ccr4-Not complex regulates both degradation and transcription of 4E-BP mRNA. These results indicate that the Ccr4-Not complex controls expression of a single gene at multiple levels and adjusts the magnitude of the total effect. Thus, our study reveals a novel regulatory mechanism of a key component of the mTOR signaling pathway at the level of gene expression.

  18. The Arabidopsis mediator complex subunits MED16, MED14, and MED2 regulate mediator and RNA polymerase II recruitment to CBF-responsive cold-regulated genes.

    Science.gov (United States)

    Hemsley, Piers A; Hurst, Charlotte H; Kaliyadasa, Ewon; Lamb, Rebecca; Knight, Marc R; De Cothi, Elizabeth A; Steele, John F; Knight, Heather

    2014-01-01

    The Mediator16 (MED16; formerly termed SENSITIVE TO FREEZING6 [SFR6]) subunit of the plant Mediator transcriptional coactivator complex regulates cold-responsive gene expression in Arabidopsis thaliana, acting downstream of the C-repeat binding factor (CBF) transcription factors to recruit the core Mediator complex to cold-regulated genes. Here, we use loss-of-function mutants to show that RNA polymerase II recruitment to CBF-responsive cold-regulated genes requires MED16, MED2, and MED14 subunits. Transcription of genes known to be regulated via CBFs binding to the C-repeat motif/drought-responsive element promoter motif requires all three Mediator subunits, as does cold acclimation-induced freezing tolerance. In addition, these three subunits are required for low temperature-induced expression of some other, but not all, cold-responsive genes, including genes that are not known targets of CBFs. Genes inducible by darkness also required MED16 but required a different combination of Mediator subunits for their expression than the genes induced by cold. Together, our data illustrate that plants control transcription of specific genes through the action of subsets of Mediator subunits; the specific combination defined by the nature of the stimulus but also by the identity of the gene induced. PMID:24415770

  19. Insights into the complex regulation of rpoS in Borrelia burgodorferi

    Science.gov (United States)

    The coordinated regulation of gene expression is required for the transmission and survival of Borrelia burgdorferi in different hosts, and the sigma factor RpoS (sigmaS), as regulated by RpoN (sigma54), has been shown to regulate key proteins in these processes. We show that rpoS has one sigma54-d...

  20. Complex Regulation Pattern of IRF3 Activation Revealed by a Novel Dimerization Reporter System.

    Science.gov (United States)

    Wang, Zining; Ji, Jingyun; Peng, Di; Ma, Feng; Cheng, Genhong; Qin, F Xiao-Feng

    2016-05-15

    Induction of type I IFN (IFN-I) is essential for host antiviral immune responses. However, IFN-I also plays divergent roles in antibacterial immunity, persistent viral infections, autoimmune diseases, and tumorigenesis. IFN regulatory factor 3 (IRF3) is the master transcription factor that controls IFN-I production via phosphorylation-dependent dimerization in most cell types in response to viral infections and various innate stimuli by pathogen-associated molecular patterns (PAMPs). To monitor the dynamic process of IRF3 activation, we developed a novel IRF3 dimerization reporter based on bimolecular luminescence complementation (BiLC) techniques, termed the IRF3-BiLC reporter. Robust induction of luciferase activity of the IRF3-BiLC reporter was observed upon viral infection and PAMP stimulation with a broad dynamic range. Knockout of TANK-binding kinase 1, the critical upstream kinase of IRF3, as well as the mutation of serine 386, the essential phosphorylation site of IRF3, completely abolished the luciferase activity of IRF3-BiLC reporter, confirming the authenticity of IRF3 activation. Taken together, these results demonstrated that the IRF3-BiLC reporter is a highly specific, reliable, and sensitive system to measure IRF3 activity. Using this reporter system, we further observed that the temporal pattern and magnitude of IRF3 activation induced by various PAMPs are highly complex with distinct cell type-specific characteristics, and IRF3 dimerization is a direct regulatory node for IFN-α/β receptor-mediated feed-forward regulation and crosstalk with other pathways. Therefore, the IRF3-BiLC reporter has multiple potential applications, including mechanistic studies as well as the identification of novel compounds that can modulate IRF3 activation. PMID:27045107

  1. The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex.

    Directory of Open Access Journals (Sweden)

    Lakshmanane Boominathan

    Full Text Available The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/- and dicer(-/- mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into

  2. The HAP complex in Fusarium verticillioides is a key regulator of growth, morphogenesis, secondary metabolism, and pathogenesis.

    Science.gov (United States)

    Ridenour, John B; Bluhm, Burton H

    2014-08-01

    Among eukaryotic organisms, the HAP complex is a conserved, multimeric transcription factor that regulates gene expression by binding to the consensus sequence CCAAT. In filamentous fungi, the HAP complex has been linked to primary and secondary metabolism, but its role in pathogenesis has not been investigated extensively. The overarching goal of this study was to elucidate the role of the HAP complex in Fusariumverticillioides, a ubiquitous and damaging pathogen of maize. To this end, orthologs of core HAP complex genes (FvHAP2, FvHAP3, and FvHAP5) were identified and deleted in F. verticillioides via a reverse genetics approach. Deletion of FvHAP2, FvHAP3, or FvHAP5 resulted in an indistinguishable phenotype among the deletion strains, including reduced radial growth and conidiation, altered colony morphology, and derepression of pigmentation. Additionally, disruption of the HAP complex impaired infection and colonization of maize stalks. Deletion strains were hypersensitive to osmotic and oxidative stress, which suggests the HAP complex of F. verticillioides may mediate responses to environmental stress during pathogenesis. This study directly implicates the HAP complex in primary and secondary metabolism in F. verticillioides and provides one of the first links between the HAP complex and virulence in a plant pathogenic fungus. PMID:24875423

  3. Complexity

    CERN Document Server

    Gershenson, Carlos

    2011-01-01

    The term complexity derives etymologically from the Latin plexus, which means interwoven. Intuitively, this implies that something complex is composed by elements that are difficult to separate. This difficulty arises from the relevant interactions that take place between components. This lack of separability is at odds with the classical scientific method - which has been used since the times of Galileo, Newton, Descartes, and Laplace - and has also influenced philosophy and engineering. In recent decades, the scientific study of complexity and complex systems has proposed a paradigm shift in science and philosophy, proposing novel methods that take into account relevant interactions.

  4. Effects of sense and antisense centromere/kinetochore complex protein-B (CENP-B) in cell cycle regulation

    Institute of Scientific and Technical Information of China (English)

    LUO Song; LIN Haiyan; QI Jianguo; WANG Yongchao

    2005-01-01

    This paper investigates the effects of sense and antisense centromere/kinetochore complex protein-B (CENP-B) in cell cycle regulation. Full-length cenpb cDNA was subcloned into pBI-EGFP eukaryotic expression vector in both sense and antisense orientation. HeLa-Tet-Off cells were transfected with sense or antisense cenpb vectors. Sense transfection of HeLa-Tet-Off cells resulted in the formation of a large centromere/kinetochore complex, and apoptosis of cells following several times of cell division. A stable antisense cenpb transfected cell line, named HACPB, was obtained. The centromere/kinetochore complex of HACPB cells became smaller than control HeLa-Tet-Off cells and scattered, and the expression of CENP-B was down-regulated. In addition, delayed cell cycle progression, inhibited malignant phenotype, restrained ability of tumor formation in nude mice, and delayed entry from G2/M phase into next G1 phase were observed in HACPB cells. Furthermore, the expression of cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) were modulated during different phases of the cell cycle. CENP-B is an essential protein for the maintenance of the structure and function of centromere/kinetochore complex, and plays important roles in cell cycle regulation.

  5. Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling.

    Science.gov (United States)

    Roberts, David M; Pronobis, Mira I; Poulton, John S; Waldmann, Jon D; Stephenson, Elise M; Hanna, Shahnaz; Peifer, Mark

    2011-06-01

    Negatively regulating signaling by targeting key effectors for ubiquitination/destruction is essential for development and oncogenesis. The tumor suppressor adenomatous polyposis coli (APC), an essential negative regulator of Wnt signaling, provides a paradigm. APC mutations occur in most colon cancers. Acting in the "destruction complex" with Axin, glycogen synthase kinase 3, and casein kinase, APC targets ßcatenin (ßcat) for phosphorylation and recognition by an E3 ubiquitin-ligase. Despite 20 years of work, the internal workings of the destruction complex and APC's role remain largely mysterious. We use both Drosophila and colon cancer cells to test hypotheses for APC's mechanism of action. Our data are inconsistent with current models suggesting that high-affinity ßcat-binding sites on APC play key roles. Instead, they suggest that multiple ßcat-binding sites act additively to fine-tune signaling via cytoplasmic retention. We identify essential roles for two putative binding sites for new partners--20-amino-acid repeat 2 and conserved sequence B--in destruction complex action. Finally, we demonstrate that APC interacts with Axin by two different modes and provide evidence that conserved sequence B helps ensure release of APC from Axin, with disassembly critical in regulating ßcat levels. Using these data, we suggest a new model for destruction complex action in development, which also provides new insights into functions of truncated APC proteins in cancer. PMID:21471006

  6. IMPROVING THE MECHANISMS OF STATE REGULATION OF THE AGRO-INDUSTRIAL COMPLEX OF THE KRASNODAR REGION IN MODERN CONDITIONS

    Directory of Open Access Journals (Sweden)

    Artemova E. I.

    2016-03-01

    Full Text Available The article examines features of the functioning of the agro-industrial complex of Russia and the Krasnodar region in the economic crisis. It substantiates the urgency of adaptation of state regulation of agro-industrial complex mechanisms to modern economic realities, we have disclosed functions and principles for the development of regional policy strategy in the agricultural sector. It is proved, that the system of state regulation of regional agro-industrial complex should correlate with the priorities of the development of its main component - agriculture and to promote structural reforms in the agricultural sector, enhance its innovation and investment potential and maintain the social orientation of the agrarian reforms. Improving the mechanisms of state support of the agro-industrial complex of Russia and the Krasnodar region requires a special approach in relation to the country's membership in the World Trade Organization. Due to this, we have proposed the adjustment of state support instruments of domestic agro-industrial complex, which involves the use of priority measures of the "green box", including an increase in funding for research in agriculture, development of an effective institutional environment, which will stimulate the efficiency and competitiveness of the agricultural sector

  7. The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents.

    Science.gov (United States)

    Saunier, Elise; Benelli, Chantal; Bortoli, Sylvie

    2016-02-15

    Cancer cells exhibit an altered metabolism which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. This provides anabolic support and selective growth advantage for cancer cells. Recently, a new concept has arisen suggesting that these metabolic changes may be due, in part, to an attenuated mitochondrial function which results from the inhibition of the pyruvate dehydrogenase complex (PDC). This mitochondrial complex links glycolysis to the Krebs cycle and the current understanding of its regulation involves the cyclic phosphorylation and dephosphorylation by specific pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs). PMID:25868605

  8. Post-transcriptional regulation of meiotic genes by a nuclear RNA silencing complex

    OpenAIRE

    Egan, Emily D.; Braun, Craig R.; Gygi, Steven P.; Moazed, Danesh

    2014-01-01

    The authors define a multiprotein nuclear RNA silencing (NURS) complex that mediates silencing of meiotic genes during vegetative growth in the fission yeast S. pombe. Meiotic gene silencing occurs post-transcriptionally through recruitment of the exosome complex to promote RNA degradation. Extensive interaction analysis and functional characterizations link the NURS complex to specific RNA-binding and processing proteins and also chromatin modification machinery.

  9. Complex autoregulation of the post-transcriptional regulator RsmA in Pseudomonas aeruginosa.

    Science.gov (United States)

    Jean-Pierre, Fabrice; Perreault, Jonathan; Déziel, Eric

    2015-09-01

    RsmA is a post-transcriptional RNA-binding protein that acts as a pleiotropic global regulator of mRNAs in the opportunistic pathogen Pseudomonas aeruginosa. Upon binding to its target, RsmA impedes the translation of the mRNA by the ribosome. The RsmA regulon affects over 500 genes, many of which have been identified as important in the pathogenicity of P. aeruginosa. Whilst the regulatory function of RsmA is relatively well characterized, the genetic regulation of rsmA itself at the transcriptional and translational levels remains poorly understood. Here, we show that RsmA is capable of self-regulation through an unorthodox mechanism. This regulation occurs via direct interaction of the protein with an RsmA-binding site located in the early portion of its coding sequence. To the best of our knowledge this is the first report of such an unusual regulation in pseudomonads. PMID:26297258

  10. Regulation of fatty acid oxidation in mouse cumulus-oocyte complexes during maturation and modulation by PPAR agonists.

    Directory of Open Access Journals (Sweden)

    Kylie R Dunning

    Full Text Available Fatty acid oxidation is an important energy source for the oocyte; however, little is known about how this metabolic pathway is regulated in cumulus-oocyte complexes. Analysis of genes involved in fatty acid oxidation showed that many are regulated by the luteinizing hormone surge during in vivo maturation, including acyl-CoA synthetases, carnitine transporters, acyl-CoA dehydrogenases and acetyl-CoA transferase, but that many are dysregulated when cumulus-oocyte complexes are matured under in vitro maturation conditions using follicle stimulating hormone and epidermal growth factor. Fatty acid oxidation, measured as production of ³H₂O from [³H]palmitic acid, occurs in mouse cumulus-oocyte complexes in response to the luteinizing hormone surge but is significantly reduced in cumulus-oocyte complexes matured in vitro. Thus we sought to determine whether fatty acid oxidation in cumulus-oocyte complexes could be modulated during in vitro maturation by lipid metabolism regulators, namely peroxisome proliferator activated receptor (PPAR agonists bezafibrate and rosiglitazone. Bezafibrate showed no effect with increasing dose, while rosiglitazone dose dependently inhibited fatty acid oxidation in cumulus-oocyte complexes during in vitro maturation. To determine the impact of rosiglitazone on oocyte developmental competence, cumulus-oocyte complexes were treated with rosiglitazone during in vitro maturation and gene expression, oocyte mitochondrial activity and embryo development following in vitro fertilization were assessed. Rosiglitazone restored Acsl1, Cpt1b and Acaa2 levels in cumulus-oocyte complexes and increased oocyte mitochondrial membrane potential yet resulted in significantly fewer embryos reaching the morula and hatching blastocyst stages. Thus fatty acid oxidation is increased in cumulus-oocyte complexes matured in vivo and deficient during in vitro maturation, a known model of poor oocyte quality. That rosiglitazone further

  11. Promoting Attachment and Emotional Regulation of Children with Complex Trauma Disorder

    Science.gov (United States)

    Aideuis, Dianna

    2007-01-01

    Complex trauma is the result of repeated or chronic traumatic experiences in childhood. The traumatic experiences have a pervasive impact on the child's physical, sensory, emotional, cognitive and social growth. This paper discusses how the proposed diagnostic category, Complex Trauma Disorder, identifies clusters of symptoms and behaviors that…

  12. Regulation of integrin trafficking, cell adhesion and cell migration by WASH and the Arp2/3 Complex

    OpenAIRE

    Duleh, Steve N.; Welch, Matthew D.

    2012-01-01

    WASH is a nucleation-promoting factor for the Arp2/3 complex that is implicated in multiple endocytic trafficking pathways including receptor recycling, cargo degradation, and retromer-mediated receptor retrieval. We sought to examine whether WASH plays an important role in trafficking of specialized cargo molecules such as integrins, for which trafficking is highly regulated during cell migration. We observed that subdomains of early/sorting endosomes associated with dynamic WASH and filamen...

  13. Sm protein down-regulation leads to defects in nuclear pore complex disassembly and distribution in C. elegans embryos

    OpenAIRE

    Joseph-Strauss, Daphna; Gorjánácz, Mátyás; Santarella-Mellwig, Rachel; Voronina, Ekaterina; Audhya, Anjon; Cohen-Fix, Orna

    2012-01-01

    Nuclear pore complexes (NPCs) are large macromolecular structures embedded in the nuclear envelope (NE), where they facilitate exchange of molecules between the cytoplasm and the nucleoplasm. In most cell types, NPCs are evenly distributed around the NE. However, the mechanisms dictating NPC distribution are largely unknown. Here, we used the model organism C. elegans to identify genes that affect NPC distribution during early embryonic divisions. We found that down-regulation of the Sm prote...

  14. Nitric Oxide-associated Protein 1 (NOA1) Is Necessary for Oxygen-dependent Regulation of Mitochondrial Respiratory Complexes*

    OpenAIRE

    Heidler, Juliana; Al-Furoukh, Natalie; Kukat, Christian; Salwig, Isabelle; Ingelmann, Marie-Elisabeth; Seibel, Peter; Krüger, Marcus; Holtz, Jürgen; Wittig, Ilka; Braun, Thomas; Szibor, Marten

    2011-01-01

    In eukaryotic cells, maintenance of cellular ATP stores depends mainly on mitochondrial oxidative phosphorylation (OXPHOS), which in turn requires sufficient cellular oxygenation. The crucial role of proper oxygenation for cellular viability is reflected by involvement of several mechanisms, which sense hypoxia and regulate activities of respiratory complexes according to available oxygen concentrations. Here, we focus on mouse nitric oxide-associated protein 1 (mNOA1), which has been identif...

  15. KCNQ1, KCNE2, and Na+-Coupled Solute Transporters Form Reciprocally Regulating Complexes that Affect Neuronal Excitability

    OpenAIRE

    Abbott, Geoffrey W.; Tai, Kwok-Keung; Neverisky, Daniel; Hansler, Alex; Hu, Zhaoyang; Torsten K. Roepke; Lerner, Daniel J.; Chen, Qiuying; Liu, Li; Zupan, Bojana; Toth, Miklos; Haynes, Robin; Huang, Xiaoping; Demirbas, Didem; Buccafusca, Roberto

    2014-01-01

    Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. Here, we found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in the myo-inositol concentration in cerebrosp...

  16. KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability

    OpenAIRE

    Abbott, GW; Tai, KK; Neverisky, DL; Hansler, A; Hu, Z; Roepke, TK; Lerner, DJ; Chen, Q.; Liu, L.; B. Zupan; Toth, M; Haynes, R; Huang, X.; Demirbas, D; Buccafusca, R

    2014-01-01

    Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid...

  17. The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1 alpha.

    Science.gov (United States)

    Gross, C; Dubois-Pot, H; Wasylyk, B

    2008-02-21

    The ternary complex factor Net/Elk3 is downregulated in hypoxia and participates in the induction by hypoxia of several genes, including c-fos, vascular endothelial growth factor and egr-1. However, the global role of Net in hypoxia remains to be elucidated. We have identified, in a large-scale analysis of RNA expression using microarrays, more than 370 genes that are regulated by Net in hypoxia. In order to gain insights into the role of Net in hypoxia, we have analysed in parallel the genes regulated by HIF-1alpha, the classical factor involved in the response to hypoxia. We identified about 190 genes that are regulated by HIF-1alpha in hypoxia. Surprisingly, when we compare the genes induced by hypoxia that require either Net or HIF-1alpha, the majority are the same (75%), suggesting that the functions of both factors are closely linked. Interestingly, in hypoxia, Net regulates the expression of several genes known to control HIF-1alpha stability, including PHD2, PHD3 and Siah2, suggesting that Net regulates the stability of HIF-1alpha. We found that inhibition of Net by RNAi leads to decreased HIF-1alpha expression at the protein level in hypoxia. These results indicate that Net participates in the transcriptional response to hypoxia by regulation of HIF-1alpha protein stability. PMID:17704799

  18. Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation

    Science.gov (United States)

    Weis, MaryAnn; Rai, Jyoti; Hudson, David M.; Dimori, Milena; Zimmerman, Sarah M.; Hogue, William R.; Swain, Frances L.; Burdine, Marie S.; Mackintosh, Samuel G.; Tackett, Alan J.; Suva, Larry J.; Eyre, David R.

    2016-01-01

    Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis. PMID:27119146

  19. Nucleoporin Nup98 Associates with Trx/MLL and NSL Histone-Modifying Complexes and Regulates Hox Gene Expression

    Directory of Open Access Journals (Sweden)

    Pau Pascual-Garcia

    2014-10-01

    Full Text Available The nuclear pore complex is a transport channel embedded in the nuclear envelope and made up of 30 different components termed nucleoporins (Nups. In addition to their classical role in transport, a subset of Nups has a conserved role in the regulation of transcription via direct binding to chromatin. The molecular details of this function remain obscure, and it is unknown how metazoan Nups are recruited to their chromatin locations or what transcription steps they regulate. Here, we demonstrate genome-wide and physical association between Nup98 and histone-modifying complexes MBR-R2/NSL and Trx/MLL. Importantly, we identify a requirement for MBD-R2 in recruitment of Nup98 to many of its genomic target sites. Consistent with its interaction with the Trx/MLL complex, Nup98 is shown to be necessary for Hox gene expression in developing fly tissues. These findings introduce roles of Nup98 in epigenetic regulation that may underlie the basis of oncogenicity of Nup98 fusions in leukemia.

  20. Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

    DEFF Research Database (Denmark)

    Jacobsen, Sylwia Owczarek; Bang, Marie Louise; Berezin, Vladimir

    2015-01-01

    -attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of the NX1 and NX3 genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1β can regulate the expression of DISC1 and induce signaling...... downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better...

  1. Molecular Hallmarks of Endogenous Chromatin Complexes Containing Master Regulators of Hematopoiesis▿ †

    OpenAIRE

    Wozniak, Ryan J.; Keles, Sunduz; Lugus, Jesse J.; Young, Ken H.; Boyer, Meghan E; Tran, Tuan M.; Choi, Kyunghee; Bresnick, Emery H.

    2008-01-01

    Combinatorial interactions among trans-acting factors establish transcriptional circuits that orchestrate cellular differentiation, survival, and development. Unlike circuits instigated by individual factors, efforts to identify gene ensembles controlled by multiple factors simultaneously are in their infancy. A paradigm has emerged in which the important regulators of hematopoiesis GATA-1 and GATA-2 function combinatorially with Scl/TAL1, another key regulator of hematopoiesis. The underlyin...

  2. Managing the complexity of communication: regulation of gap junctions by post-translational modification

    OpenAIRE

    Axelsen, Lene N.; Calloe, Kirstine; Holstein-Rathlou, Niels-Henrik; Nielsen, Morten S.

    2013-01-01

    Gap junctions are comprised of connexins that form cell-to-cell channels which couple neighboring cells to accommodate the exchange of information. The need for communication does, however, change over time and therefore must be tightly controlled. Although the regulation of connexin protein expression by transcription and translation is of great importance, the trafficking, channel activity and degradation are also under tight control. The function of connexins can be regulated by several po...

  3. Managing the complexity of communication; regulation of gap junctions by post-translational modification

    OpenAIRE

    MortenSchakNielsen; KirstineCalloe

    2013-01-01

    Gap junctions are comprised of connexins that form cell-to-cell channels which couple neighboring cells to accommodate the exchange of information. The need for communication does, however, change over time and therefore must be tightly controlled. Although the regulation of connexin protein expression by transcription and translation is of great importance, the trafficking, channel activity and degradation are also under tight control. The function of connexins can be regulated by several po...

  4. The Isl1/Ldb1 complex orchestrates heart-specific chromatin organization and transcriptional regulation

    OpenAIRE

    Caputo, Luca

    2016-01-01

    Cardiac progenitor cells hold great potential for regenerative therapies in heart disorders. However, the molecular mechanisms regulating cardiac progenitor cell expansion and differentiation remain poorly defined. Here we show that the multi- adaptor protein Ldb1, which mediates interactions between different classes of LIM domain transcription factors, is a multifunctional regulator of cardiac progenitor cell differentiation. Ldb1-deficient embryonic stem cells (ESCs) show a markedly decrea...

  5. Regulation of the Drosophila Enhancer of split and invected-engrailed gene complexes by sister chromatid cohesion proteins.

    Directory of Open Access Journals (Sweden)

    Cheri A Schaaf

    Full Text Available The cohesin protein complex was first recognized for holding sister chromatids together and ensuring proper chromosome segregation. Cohesin also regulates gene expression, but the mechanisms are unknown. Cohesin associates preferentially with active genes, and is generally absent from regions in which histone H3 is methylated by the Enhancer of zeste [E(z] Polycomb group silencing protein. Here we show that transcription is hypersensitive to cohesin levels in two exceptional cases where cohesin and the E(z-mediated histone methylation simultaneously coat the entire Enhancer of split and invected-engrailed gene complexes in cells derived from Drosophila central nervous system. These gene complexes are modestly transcribed, and produce seven of the twelve transcripts that increase the most with cohesin knockdown genome-wide. Cohesin mutations alter eye development in the same manner as increased Enhancer of split activity, suggesting that similar regulation occurs in vivo. We propose that cohesin helps restrain transcription of these gene complexes, and that deregulation of similarly cohesin-hypersensitive genes may underlie developmental deficits in Cornelia de Lange syndrome.

  6. Regulation of the Tumor-Suppressor Function of the Class III Phosphatidylinositol 3-Kinase Complex by Ubiquitin and SUMO

    Energy Technology Data Exchange (ETDEWEB)

    Reidick, Christina [Biochemie Intrazellulärer Transportprozesse, Ruhr-Universität Bochum, Bochum 44801 (Germany); El Magraoui, Fouzi; Meyer, Helmut E. [Biomedical Research, Human Brain Proteomics II, Leibniz-Institut für Analytische Wissenschaften-ISAS, Dortmund 44139 (Germany); Stenmark, Harald [Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo 0310 (Norway); Platta, Harald W., E-mail: harald.platta@rub.de [Biochemie Intrazellulärer Transportprozesse, Ruhr-Universität Bochum, Bochum 44801 (Germany)

    2014-12-23

    The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1. Furthermore, a growing list of regulatory proteins associates with VPS34 via Beclin 1. These accessory factors define distinct subunit compositions and thereby guide the PI3K-III complex to its different cellular and physiological roles. Here we discuss the regulation of the PI3K-III complex components by ubiquitination and SUMOylation. Especially Beclin 1 has emerged as a highly regulated protein, which can be modified with Lys11-, Lys48- or Lys63-linked polyubiquitin chains catalyzed by distinct E3 ligases from the RING-, HECT-, RBR- or Cullin-type. We also point out other cross-links of these ligases with autophagy in order to discuss how these data might be merged into a general concept.

  7. The Organizational-Economic Mechanism Of Regulation Of Development Fishery Complex Of Ukraine

    OpenAIRE

    Catherine Ryzhova

    2011-01-01

    The article is devoted to research and search of organizational-economic mechanisms of steady development fishery complex for increase and directions his improvement for increase in manufacture and realization of fish production.

  8. Dynamin Forms a Src Kinase–sensitive Complex with Cbl and Regulates Podosomes and Osteoclast Activity

    OpenAIRE

    Bruzzaniti, Angela; Neff, Lynn; Sanjay, Archana; Horne, William C.; De Camilli, Pietro; Baron, Roland

    2005-01-01

    Podosomes are highly dynamic actin-containing adhesion structures found in osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytos...

  9. The Hrs/Stam complex acts as a positive and negative regulator of RTK signaling during Drosophila development.

    Directory of Open Access Journals (Sweden)

    Hélène Chanut-Delalande

    Full Text Available BACKGROUND: Endocytosis is a key regulatory step of diverse signalling pathways, including receptor tyrosine kinase (RTK signalling. Hrs and Stam constitute the ESCRT-0 complex that controls the initial selection of ubiquitinated proteins, which will subsequently be degraded in lysosomes. It has been well established ex vivo and during Drosophila embryogenesis that Hrs promotes EGFR down regulation. We have recently isolated the first mutations of stam in flies and shown that Stam is required for air sac morphogenesis, a larval respiratory structure whose formation critically depends on finely tuned levels of FGFR activity. This suggest that Stam, putatively within the ESCRT-0 complex, modulates FGF signalling, a possibility that has not been examined in Drosophila yet. PRINCIPAL FINDINGS: Here, we assessed the role of the Hrs/Stam complex in the regulation of signalling activity during Drosophila development. We show that stam and hrs are required for efficient FGFR signalling in the tracheal system, both during cell migration in the air sac primordium and during the formation of fine cytoplasmic extensions in terminal cells. We find that stam and hrs mutant cells display altered FGFR/Btl localisation, likely contributing to impaired signalling levels. Electron microscopy analyses indicate that endosome maturation is impaired at distinct steps by hrs and stam mutations. These somewhat unexpected results prompted us to further explore the function of stam and hrs in EGFR signalling. We show that while stam and hrs together downregulate EGFR signalling in the embryo, they are required for full activation of EGFR signalling during wing development. CONCLUSIONS/SIGNIFICANCE: Our study shows that the ESCRT-0 complex differentially regulates RTK signalling, either positively or negatively depending on tissues and developmental stages, further highlighting the importance of endocytosis in modulating signalling pathways during development.

  10. Managing the complexity of communication: regulation of gap junctions by post-translational modification

    DEFF Research Database (Denmark)

    Axelsen, Lene Nygaard; Callø, Kirstine; von Holstein-Rathlou, Niels-Henrik; Nielsen, Morten S

    2013-01-01

    expression by transcription and translation is of great importance, the trafficking, channel activity and degradation are also under tight control. The function of connexins can be regulated by several post translational modifications, which affect numerous parameters; including number of channels, open...... probability, single channel conductance or selectivity. The most extensively investigated post translational modifications are phosphorylations, which have been documented in all mammalian connexins. Besides phosphorylations, some connexins are known to be ubiquitinated, SUMOylated, nitrosylated, hydroxylated......, acetylated, methylated, and γ-carboxyglutamated. The aim of the present review is to summarize our current knowledge of post translational regulation of the connexin family of proteins....

  11. The apical complex provides a regulated gateway for secretion of invasion factors in Toxoplasma.

    Directory of Open Access Journals (Sweden)

    Nicholas J Katris

    2014-04-01

    Full Text Available The apical complex is the definitive cell structure of phylum Apicomplexa, and is the focus of the events of host cell penetration and the establishment of intracellular parasitism. Despite the importance of this structure, its molecular composition is relatively poorly known and few studies have experimentally tested its functions. We have characterized a novel Toxoplasma gondii protein, RNG2, that is located at the apical polar ring--the common structural element of apical complexes. During cell division, RNG2 is first recruited to centrosomes immediately after their duplication, confirming that assembly of the new apical complex commences as one of the earliest events of cell replication. RNG2 subsequently forms a ring, with the carboxy- and amino-termini anchored to the apical polar ring and mobile conoid, respectively, linking these two structures. Super-resolution microscopy resolves these two termini, and reveals that RNG2 orientation flips during invasion when the conoid is extruded. Inducible knockdown of RNG2 strongly inhibits host cell invasion. Consistent with this, secretion of micronemes is prevented in the absence of RNG2. This block, however, can be fully or partially overcome by exogenous stimulation of calcium or cGMP signaling pathways, respectively, implicating the apical complex directly in these signaling events. RNG2 demonstrates for the first time a role for the apical complex in controlling secretion of invasion factors in this important group of parasites.

  12. Dynamin Forms a Src Kinase–sensitive Complex with Cbl and Regulates Podosomes and Osteoclast Activity

    Science.gov (United States)

    Bruzzaniti, Angela; Neff, Lynn; Sanjay, Archana; Horne, William C.; De Camilli, Pietro; Baron, Roland

    2005-01-01

    Podosomes are highly dynamic actin-containing adhesion structures found in osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover. We found that dynamin colocalizes with Cbl in the actin-rich podosome belt of osteoclasts and that dynamin forms a complex with Cbl in osteoclasts and when overexpressed in 293VnR or SYF cells. The association of dynamin with Cbl in osteoclasts was decreased by Src tyrosine kinase activity and we found that destabilization of the dynamin-Cbl complex involves the recruitment of Src through the proline-rich domain of Cbl. Overexpression of dynamin increased osteoclast bone resorbing activity and migration, whereas overexpression of dynK44A decreased osteoclast resorption and migration. These studies suggest that dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in osteoclast adhesion, migration, and resorption. PMID:15872089

  13. Dynamin forms a Src kinase-sensitive complex with Cbl and regulates podosomes and osteoclast activity.

    Science.gov (United States)

    Bruzzaniti, Angela; Neff, Lynn; Sanjay, Archana; Horne, William C; De Camilli, Pietro; Baron, Roland

    2005-07-01

    Podosomes are highly dynamic actin-containing adhesion structures found in osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover. We found that dynamin colocalizes with Cbl in the actin-rich podosome belt of osteoclasts and that dynamin forms a complex with Cbl in osteoclasts and when overexpressed in 293VnR or SYF cells. The association of dynamin with Cbl in osteoclasts was decreased by Src tyrosine kinase activity and we found that destabilization of the dynamin-Cbl complex involves the recruitment of Src through the proline-rich domain of Cbl. Overexpression of dynamin increased osteoclast bone resorbing activity and migration, whereas overexpression of dynK44A decreased osteoclast resorption and migration. These studies suggest that dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in osteoclast adhesion, migration, and resorption. PMID:15872089

  14. Modulation of Tcf3 repressor complex composition regulates cdx4 expression in zebrafish

    OpenAIRE

    Ro, Hyunju; Dawid, Igor B.

    2011-01-01

    Here, E4f1 is identified as a regulator of Tcf3 activity: causing dissociation of corepressor factors and thus promoting Tcf3's transcriptional activator function. E4f1 is important for Tcf3-mediated induction of Cdx4 during zebrafish development.

  15. Decree 435/994 Environmental Impacts : establish a standard joint complex named Evaluation Regulations

    International Nuclear Information System (INIS)

    The Regulation of Evaluation of environmental Impact in the chapter I art.2 item 14 it establishes that It will require the previous Environmental Authorization the activities that refer to the construction of production factories and transformation of Nuclear Energy r, without damage of that settled down for the articulate 215 of the law 16.226 of October 29 1991

  16. Exploring the Complex Relations between Achievement Emotions and Self-Regulated Learning Behaviors in Online Learning

    Science.gov (United States)

    Artino, Anthony R., Jr.; Jones, Kenneth D., II

    2012-01-01

    Online learning continues to grow, but there is limited empirical research on the personal factors that influence success in online contexts. This investigation addresses this research gap by exploring the relations between several discrete achievement-related emotions (boredom, frustration, and enjoyment) and self-regulated learning behaviors…

  17. How Do Students Regulate their Learning of Complex Systems with Hypermedia?.

    Science.gov (United States)

    Azevedo, Roger; Seibert, Diane; Guthrie, John T.; Cromley, Jennifer G.; Wang, Huei-yu; Tron, Myriam

    This study examined the role of different goal-setting instructional interventions in facilitating students' shift to more sophisticated mental models of the circulatory system as indicated by both performance and process data. Researchers adopted the information processing model of self-regulated learning of P. Winne and colleagues (1998, 2001)…

  18. Polycomb repressive complex 2 regulates MiR-200b in retinal endothelial cells: potential relevance in diabetic retinopathy.

    Directory of Open Access Journals (Sweden)

    Michael Anthony Ruiz

    Full Text Available Glucose-induced augmented vascular endothelial growth factor (VEGF production is a key event in diabetic retinopathy. We have previously demonstrated that downregulation of miR-200b increases VEGF, mediating structural and functional changes in the retina in diabetes. However, mechanisms regulating miR-200b in diabetes are not known. Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2, has been shown to repress miRNAs in neoplastic process. We hypothesized that, in diabetes, PRC2 represses miR-200b through its histone H3 lysine-27 trimethylation mark. We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation and that inhibition of PRC2 increases miR-200b while reducing VEGF. Furthermore, retinal tissue from animal models of diabetes showed increased expression of major PRC2 components, demonstrating in vivo relevance. This research established a repressive relationship between PRC2 and miR-200b, providing evidence of a novel mechanism of miRNA regulation through histone methylation.

  19. Kainate Receptors Coexist in a Functional Complex with KCC2 and Regulate Chloride Homeostasis in Hippocampal Neurons

    Directory of Open Access Journals (Sweden)

    Vivek Mahadevan

    2014-06-01

    Full Text Available KCC2 is the neuron-specific K+-Cl− cotransporter required for maintaining low intracellular Cl−, which is essential for fast inhibitory synaptic transmission in the mature CNS. Despite the requirement of KCC2 for inhibitory synaptic transmission, understanding of the cellular mechanisms that regulate KCC2 expression and function is rudimentary. We examined KCC2 in its native protein complex in vivo to identify key KCC2-interacting partners that regulate KCC2 function. Using blue native-polyacrylamide gel electrophoresis (BN-PAGE, we determined that native KCC2 exists in a macromolecular complex with kainate-type glutamate receptors (KARs. We found that KAR subunits are required for KCC2 oligomerization and surface expression. In accordance with this finding, acute and chronic genetic deletion of KARs decreased KCC2 function and weakened synaptic inhibition in hippocampal neurons. Our results reveal KARs as regulators of KCC2, significantly advancing our growing understanding of the tight interplay between excitation and inhibition.

  20. HAUSP-nucleolin interaction is regulated by p53-Mdm2 complex in response to DNA damage response.

    Science.gov (United States)

    Lim, Key-Hwan; Park, Jang-Joon; Gu, Bon-Hee; Kim, Jin-Ock; Park, Sang Gyu; Baek, Kwang-Hyun

    2015-01-01

    HAUSP (herpes virus-associated ubiquitin specific protease, known as ubiquitin specific protease 7), one of DUBs, regulates the dynamics of the p53 and Mdm2 network in response to DNA damage by deubiquitinating both p53 and its E3 ubiquitin ligase, Mdm2. Its concerted action increases the level of functional p53 by preventing proteasome-dependent degradation of p53. However, the protein substrates that are targeted by HAUSP to mediate DNA damage responses in the context of the HAUSP-p53-Mdm2 complex are not fully identified. Here, we identified nucleolin as a new substrate for HAUSP by proteomic analysis. Nucleolin has two HAUSP binding sites in its N- and C-terminal regions, and the mutation of HAUSP interacting peptides on nucleolin disrupts their interaction and it leads to the increased level of nucleolin ubiquitination. In addition, HAUSP regulates the stability of nucleolin by removing ubiquitin from nucleolin. Nucleolin exists as a component of the HAUSP-p53-Mdm2 complex, and both Mdm2 and p53 are required for the interaction between HAUSP and nucleolin. Importantly, the irradiation increases the HAUSP-nucleolin interaction, leading to nucleolin stabilization significantly. Taken together, this study reveals a new component of the HAUSP-p53-Mdm2 complex that governs dynamic cellular responses to DNA damage. PMID:26238070

  1. E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer

    DEFF Research Database (Denmark)

    Lu, Z; Luo, R Z; Peng, H;

    2006-01-01

    1 and 4. While the retinoblastoma protein, pRB, alone had no effect on ARHI promoter activity, repression by E2F1, but not E2F4, was enhanced by the coexpression of pRB. Taken together, our results suggest that E2F1, 4 and their complexes with HDAC play an important role in downregulating the...

  2. The role of the pyruvate dehydrogenase complex in the regulation of human skeletal muscle fuel metabolism

    OpenAIRE

    Laithwaite, David

    2009-01-01

    The pyruvate dehydrogenase complex (PDC) is the rate limiting step in the entry of glucose derived pyruvate into the tricarboxylic acid (TCA) cycle. As such it plays an important role in the control of the use of carbohydrate as the source of oxidative energy for skeletal muscle contraction. The first experimental chapter investigates the effect of dichloroacetate pre-treatment during low-intensity (

  3. The effect of complex radioactive contamination on the parametrs of metabolism regulation systems

    International Nuclear Information System (INIS)

    Analysis of the indices of various chains of regulation system of peroxide oxidation of lipids in spleen, liver and brain of 6 species of rodents caught in the 30 km ChNPP area in 1987 in locations with different radioactive contamination level was carried out. Experimental data indicated a significant sensitivity of the parameters of metabolism regulation systems of the animals inspected. There was evidence for monotonous biophysical and biochemical variations in tissues of wild rodents dependent on the environmental radiation level in their locations during long-term low-dose exposure on their organisms. High vulnerability of spleen in all species of rodents and the specific features of brain's and liver's sensitivity to the factors considered are pointed out. refs. 21; figs. 2; tabs. 4

  4. Complex relations between metacognitive judgment and metacognitive control in self-regulated learning

    OpenAIRE

    Sha, Li

    2008-01-01

    This study explores whether and how the relationship between metacognitive monitoring and metacognitive control in self-regulated learning (SRL) is mediated by personal factors such as motivation, personal epistemology, metacognitive awareness, and other individual difference variables. An eye tracking system was used to accurately capture data pertaining to two aspects of metacognitive processes, monitoring and control, in SRL processes. These data were acquired while participants were engag...

  5. Another player joins the complex field of sugar-regulated gene expression in plants

    Energy Technology Data Exchange (ETDEWEB)

    Gibson, Susan I.; Graham, Ian A.

    1999-04-01

    This article summarizes recent progress in understanding the molecular mechanisms by which soluble sugar levels affect plant development and gene expression. The article focuses on the role played by a newly identified protein, the PRL1 protein. The PRL1 protein has been found to interact with the SNF1 protein. Previously, SNF1 was shown to function in sugar-regulated gene expression in yeast. Mutations in the gene encoding PRL1 confer increased sensitivity to sugar and to several phytohormones.

  6. Function and Mode of Regulation of Endothelial Major Histocompatibility Complex Class II

    OpenAIRE

    Alexander, Irina; Edelman, Elazer R.; Methe, Heiko

    2009-01-01

    Tissue engineering is a promising approach to implement endothelial cells as a cellular delivery therapy for vascular disease. We and others previously demonstrated that endothelial cells embedded in three-dimensional collagen-based matrices retain their full biosecretory spectrum, enabling them to serve as powerful regulators of vascular diseases. Fascinatingly, matrix embedding of endothelial cells not only allows for their implantation but also seems to provide protection from allo- and xe...

  7. Regulation of cell–cell adhesion by the cadherin–catenin complex

    OpenAIRE

    Nelson, W. James

    2008-01-01

    Ca2+-dependent cell–cell adhesion is regulated by the cadherin family of cell adhesion proteins. Cadherins form trans-interactions on opposing cell surfaces which result in weak cell–cell adhesion. Stronger cell–cell adhesion occurs by clustering of cadherins and through changes in the organization of the actin cytoskeleton. Although cadherins were thought to bind directly to the actin cytoskeleton through cytoplasmic proteins, termed α- and β-catenin, recent studies with purified proteins in...

  8. Ldb1 complexes: The new master-regulators of erythroid gene transcription

    OpenAIRE

    Love, Paul E.; Warzecha, Claude; Li, Liqi

    2013-01-01

    Elucidation of the genetic pathways that control red blood cell development has been a central goal of erythropoiesis research over the past decade. Notably, data from several recent studies have provided new insights into the regulation of erythroid gene transcription. Transcription profiling demonstrates that erythopoiesis is mainly controlled by a small group of lineage-restricted transcription factors (Gata1, Tal1, and Klf1). Binding site mapping using ChIP-Seq indicates that most DNA bou...

  9. DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling.

    Science.gov (United States)

    Richter-Dennerlein, Ricarda; Korwitz, Anne; Haag, Mathias; Tatsuta, Takashi; Dargazanli, Sascha; Baker, Michael; Decker, Thorsten; Lamkemeyer, Tobias; Rugarli, Elena I; Langer, Thomas

    2014-07-01

    Prohibitins form large protein and lipid scaffolds in the inner membrane of mitochondria that are required for mitochondrial morphogenesis, neuronal survival, and normal lifespan. Here, we have defined the interactome of PHB2 in mitochondria and identified DNAJC19, mutated in dilated cardiomyopathy with ataxia, as binding partner of PHB complexes. We observed impaired cell growth, defective cristae morphogenesis, and similar transcriptional responses in the absence of either DNAJC19 or PHB2. The loss of PHB/DNAJC19 complexes affects cardiolipin acylation and leads to the accumulation of cardiolipin species with altered acyl chains. Similar defects occur in cells lacking the transacylase tafazzin, which is mutated in Barth syndrome. Our experiments suggest that PHB/DNAJC19 membrane domains regulate cardiolipin remodeling by tafazzin and explain similar clinical symptoms in two inherited cardiomyopathies by an impaired cardiolipin metabolism in mitochondrial membranes. PMID:24856930

  10. A structurally plastic ribonucleoprotein complex mediates post-transcriptional gene regulation in HIV-1.

    Science.gov (United States)

    Fernandes, Jason D; Booth, David S; Frankel, Alan D

    2016-07-01

    HIV replication requires the nuclear export of essential, intron-containing viral RNAs. To facilitate export, HIV encodes the viral accessory protein Rev which binds unspliced and partially spliced viral RNAs and creates a ribonucleoprotein complex that recruits the cellular Chromosome maintenance factor 1 export machinery. Exporting RNAs in this manner bypasses the necessity for complete splicing as a prerequisite for mRNA export, and allows intron-containing RNAs to reach the cytoplasm intact for translation and virus packaging. Recent structural studies have revealed that this entire complex exhibits remarkable plasticity at many levels of organization, including RNA folding, protein-RNA recognition, multimer formation, and host factor recruitment. In this review, we explore each aspect of plasticity from structural, functional, and possible therapeutic viewpoints. WIREs RNA 2016, 7:470-486. doi: 10.1002/wrna.1342 For further resources related to this article, please visit the WIREs website. PMID:26929078

  11. New Approach for Nuclear Safety and Regulation - Application of Complexity Theory and System Dynamics

    International Nuclear Information System (INIS)

    The methodology being used today for assuring nuclear safety is based on analytic approaches. In the 21st century, holistic approaches are increasingly used over traditional analytic method that is based on reductionism. Presently, it leads to interest in complexity theory or system dynamics. In this paper, we review global academic trends, social environments, concept of nuclear safety and regulatory frameworks for nuclear safety. We propose a new safety paradigm and also regulatory approach using holistic approach and system dynamics now in fashion

  12. WASH and the Arp2/3 complex regulate endosome shape and trafficking

    OpenAIRE

    Duleh, Steve N.; Welch, Matthew D.

    2010-01-01

    Activators of the Arp2/3 complex, termed nucleation-promoting factors (NPFs), are required for the proper spatial and temporal control of actin assembly in cells. Mammalian cells express several NPFs, each of which functions in a distinct cellular process, including WASP and N-WASP in phagocytosis and endocytosis, WAVE and JMY in cell migration, and WHAMM in ER-to-Golgi transport. Although another NPF called WASH was recently identified, the cellular localization and function of this protein ...

  13. Mammalian complex I: A regulable and vulnerable pacemaker in mitochlondrial respiratory function

    Czech Academy of Sciences Publication Activity Database

    Papa, S.; De Rasmo, D.; Scacco, S.; Signorile, A.; Dobrová, Zuzana; Palmisano, G.; Sardanelli, A. M.; Papa, F.; Panelli, D.; Scaringi, R.; Santeramo, A.

    2008-01-01

    Roč. 1777, 7-8 (2008), s. 719-728. ISSN 0005-2728 Grant ostatní: IT(IT) National Project on "Molecular Mechanisms, Physiology and Pathology of Membrane Bioenergetics System" 2005-Ministero dell Istruzione, Univ. Ricerca, Italy, Res. grant Univ. Bari, Research Foundation cassa di Risparmio di Puglia Institutional research plan: CEZ:AV0Z50200510 Keywords : complex I * proton pump * mitochondrial import Subject RIV: EE - Microbiology, Virology Impact factor: 4.447, year: 2008

  14. Control of electron transport routes through redox-regulated redistribution of respiratory complexes

    OpenAIRE

    Liu, Lu-Ning; Samantha J Bryan; Huang, Fang; Yu, Jianfeng; Nixon, Peter J.; Rich, Peter R.; Mullineaux, Conrad W.

    2012-01-01

    In cyanobacteria, respiratory electron transport takes place in close proximity to photosynthetic electron transport, because the complexes required for both processes are located within the thylakoid membranes. The balance of electron transport routes is crucial for cell physiology, yet the factors that control the predominance of particular pathways are poorly understood. Here we use a combination of tagging with green fluorescent protein and confocal fluorescence microscopy in live cells o...

  15. Recombinational DNA repair is regulated by compartmentalization of DNA lesions at the nuclear pore complex

    DEFF Research Database (Denmark)

    Géli, Vincent; Lisby, Michael

    2015-01-01

    The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of "difficult to repair" lesions such as double-strand breaks without a repair template and eroded telomeres in telomerase-deficient cells. In addition to such pathological situations, a recent study by Su and colle...... lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC-facilitated repair....

  16. Three-dimensional regulation of radial glial functions by Lis1-Nde1 and dystrophin glycoprotein complexes.

    Directory of Open Access Journals (Sweden)

    Ashley S Pawlisz

    2011-10-01

    Full Text Available Radial glial cells (RGCs are distinctive neural stem cells with an extraordinary slender bipolar morphology and dual functions as precursors and migration scaffolds for cortical neurons. Here we show a novel mechanism by which the Lis1-Nde1 complex maintains RGC functions through stabilizing the dystrophin/dystroglycan glycoprotein complex (DGC. A direct interaction between Nde1 and utrophin/dystrophin allows for the assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of RGCs to stabilize their lateral membrane, cell-cell adhesion, and radial morphology. Lis1-Nde1 mutations destabilized the DGC and resulted in deformed, disjointed RGCs and disrupted basal lamina. Besides impaired RGC self-renewal and neuronal migration arrests, Lis1-Nde1 deficiencies also led to neuronal over-migration. Additional to phenotypic resemblances of Lis1-Nde1 with DGC, strong synergistic interactions were found between Nde1 and dystroglycan in RGCs. As functional insufficiencies of LIS1, NDE1, and dystroglycan all cause lissencephaly syndromes, our data demonstrated that a three-dimensional regulation of RGC's cytoarchitecture by the Lis1-Nde1-DGC complex determines the number and spatial organization of cortical neurons as well as the size and shape of the cerebral cortex.

  17. Mcm1p-Induced DNA Bending Regulates the Formation of Ternary Transcription Factor Complexes

    OpenAIRE

    Lim, Fei-Ling; Hayes, Andrew; West, Adam G; Pic-Taylor, Aline; Darieva, Zoulfia; Morgan, Brian A; Oliver, Stephen G.; Sharrocks, Andrew D.

    2003-01-01

    The yeast MADS-box transcription factor Mcm1p plays an important regulatory role in several diverse cellular processes. In common with a subset of other MADS-box transcription factors, Mcm1p elicits substantial DNA bending. However, the role of protein-induced bending by MADS-box proteins in eukaryotic gene regulation is not understood. Here, we demonstrate an important role for Mcm1p-mediated DNA bending in determining local promoter architecture and permitting the formation of ternary trans...

  18. let-7 Modulates Chromatin Configuration and Target Gene Repression through Regulation of the ARID3B Complex

    Directory of Open Access Journals (Sweden)

    Tsai-Tsen Liao

    2016-01-01

    Full Text Available Let-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B, ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B.

  19. Cryo-EM of Mitotic Checkpoint Complex-Bound APC/C Reveals Reciprocal and Conformational Regulation of Ubiquitin Ligation.

    Science.gov (United States)

    Yamaguchi, Masaya; VanderLinden, Ryan; Weissmann, Florian; Qiao, Renping; Dube, Prakash; Brown, Nicholas G; Haselbach, David; Zhang, Wei; Sidhu, Sachdev S; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A

    2016-08-18

    The mitotic checkpoint complex (MCC) coordinates proper chromosome biorientation on the spindle with ubiquitination activities of CDC20-activated anaphase-promoting complex/cyclosome (APC/C(CDC20)). APC/C(CDC20) and two E2s, UBE2C and UBE2S, catalyze ubiquitination through distinct architectures for linking ubiquitin (UB) to substrates and elongating polyUB chains, respectively. MCC, which contains a second molecule of CDC20, blocks APC/C(CDC20)-UBE2C-dependent ubiquitination of Securin and Cyclins, while differentially determining or inhibiting CDC20 ubiquitination to regulate spindle surveillance, checkpoint activation, and checkpoint termination. Here electron microscopy reveals conformational variation of APC/C(CDC20)-MCC underlying this multifaceted regulation. MCC binds APC/C-bound CDC20 to inhibit substrate access. However, rotation about the CDC20-MCC assembly and conformational variability of APC/C modulate UBE2C-catalyzed ubiquitination of MCC's CDC20 molecule. Access of UBE2C is limiting for subsequent polyubiquitination by UBE2S. We propose that conformational dynamics of APC/C(CDC20)-MCC modulate E2 activation and determine distinctive ubiquitination activities as part of a response mechanism ensuring accurate sister chromatid segregation. PMID:27522463

  20. Crystal structure of the conserved herpesvirus fusion regulator complex gH—gL

    Energy Technology Data Exchange (ETDEWEB)

    Chowdary, Tirumala K.; Cairns, Tina M.; Atanasiu, Doina; Cohen, Gary H.; Eisenberg, Roselyn J.; Heldwein, Ekaterina E. [UPENN; (Tufts-MED)

    2015-02-09

    Herpesviruses, which cause many incurable diseases, infect cells by fusing viral and cellular membranes. Whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpesviruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH–gL, plus other nonconserved components. gB is a class III viral fusogen, but unlike other members of its class, it does not function alone. We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2. gH–gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH–gL activates gB for fusion, possibly through direct binding. Formation of a gB–gH–gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB–gH–gL interface a promising antiviral target.

  1. Photosynthate Regulation of the Root System Architecture Mediated by the Heterotrimeric G Protein Complex in Arabidopsis.

    Science.gov (United States)

    Mudgil, Yashwanti; Karve, Abhijit; Teixeira, Paulo J P L; Jiang, Kun; Tunc-Ozdemir, Meral; Jones, Alan M

    2016-01-01

    Assimilate partitioning to the root system is a desirable developmental trait to control but little is known of the signaling pathway underlying partitioning. A null mutation in the gene encoding the Gβ subunit of the heterotrimeric G protein complex, a nexus for a variety of signaling pathways, confers altered sugar partitioning in roots. While fixed carbon rapidly reached the roots of wild type and agb1-2 mutant seedlings, agb1 roots had more of this fixed carbon in the form of glucose, fructose, and sucrose which manifested as a higher lateral root density. Upon glucose treatment, the agb1-2 mutant had abnormal gene expression in the root tip validated by transcriptome analysis. In addition, PIN2 membrane localization was altered in the agb1-2 mutant. The heterotrimeric G protein complex integrates photosynthesis-derived sugar signaling incorporating both membrane-and transcriptional-based mechanisms. The time constants for these signaling mechanisms are in the same range as photosynthate delivery to the root, raising the possibility that root cells are able to use changes in carbon fixation in real time to adjust growth behavior. PMID:27610112

  2. P120-Catenin Regulates Early Trafficking Stages of the N-Cadherin Precursor Complex.

    Directory of Open Access Journals (Sweden)

    Diana P Wehrendt

    Full Text Available It is well established that binding of p120 catenin to the cytoplasmic domain of surface cadherin prevents cadherin endocytosis and degradation, contributing to cell-cell adhesion. In the present work we show that p120 catenin bound to the N-cadherin precursor, contributes to its anterograde movement from the endoplasmic reticulum (ER to the Golgi complex. In HeLa cells, depletion of p120 expression, or blocking its binding to N-cadherin, increased the accumulation of the precursor in the ER, while it decreased the localization of mature N-cadherin at intercellular junctions. Reconstitution experiments in p120-deficient SW48 cells with all three major isoforms of p120 (1, 3 and 4 had similar capacity to promote the processing of the N-cadherin precursor to the mature form, and its localization at cell-cell junctions. P120 catenin and protein tyrosine phosphatase PTP1B facilitated the recruitment of the N-ethylmaleimide sensitive factor (NSF, an ATPase involved in vesicular trafficking, to the N-cadherin precursor complex. Dominant negative NSF E329Q impaired N-cadherin trafficking, maturation and localization at cell-cell junctions. Our results uncover a new role for p120 catenin bound to the N-cadherin precursor ensuring its trafficking through the biosynthetic pathway towards the cell surface.

  3. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

    LENUS (Irish Health Repository)

    Bergin, David A

    2010-12-01

    Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

  4. WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

    OpenAIRE

    Jia, Da; Gomez, Timothy S.; Metlagel, Zoltan; Umetani, Junko; Otwinowski, Zbyszek; Rosen, Michael K.; BILLADEAU, DANIEL D.

    2010-01-01

    We recently showed that the Wiskott–Aldrich syndrome protein (WASP) family member, WASH, localizes to endosomal subdomains and regulates endocytic vesicle scission in an Arp2/3-dependent manner. Mechanisms regulating WASH activity are unknown. Here we show that WASH functions in cells within a 500 kDa core complex containing Strumpellin, FAM21, KIAA1033 (SWIP), and CCDC53. Although recombinant WASH is constitutively active toward the Arp2/3 complex, the reconstituted core assembly is inhibite...

  5. The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels

    Directory of Open Access Journals (Sweden)

    Anne-Cécile eBoulay

    2015-02-01

    Full Text Available Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet, around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction protein Connexin 43 and 30 (Cx43 and Cx30 allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30Δ/Δ, we showed that absence of Cx30 does not affect blood-brain barrier (BBB organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding γ-Sarcoglycan (SG, a member of the Dystrophin-associated protein complex (DAPC connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30T5M/T5M mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the expression of other Sarcoglycan complex (SGC molecules in the cerebrovascular system and showed the presence of α-, β-, δ-, γ-, ε- and ζ- SG, as well as Sarcospan. Their expression was however not modified in Cx30Δ/Δ. These results suggest that a full SGC might be present in the cerebrovascular system, and that expression of one of its member, γ-Sarcoglycan, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions.

  6. The Energy Markets' complexity and the need for a multilevel regulation

    International Nuclear Information System (INIS)

    The energy markets are very complex, because, on the one hand, they imply several different activities and, on the other hand, they involve various levels of government. The energy market is divided indeed in different segments: supply (generation or purchasing), transmission, distribution and sale, which are allocated at different levels of government, from the international and European level (with reference to the security of energy supply), to the local level (with specific regard to the distribution and sale). This complexity makes the energy sector particularly critical, under the pressure of political interests and economical needs. Another sensitive point is linked with the environmental protection, since the consumption of energy is one of the most polluting human activities, and the demand of energy is growing up together with the economical growth of the developing Countries. This problem is increasingly discussed at the international level, with reference to the climate change issue, in order to plan a sustainable development for the whole globe: because of it, the Kyoto Protocol was issued within the United Nation Framework Convention on Climate Change. It establishes legally binding commitments for the reduction of four greenhouse gases for all the 183 ratifying Countries, according the principle of common but differentiated responsibilities, and provides for the promotion of renewable energy. The European Union ratified the Protocol implementing the relative obligations through, for instance, the creation of the EU Emissions Trading Scheme (ETS). The European Union most of all addressed the competitive issue, since the 70s, in order to achieve the result to create a free energy market in Europe. The last results of the European energy policy were the directives on electricity and natural gas in 2004, that imposed the complete opening of the energy markets in almost all the European Countries (with few exceptions). The implementation of the European

  7. An integrated RNA-Seq and network study reveals a complex regulation process of rice embryo during seed germination.

    Science.gov (United States)

    Wei, Ting; He, Zilong; Tan, XinYu; Liu, Xue; Yuan, Xiao; Luo, Yingfeng; Hu, Songnian

    2015-08-14

    Seed germination is a crucial stage for plant development and agricultural production. To investigate its complex regulation process, the RNA-Seq study of rice embryo was conducted at three time points of 0, 12 and 48 h post imbibition (HPI). Dynamic transcriptional alterations were observed, especially in the early stage (0-12 HPI). Seed related genes, especially those encoding desiccation inducible proteins and storage reserves in embryo, decreased drastically after imbibition. The expression profiles of phytohormone related genes indicated distinct roles of abscisic acid (ABA), gibberellin (GA) and brassinosteroid (BR) in germination. Moreover, network analysis revealed the importance of protein phosphorylation in phytohormone interactions. Network and gene ontology (GO) analyses suggested that transcription factors (TFs) played a regulatory role in functional transitions during germination, and the enriched TF families at 0 HPI implied a regulation of epigenetic modification in dry seeds. In addition, 35 germination-specific TF genes in embryo were identified and seven genes were verified by qRT-PCR. Besides, enriched TF binding sites (TFBSs) supported physiological changes in germination. Overall, this study expands our comprehensive knowledge of multiple regulation factors underlying rice seed germination. PMID:26116530

  8. Magnetically Regulated Star Formation in 3D: The Case of Taurus Molecular Cloud Complex

    CERN Document Server

    Nakamura, Fumitaka

    2008-01-01

    We carry out three-dimensional MHD simulations of star formation in turbulent, magnetized clouds, including ambipolar diffusion and feedback from protostellar outflows. The calculations focus on relatively diffuse clouds threaded by a strong magnetic field capable of resisting severe tangling by turbulent motions and retarding global gravitational contraction in the cross-field direction. They are motivated by observations of the Taurus molecular cloud complex (and, to a lesser extent, Pipe Nebula), which shows an ordered large-scale magnetic field, as well as elongated condensations that are generally perpendicular to the large-scale field. We find that stars form in earnest in such clouds when enough material has settled gravitationally along the field lines that the mass-to-flux ratios of the condensations approach the critical value. Only a small fraction (of order 1% or less) of the nearly magnetically-critical, condensed material is turned into stars per local free-fall time, however. The slow star form...

  9. Structure, Function, and Regulation of Antenna Complexes of Green Photosynthetic Bacteria; FINAL

    International Nuclear Information System (INIS)

    This project is concerned with the structure and function of the chlorosome antennas found in green photosynthetic bacteria. Chlorosomes are ellipsoidal structures attached to the cytoplasmic side of the inner cell membrane. These antenna complexes provide a very large absorption cross section for light capture. Evidence is overwhelming that the chlorosome represents a very different type of antenna from that found in any other photosynthetic system yet studied. It is now clear that chlorosomes do not contain traditional pigment-proteins, in which the pigments bind to specific sites on proteins. Instead, the chlorosome pigments are organized in vivo into pigment oligomers in which direct pigment-pigment interactions are of dominant importance. Our group has used a multidisciplinary approach to investigate this unique system, including model systems, ultrafast spectroscopy, molecular biology, protein chemistry and X-ray crystallography

  10. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider.

    Science.gov (United States)

    Schellekens, Huub; Stegemann, Sven; Weinstein, Vera; de Vlieger, Jon S B; Flühmann, Beat; Mühlebach, Stefan; Gaspar, Rogério; Shah, Vinod P; Crommelin, Daan J A

    2014-01-01

    The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well

  11. Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors

    Energy Technology Data Exchange (ETDEWEB)

    Rössler, Oliver G.; Glatzel, Daniel; Thiel, Gerald, E-mail: gerald.thiel@uks.eu

    2015-03-01

    Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as resveratrol-responsive elements. Thus, resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1. - Highlights: • The plant polyphenol resveratrol upregulates Egr-1 expression and activity. • The stimulation of Egr-1 requires the protein kinases ERK and Raf. • Resveratrol treatment upregulates the transcriptional activation potential of Elk-1. • Resveratrol-induced stimulation of Egr-1 requires ternary complex factors. • Two distinct resveratrol-responsive elements were identified.

  12. Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Jung Min; Yun, Sung Ji; Kim, Young Whan; Jin, Seo Yeon; Lee, Hye Sun [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Song, Sang Heon [Department of Internal Medicine, Pusan National University Hospital, Busan (Korea, Republic of); Shin, Hwa Kyoung [Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan (Korea, Republic of); Bae, Sun Sik, E-mail: sunsik@pusan.ac.kr [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of)

    2015-08-14

    Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs.

  13. Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors

    International Nuclear Information System (INIS)

    Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as resveratrol-responsive elements. Thus, resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1. - Highlights: • The plant polyphenol resveratrol upregulates Egr-1 expression and activity. • The stimulation of Egr-1 requires the protein kinases ERK and Raf. • Resveratrol treatment upregulates the transcriptional activation potential of Elk-1. • Resveratrol-induced stimulation of Egr-1 requires ternary complex factors. • Two distinct resveratrol-responsive elements were identified

  14. Regulation of Muscle Pyruvate Dehydrogenase Complex in Insulin Resistance: Effects of Exercise and Dichloroacetate

    Directory of Open Access Journals (Sweden)

    Dumitru Constantin-Teodosiu

    2013-10-01

    Full Text Available Since the mitochondrial pyruvate dehydrogenase complex (PDC controls the rate of carbohydrate oxidation, impairment of PDC activity mediated by high-fat intake has been advocated as a causative factor for the skeletal muscle insulin resistance, metabolic syndrome, and the onset of type 2 diabetes (T2D. There are also situations where muscle insulin resistance can occur independently from high-fat dietary intake such as sepsis, inflammation, or drug administration though they all may share the same underlying mechanism, i.e., via activation of forkhead box family of transcription factors, and to a lower extent via peroxisome proliferator-activated receptors. The main feature of T2D is a chronic elevation in blood glucose levels. Chronic systemic hyperglycaemia is toxic and can lead to cellular dysfunction that may become irreversible over time due to deterioration of the pericyte cell's ability to provide vascular stability and control to endothelial proliferation. Therefore, it may not be surprising that T2D's complications are mainly macrovascular and microvascular related, i.e., neuropathy, retinopathy, nephropathy, coronary artery, and peripheral vascular diseases. However, life style intervention such as exercise, which is the most potent physiological activator of muscle PDC, along with pharmacological intervention such as administration of dichloroacetate or L-carnitine can prove to be viable strategies for treating muscle insulin resistance in obesity and T2D as they can potentially restore whole body glucose disposal.

  15. Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2.

    Science.gov (United States)

    Kinkel, Sarah A; Galeev, Roman; Flensburg, Christoffer; Keniry, Andrew; Breslin, Kelsey; Gilan, Omer; Lee, Stanley; Liu, Joy; Chen, Kelan; Gearing, Linden J; Moore, Darcy L; Alexander, Warren S; Dawson, Mark; Majewski, Ian J; Oshlack, Alicia; Larsson, Jonas; Blewitt, Marnie E

    2015-03-19

    Polycomb repressive complex 2 (PRC2) plays a key role in hematopoietic stem and progenitor cell (HSPC) function. Analyses of mouse mutants harboring deletions of core components have implicated PRC2 in fine-tuning multiple pathways that instruct HSPC behavior, yet how PRC2 is targeted to specific genomic loci within HSPCs remains unknown. Here we use short hairpin RNA-mediated knockdown to survey the function of PRC2 accessory factors that were defined in embryonic stem cells (ESCs) by testing the competitive reconstitution capacity of transduced murine HSPCs. We find that, similar to the phenotype observed upon depletion of core subunit Suz12, depleting Jarid2 enhances the competitive transplantation capacity of both fetal and adult mouse HSPCs. Furthermore, we demonstrate that depletion of JARID2 enhances the in vitro expansion and in vivo reconstitution capacity of human HSPCs. Gene expression profiling revealed common Suz12 and Jarid2 target genes that are enriched for the H3K27me3 mark established by PRC2. These data implicate Jarid2 as an important component of PRC2 that has a central role in coordinating HSPC function. PMID:25645357

  16. Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2

    Science.gov (United States)

    Kinkel, Sarah A.; Galeev, Roman; Flensburg, Christoffer; Keniry, Andrew; Breslin, Kelsey; Gilan, Omer; Lee, Stanley; Liu, Joy; Chen, Kelan; Gearing, Linden J.; Moore, Darcy L.; Alexander, Warren S.; Dawson, Mark; Majewski, Ian J.; Oshlack, Alicia; Larsson, Jonas

    2015-01-01

    Polycomb repressive complex 2 (PRC2) plays a key role in hematopoietic stem and progenitor cell (HSPC) function. Analyses of mouse mutants harboring deletions of core components have implicated PRC2 in fine-tuning multiple pathways that instruct HSPC behavior, yet how PRC2 is targeted to specific genomic loci within HSPCs remains unknown. Here we use short hairpin RNA–mediated knockdown to survey the function of PRC2 accessory factors that were defined in embryonic stem cells (ESCs) by testing the competitive reconstitution capacity of transduced murine HSPCs. We find that, similar to the phenotype observed upon depletion of core subunit Suz12, depleting Jarid2 enhances the competitive transplantation capacity of both fetal and adult mouse HSPCs. Furthermore, we demonstrate that depletion of JARID2 enhances the in vitro expansion and in vivo reconstitution capacity of human HSPCs. Gene expression profiling revealed common Suz12 and Jarid2 target genes that are enriched for the H3K27me3 mark established by PRC2. These data implicate Jarid2 as an important component of PRC2 that has a central role in coordinating HSPC function. PMID:25645357

  17. FER1 and FER2 encoding two ferritin complexes in Chlamydomonas reinhardtii chloroplasts are regulated by iron.

    Science.gov (United States)

    Long, Joanne C; Sommer, Frederik; Allen, Michael D; Lu, Shu-Fen; Merchant, Sabeeha S

    2008-05-01

    Two unlinked genes FER1 and FER2 encoding ferritin subunits were identified in the Chlamydomonas genome. An improved FER2 gene model, built on the basis of manual sequencing and incorporation of unplaced reads, indicated 49% identity between the ferritin subunits. Both FER1 and FER2 transcripts are increased in abundance as iron nutrition is decreased but the pattern for each gene is distinct. Using subunit-specific antibodies, we monitored expression at the protein level. In response to low iron, ferritin1 subunits and the ferritin1 complex are increased in parallel to the increase in FER1 mRNA. Nevertheless, the iron content of the ferritin1 complex is decreased. This suggests that increased expression results in increased capacity for iron binding in the chloroplast of iron-limited cells, which supports a role for ferritin1 as an iron buffer. On the other hand, ferritin2 abundance is decreased in iron-deprived cells, indicative of the operation of iron-nutrition-responsive regulation at the translational or post-translational level for FER2. Both ferritin subunits are plastid localized but ferritin1 is quantitatively recovered in soluble extracts of cells while ferritin2 is found in the particulate fraction. Partial purification of the ferritin1 complex indicates that the two ferritins are associated in distinct complexes and do not coassemble. The ratio of ferritin1 to ferritin2 is 70:1 in iron-replete cells, suggestive of a more dominant role of ferritin1 in iron homeostasis. The Volvox genome contains orthologs of each FER gene, indicating that the duplication of FER genes and potential diversification of function occurred prior to the divergence of species in the Volvocales. PMID:18493046

  18. Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

    Directory of Open Access Journals (Sweden)

    Coderre Terence J

    2009-09-01

    Full Text Available Abstract Background During the chronic stage of Complex Regional Pain Syndrome (CRPS, impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients.

  19. Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism

    Science.gov (United States)

    Lakisic, Goran; Wendling, Olivia; Libertini, Emanuele; Radford, Elizabeth J.; Le Guillou, Morwenna; Champy, Marie-France; Wattenhofer-Donzé, Marie; Soubigou, Guillaume; Ait-Si-Ali, Slimane; Feunteun, Jean; Sorg, Tania; Coppée, Jean-Yves; Ferguson-Smith, Anne C.; Cossart, Pascale; Bierne, Hélène

    2016-01-01

    BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases. PMID:26938916

  20. Cyclophilin E functions as a negative regulator to influenza virus replication by impairing the formation of the viral ribonucleoprotein complex.

    Directory of Open Access Journals (Sweden)

    Zengfu Wang

    Full Text Available BACKGROUND: The nucleoprotein (NP of influenza A virus is a multifunctional protein that plays a critical role in the replication and transcription of the viral genome. Therefore, examining host factors that interact with NP may shed light on the mechanism of host restriction barriers and the tissue tropism of influenza A virus. Here, Cyclophilin E (CypE, a member of the peptidyl-propyl cis-trans isomerase (PPIase family, was found to bind to NP and inhibit viral replication and transcription. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, CypE was found to interact with NP but not with the other components of the viral ribonucleoprotein complex (VRNP: PB1, PB2, and PA. Mutagenesis data revealed that the CypE domain comprised of residues 137-186 is responsible for its binding to NP. Functional analysis results indicated that CypE is a negative regulator in the influenza virus life cycle. Furthermore, knock-down of CypE resulted in increased levels of three types of viral RNA, suggesting that CypE negatively affects viral replication and transcription. Moreover, up-regulation of CypE inhibited the activity of influenza viral polymerase. We determined that the molecular mechanism by which CypE negatively regulates influenza virus replication and transcription is by interfering with NP self-association and the NP-PB1 and NP-PB2 interactions. CONCLUSIONS/SIGNIFICANCE: CypE is a host restriction factor that inhibits the functions of NP, as well as viral replication and transcription, by impairing the formation of the vRNP. The data presented here will help us to better understand the molecular mechanisms of host restriction barriers, host adaptation, and tissue tropism of influenza A virus.

  1. HuR-Regulated mRNAs Associated with Nuclear hnRNP A1-RNP Complexes

    Directory of Open Access Journals (Sweden)

    Apostolia Guialis

    2013-10-01

    Full Text Available Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of immunoselected hnRNP complexes and having a major nuclear localization. Specifically, we present here the application of the RNA-immunoprecipitation (RIP-Chip technology to identify a population of nuclear transcripts associated with hnRNP A1-RNPs as isolated from the nuclear extract of either HuR WT or HuR-depleted (KO mouse embryonic fibroblast (MEF cells. The outcome of this analysis was a list of target genes regulated via HuR for their association (either increased or reduced with the nuclear hnRNP A1-RNP complexes. Real time PCR analysis was applied to validate a selected number of nuclear mRNA transcripts, as well as to identify pre-spliced transcripts (in addition to their mature mRNA counterpart within the isolated nuclear hnRNP A1-RNPs. The differentially enriched mRNAs were found to belong to GO categories relevant to biological processes anticipated for hnRNP A1 and HuR (such as transport, transcription, translation, apoptosis and cell cycle indicating their concerted function in mRNA metabolism.

  2. KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability.

    Science.gov (United States)

    Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L; Hansler, Alex; Hu, Zhaoyang; Roepke, Torsten K; Lerner, Daniel J; Chen, Qiuying; Liu, Li; Zupan, Bojana; Toth, Miklos; Haynes, Robin; Huang, Xiaoping; Demirbas, Didem; Buccafusca, Roberto; Gross, Steven S; Kanda, Vikram A; Berry, Gerard T

    2014-03-01

    Na(+)-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K(+) channel β subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2(-/-) mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na(+)-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but was inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K(+) channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activities of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1 but were suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk. PMID:24595108

  3. Drosophila Torsin Protein Regulates Motor Control and Stress Sensitivity and Forms a Complex with Fragile-X Mental Retardation Protein

    Science.gov (United States)

    Ahn, Hyo-Min; Koh, Young Ho

    2016-01-01

    We investigated unknown in vivo functions of Torsin by using Drosophila as a model. Downregulation of Drosophila Torsin (DTor) by DTor-specific inhibitory double-stranded RNA (RNAi) induced abnormal locomotor behavior and increased susceptibility to H2O2. In addition, altered expression of DTor significantly increased the numbers of synaptic boutons. One important biochemical consequence of DTor-RNAi expression in fly brains was upregulation of alcohol dehydrogenase (ADH). Altered expression of ADH has also been reported in Drosophila Fragile-X mental retardation protein (DFMRP) mutant flies. Interestingly, expression of DFMRP was altered in DTor mutant flies, and DTor and DFMRP were present in the same protein complexes. In addition, DTor and DFMRP immunoreactivities were partially colocalized in several cellular organelles in larval muscles. Furthermore, there were no significant differences between synaptic morphologies of dfmrp null mutants and dfmrp mutants expressing DTor-RNAi. Taken together, our evidences suggested that DTor and DFMRP might be present in the same signaling pathway regulating synaptic plasticity. In addition, we also found that human Torsin1A and human FMRP were present in the same protein complexes, suggesting that this phenomenon is evolutionarily conserved. PMID:27313903

  4. Deguelin regulates nuclear pore complex proteins Nup98 and Nup88 in U937 cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Hong-li LIU; Yan CHEN; Guo-hui CUI; Qiu-ling WU; Jing HE; Wei-hua CHEN; Jian-feng ZHOU

    2005-01-01

    Aim: To investigate the anticancer effects and the molecular mechanisms of deguelin on human U937 leukemia cells, and to explore the underlying mechanism regulating nucleoporin 98 (Nup98) and nucleoporin 88 (Nup88) in vitro. Methods: The effects of deguelin on the growth of U937 cells were studied by MTT assay.The effect of deguelin on the cell cycle of U937 cells was studied by using a propidium iodide method. The localization of the nuclear pore complex proteins Nup98 and Nup88 was investigated by using immunofluorescence and immunoelectron microscopy. The expression of Nup98 and Nup88 in U937 cells was investigated by using flow cytometry and Western blot. Results: The proliferation of U937 cells was inhibited in the deguelin-treated group, with a 24-h IC50 value of 21.61 nmol/L and a 36-h IC50 value of 17.07 nmol/L. U937 cells treated with deguelin had reduced percentages of cells in the G0/G1 phase, whereas cells accumulated in the S and G2/M phases. Nup88 and Nup98 were found on both the nuclear and cytoplasmic sides of the U937 cells by using immunofluorescence and immunoelectron microscopy. The expression of Nup98 was upregulated and that of the Nup88 protein was downregulated in U937 cells treated with deguelin.Conclusion: Deguelin is able to inhibit the proliferation of U937 cells by regulating the cell cycle such that cells are arrested at the S and G2/M phases, so that the proportion of cells in the G0/G1 phase decreases. The antitumor effects of deguelin are related to upregulating the expression of Nup98 and downregulating the expression of Nup88 protein in U937 cells.

  5. Identification of a BET Family Bromodomain/Casein Kinase II/TAF-Containing Complex as a Regulator of Mitotic Condensin Function

    OpenAIRE

    Hyun-Soo Kim; Rituparna Mukhopadhyay; Scott B. Rothbart; Andrea C. Silva; Vincent Vanoosthuyse; Ernest Radovani; Thomas Kislinger; Assen Roguev; Colm J. Ryan; Jiewei Xu; Harlizawati Jahari; Kevin G. Hardwick; Jack F. Greenblatt; Nevan J. Krogan; Jeffrey S. Fillingham

    2014-01-01

    Condensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), casein kinase II (CKII), and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern...

  6. Cyclic AMP (cAMP) Receptor Protein-cAMP Complex Regulates Heparosan Production in Escherichia coli Strain Nissle 1917.

    Science.gov (United States)

    Yan, Huihui; Bao, Feifei; Zhao, Liping; Yu, Yanying; Tang, Jiaqin; Zhou, Xianxuan

    2015-11-01

    Heparosan serves as the starting carbon backbone for the chemoenzymatic synthesis of heparin, a widely used clinical anticoagulant drug. The availability of heparosan is a significant concern for the cost-effective synthesis of bioengineered heparin. The carbon source is known as the pivotal factor affecting heparosan production. However, the mechanism by which carbon sources control the biosynthesis of heparosan is unclear. In this study, we found that the biosynthesis of heparosan was influenced by different carbon sources. Glucose inhibits the biosynthesis of heparosan, while the addition of either fructose or mannose increases the yield of heparosan. Further study demonstrated that the cyclic AMP (cAMP)-cAMP receptor protein (CRP) complex binds to the upstream region of the region 3 promoter and stimulates the transcription of the gene cluster for heparosan biosynthesis. Site-directed mutagenesis of the CRP binding site abolished its capability of binding CRP and eliminated the stimulative effect on transcription. (1)H nuclear magnetic resonance (NMR) analysis was further performed to determine the Escherichia coli strain Nissle 1917 (EcN) heparosan structure and quantify extracellular heparosan production. Our results add to the understanding of the regulation of heparosan biosynthesis and may contribute to the study of other exopolysaccharide-producing strains. PMID:26319872

  7. The axe-txe complex of Enterococcus faecium presents a multilayered mode of toxin-antitoxin gene expression regulation.

    Directory of Open Access Journals (Sweden)

    Lidia Boss

    Full Text Available Multidrug-resistant variants of human pathogens from the genus Enterococcus represent a significant health threat as leading agents of nosocomial infections. The easy acquisition of plasmid-borne genes is intimately involved in the spread of antibiotic resistance in enterococci. Toxin-antitoxin (TA systems play a major role in both maintenance of mobile genetic elements that specify antibiotic resistance, and in bacterial persistence and virulence. Expression of toxin and antitoxin genes must be in balance as inappropriate levels of toxin can be dangerous to the host. The controlled production of toxin and antitoxin is usually achieved by transcriptional autoregulation of TA operons. One of the most prevalent TA modules in enterococcal species is axe-txe which is detected in a majority of clinical isolates. Here, we demonstrate that the axe-txe cassette presents a complex pattern of gene expression regulation. Axe-Txe cooperatively autorepress expression from a major promoter upstream of the cassette. However, an internal promoter that drives the production of a newly discovered transcript from within axe gene combined with a possible modulation in mRNA stability play important roles in the modulation of Axe:Txe ratio to ensure controlled release of the toxin.

  8. hELP3 Subunit of the Elongator Complex Regulates the Transcription of HSP70 Gene in Human Cells

    Institute of Scientific and Technical Information of China (English)

    Qiuju HAN; Xiaozhe HOU; Dongmei SU; Lina PAN; Jizhou DUAN; Liguo CUI; Baiqu HUANG; Jun LU

    2007-01-01

    The human Elongator complex is remarkably similar to its yeast counterpart in several aspects.In a previous study, we analyzed the functions of the human elongation protein 3 (hELP3) subunit of the human Elongator by using an in vivo yeast complementation system. However, direct evidence for hELP3 functions in regulating gene expression in human cells was not obtained. In this study, we used hELP3 antisense oligonucleotide inhibitors to knock down hELP3 gene expression to investigate its function in human 293T cells. The results showed that specific reduction of hELP3 mRNA and protein caused a significant suppression of HSP70-2 gene expression, and this was accompanied by histone H3 hypoacetylation and decreased RNA polymerase Ⅱ density at the HSP70-2 gene. Moreover, the data also showed that hELP3 exerted the transcriptional regulatory function directly through its presence on the HSP70-2 gene. Data presented in this report provide further insight and direct evidence of the functions of hELP3 in HSP70-2 gene transcriptional elongation in human cells.

  9. Light-harvesting complexes in photosystem II regulate glutathione-induced sensitivity of Arabidopsis guard cells to abscisic acid.

    Science.gov (United States)

    Jahan, Md Sarwar; Nozulaidi, Mohd; Khairi, Mohd; Mat, Nashriyah

    2016-05-20

    Light-harvesting complexes (LHCs) in photosystem II (PSII) regulate glutathione (GSH) functions in plants. To investigate whether LHCs control GSH biosynthesis that modifies guard cell abscisic acid (ABA) sensitivity, we evaluated GSH content, stomatal aperture, reactive oxygen species (ROS), weight loss and plant growth using a ch1-1 mutant that was defective of LHCs and compared this with wild-type (WT) Arabidopsis thaliana plants. Glutathione monoethyl ester (GSHmee) increased but 1-chloro-2,4 dinitrobenzene (CDNB) decreased the GSH content in the guard cells. The guard cells of the ch1-1 mutants accumulated significantly less GSH than the WT plants. The guard cells of the ch1-1 mutants also showed higher sensitivity to ABA than the WT plants. The CDNB treatment increased but the GSHmee treatment decreased the ABA sensitivity of the guard cells without affecting ABA-induced ROS production. Dark and light treatments altered the GSH content and stomatal aperture of the guard cells of ch1-1 and WT plants, irrespective of CDNB and GSHmee. The ch1-1 mutant contained fewer guard cells and displayed poor growth, late flowering and stumpy weight loss compared with the WT plants. This study suggests that defective LHCs reduced the GSH content in the guard cells and increased sensitivity to ABA, resulting in stomatal closure. PMID:26970687

  10. l-Valine Production during Growth of Pyruvate Dehydrogenase Complex- Deficient Corynebacterium glutamicum in the Presence of Ethanol or by Inactivation of the Transcriptional Regulator SugR▿

    OpenAIRE

    Blombach, Bastian; Arndt, Annette; Auchter, Marc; Eikmanns, Bernhard J.

    2008-01-01

    Pyruvate dehydrogenase complex-deficient strains of Corynebacterium glutamicum produce l-valine from glucose only after depletion of the acetate required for growth. Here we show that inactivation of the DeoR-type transcriptional regulator SugR or replacement of acetate by ethanol already in course of the growth phase results in efficient l-valine production.

  11. Genome-wide screening of regulators of catalase expression: role of a transcription complex and histone and tRNA modification complexes on adaptation to stress

    OpenAIRE

    Garc??a Rodr??guez, Patricia; Encinar del Dedo, Javier; Ayt?? del Olmo, Jos??; Hidalgo Hernando, Elena

    2016-01-01

    In response to environmental cues, the mitogen-activated protein kinase Sty1-driven signaling cascade activates hundreds of genes to induce a robust anti-stress cellular response in fission yeast. Thus, upon stress imposition Sty1 transiently accumulates in the nucleus where it up-regulates transcription through the Atf1 transcription factor. Several regulators of transcription and translation have been identified as important to mount an integral response to oxidative stress, such as the Spt...

  12. Chaperonin containing T-complex polypeptide subunit eta (CCT-eta is a specific regulator of fibroblast motility and contractility.

    Directory of Open Access Journals (Sweden)

    Latha Satish

    Full Text Available Integumentary wounds in mammalian fetuses heal without scar; this scarless wound healing is intrinsic to fetal tissues and is notable for absence of the contraction seen in postnatal (adult wounds. The precise molecular signals determining the scarless phenotype remain unclear. We have previously reported that the eta subunit of the chaperonin containing T-complex polypeptide (CCT-eta is specifically reduced in healing fetal wounds in a rabbit model. In this study, we examine the role of CCT-eta in fibroblast motility and contractility, properties essential to wound healing and scar formation. We demonstrate that CCT-eta (but not CCT-beta is underexpressed in fetal fibroblasts compared to adult fibroblasts. An in vitro wound healing assay demonstrated that adult fibroblasts showed increased cell migration in response to epidermal growth factor (EGF and platelet derived growth factor (PDGF stimulation, whereas fetal fibroblasts were unresponsive. Downregulation of CCT-eta in adult fibroblasts with short inhibitory RNA (siRNA reduced cellular motility, both basal and growth factor-induced; in contrast, siRNA against CCT-beta had no such effect. Adult fibroblasts were more inherently contractile than fetal fibroblasts by cellular traction force microscopy; this contractility was increased by treatment with EGF and PDGF. CCT-eta siRNA inhibited the PDGF-induction of adult fibroblast contractility, whereas CCT-beta siRNA had no such effect. In each of these instances, the effect of downregulating CCT-eta was to modulate the behavior of adult fibroblasts so as to more closely approximate the characteristics of fetal fibroblasts. We next examined the effect of CCT-eta modulation on alpha-smooth muscle actin (alpha-SMA expression, a gene product well known to play a critical role in adult wound healing. Fetal fibroblasts were found to constitutively express less alpha-SMA than adult cells. Reduction of CCT-eta with siRNA had minimal effect on cellular

  13. Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts. : CK1 negatively regulates the E-cadherin complex

    OpenAIRE

    Dupre-Crochet, Sophie; Figueroa, Angelica; Hogan, Catherine; Ferber, Emma,; Uli Bialucha, Carl; Adams, Joanna; Richardson, Emily,; Fujita, Yasuyuki

    2007-01-01

    Cadherins are the most crucial membrane proteins for the formation of tight and compact cell-cell contacts. Cadherin-based cell-cell adhesions are dynamically established and/or disrupted during various physiological and pathological processes. However, the molecular mechanisms that regulate cell-cell contacts are not fully understood. In this paper, we report a novel functional role of casein kinase 1 (CK1) in the regulation of cell-cell contacts. Firstly, we observed that IC261, a specific ...

  14. Developmental regulation and complex organization of the promoter of the non-coding hsr gene of Drosophila melanogaster

    Indian Academy of Sciences (India)

    S C Lakhotia; T K Rajendra; K V Prasanth

    2001-03-01

    The nucleus-limited large non-coding hsrω-n RNA product of the 93D or the hsrω gene of Drosophila melanogaster binds to a variety of RNA-binding proteins involved in nuclear RNA processing. We examined the developmental and heat shock induced expression of this gene by in situ hybridization of nonradioactively labelled riboprobe to cellular transcripts in intact embryos, larval and adult somatic tissues of wild type and an enhancer-trap line carrying the hsrω05241 allele due to insertion of a P-LacZ-rosy+ transposon at — 130 bp position of the hsrω promoter. We also examined LacZ expression in the enhancer-trap line and in two transgenic lines carrying different lengths of the hsrω promoter upstream of the LacZ reporter. The hsrω gene is expressed widely at all developmental stages; in later embryonic stages, its expression in the developing central nervous system was prominent. In spite of insertion of a big transposon in the promoter, expression of the hsrω05241 allele in the enhancer-trap line, as revealed by in situ hybridization to hsrω transcripts in cells, was similar to that of the wild type allele in all the embryonic, larval and adult somatic tissues examined. Expression of the LacZ gene in this enhancer-trap line was similar to that of the hsrω RNA in all diploid cell types in embryos and larvae but in the polytene cells, the LacZ gene did not express at all, neither during normal development nor after heat shock. Comparison of the expression patterns of hsrω gene and those of the LacZ reporter gene under its various promoter regions in the enhancer-trap and transgenic lines revealed a complex pattern of regulation, which seems to be essential for its dynamically varying expression in diverse cell types.

  15. Modernization of the Mechanism of State Regulation of Regional Russian Agro-Industrial Complex Under New Social and Economic Constructs

    Directory of Open Access Journals (Sweden)

    Babich Tatyana Vladimirovna

    2014-11-01

    Full Text Available The article highlights the obstacles in building the necessary amount of food and in ensuring the full import substitution based on the efficient use of the available resources: Russia’s lagging behind economically developed countries in the technical and technological modernization of agricultural sectors; low-rate processes of production intensification in the ongoing targeted programs; insufficient use of existing competitive advantages of individual regions. Consequently, in the current environment of increased competition between agricultural commodity producers of different countries, the mechanism of Russian agriculture state support needs to be improved. Based on the analysis of threats due to Russia’s entry into the WTO in terms of sanctions imposed by the European Union in relation to the events in Ukraine, the authors proposed and justified measures aimed at modernizing the mechanism of state regulation of regional agriculture of Russia in the new economic and social constructs. In order to develop a high-tech industrial chain in agricultural business, the authors have developed the mechanism of functioning production and logistics agrocenter organized to bring together competences and cooperation between enterprises in different industries. Agrocenter is a special investment area, which should be provided with all necessary infrastructure and professional management for subsequent placement on the same territory: commercial resident working in the agricultural sector; commercial residents working in the transport and warehouse complex; financial market enterprises and organizations for quality control and certification; consulting firms for the development and promotion agrocenter; consumers of agricultural products: manufacturing, wholesale and retail, commercial enterprises, social sphere.

  16. G1/S-regulated E2F-containing protein complexes bind to the mouse thymidine kinase gene promoter

    DEFF Research Database (Denmark)

    Dou, Q P; Zhao, S; Levin, A H;

    1994-01-01

    complexes were also investigated. Studies using specific antibodies revealed that p107, a retinoblastoma-like protein, was present in both E2F-G0/G1 and E2F.S, whereas cyclin E.cyclin A.cdk2 were only present in E2F.S complex(es). These data suggest that removal of the p107-containing E2F.G0/G1 complex, a...

  17. "Hypothesis for the Modern RNA World": A pervasive Non-coding RNA-Based Genetic Regulation is a Prerequisite for the Emergence of Multicellular Complexity

    Science.gov (United States)

    Lozada-Chávez, Irma; Stadler, Peter F.; Prohaska, Sonja J.

    2011-12-01

    The transitions to multicellularity mark the most pivotal and distinctive events in life's history on Earth. Although several transitions to "simple" multicellularity (SM) have been recorded in both bacterial and eukaryotic clades, transitions to complex multicellularity (CM) have only happened a few times in eukaryotes. A large number of cell types (associated with large body size), increased energy consumption per gene expressed, and an increment of non-protein-coding DNA positively correlate with CM. These three factors can indeed be understood as the causes and consequences of the regulation of gene expression. Here, we discuss how a vast expansion of non-protein-coding RNA (ncRNAs) regulators rather than large numbers of novel protein regulators can easily contribute to the emergence of CM. We also propose that the evolutionary advantage of RNA-based gene regulation derives from the robustness of the RNA structure that makes it easy to combine genetic drift with functional exploration. We describe a model which aims to explain how the evolutionary dynamic of ncRNAs becomes dominated by the accessibility of advantageous mutations to innovate regulation in complex multicellular organisms. The information and models discussed here outline the hypothesis that pervasive ncRNA-based regulatory systems, only capable of being expanded and explored in higher eukaryotes, are prerequisite to complex multicellularity. Thereby, regulatory RNA molecules in Eukarya have allowed intensification of morphological complexity by stabilizing critical phenotypes and controlling developmental precision. Although the origin of RNA on early Earth is still controversial, it is becoming clear that once RNA emerged into a protocellular system, its relevance within the evolution of biological systems has been greater than we previously thought.

  18. Leucine-induced activation of translational initiation is partly regulated by the branched-chain α-keto acid dehydrogenase complex in C2C12 cells

    International Nuclear Information System (INIS)

    Branched-chain amino acid leucine has been shown to activate the translational regulators through the mammalian target of rapamycin. However, the leucine's effects are self-limiting because leucine promotes its own disposal by an oxidative pathway. The irreversible and rate-limiting step in the leucine oxidation pathway is catalyzed by the branched-chain α-keto acid dehydrogenase (BCKDH) complex. The complex contains E1 (α2β2), E2, and E3 subunits, and its activity is abolished by phosphorylation of the E1α subunit by BCKDH kinase. The relationship between the activity of BCKDH complex and leucine-mediated activation of the protein translation was investigated using the technique of RNA interference. The activity of BCKDH complex in C2C12 cell was modulated by transfection of small interfering RNA (siRNA) for BCKDH E2 subunit or BCKDH kinase. Transfection of siRNAs decreased the mRNA expression and protein amount of corresponding gene. Suppression of either E2 subunit or kinase produced opposite effects on the cell proliferation and the activation of translational regulators by leucine. Suppression of BCKDH kinase for 48 h resulted in decreasing cell proliferation. In contrast, E2 suppression led to increased amount of total cellular protein. The phosphorylation of p70 S6 kinase by leucine was increased in E2-siRNA transfected C2C12 cells, whereas the leucine's effect was diminished in kinase-siRNA transfected cells. These results suggest that the activation of the translational regulators by leucine was partly regulated by the activity of BCKDH complex

  19. Cell Wall N-Linked Mannoprotein Biosynthesis Requires Goa1p, a Putative Regulator of Mitochondrial Complex I in Candida albicans

    OpenAIRE

    She, Xiaodong; Calderone, Richard; Kruppa, Michael; Lowman, Douglas; Williams, David; Zhang, Lili; Gao, Ying; Khamooshi, Kasra; Liu, Weida; Li, Dongmei

    2016-01-01

    The Goa1p of Candida albicans regulates mitochondrial Complex I (CI) activities in its role as a putative CI accessory protein. Transcriptional profiling of goa1∆ revealed a down regulation of genes encoding β-oligomannosyl transferases. Herein, we present data on cell wall phenotypes of goa1∆ (strain GOA31). We used transmission electron microscopy (TEM), GPC/MALLS, and NMR to compare GOA31 to a gene-reconstituted strain (GOA32) and parental cells. We note by TEM a reduction in outer wall fi...

  20. The fission yeast protein p73res2 is an essential component of the mitotic MBF complex and a master regulator of meiosis.

    OpenAIRE

    Ayté, J; Leis, J F; DeCaprio, J A

    1997-01-01

    Depending on environmental conditions, Schizosaccharomyces pombe can remain in the stationary phase or enter into either premitotic or premeiotic DNA synthesis. This decision point is known as Start. In the mitotic cell cycle, regulation of G1/S-specific gene expression is dependent upon the MBF (Mlu1 binding factor) complex, known to contain p85cdc10 and p72res1. Here we demonstrate that p73res2 controls cell cycle progression via its participation in the MBF complex, interacting directly wi...

  1. Crystallization and preliminary crystallographic analysis of the transcriptional regulator RfaH from Escherichia coli and its complex with ops DNA

    International Nuclear Information System (INIS)

    The E. coli transcriptional regulator RfaH was cloned, expressed, purified and crystallized and the complex of RfaH with its target DNA oligonucleotide was cocrystallized. Complete diffraction data sets were collected for the apo protein and its nucleic acid complex at 2.4 and at 1.6 Å resolution, respectively. The bacterial transcriptional factor and virulence regulator RfaH binds to rapidly moving transcription elongation complexes through specific interactions with the exposed segment of the non-template DNA strand. To elucidate this unusual mechanism of recruitment, determination of the three-dimensional structure of RfaH and its complex with DNA was initiated. To this end, the Escherichia coli rfaH gene was cloned and expressed. The purified protein was crystallized by the sitting-drop vapor-diffusion technique. The space group was P6122 or P6522, with unit-cell parameters a = b = 45.46, c = 599.93 Å. A complex of RfaH and a nine-nucleotide oligodeoxyribonucleotide was crystallized by the same technique, but under different crystallization conditions, yielding crystals that belonged to space group P1 (unit-cell parameters a = 36.79, b = 44.01, c = 62.37 Å, α = 80.62, β = 75.37, γ = 75.41°). Complete diffraction data sets were collected for RfaH and its complex with DNA at 2.4 and 1.6 Å resolution, respectively. Crystals of selenomethionine-labeled proteins in both crystal forms were obtained by cross-microseeding using the native microcrystals. The structure determination of RfaH and its complex with DNA is in progress

  2. Crystallization and preliminary crystallographic analysis of the transcriptional regulator RfaH from Escherichia coli and its complex with ops DNA

    Energy Technology Data Exchange (ETDEWEB)

    Vassylyeva, Marina N. [Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 402B Kaul Genetics Building, 720 20th Street South, Birmingham, AL 35294 (United States); Svetlov, Vladimir [Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (United States); Klyuyev, Sergiy; Devedjiev, Yancho D. [Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 402B Kaul Genetics Building, 720 20th Street South, Birmingham, AL 35294 (United States); Artsimovitch, Irina, E-mail: artsimovitch.1@osu.edu [Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (United States); Vassylyev, Dmitry G., E-mail: artsimovitch.1@osu.edu [Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 402B Kaul Genetics Building, 720 20th Street South, Birmingham, AL 35294 (United States)

    2006-10-01

    The E. coli transcriptional regulator RfaH was cloned, expressed, purified and crystallized and the complex of RfaH with its target DNA oligonucleotide was cocrystallized. Complete diffraction data sets were collected for the apo protein and its nucleic acid complex at 2.4 and at 1.6 Å resolution, respectively. The bacterial transcriptional factor and virulence regulator RfaH binds to rapidly moving transcription elongation complexes through specific interactions with the exposed segment of the non-template DNA strand. To elucidate this unusual mechanism of recruitment, determination of the three-dimensional structure of RfaH and its complex with DNA was initiated. To this end, the Escherichia coli rfaH gene was cloned and expressed. The purified protein was crystallized by the sitting-drop vapor-diffusion technique. The space group was P6{sub 1}22 or P6{sub 5}22, with unit-cell parameters a = b = 45.46, c = 599.93 Å. A complex of RfaH and a nine-nucleotide oligodeoxyribonucleotide was crystallized by the same technique, but under different crystallization conditions, yielding crystals that belonged to space group P1 (unit-cell parameters a = 36.79, b = 44.01, c = 62.37 Å, α = 80.62, β = 75.37, γ = 75.41°). Complete diffraction data sets were collected for RfaH and its complex with DNA at 2.4 and 1.6 Å resolution, respectively. Crystals of selenomethionine-labeled proteins in both crystal forms were obtained by cross-microseeding using the native microcrystals. The structure determination of RfaH and its complex with DNA is in progress.

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

    Science.gov (United States)

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

    2012-01-01

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

  4. Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling

    OpenAIRE

    Roberts, David M.; Pronobis, Mira I.; Poulton, John S; Waldmann, Jon D.; Stephenson, Elise M.; Hanna, Shahnaz; Peifer, Mark

    2011-01-01

    Negatively regulating signaling by targeting key effectors for ubiquitina­tion/destruction is essential for development and oncogenesis. The tumor suppressor adenomatous polyposis coli (APC), an essential negative regulator of Wnt signaling, provides a paradigm. APC mutations occur in most colon cancers. Acting in the “destruction complex” with Axin, glycogen synthase kinase 3, and casein kinase, APC targets ßcatenin (ßcat) for phosphorylation and recognition by an E3 ubiquitin-ligase. Despit...

  5. GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes

    OpenAIRE

    Orlandi, Cesare; Posokhova, Ekaterina; Masuho, Ikuo; Ray, Thomas A; Hasan, Nazarul; Gregg, Ronald G; Martemyanov, Kirill A.

    2012-01-01

    The extent and temporal characteristics of G protein–coupled receptor (GPCR) signaling are shaped by the regulator of G protein signaling (RGS) proteins, which promote G protein deactivation. With hundreds of GPCRs and dozens of RGS proteins, compartmentalization plays a key role in establishing signaling specificity. However, the molecular details and mechanisms of this process are poorly understood. In this paper, we report that the R7 group of RGS regulators is controlled by interaction wi...

  6. Cell Cycle-dependent Regulation of the Forkhead Transcription Factor FOXK2 by CDK·Cyclin Complexes*

    OpenAIRE

    Marais, Anett; Ji, Zongling; Child, Emma S.; Krause, Eberhard; Mann, David J.; Sharrocks, Andrew D.

    2010-01-01

    Several mammalian forkhead transcription factors have been shown to impact on cell cycle regulation and are themselves linked to cell cycle control systems. Here we have investigated the little studied mammalian forkhead transcription factor FOXK2 and demonstrate that it is subject to control by cell cycle-regulated protein kinases. FOXK2 exhibits a periodic rise in its phosphorylation levels during the cell cycle, with hyperphosphorylation occurring in mitotic cells. Hyperphosphorylation occ...

  7. A complex genetic switch involving overlapping divergent promoters and DNA looping regulates expression of conjugation genes of a gram-positive plasmid.

    Directory of Open Access Journals (Sweden)

    Gayetri Ramachandran

    2014-10-01

    Full Text Available Plasmid conjugation plays a significant role in the dissemination of antibiotic resistance and pathogenicity determinants. Understanding how conjugation is regulated is important to gain insights into these features. Little is known about regulation of conjugation systems present on plasmids from Gram-positive bacteria. pLS20 is a native conjugative plasmid from the Gram-positive bacterium Bacillus subtilis. Recently the key players that repress and activate pLS20 conjugation have been identified. Here we studied in detail the molecular mechanism regulating the pLS20 conjugation genes using both in vivo and in vitro approaches. Our results show that conjugation is subject to the control of a complex genetic switch where at least three levels of regulation are integrated. The first of the three layers involves overlapping divergent promoters of different strengths regulating expression of the conjugation genes and the key transcriptional regulator RcoLS20. The second layer involves a triple function of RcoLS20 being a repressor of the main conjugation promoter and an activator and repressor of its own promoter at low and high concentrations, respectively. The third level of regulation concerns formation of a DNA loop mediated by simultaneous binding of tetrameric RcoLS20 to two operators, one of which overlaps with the divergent promoters. The combination of these three layers of regulation in the same switch allows the main conjugation promoter to be tightly repressed during conditions unfavorable to conjugation while maintaining the sensitivity to accurately switch on the conjugation genes when appropriate conditions occur. The implications of the regulatory switch and comparison with other genetic switches involving DNA looping are discussed.

  8. Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity.

    Science.gov (United States)

    Kourtidis, Antonis; Ngok, Siu P; Pulimeno, Pamela; Feathers, Ryan W; Carpio, Lomeli R; Baker, Tiffany R; Carr, Jennifer M; Yan, Irene K; Borges, Sahra; Perez, Edith A; Storz, Peter; Copland, John A; Patel, Tushar; Thompson, E Aubrey; Citi, Sandra; Anastasiadis, Panos Z

    2015-09-01

    E-cadherin and p120 catenin (p120) are essential for epithelial homeostasis, but can also exert pro-tumorigenic activities. Here, we resolve this apparent paradox by identifying two spatially and functionally distinct junctional complexes in non-transformed polarized epithelial cells: one growth suppressing at the apical zonula adherens (ZA), defined by the p120 partner PLEKHA7 and a non-nuclear subset of the core microprocessor components DROSHA and DGCR8, and one growth promoting at basolateral areas of cell-cell contact containing tyrosine-phosphorylated p120 and active Src. Recruitment of DROSHA and DGCR8 to the ZA is PLEKHA7 dependent. The PLEKHA7-microprocessor complex co-precipitates with primary microRNAs (pri-miRNAs) and possesses pri-miRNA processing activity. PLEKHA7 regulates the levels of select miRNAs, in particular processing of miR-30b, to suppress expression of cell transforming markers promoted by the basolateral complex, including SNAI1, MYC and CCND1. Our work identifies a mechanism through which adhesion complexes regulate cellular behaviour and reveals their surprising association with the microprocessor. PMID:26302406

  9. PRC2 regulates RNA polymerase III transcribed non-translated RNA gene transcription through EZH2 and SUZ12 interaction with TFIIIC complex

    Institute of Scientific and Technical Information of China (English)

    Liu Chang; Li Shuai; Dai Xiaoyan; Ma Ji; Wan Junhu; Jiang Hao; Wang Peng; Liu Zhaoli; Zhang Hongquan

    2015-01-01

    Polycomb repression complex 2 ( PRC2 ) component EZH2 tri-methylates H3 K27 and exerts ep-igenetic repression on target gene expression. EZH2-mediated epigenetic control of RNA polymerase II(Pol II) transcribed coding gene transcription has been well established. However, little is known about EZH2-mediated epigenetic regulation of RNA polymerase III( Pol III) transcription. Here we present a paradigm that EZH2 is in-volved in the repression of Pol III transcription via interaction with transcriptional factor complex IIIC ( TFIIIC ) . EZH2 and H3K27 me3 cooccupy the promoter of tRNATyr, 5S rRNA and 7SL RNA genes. Depletion of EZH2 or inhibition of EZH2 methyl transferase activity led to upregulation of Pol III target gene transcription. EZH2-media-ted repression of Pol III transcribed gene expression requires presence of SUZ12 . SUZ12 was able to interact with TFIIIC complex and knockdown of SUZ12 decreased occupancy of EZH2 and H3 K27 me3 at the promoter of Pol III target genes. Our findings pointed out a previously unidentified role of PRC2 complex in suppressing transcription of Pol III transcribed non-translated RNA genes, putting Pol III on a new layer of epigenetic regulation.

  10. Regulating with imagery and the complexity of basic emotions. Comment on "The quartet theory of human emotions: An integrative and neurofunctional model" by S. Koelsch et al.

    Science.gov (United States)

    Meyer, Marcel; Kuchinke, Lars

    2015-06-01

    Literature, music and the arts have long attested to the complexity of human emotions. Hitherto, psychological and biological theories of emotions have largely neglected this rich heritage. In their review Koelsch and colleagues [1] have embarked upon the pioneering endeavour of integrating the diverse perspectives in emotion research. Noting that the focus of prior neurobiological theories relies mainly on animal studies, the authors sought to complement this body of research with a model of complex ("moral") emotions in humans (henceforth: complex emotions). According to this novel framework, there are four main interacting affective centres in the brain. Each centre is associated with a dominant affective function, such as ascending activation (brainstem), pain/pleasure (diencephalon), attachment-related affects (hippocampus) or moral emotions and unconscious cognitive appraisal (orbitofrontal cortex). Furthermore, language is ascribed a key role in (a) the communication of subjective feeling (reconfiguration) and (b) in the conscious regulation of emotions (by means of logic and rational thought).

  11. Mitotic regulator Nlp interacts with XPA/ERCC1 complexes and regulates nucleotide excision repair (NER) in response to UV radiation.

    Science.gov (United States)

    Ma, Xiao-Juan; Shang, Li; Zhang, Wei-Min; Wang, Ming-Rong; Zhan, Qi-Min

    2016-04-10

    Cellular response to DNA damage, including ionizing radiation (IR) and UV radiation, is critical for the maintenance of genomic fidelity. Defects of DNA repair often result in genomic instability and malignant cell transformation. Centrosomal protein Nlp (ninein-like protein) has been characterized as an important cell cycle regulator that is required for proper mitotic progression. In this study, we demonstrate that Nlp is able to improve nucleotide excision repair (NER) activity and protects cells against UV radiation. Upon exposure of cells to UVC, Nlp is translocated into the nucleus. The C-terminus (1030-1382) of Nlp is necessary and sufficient for its nuclear import. Upon UVC radiation, Nlp interacts with XPA and ERCC1, and enhances their association. Interestingly, down-regulated expression of Nlp is found to be associated with human skin cancers, indicating that dysregulated Nlp might be related to the development of human skin cancers. Taken together, this study identifies mitotic protein Nlp as a new and important member of NER pathway and thus provides novel insights into understanding of regulatory machinery involved in NER. PMID:26805762

  12. Regulation of cumulus expansion and hyaluronan synthesis in porcine oocyte-cumulus complexes during in vitro maturation

    Czech Academy of Sciences Publication Activity Database

    Nagyová, Eva

    2012-01-01

    Roč. 46, č. 3 (2012), s. 225-235. ISSN 1210-0668 Institutional support: RVO:67985904 Keywords : oocyte-cumulus complex * hyaluronan * progesterone Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition

  13. of bullies and buddies : socio-spatial behavior and emotional regulation drives primate-like social complexity in silico

    NARCIS (Netherlands)

    Evers, Ellen

    2014-01-01

    Groups of primates form complex spatial and social structures. Often, dominance rank is reflected in an individual's spatial position within the group, and individuals maintain individualized reciprocal relationships with affiliates, which reflect earlier interactions. The hypothesized underlying me

  14. Functional interplay between chromatin remodeling complexes RSC, SWI/SNF and ISWI in regulation of yeast heat shock genes

    OpenAIRE

    Erkina, T. Y.; Zou, Y.; Freeling, S.; Vorobyev, V. I.; Erkine, A. M.

    2009-01-01

    Chromatin remodeling is an essential part of transcription initiation. We show that at heat shock gene promoters functional interactions between individual ATP-dependent chromatin remodeling complexes play critical role in both nucleosome displacement and Pol II recruitment. Using HSP12, HSP82 and SSA4 gene promoters as reporters, we demonstrated that while inactivation of SNF2, a critical ATPase of the SWI/SNF complex, primarily affects the HSP12 promoter, depletion of STH1- a SNF2 homolog f...

  15. of bullies and buddies : socio-spatial behavior and emotional regulation drives primate-like social complexity in silico

    OpenAIRE

    Evers, Ellen

    2014-01-01

    Groups of primates form complex spatial and social structures. Often, dominance rank is reflected in an individual's spatial position within the group, and individuals maintain individualized reciprocal relationships with affiliates, which reflect earlier interactions. The hypothesized underlying mechanisms and the cognitive capacities thought necessary differ in their complexity. While primates have been shown to possess advanced socio-cognitive abilities, computer models have proven that co...

  16. FLP-4 neuropeptide and its receptor in a neuronal circuit regulate preference choice through functions of ASH-2 trithorax complex in Caenorhabditis elegans.

    Science.gov (United States)

    Yu, Yonglin; Zhi, Lingtong; Guan, Xiangmin; Wang, Daoyong; Wang, Dayong

    2016-01-01

    Preference choice on food is an important response strategy for animals living in the environment. Using assay system of preference choice on bacterial foods, OP50 and PA14, we identified the involvement of ADL sensory neurons in the control of preference choice in Caenorhabditis elegans. Both genetically silencing and ChR2-mediated activation of ADL sensory neurons significantly affected preference choice. ADL regulated preference choice by inhibiting function of G protein-coupled receptor (GPCR)/SRH-220. ADL sensory neurons might regulate preference choice through peptidergic signals of FLP-4 and NLP-10, and function of FLP-4 or NLP-10 in regulating preference choice was regulated by SRH-220. FLP-4 released from ADL sensory neurons further regulated preference choice through its receptor of NPR-4 in AIB interneurons. In AIB interneurons, NPR-4 was involved in the control of preference choice by activating the functions of ASH-2 trithorax complex consisting of SET-2, ASH-2, and WDR-5, implying the crucial role of molecular machinery of trimethylation of histone H3K4 in the preference choice control. The identified novel neuronal circuit and the underlying molecular mechanisms will strengthen our understanding neuronal basis of preference choice in animals. PMID:26887501

  17. The Drosophila IKK-related kinase (Ik2 and Spindle-F proteins are part of a complex that regulates cytoskeleton organization during oogenesis

    Directory of Open Access Journals (Sweden)

    Shaanan Boaz

    2008-09-01

    Full Text Available Abstract Background IkappaB kinases (IKKs regulate the activity of Rel/NF-kappaB transcription factors by targeting their inhibitory partner proteins, IkappaBs, for degradation. The Drosophila genome encodes two members of the IKK family. Whereas the first is a kinase essential for activation of the NF-kappaB pathway, the latter does not act as IkappaB kinase. Instead, recent findings indicate that Ik2 regulates F-actin assembly by mediating the function of nonapoptotic caspases via degradation of DIAP1. Also, it has been suggested that ik2 regulates interactions between the minus ends of the microtubules and the actin-rich cortex in the oocyte. Since spn-F mutants display oocyte defects similar to those of ik2 mutant, we decided to investigate whether Spn-F could be a direct regulatory target of Ik2. Results We found that Ik2 binds physically to Spn-F, biomolecular interaction analysis of Spn-F and Ik2 demonstrating that both proteins bind directly and form a complex. We showed that Ik2 phosphorylates Spn-F and demonstrated that this phosphorylation does not lead to Spn-F degradation. Ik2 is localized to the anterior ring of the oocyte and to punctate structures in the nurse cells together with Spn-F protein, and both proteins are mutually required for their localization. Conclusion We conclude that Ik2 and Spn-F form a complex, which regulates cytoskeleton organization during Drosophila oogenesis and in which Spn-F is the direct regulatory target for Ik2. Interestingly, Ik2 in this complex does not function as a typical IKK in that it does not direct SpnF for degradation following phosphorylation.

  18. The pneumococcal MgaSpn virulence transcriptional regulator generates multimeric complexes on linear double-stranded DNA

    OpenAIRE

    Solano-Collado, Virtu; Lurz, Rudi; Espinosa, Manuel; Bravo, Alicia

    2013-01-01

    The MgaSpn transcriptional regulator contributes to the virulence of Streptococcus pneumoniae. It is thought to be a member of the Mga/AtxA family of global regulators. MgaSpn was shown to activate in vivo the P1623B promoter, which is divergent from the promoter (Pmga) of its own gene. This activation required a 70-bp region (PB activation region) located between both promoters. In this work, we purified an untagged form of the MgaSpn protein, which formed dimers in solution. By gel retardat...

  19. Endoplasmic reticulum chaperone glucose regulated protein 170-Pokemon complexes elicit a robust antitumor immune response in vivo.

    Science.gov (United States)

    Yuan, Bangqing; Xian, Ronghua; Wu, Xianqu; Jing, Junjie; Chen, Kangning; Liu, Guojun; Zhou, Zhenhua

    2012-07-01

    Previous evidence suggested that the stress protein grp170 can function as a highly efficient molecular chaperone, binding to large protein substrates and acting as a potent vaccine against specific tumors when purified from the same tumor. In addition, Pokemon can be found in almost all malignant tumor cells and is regarded to be a promising candidate for the treatment of tumors. However, the potential of the grp170-Pokemon chaperone complex has not been well described. In the present study, the natural chaperone complex between grp170 and the Pokemon was formed by heat shock, and its immunogenicity was detected by ELISPOT and (51)Cr-release assays in vitro and by tumor bearing models in vivo. Our results demonstrated that the grp170-Pokemon chaperone complex could elicit T cell responses as determined by ELISPOT and (51)Cr-release assays. In addition, immunized C57BL/6 mice were challenged with subcutaneous (s.c.) injection of Lewis cancer cells to induce primary tumors. Treatment of mice with the grp170-Pokemon chaperone complex also significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. Our results indicated that the grp170-Pokemon chaperone complex might represent a powerful approach to tumor immunotherapy and have significant potential for clinical application. PMID:22317751

  20. Proteomics Analysis with a Nano Random Forest Approach Reveals Novel Functional Interactions Regulated by SMC Complexes on Mitotic Chromosomes.

    Science.gov (United States)

    Ohta, Shinya; Montaño-Gutierrez, Luis F; de Lima Alves, Flavia; Ogawa, Hiromi; Toramoto, Iyo; Sato, Nobuko; Morrison, Ciaran G; Takeda, Shunichi; Hudson, Damien F; Rappsilber, Juri; Earnshaw, William C

    2016-08-01

    Packaging of DNA into condensed chromosomes during mitosis is essential for the faithful segregation of the genome into daughter nuclei. Although the structure and composition of mitotic chromosomes have been studied for over 30 years, these aspects are yet to be fully elucidated. Here, we used stable isotope labeling with amino acids in cell culture to compare the proteomes of mitotic chromosomes isolated from cell lines harboring conditional knockouts of members of the condensin (SMC2, CAP-H, CAP-D3), cohesin (Scc1/Rad21), and SMC5/6 (SMC5) complexes. Our analysis revealed that these complexes associate with chromosomes independently of each other, with the SMC5/6 complex showing no significant dependence on any other chromosomal proteins during mitosis. To identify subtle relationships between chromosomal proteins, we employed a nano Random Forest (nanoRF) approach to detect protein complexes and the relationships between them. Our nanoRF results suggested that as few as 113 of 5058 detected chromosomal proteins are functionally linked to chromosome structure and segregation. Furthermore, nanoRF data revealed 23 proteins that were not previously suspected to have functional interactions with complexes playing important roles in mitosis. Subsequent small-interfering-RNA-based validation and localization tracking by green fluorescent protein-tagging highlighted novel candidates that might play significant roles in mitotic progression. PMID:27231315

  1. The Role of Self-Regulated Learning in Fostering Students' Conceptual Understanding of Complex Systems with Hypermedia

    Science.gov (United States)

    Azevedo, Roger; Guthrie, John T.; Seibert, Diane

    2004-01-01

    This study examines the role of self-regulated learning (SRL) in facilitating students' shifts to more sophisticated mental models of the circulatory system as indicated by both performance and process data. We began with Winne and colleagues' information processing model of SRL (Winne, 2001; Winne & Hadwin, 1998) and used it to examine how…

  2. Stearoyl coenzyme A desaturase 1 is associated with hepatitis C virus replication complex and regulates viral replication

    DEFF Research Database (Denmark)

    Nguyen, LN; Lim, YS; Pham, Long; Shin, HY; Kim, YS; Hwang, SB

    2014-01-01

    The hepatitis C virus (HCV) life cycle is tightly regulated by lipid metabolism of host cells. In order to identify host factors involved in HCV propagation, we have recently screened a small interfering RNA (siRNA) library targeting host genes that control lipid metabolism and lipid droplet...

  3. Differential binding partners of the Mis18α/β YIPPEE domains regulates the Mis18 complex recruitment to centromeres

    OpenAIRE

    Madison E. Stellfox; Isaac K. Nardi; Christina M. Knippler; Daniel R. Foltz

    2016-01-01

    The Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A-specific assembly factor HJURP (Holliday junction recognition protein). The human Mis18 complex consists of Mis18α, Mis18β, and Mis18 binding protein 1 (Mis18BP1/hsKNL2). Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18α dir...

  4. Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription.

    Science.gov (United States)

    Liu, Zhihui; Lam, Norris; Thiele, Carol J

    2015-09-29

    The zinc finger transcription factor CASZ1 has been found to control neural fate-determination in flies, regulate murine and frog cardiac development, control murine retinal cell progenitor expansion and function as a tumor suppressor gene in humans. However, the molecular mechanism by which CASZ1 regulates gene transcription to exert these diverse biological functions has not been described. Here we identify co-factors that are recruited by CASZ1b to regulate gene transcription using co-immunoprecipitation (co-IP) and mass spectrometry assays. We find that CASZ1b binds to the nucleosome remodeling and histone deacetylase (NuRD) complex, histones and DNA repair proteins. Mutagenesis of the CASZ1b protein assay demonstrates that the N-terminus of CASZ1b is required for NuRD binding, and a poly(ADP-ribose) binding motif in the CASZ1b protein is required for histone H3 and DNA repair proteins binding. The N-terminus of CASZ1b fused to an artificial DNA-binding domain (GAL4DBD) causes a significant repression of transcription (5xUAS-luciferase assay), which could be blocked by treatment with an HDAC inhibitor. Realtime PCR results show that the transcriptional activity of CASZ1b mutants that abrogate NuRD or histone H3/DNA binding is significantly decreased. This indicates a model in which CASZ1b binds to chromatin and recruits NuRD complexes to orchestrate epigenetic-mediated transcriptional programs. PMID:26296975

  5. Identification of a BET family bromodomain/casein kinase II/TAF-containing complex as a regulator of mitotic condensin function.

    Science.gov (United States)

    Kim, Hyun-Soo; Mukhopadhyay, Rituparna; Rothbart, Scott B; Silva, Andrea C; Vanoosthuyse, Vincent; Radovani, Ernest; Kislinger, Thomas; Roguev, Assen; Ryan, Colm J; Xu, Jiewei; Jahari, Harlizawati; Hardwick, Kevin G; Greenblatt, Jack F; Krogan, Nevan J; Fillingham, Jeffrey S; Strahl, Brian D; Bouhassira, Eric E; Edelmann, Winfried; Keogh, Michael-Christopher

    2014-03-13

    Condensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), casein kinase II (CKII), and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern of NCT binding at the core centromere, the region of maximal condensin enrichment, tracks the abundance of acetylated histone H4, as regulated by the Hat1-Mis16 acetyltransferase complex and recognized by the first Nrc1 bromodomain. Strikingly, mutants in NCT or Hat1-Mis16 restore the formation of segregation-competent chromosomes in cells containing defective condensin. These results are consistent with a model where NCT targets CKII to chromatin in a cell-cycle-directed manner in order to modulate the activity of condensin during chromosome condensation and decondensation. PMID:24565511

  6. Identification of a BET Family Bromodomain/Casein Kinase II/TAF-Containing Complex as a Regulator of Mitotic Condensin Function

    Directory of Open Access Journals (Sweden)

    Hyun-Soo Kim

    2014-03-01

    Full Text Available Condensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02, casein kinase II (CKII, and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern of NCT binding at the core centromere, the region of maximal condensin enrichment, tracks the abundance of acetylated histone H4, as regulated by the Hat1-Mis16 acetyltransferase complex and recognized by the first Nrc1 bromodomain. Strikingly, mutants in NCT or Hat1-Mis16 restore the formation of segregation-competent chromosomes in cells containing defective condensin. These results are consistent with a model where NCT targets CKII to chromatin in a cell-cycle-directed manner in order to modulate the activity of condensin during chromosome condensation and decondensation.

  7. Regulation of protein kinase Cδ downregulation by protein kinase Cε and mammalian target of rapamycin complex 2

    OpenAIRE

    Basu, Alakananda; Sridharan, Savitha; Persaud, Shalini

    2009-01-01

    Phosphorylation and dephosphorylation of PKCs can regulate their activity, stability and function. We have previously shown that downregulation of PKCδ by tumor promoting phorbol esters was compromised when HeLa cells acquired resistance to cisplatin (HeLa/CP). In the present study, we have used these cells to understand the mechanism of PKCδ downregulation. A brief treatment of HeLa cells with phorbol 12,13-dibutyrate (PDBu) induced phosphorylation of PKCδ at the activation loop (Thr505), tu...

  8. Complex Regulation of Plant Phosphate Transporters and the Gap between Molecular Mechanisms and Practical Application: What Is Missing?

    Science.gov (United States)

    Gu, Mian; Chen, Aiqun; Sun, Shubin; Xu, Guohua

    2016-03-01

    It has been almost 25 years since the first report of the gene encoding a high-affinity phosphate transporter (PT), PHO84, in yeast. Since then, an increasing number of yeast PHO84 homologs as well as other genes encoding proteins with phosphate (Pi) transport activities have been identified and functionally characterized in diverse plant species. Great progress has been made also in deciphering the molecular mechanism underlying the regulation of the abundance and/or activity of these genes and their products. The regulatory genes affect plant Pi homeostasis commonly through direct or indirect regulation of the abundance of PTs at different levels. However, little has been achieved in the use of PTs for developing genetically modified crops with high phosphorus use efficiency (PUE). This might be a consequence of overemphasizing Pi uptake from the rhizosphere and lack of knowledge about the roles of PTs in Pi transport and recycling within the plant that are required to optimize PUE. Here, we mainly focused on the genes encoding proteins with Pi transport activities and the emerging understanding of their regulation at the transcriptional, post-transcriptional, translational, and post-translational levels. In addition, we propose potential strategies for effective use of PTs in improving plant growth and development. PMID:26714050

  9. Identification of an iron-regulated outer membrane protein of Neisseria meningitidis involved in the utilization of hemoglobin complexed to haptoglobin.

    OpenAIRE

    Lewis, L. A.; Dyer, D W

    1995-01-01

    Hemoglobin complexed to the plasma protein haptoglobin can be used by Neisseria meningitidis as a source of iron to support growth in vitro. An N meningitidis mutant, DNM2E4, was generated by insertion of the mini-Tn3erm transposon into the gene coding for an 85-kDa iron-regulated outer membrane protein. Membrane proteins prepared from DNM2E4 were identical to those of the wild-type strain except that the 85-kDa protein was not produced. This mutant was unable to use hemoglobin-haptoglobin co...

  10. miR-133a Regulates Vitamin K 2,3-Epoxide Reductase Complex Subunit 1 (VKORC1), a Key Protein in the Vitamin K Cycle

    OpenAIRE

    Pérez-Andreu, Virginia; Teruel, Raúl; Corral, Javier; Roldán, Vanessa; García-Barberá, Nuria; Salloum-Asfar, Salam; Gómez-Lechón, María José; Bourgeois, Stephane; Deloukas, Panos; Wadelius, Mia; Vicente, Vicente; González-Conejero, Rocío; Martínez, Constantino

    2012-01-01

    Regulation of key proteins by microRNAs (miRNAs) is an emergent field in biomedicine. Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is a relevant molecule for cardiovascular diseases, since it is the target of oral anticoagulant drugs and plays a role in soft tissue calcification. The objective of this study was to determine the influence of miRNAs on the expression of VKORC1. Potential miRNAs targeting VKORC1 mRNA were searched by using online algorithms. Validation studies were...

  11. Escherichia coli prereplication complex assembly is regulated by dynamic interplay among Fis, IHF and DnaA.

    Science.gov (United States)

    Ryan, Valorie T; Grimwade, Julia E; Camara, Johanna E; Crooke, Elliott; Leonard, Alan C

    2004-03-01

    Initiator DnaA and DNA bending proteins, Fis and IHF, comprise prereplication complexes (pre-RC) that unwind the Escherichia coli chromosome's origin of replication, oriC. Loss of either Fis or IHF perturbs synchronous initiation from oriC copies in rapidly growing E. coli. Based on dimethylsulphate (DMS) footprinting of purified proteins, we observed a dynamic interplay among Fis, IHF and DnaA on supercoiled oriC templates. Low levels of Fis inhibited oriC unwinding by blocking both IHF and DnaA binding to low affinity sites. As the concentration of DnaA was increased, Fis repression was relieved and IHF rapidly redistributed DnaA to all unfilled binding sites on oriC. This behaviour in vitro is analogous to observed assembly of pre-RC in synchronized E. coli. We propose that as new DnaA is synthesized in E. coli, opposing activities of Fis and IHF ensure an abrupt transition from a repressed complex with unfilled weak affinity DnaA binding sites to a completely loaded unwound complex, increasing both the precision of DNA replication timing and initiation synchrony. PMID:14982629

  12. LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex.

    Science.gov (United States)

    Cirnaru, Maria D; Marte, Antonella; Belluzzi, Elisa; Russo, Isabella; Gabrielli, Martina; Longo, Francesco; Arcuri, Ludovico; Murru, Luca; Bubacco, Luigi; Matteoli, Michela; Fedele, Ernesto; Sala, Carlo; Passafaro, Maria; Morari, Michele; Greggio, Elisa; Onofri, Franco; Piccoli, Giovanni

    2014-01-01

    Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecular hub connecting synaptic vesicles to cytoskeletal elements via a complex panel of protein-protein interactions. Here we investigated the impact of pharmacological inhibition of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced the frequency of spontaneous currents, the rate of synaptic vesicle trafficking and the release of neurotransmitter from isolated synaptosomes. The investigation of complementary models lacking LRRK2 expression allowed us to exclude potential off-side effects of kinase inhibitors on synaptic functions. Next we studied whether kinase inhibition affects LRRK2 heterologous interactions. We found that the binding among LRRK2, presynaptic proteins and synaptic vesicles is affected by kinase inhibition. Our results suggest that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex. PMID:24904275

  13. Differential effects of salen and manganese-salen complex (EUK-8) on the regulation of cellular cadmium uptake and toxicity.

    Science.gov (United States)

    Yang, Pei-Ming; Chiu, Shu-Jun; Lin, Lih-Yuan

    2005-05-01

    Cadmium (Cd) stimulates the production of reactive oxygen species (ROS) and causes cell damage. We investigated here the feasibility of using a cell permeable superoxide dismutase/catalase mimetic, EUK-8, to reduce the Cd-induced ROS and cytotoxicity in Chinese hamster ovary cells. EUK-8 reduces the ROS level caused by Cd treatment. EUK-8 also curtails propidium iodide (PI) influx and increases the viability of Cd-treated cells. The efficacy of EUK-8 as a Cd antidote diminishes gradually when added at a later stage of Cd treatment. EUK-8 blocks Cd transport into cells. It is ineffective in accelerating the efflux of metals from the cells. EUK-8 is a Mn-salen complex. Mn decreases the uptake and cytotoxicity of Cd, while salen perturbs the membrane integrity and increases the uptake and cytotoxicity of Cd. Salen is able to bind Cd, and the Cd-salen complex formed does not perturb the integrity of cell membranes and thus the influx of metal is not enhanced. Our results reveal a differential effect of salen and Mn-salen complex on the transport of Cd with subsequent different levels of cell damage. PMID:15689422

  14. Differential binding partners of the Mis18α/β YIPPEE domains regulates the Mis18 complex recruitment to centromeres

    Science.gov (United States)

    Knippler, Christina M.; Foltz, Daniel R.

    2016-01-01

    The Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A specific assembly factor HJURP (Holliday junction recognition protein). The human Mis18 complex consists of Mis18α, Mis18β and Mis18 binding protein 1 (Mis18BP1/hsKNL2). Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18α directly interacts with the N-terminus of Mis18BP1; whereas, Mis18β directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes. The N-terminus of Mis18BP1, containing both the Mis18α and CENP-C binding domains, is necessary and sufficient for centromeric localization. Therefore, the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition. PMID:27239045

  15. Differential Binding Partners of the Mis18α/β YIPPEE Domains Regulate Mis18 Complex Recruitment to Centromeres

    Directory of Open Access Journals (Sweden)

    Madison E. Stellfox

    2016-06-01

    Full Text Available The Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A-specific assembly factor HJURP (Holliday junction recognition protein. The human Mis18 complex consists of Mis18α, Mis18β, and Mis18 binding protein 1 (Mis18BP1/hsKNL2. Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18α directly interacts with the N terminus of Mis18BP1, whereas Mis18β directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes. The N terminus of Mis18BP1, containing both the Mis18α and CENP-C binding domains, is necessary and sufficient for centromeric localization. Therefore, the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition.

  16. Differential Binding Partners of the Mis18α/β YIPPEE Domains Regulate Mis18 Complex Recruitment to Centromeres.

    Science.gov (United States)

    Stellfox, Madison E; Nardi, Isaac K; Knippler, Christina M; Foltz, Daniel R

    2016-06-01

    The Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A-specific assembly factor HJURP (Holliday junction recognition protein). The human Mis18 complex consists of Mis18α, Mis18β, and Mis18 binding protein 1 (Mis18BP1/hsKNL2). Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18α directly interacts with the N terminus of Mis18BP1, whereas Mis18β directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes. The N terminus of Mis18BP1, containing both the Mis18α and CENP-C binding domains, is necessary and sufficient for centromeric localization. Therefore, the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition. PMID:27239045

  17. Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export

    Directory of Open Access Journals (Sweden)

    Marriott Susan J

    2007-12-01

    Full Text Available Abstract Background The HTLV-I oncoprotein, Tax, is a pleiotropic protein whose activity is partially regulated by its ability to interact with, and perturb the functions of, numerous cellular proteins. Tax is predominantly a nuclear protein that localizes to nuclear foci known as Tax Speckled Structures (TSS. We recently reported that the localization of Tax and its interactions with cellular proteins are altered in response to various forms of genotoxic and cellular stress. The level of cytoplasmic Tax increases in response to stress and this relocalization depends upon the interaction of Tax with CRM1. Cellular pathways and signals that regulate the subcellular localization of Tax remain to be determined. However, post-translational modifications including sumoylation and ubiquitination are known to influence the subcellular localization of Tax and its interactions with cellular proteins. The sumoylated form of Tax exists predominantly in the nucleus while ubiquitinated Tax exists predominantly in the cytoplasm. Therefore, we hypothesized that post-translational modifications of Tax that occur in response to DNA damage regulate the localization of Tax and its interactions with cellular proteins. Results We found a significant increase in mono-ubiquitination of Tax in response to UV irradiation. Mutation of specific lysine residues (K280 and K284 within Tax inhibited DNA damage-induced ubiquitination. In contrast to wild-type Tax, which undergoes transient nucleocytoplasmic shuttling in response to DNA damage, the K280 and K284 mutants were retained in nuclear foci following UV irradiation and remained co-localized with the cellular TSS protein, sc35. Conclusion This study demonstrates that the localization of Tax, and its interactions with cellular proteins, are dynamic following DNA damage and depend on the post-translational modification status of Tax. Specifically, DNA damage induces the ubiquitination of Tax at K280 and K284

  18. Regulation of gamma-secretase complex assembly in the early secretory pathway -from Alzheimer's disease to monosomy 1p36-

    OpenAIRE

    Spasic, Dragana

    2009-01-01

    g-secretase, consisting of presenilin (PSEN), nicastrin (NCT), presenili n enhancer-2 (PEN2), and anterior pharynx defective-1 (APH1), cleaves ty pe I membrane proteins like amyloid precursor protein and Notch in a pro cess of regulated intramembrane proteolysis. PSEN1 is a polytopic membra ne protein, the topology of which remained an issue of controversy. We r evisited this by inserting glycosylation consensus sequences in human PS EN1 and expressing the obtained mutants in a PSEN1 and 2 kn...

  19. JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation

    OpenAIRE

    Sun, Luyang; Shi, Lei; Li, Wenqian; Yu, Wenhua; Liang, Jing; Zhang, Hua; Yang, Xiaohan; Wang, Yan; Li, Ruifang; Yao, Xingrong; Yi, Xia; Shang, Yongfeng

    2009-01-01

    The p53 tumor suppressor plays a central role in integrating cellular responses to various stresses. Tight regulation of p53 is thus essential for the maintenance of genome integrity and normal cell proliferation. Currently, several ubiquitin ligases, including the single-subunit RING-finger types—MDM2, Pirh2, and COP1—and the HECT-domain type—ARF-BP1—have been reported to target p53 for degradation. Here, we report the identification of a human Kelch domain-containing F-box protein, JFK. We ...

  20. Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

    OpenAIRE

    Li, Yuting; Li, Haohong; Liu, Xing; Bao, Guobin; Tao, Yezheng; Wu, Ziyan; Xia, Peng; Wu, Chunfu; Li, Baoming; Ma, Lan

    2009-01-01

    β-arrestins, key regulators of receptor signaling, are highly expressed in the central nervous system, but their roles in brain physiology are largely unknown. Here we show that β-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, β-arrestin-2 translocates to amygdalar membrane where it interacts with PDE-4, a cAMP-degrading enzyme, to inhibit PKA activation. Arrb2−/− mice exhibit impaired conditio...

  1. Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation.

    Science.gov (United States)

    Lechtenberg, Bernhard C; Rajput, Akhil; Sanishvili, Ruslan; Dobaczewska, Małgorzata K; Ware, Carl F; Mace, Peter D; Riedl, Stefan J

    2016-01-28

    Ubiquitination is a central process affecting all facets of cellular signalling and function. A critical step in ubiquitination is the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate or a growing ubiquitin chain, which is mediated by E3 ubiquitin ligases. RING-type E3 ligases typically facilitate the transfer of ubiquitin from the E2 directly to the substrate. The RING-between-RING (RBR) family of RING-type E3 ligases, however, breaks this paradigm by forming a covalent intermediate with ubiquitin similarly to HECT-type E3 ligases. The RBR family includes Parkin and HOIP, the central catalytic factor of the LUBAC (linear ubiquitin chain assembly complex). While structural insights into the RBR E3 ligases Parkin and HHARI in their overall auto-inhibited forms are available, no structures exist of intact fully active RBR E3 ligases or any of their complexes. Thus, the RBR mechanism of action has remained largely unknown. Here we present the first structure, to our knowledge, of the fully active human HOIP RBR in its transfer complex with an E2~ubiquitin conjugate, which elucidates the intricate nature of RBR E3 ligases. The active HOIP RBR adopts a conformation markedly different from that of auto-inhibited RBRs. HOIP RBR binds the E2~ubiquitin conjugate in an elongated fashion, with the E2 and E3 catalytic centres ideally aligned for ubiquitin transfer, which structurally both requires and enables a HECT-like mechanism. In addition, three distinct helix-IBR-fold motifs inherent to RBRs form ubiquitin-binding regions that engage the activated ubiquitin of the E2~ubiquitin conjugate and, surprisingly, an additional regulatory ubiquitin molecule. The features uncovered reveal critical states of the HOIP RBR E3 ligase cycle, and comparison with Parkin and HHARI suggests a general mechanism for RBR E3 ligases. PMID:26789245

  2. The Mitochondrial Complex I Activity Is Reduced in Cells with Impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Function

    OpenAIRE

    Valdivieso, Angel G.; Clauzure, Mariángeles; Marín, María C.; Taminelli, Guillermo L.; Massip Copiz, María M.; Sánchez, Francisco; Schulman, Gustavo; Teiber, María L.; Santa-Coloma, Tomás A.

    2012-01-01

    Cystic fibrosis (CF) is a frequent and lethal autosomal recessive disease. It results from different possible mutations in the CFTR gene, which encodes the CFTR chloride channel. We have previously studied the differential expression of genes in CF and CF corrected cell lines, and found a reduced expression of MTND4 in CF cells. MTND4 is a mitochondrial gene encoding the MTND4 subunit of the mitochondrial Complex I (mCx-I). Since this subunit is essential for the assembly and activity of mCx-...

  3. Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation

    OpenAIRE

    Ammar, Youssef Ben; Takeda, Soichi; Hisamitsu, Takashi; Mori, Hidezo; Wakabayashi, Shigeo

    2006-01-01

    The plasma membrane Na+/H+ exchangers (NHE) require calcineurin B homologous protein (CHP) as an obligatory binding partner for ion transport. Here, we report the first crystal structure of CHP (CHP2 isoform) in complex with its binding domain in NHE1. We show that the cytoplasmic α-helix of NHE1 is inserted into the hydrophobic cleft formed by N- and C-lobes of CHP2 and that the size and shape of this crevice together with hydrogen bond formation at multiple positions assure a high degree of...

  4. The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM–EGL-15/FGFR Receptor Complex

    Directory of Open Access Journals (Sweden)

    Carlos A. Díaz-Balzac

    2015-06-01

    Full Text Available Neurite branching is essential for correct assembly of neural circuits, yet it remains a poorly understood process. For example, the neural cell adhesion molecule KAL-1/anosmin-1, which is mutated in Kallmann syndrome, regulates neurite branching through mechanisms largely unknown. Here, we show that KAL-1/anosmin-1 mediates neurite branching as an autocrine co-factor with EGL-17/FGF through a receptor complex consisting of the conserved cell adhesion molecule SAX-7/L1CAM and the fibroblast growth factor receptor EGL-15/FGFR. This protein complex, which appears conserved in humans, requires the immunoglobulin (Ig domains of SAX-7/L1CAM and the FN(III domains of KAL-1/anosmin-1 for formation in vitro as well as function in vivo. The kinase domain of the EGL-15/FGFR is required for branching, and genetic evidence suggests that ras-mediated signaling downstream of EGL-15/FGFR is necessary to effect branching. Our studies establish a molecular pathway that regulates neurite branching during development of the nervous system.

  5. The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

    Science.gov (United States)

    Liu, Min; Li, Yajuan; Liu, Aiguo; Li, Ruifeng; Su, Ying; Du, Juan; Li, Cheng; Zhu, Alan Jian

    2016-01-01

    Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC. DOI: http://dx.doi.org/10.7554/eLife.17200.001 PMID:27536874

  6. The mitochondrial complex I activity is reduced in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR function.

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    Angel G Valdivieso

    Full Text Available Cystic fibrosis (CF is a frequent and lethal autosomal recessive disease. It results from different possible mutations in the CFTR gene, which encodes the CFTR chloride channel. We have previously studied the differential expression of genes in CF and CF corrected cell lines, and found a reduced expression of MTND4 in CF cells. MTND4 is a mitochondrial gene encoding the MTND4 subunit of the mitochondrial Complex I (mCx-I. Since this subunit is essential for the assembly and activity of mCx-I, we have now studied whether the activity of this complex was also affected in CF cells. By using Blue Native-PAGE, the in-gel activity (IGA of the mCx-I was found reduced in CFDE and IB3-1 cells (CF cell lines compared with CFDE/6RepCFTR and S9 cells, respectively (CFDE and IB3-1 cells ectopically expressing wild-type CFTR. Moreover, colon carcinoma T84 and Caco-2 cells, which express wt-CFTR, either treated with CFTR inhibitors (glibenclamide, CFTR(inh-172 or GlyH101 or transfected with a CFTR-specific shRNAi, showed a significant reduction on the IGA of mCx-I. The reduction of the mCx-I activity caused by CFTR inhibition under physiological or pathological conditions may have a profound impact on mitochondrial functions of CF and non-CF cells.

  7. Energetic modeling and single-molecule verification of dynamic regulation on receptor complexes by actin corrals and lipid raft domains

    Science.gov (United States)

    Lin, Chien Y.; Huang, Jung Y.; Lo, Leu-Wei

    2014-12-01

    We developed an energetic model by integrating the generalized Langevin equation with the Cahn-Hilliard equation to simulate the diffusive behaviors of receptor proteins in the plasma membrane of a living cell. Simulation results are presented to elaborate the confinement effects from actin corrals and protein-induced lipid domains. Single-molecule tracking data of epidermal growth factor receptors (EGFR) acquired on live HeLa cells agree with the simulation results and the mechanism that controls the diffusion of single-molecule receptors is clarified. We discovered that after ligand binding, EGFR molecules move into lipid nanodomains. The transition rates between different diffusion states of liganded EGFR molecules are regulated by the lipid domains. Our method successfully captures dynamic interactions of receptors at the single-molecule level and provides insight into the functional architecture of both the diffusing EGFR molecules and their local cellular environment.

  8. Complex marine natural products as potential epigenetic and production regulators of antibiotics from a marine Pseudomonas aeruginosa

    Science.gov (United States)

    Wang, Bin; Waters, Amanda L.; Sims, James W.; Fullmer, Alexis; Ellison, Serena; Hamann, Mark T.

    2013-01-01

    Marine microbes are capable of producing secondary metabolites for defense and competition. Factors exerting an impact on secondary metabolite production of microbial communities included bioactive natural products and co-culturing. These external influences may have practical applications such as increased yields or the generation of new metabolites from otherwise silent genes in addition to reducing or limiting the production of undesirable metabolites. In this paper, we discuss the metabolic profiles of a marine Pseudomonas aeruginosa in the presence of a number of potential chemical epigenetic regulators, adjusting carbon sources and co-culturing with other microbes to induce a competitive response. As a result of these stressors certain groups of antibiotics or antimalarial agents were increased most notably when treating P. aeruginosa with sceptrin and co-culturing with another Pseudomonas sp. An interesting cross-talking event between these two Pseudomonas species when cultured together and exposed to sceptrin was observed. PMID:23563743

  9. Transcriptomic Profiling Reveals Complex Molecular Regulation in Cotton Genic Male Sterile Mutant Yu98-8A.

    Directory of Open Access Journals (Sweden)

    Weiping Fang

    Full Text Available Although cotton genic male sterility (GMS plays an important role in the utilization of hybrid vigor, its precise molecular mechanism remains unclear. To characterize the molecular events of pollen abortion, transcriptome analysis, combined with histological observations, was conducted in the cotton GMS line, Yu98-8A. A total of 2,412 genes were identified as significant differentially expressed genes (DEGs before and during the critical pollen abortion stages. Bioinformatics and biochemical analysis showed that the DEGs mainly associated with sugars and starch metabolism, oxidative phosphorylation, and plant endogenous hormones play a critical and complicated role in pollen abortion. These findings extend a better understanding of the molecular events involved in the regulation of pollen abortion in genic male sterile cotton, which may provide a foundation for further research studies on cotton heterosis breeding.

  10. The J-protein AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling.

    Science.gov (United States)

    Jia, Ning; Lv, Ting-Ting; Li, Mi-Xin; Wei, Shan-Shan; Li, Yan-Yi; Zhao, Chun-Lan; Li, Bing

    2016-05-01

    AtDjB1 is a mitochondria-located J-protein in Arabidopsis thaliana It is involved in the regulation of plant growth and development; however, the exact mechanisms remain to be determined. We performed comparison analyses of phenotypes, auxin signalling, redox status, mitochondrial structure and function using wild-type plants, AtDjB1 mutants, rescued AtDjB1 mutants by AtDjB1 or YUCCA2 (an auxin synthesis gene), and AtDjB1 overexpression plants. AtDjB1 mutants (atj1-1 or atj1-4) exhibited inhibition of growth and development and reductions in the level of IAA and the expression of YUCCA genes compared to wild-type plants. The introduction of AtDjB1 or YUCCA2 into atj1-1 largely rescued phenotypic defects and the IAA level, indicating that AtDjB1 probably regulates growth and development via auxin. Furthermore, atj1-1 plants displayed a significant reduction in amount/activity of mitochondrial complex I compared to wild-type plants; this resulted in the accumulation of reactive oxygen species (ROS). Moreover, exogenous H2O2 markedly inhibited the expression of YUCCA genes in wild-type plants. In contrast, the reducing agent ascorbate increased the expression of YUCCA genes and IAA level in atj1-1 plants, indicating that the low auxin level observed in atj1-1 was probably due to the high oxidation status. Overall, the data presented here suggest that AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling in Arabidopsis. PMID:27117341

  11. Phospho-regulated Drosophila adducin is a determinant of synaptic plasticity in a complex with Dlg and PIP2 at the larval neuromuscular junction

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    Simon Ji Hau Wang

    2014-11-01

    Full Text Available Adducin is a ubiquitously expressed actin- and spectrin-binding protein involved in cytoskeleton organization, and is regulated through phosphorylation of the myristoylated alanine-rich C-terminal kinase (MARCKS-homology domain by protein kinase C (PKC. We have previously shown that the Drosophila adducin, Hu-li tai shao (Hts, plays a role in larval neuromuscular junction (NMJ growth. Here, we find that the predominant isoforms of Hts at the NMJ contain the MARCKS-homology domain, which is important for interactions with Discs large (Dlg and phosphatidylinositol 4,5-bisphosphate (PIP2. Through the use of Proximity Ligation Assay (PLA, we show that the adducin-like Hts isoforms are in complexes with Dlg and PIP2 at the NMJ. We provide evidence that Hts promotes the phosphorylation and delocalization of Dlg at the NMJ through regulation of the transcript distribution of the PAR-1 and CaMKII kinases in the muscle. We also show that Hts interactions with Dlg and PIP2 are impeded through phosphorylation of the MARCKS-homology domain. These results are further evidence that Hts is a signaling-responsive regulator of synaptic plasticity in Drosophila.

  12. Radioecological effects upon the nuclear translocation of androgen-receptor complexes as the cause of endocrine regulation disorders

    International Nuclear Information System (INIS)

    Male albino rats were conditioned during 1 mo in reference point 'Prypyats'' (800 m from the Chernobyl NPP) at gamma-phone ≥0.5 mSv/h and than their androgen receptor system' parameters in reproductive (prostate) and somatic (liver) organs, i.e. nuclear acceptation of androgen receptor complexes (ARC) were measured. Radioecological effects (≥0,36 Gy) upon nuclear translocation of ARC's in prostate and liver were similar, consisting of about 2.7-time decrease for relevant values, thus proving some fall in the working activity of the receptor system. The revealed phenomenon supposed to be an essential cause of depression in reproductive potential of gonad cells and detoxicating abilities of hepatocytes for sensitive residents at exposures to prolonged low doses' impacts of ionizing irradiation of Chernobyl 30-km zone. (Authors)

  13. A heterodimeric complex of the LRR proteins LRIM1 and APL1C regulates complement-like immunity in Anopheles gambiae

    Energy Technology Data Exchange (ETDEWEB)

    Baxter, Richard H.G.; Steinert, Stefanie; Chelliah, Yogarany; Volohonsky, Gloria; Levashina, Elena A.; Deisenhofer, Johann (CNRS-UMR); (UTSMC)

    2012-01-20

    The leucine-rich repeat (LRR) proteins LRIM1 and APL1C control the function of the complement-like protein TEP1 in Anopheles mosquitoes. The molecular structure of LRIM1 and APL1C and the basis of their interaction with TEP1 represent a new type of innate immune complex. The LRIM1/APL1C complex specifically binds and solubilizes a cleaved form of TEP1 without an intact thioester bond. The LRIM1 and APL1C LRR domains have a large radius of curvature, glycosylated concave face, and a novel C-terminal capping motif. The LRIM1/APL1C complex is a heterodimer with a single intermolecular disulfide bond. The structure of the LRIM1/APL1C heterodimer reveals an interface between the two LRR domains and an extensive C-terminal coiled-coil domain. We propose that a cleaved form of TEP1 may act as a convertase for activation of other TEP1 molecules and that the LRIM1/APL1C heterodimer regulates formation of this TEP1 convertase.

  14. Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the β-catenin destruction complex.

    Science.gov (United States)

    Tran, Hoanh; Polakis, Paul

    2012-08-17

    The adenomatous polyposis coli (APC) tumor suppressor forms a complex with Axin and GSK3β to promote the phosphorylation and degradation of β-catenin, a key co-activator of Wnt-induced transcription. Here, we establish that APC is modified predominantly with K63-linked ubiquitin chains when it is bound to Axin in unstimulated HEK293 cells. Wnt3a stimulation induced a time-dependent loss of K63-polyubiquitin adducts from APC, an effect synchronous with the dissociation of Axin from APC and the stabilization of cytosolic β-catenin. RNAi-mediated depletion of Axin or β-catenin, which negated the association between APC and Axin, resulted in the absence of K63-adducts on APC. Overexpression of wild-type and phosphodegron-mutant β-catenin, combined with analysis of thirteen human cancer cell lines that harbor oncogenic mutations in APC, Axin, or β-catenin, support the hypothesis that a fully assembled APC-Axin-GSK3β-phospho-β-catenin complex is necessary for the K63-polyubiquitylation of APC. Intriguingly, the degree of this modification on APC appears to correlate inversely with the levels of β-catenin in cells. Together, our results indicate that K63-linked polyubiquitin adducts on APC regulate the assembly and/or efficiency of the β-catenin destruction complex. PMID:22761442

  15. Investigating complex basal ganglia circuitry in the regulation of motor behaviour, with particular focus on orofacial movement.

    Science.gov (United States)

    Ikeda, Hiroko; Adachi, Kazunori; Fujita, Satoshi; Tomiyama, Katsunori; Saigusa, Tadashi; Kobayashi, Masayuki; Koshikawa, Noriaki; Waddington, John L

    2015-02-01

    Current concepts of basal ganglia function have evolved from the essentially motoric, to include a range of extramotoric functions that involve not only dopaminergic but also cholinergic, γ-aminobutyric acid (GABA)ergic and glutamatergic mechanisms. We consider these mechanisms and their efferent systems, including spiralling, feed-forward striato-nigro-striatal circuitry, involving the dorsal and ventral striatum and the nucleus accumbens (NAc) core and shell. These processes are illustrated using three behavioural models: turning-pivoting, orofacial movements in rats and orofacial movements in genetically modified mice. Turning-pivoting indicates that dopamine-dependent behaviour elicited from the NAc shell is funnelled through the NAc-nigro-striato-nigro-pedunculopontine pathway, whereas acetylcholine-dependent behaviour elicited from the NAc shell is funnelled through the NAc-ventral pallidum-mediodorsal thalamus pathway. Cooperative/synergistic interactions between striatal D1-like and D2-like dopamine receptors regulate individual topographies of orofacial movements that are funnelled through striatal projection pathways and involve interactions with GABAergic and glutamatergic receptor subtypes. This application of concerted behavioural, neurochemical and neurophysiological techniques implicates a network that is yet broader and interacts with other neurotransmitters and neuropeptides within subcortical, cortical and brainstem regions to 'sculpt' aspects of behaviour into its topographical collective. PMID:25485640

  16. APC/β-catenin-rich complexes at membrane protrusions regulate mammary tumor cell migration and mesenchymal morphology

    International Nuclear Information System (INIS)

    The APC tumor suppressor is mutated or downregulated in many tumor types, and is prominently localized to punctate clusters at protrusion tips in migratory cells, such as in astrocytes where it has been implicated in directed cell motility. Although APC loss is considered an initiating event in colorectal cancer, for example, it is less clear what role APC plays in tumor cell motility and whether loss of APC might be an important promoter of tumor progression in addition to initiation. The localization of APC and β-catenin was analyzed in multiple cell lines, including non-transformed epithelial lines treated with a proteasome inhibitor or TGFβ to induce an epithelial-to-mesenchymal transition (EMT), as well as several breast cancer lines, by immunofluorescence. APC expression was knocked down in 4T07 mammary tumor cells using lentiviral-mediated delivery of APC-specific short-hairpin (sh) RNAs, and assessed using quantitative (q) reverse-transcriptase (RT)-PCR and western blotting. Tumor cell motility was analyzed by performing wound-filling assays, and morphology via immunofluorescence (IF) and phase-contrast microscopy. Additionally, proliferation was measured using BrdU incorporation, and TCF reporter assays were performed to determine β-catenin/TCF-mediated transcriptional activity. APC/β-catenin-rich complexes were observed at protrusion ends of migratory epithelial cells treated with a proteasome inhibitor or when EMT has been induced and in tumor cells with a mesenchymal, spindle-like morphology. 4T07 tumor cells with reduced APC levels were significantly less motile and had a more rounded morphology; yet, they did not differ significantly in proliferation or β-catenin/TCF transcriptional activity. Furthermore, we found that APC/β-catenin-rich complexes at protrusion ends were dependent upon an intact microtubule cytoskeleton. These findings indicate that membrane protrusions with APC/β-catenin-containing puncta control the migratory potential and

  17. Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway

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    Yiyu Lu

    2016-05-01

    Full Text Available Ruthenium (Ru complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes—2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II carbonyl (Ru1 and 5,10,15,20-Tetraphenyl-21H,23H-porphine Ru(II carbonyl (Ru2—against human hepatocellular carcinoma (HCC cells. These Ru complexes effectively inhibited the cellular growth of three human hepatocellular carcinoma (HCC cells, with IC50 values ranging from 2.7–7.3 μM. In contrast, the complexes exhibited lower toxicity towards L02 human liver normal cells with IC50 values of 20.4 and 24.8 μM, respectively. Moreover, Ru2 significantly inhibited HepG2 cell migration and invasion, and these effects were dose-dependent. The mechanistic studies demonstrated that Ru2 induced HCC cell apoptosis, as evidenced by DNA fragmentation and nuclear condensation, which was predominately triggered via caspase family member activation. Furthermore, HCC cell treatment significantly decreased the expression levels of Nrf2 and its downstream effectors, NAD(PH: quinone oxidoreductase 1 (NQO1 and heme oxygenase 1 (HO1. Ru2 also exhibited potent in vivo anticancer efficacy in a tumor-bearing nude mouse model, as demonstrated by a time- and dose-dependent inhibition on tumor growth. The results demonstrate the therapeutic potential of Ru complexes against HCC via Nrf2 pathway regulation.

  18. Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway

    Science.gov (United States)

    Lu, Yiyu; Shen, Ting; Yang, Hua; Gu, Weiguang

    2016-01-01

    Ruthenium (Ru) complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes—2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II) carbonyl (Ru1) and 5,10,15,20-Tetraphenyl-21H,23H-porphine Ru(II) carbonyl (Ru2)—against human hepatocellular carcinoma (HCC) cells. These Ru complexes effectively inhibited the cellular growth of three human hepatocellular carcinoma (HCC) cells, with IC50 values ranging from 2.7–7.3 μM. In contrast, the complexes exhibited lower toxicity towards L02 human liver normal cells with IC50 values of 20.4 and 24.8 μM, respectively. Moreover, Ru2 significantly inhibited HepG2 cell migration and invasion, and these effects were dose-dependent. The mechanistic studies demonstrated that Ru2 induced HCC cell apoptosis, as evidenced by DNA fragmentation and nuclear condensation, which was predominately triggered via caspase family member activation. Furthermore, HCC cell treatment significantly decreased the expression levels of Nrf2 and its downstream effectors, NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1). Ru2 also exhibited potent in vivo anticancer efficacy in a tumor-bearing nude mouse model, as demonstrated by a time- and dose-dependent inhibition on tumor growth. The results demonstrate the therapeutic potential of Ru complexes against HCC via Nrf2 pathway regulation. PMID:27213353

  19. Telomerase Regulation

    OpenAIRE

    Cifuentes-Rojas, Catherine; Dorothy E Shippen

    2011-01-01

    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,...

  20. Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation.

    Science.gov (United States)

    Mulligan, Megan K; Wang, Xusheng; Adler, Adrienne L; Mozhui, Khyobeni; Lu, Lu; Williams, Robert W

    2012-01-01

    GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents--C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel--Gabra1, Gabrb2, and Gabrg2--and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3' UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4-100 fold

  1. Complex control of GABA(A receptor subunit mRNA expression: variation, covariation, and genetic regulation.

    Directory of Open Access Journals (Sweden)

    Megan K Mulligan

    Full Text Available GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents--C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel--Gabra1, Gabrb2, and Gabrg2--and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3' UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal, even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer

  2. [Small-scale evaluation of the efficacy of growth-regulating insecticides on larvae of the Simulium damnosum complex (Diptera: Simuliidae)].

    Science.gov (United States)

    Doannio, J M; Dossou-Yovo, J; Duval, J; Hougard, J M

    1992-09-01

    The efficacy of insect growth regulators was assessed in small scale tests on larvae of the Simulium damnosum complex (Diptera: Simuliidae) in the Ivory Coast. Three compounds [OMS 2015 (triflumuron), OMS 3009 (teflubenzuron), OMS 3013 (chlorfluazuron)] belong to the group of benzoylphenyl-urea substitutes; these IGR's are supposed to inhibit chitin synthesis. Two other compounds are Juvenile Hormone Analogs (JHA's) (OMS 3007 and OMS 3019). The last compound (OMS 3010) is a phenoxycarbamate. The first three compounds had a low efficacy on blackfly larvae, which is consistent with the literature data for another compound of this group: diflubenzuron. The other three compounds (OMS 3007, OMS 3010 and OMS 3019) were much more efficient, OMS 3010 and OMS 3019 showing high activity at low concentrations. These results would justify further studies on the effect of larval age and exposure parameters, and eventually full scale river tests. PMID:1476468

  3. Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism.

    Science.gov (United States)

    Santini, Emanuela; Feyder, Michael; Gangarossa, Giuseppe; Bateup, Helen S; Greengard, Paul; Fisone, Gilberto

    2012-08-10

    Dyskinesia, a motor complication caused by prolonged administration of the antiparkinsonian drug l-3,4-dihydroxyphenylalanine (l-DOPA), is accompanied by activation of cAMP signaling and hyperphosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Here, we show that the abnormal phosphorylation of DARPP-32 occurs specifically in medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1R). Using mice in which DARPP-32 is selectively deleted in D1R-expressing MSNs, we demonstrate that this protein is required for l-DOPA-induced activation of the extracellular signal-regulated protein kinases 1 and 2 and the mammalian target of rapamycin complex 1 (mTORC1) pathways, which are implicated in dyskinesia. We also show that mutation of the phosphorylation site for cAMP-dependent protein kinase on DARPP-32 attenuates l-DOPA-induced dyskinesia and reduces the concomitant activations of ERK and mTORC1 signaling. These studies demonstrate that, in D1R-expressing MSNs, l-DOPA-induced activation of ERK and mTORC1 requires DARPP-32 and indicates the importance of the cAMP/DARPP-32 signaling cascade in dyskinesia. PMID:22753408

  4. Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism*

    Science.gov (United States)

    Santini, Emanuela; Feyder, Michael; Gangarossa, Giuseppe; Bateup, Helen S.; Greengard, Paul; Fisone, Gilberto

    2012-01-01

    Dyskinesia, a motor complication caused by prolonged administration of the antiparkinsonian drug l-3,4-dihydroxyphenylalanine (l-DOPA), is accompanied by activation of cAMP signaling and hyperphosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Here, we show that the abnormal phosphorylation of DARPP-32 occurs specifically in medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1R). Using mice in which DARPP-32 is selectively deleted in D1R-expressing MSNs, we demonstrate that this protein is required for l-DOPA-induced activation of the extracellular signal-regulated protein kinases 1 and 2 and the mammalian target of rapamycin complex 1 (mTORC1) pathways, which are implicated in dyskinesia. We also show that mutation of the phosphorylation site for cAMP-dependent protein kinase on DARPP-32 attenuates l-DOPA-induced dyskinesia and reduces the concomitant activations of ERK and mTORC1 signaling. These studies demonstrate that, in D1R-expressing MSNs, l-DOPA-induced activation of ERK and mTORC1 requires DARPP-32 and indicates the importance of the cAMP/DARPP-32 signaling cascade in dyskinesia. PMID:22753408

  5. The bHLH factors Dpn and members of the E(spl complex mediate the function of Notch signalling regulating cell proliferation during wing disc development

    Directory of Open Access Journals (Sweden)

    Beatriz P. San Juan

    2012-05-01

    The Notch signalling pathway plays an essential role in the intricate control of cell proliferation and pattern formation in many organs during animal development. In addition, mutations in most members of this pathway are well characterized and frequently lead to tumour formation. The Drosophila imaginal wing discs have provided a suitable model system for the genetic and molecular analysis of the different pathway functions. During disc development, Notch signalling at the presumptive wing margin is necessary for the restricted activation of genes required for pattern formation control and disc proliferation. Interestingly, in different cellular contexts within the wing disc, Notch can either promote cell proliferation or can block the G1-S transition by negatively regulating the expression of dmyc and bantam micro RNA. The target genes of Notch signalling that are required for these functions have not been identified. Here, we show that the Hes vertebrate homolog, deadpan (dpn, and the Enhancer-of-split complex (E(splC genes act redundantly and cooperatively to mediate the Notch signalling function regulating cell proliferation during wing disc development.

  6. The mediator complex subunit Med10 regulates heart valve formation in zebrafish by controlling Tbx2b-mediated Has2 expression and cardiac jelly formation.

    Science.gov (United States)

    Just, Steffen; Hirth, Sofia; Berger, Ina M; Fishman, Mark C; Rottbauer, Wolfgang

    2016-09-01

    In search for novel key regulators of cardiac valve formation, we isolated the zebrafish cardiac valve mutant ping pong (png). We find that an insertional promoter mutation within the zebrafish mediator complex subunit 10 (med10) gene is leading to impaired heart valve formation. Expression of the T-box transcription factor 2b (Tbx2b), known to be essential in cardiac valve development, is severely reduced in png mutant hearts. We demonstrate here that transient reconstitution of Tbx2b expression rescues AV canal development in png mutant zebrafish. By contrast, overexpression of Forkhead box N4 (Foxn4), a known upstream regulator of Tbx2b, is not capable to reconstitute tbx2b expression and heart valve formation in Med10-deficient png mutant hearts. Interestingly, hyaluronan synthase 2 (has2), a known downstream target of Tbx2 and producer of hyaluronan (HA) - a major ECM component of the cardiac jelly and critical for proper heart valve development - is completely absent in ping pong mutant hearts. We propose here a rather unique role of Med10 in orchestrating cardiac valve formation by mediating Foxn4 dependent tbx2b transcription, expression of Has2 and subsequently proper development of the cardiac jelly. PMID:27343557

  7. Regulating Effect of Complex Probiotics Granules on Intestinal Flora%复合乳酸菌粉调节肠道菌群作用的研究

    Institute of Scientific and Technical Information of China (English)

    朱韶娟

    2011-01-01

    The effect of the probiotics (Lactobacillus acidophilus + Bifidobacterium lactis) and xylooligosaccharide complex granules on regulating intestinal flora was tested according to "the method for the assessment of regulating gastrointestinal tract flora function" established in " Technical standards for testing & assessment of health food (2003)". The product can significantly enlarge the quantity number of the intestinal Lactobacillus and bifidobacterium lactis.%研究复合乳酸菌粉(嗜酸乳杆菌+乳双歧杆菌)及低聚未糖的益生菌冲剂在调节儿童肠道菌群方面的作用,研究方法依照《保健食品检验与评价技术规范-2003版》之“调节肠道菌群作用检验方法”.结果表明,该复合益生菌产品,在14 d动物实验和15d人体实验中,双歧杆菌和乳杆菌数量均有极显著增加,摄入该复合益生菌产品具有调节肠道菌群的保健作用.

  8. Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9

    Directory of Open Access Journals (Sweden)

    Michael A. Hadders

    2012-03-01

    Full Text Available Activation of the complement system results in formation of membrane attack complexes (MACs, pores that disrupt lipid bilayers and lyse bacteria and other pathogens. Here, we present the crystal structure of the first assembly intermediate, C5b6, together with a cryo-electron microscopy reconstruction of a soluble, regulated form of the pore, sC5b9. Cleavage of C5 to C5b results in marked conformational changes, distinct from those observed in the homologous C3-to-C3b transition. C6 captures this conformation, which is preserved in the larger sC5b9 assembly. Together with antibody labeling, these structures reveal that complement components associate through sideways alignment of the central MAC-perforin (MACPF domains, resulting in a C5b6-C7-C8β-C8α-C9 arc. Soluble regulatory proteins below the arc indicate a potential dual mechanism in protection from pore formation. These results provide a structural framework for understanding MAC pore formation and regulation, processes important for fighting infections and preventing complement-mediated tissue damage.

  9. HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex

    Directory of Open Access Journals (Sweden)

    He-Ting Mao

    2016-05-01

    Full Text Available During virus infection, the cascade signaling pathway that leads to the production of proinflammatory cytokines is controlled at multiple levels to avoid detrimental overreaction. HACE1 has been characterized as an important tumor suppressor. Here, we identified HACE1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of HACE1 inhibited Sendai virus- or poly (I:C-induced signaling and resulted in reduced IFNB1 production and enhanced virus replication. Knockdown of HACE1 expression exhibited the opposite effects. Ubiquitin E3 ligase activity of the dead mutant HACE1/C876A had a comparable inhibitory function as WT HACE1, suggesting that the suppressive function of HACE1 on virus-induced signaling is independent of its E3 ligase activity. Further study indicated that HACE1 acted downstream of MAVS and upstream of TBK1. Mechanistic studies showed that HACE1 exerts its inhibitory role on virus-induced signaling by disrupting the MAVS-TRAF3 complex. Therefore, we uncovered a novel function of HACE1 in innate immunity regulation.

  10. Down-regulation of the zinc-finger homeobox protein TSHZ2 releases GLI1 from the nuclear repressor complex to restore its transcriptional activity during mammary tumorigenesis.

    Science.gov (United States)

    Riku, Miho; Inaguma, Shingo; Ito, Hideaki; Tsunoda, Takumi; Ikeda, Hiroshi; Kasai, Kenji

    2016-02-01

    Although breast cancer is one of the most common malignancies, the molecular mechanisms underlying its development and progression are not fully understood. To identify key molecules involved, we screened publicly available microarray datasets for genes differentially expressed between breast cancers and normal mammary glands. We found that three of the genes predicted in this analysis were differentially expressed among human mammary tissues and cell lines. Of these genes, we focused on the role of the zinc-finger homeobox protein TSHZ2, which is down-regulated in breast cancer cells. We found that TSHZ2 is a nuclear protein harboring a bipartite nuclear localization signal, and we confirmed its function as a C-terminal binding protein (CtBP)-dependent transcriptional repressor. Through comprehensive screening, we identified TSHZ2-suppressing genes such as AEBP1 and CXCR4, which are conversely up-regulated by GLI1, the downstream transcription factor of Hedgehog signaling. We found that GLI1 forms a ternary complex with CtBP2 in the presence of TSHZ2 and that the transcriptional activity of GLI1 is suppressed by TSHZ2 in a CtBP-dependent manner. Indeed, knockdown of TSHZ2 increases the expression of AEBP1 and CXCR4 in TSHZ2-expressing immortalized mammary duct epithelium. Concordantly, immunohistochemical staining of mammary glands revealed that normal duct cells expresses GLI1 in the nucleus along with TSHZ2 and CtBP2, whereas invasive ductal carcinoma cells, which does not express TSHZ2, show the increase in the expression of AEBP1 and CXCR4 and in the cytoplasmic localization of GLI1. Thus, we propose that down-regulation of TSHZ2 is crucial for mammary tumorigenesis via the activation of GLI1. PMID:26744317

  11. The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation.

    Science.gov (United States)

    Rodor, Julie; Pan, Qun; Blencowe, Benjamin J; Eyras, Eduardo; Cáceres, Javier F

    2016-09-01

    Acinus (apoptotic chromatin condensation inducer in the nucleus) is an RNA-binding protein (RBP) originally identified for its role in apoptosis. It was later found to be an auxiliary component of the exon junction complex (EJC), which is deposited at exon junctions as a consequence of pre-mRNA splicing. To uncover the cellular functions of Acinus and investigate its role in splicing, we mapped its endogenous RNA targets using the cross-linking immunoprecipitation protocol (iCLIP). We observed that Acinus binds to pre-mRNAs, associating specifically to a subset of suboptimal introns, but also to spliced mRNAs. We also confirmed the presence of Acinus as a peripheral factor of the EJC. RNA-seq was used to investigate changes in gene expression and alternative splicing following siRNA-mediated depletion of Acinus in HeLa cells. This analysis revealed that Acinus is preferentially required for the inclusion of specific alternative cassette exons and also controls the faithful splicing of a subset of introns. Moreover, a large number of splicing changes can be related to Acinus binding, suggesting a direct role of Acinus in exon and intron definition. In particular, Acinus regulates the splicing of DFFA/ICAD transcript, a major regulator of DNA fragmentation. Globally, the genome-wide identification of RNA targets of Acinus revealed its role in splicing regulation as well as its involvement in other cellular pathways, including cell cycle progression. Altogether, this study uncovers new cellular functions of an RBP transiently associated with the EJC. PMID:27365209

  12. Regulation of lipid droplet dynamics in Saccharomyces cerevisiae depends on the Rab7-like Ypt7p, HOPS complex and V1-ATPase

    Directory of Open Access Journals (Sweden)

    Isabelle Bouchez

    2015-07-01

    Full Text Available It has now been clearly shown that lipid droplets (LDs play a dynamic role in the cell. This was reinforced by LD proteomics which suggest that a significant number of trafficking proteins are associated with this organelle. Using microscopy, we showed that LDs partly co-localize with the vacuole in S. cerevisiae. Immunoblot experiments confirmed the association of the vacuolar Rab GTPase Rab7-like Ypt7p with LDs. We observed an increase in fatty acid content and LD number in ypt7Δ mutant and also changes in LD morphology and intra LD fusions, revealing a direct role for Ypt7p in LD dynamics. Using co-immunoprecipitation, we isolated potential Ypt7p partners including, Vma13p, the H subunit of the V1 part of the vacuolar (H+ ATPase (V-ATPase. Deletion of the VMA13 gene, as well as deletion of three other subunits of the V1 part of the V-ATPase, also increased the cell fatty acid content and LD number. Mutants of the Homotypic fusion and vacuole protein sorting (HOPS complex showed similar phenotypes. Here, we demonstrated that LD dynamics and membrane trafficking between the vacuole and LDs are regulated by the Rab7-like Ypt7p and are impaired when the HOPS complex and the V1 domain of the V-ATPase are defective.

  13. Down regulation of the TCR complex CD3 ζ-chain on CD3+ T cells: a potential mechanism for helminth mediated immune modulation

    Directory of Open Access Journals (Sweden)

    Laura Jane Appleby

    2015-02-01

    Full Text Available The CD3ζ forms part of the T cell receptor (TCR where it plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways leading to T cell effector functions. Down regulation of CD3ζ leads to impairment of immune responses including reduced cell proliferation and cytokine production. In experimental models helminth parasites have been shown to modulate immune responses directed against them and unrelated antigens, so called bystander antigens, but there is a lack of studies validating these observations in humans. This study focused on investigated the relationship between expression levels of the TCR CD3ζ chain with lymphocyte cell proliferation during human infection with the helminth parasite, Schistosoma haematobium which causes uro-genital schistosomiasis. Using flow cytometry, peripheral blood mononuclear cells (PBMCs from individuals naturally exposed to S. haematobium in rural Zimbabwe were phenotyped, and expression levels of CD3ζ on T cells were related to intensity of infection. In this population, parasite infection intensity was inversely related to CD3ζ expression levels (p<0.05, consistent with down-regulation of CD3ζ expression during helminth infection. Furthermore, PBMC proliferation was positively related to expression levels of CD3ζ (p<0.05 after allowing for confounding variables (host age, sex, infection level. CD3ζ expression levels had a differing relationship between immune correlates of susceptibility and immunity, measured by antibody responses, indicating a complex relationship between immune activation status and immunity. The relationships between the CD3ζ chain of the TCR and schistosome infection, PBMC proliferation and schistosome-specific antibody responses have not previously been reported, and these results may indicate a mechanism for the impaired T cell proliferative responses observed during human schistosome infection.

  14. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

    International Nuclear Information System (INIS)

    Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin

  15. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.

    Science.gov (United States)

    Ward, Lucas D; Kellis, Manolis

    2016-01-01

    More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. This has increased the urgency of understanding the regulatory genome as a key component for translating genetic results into mechanistic insights and ultimately therapeutics. To address this challenge, we developed HaploReg (http://compbio.mit.edu/HaploReg) to aid the functional dissection of genome-wide association study (GWAS) results, the prediction of putative causal variants in haplotype blocks, the prediction of likely cell types of action, and the prediction of candidate target genes by systematic mining of comparative, epigenomic and regulatory annotations. Since first launching the website in 2011, we have greatly expanded HaploReg, increasing the number of chromatin state maps to 127 reference epigenomes from ENCODE 2012 and Roadmap Epigenomics, incorporating regulator binding data, expanding regulatory motif disruption annotations, and integrating expression quantitative trait locus (eQTL) variants and their tissue-specific target genes from GTEx, Geuvadis, and other recent studies. We present these updates as HaploReg v4, and illustrate a use case of HaploReg for attention deficit hyperactivity disorder (ADHD)-associated SNPs with putative brain regulatory mechanisms. PMID:26657631

  16. Assessment and remediation of odor emissions from a complex industrial facility (Ambient air odor regulations in Canada and the United States)

    International Nuclear Information System (INIS)

    This paper describes the findings of a review and presents examples of ambient air odor regulations in Canada and the United States. State and provincial odor regulations were reviewed and other metropolitan cities or counties (regions) that have separate odor regulations were also included. The key topics addressed in this paper include an assessment of the methods used for odor regulation and the methods used to evaluate the odor impact to determine compliance with the regulation. Three types of ambient air odor regulations were identified: 1. 28 States, Provinces and regions (jurisdictions) have specific odor regulations. These regulations generally define what constitutes an odor impact and typically provide requirements for remedial measures; 2. 25 jurisdictions regulate odors by a general prohibition regulation. These regulations define odor in ambient air as a condition of air pollution, nuisance or objectionable odor that would typically prevent persons from the enjoyment of life and property; and 3. 13 jurisdictions do not have specific or general prohibition regulations regarding odors. For the jurisdictions that have specific or general prohibition odor regulations, there are a number of different techniques used to define what constitutes an odor impact. Odor impacts are typically defined in a regulation by one (or more) of the following techniques: dilution to threshold, or odor unit limit; determination of odor emission rates; odor concentration limits for selected chemicals (ppm); comparison with the n-butanol intensity scale (1 to 8); and investigation by an agency investigator. Compliance with odor regulations is typically determined using one (or more) of the following field methods: odor stack testing and dispersion modelling; odor panel analysis of stack or ambient air samples; chemical monitoring (ppm); odor school certified / agency investigator; and scentometer. (author)

  17. ARS5 is a component of the 26S proteasome complex, and negatively regulates thiol biosynthesis and arsenic tolerance in Arabidopsis.

    Science.gov (United States)

    Sung, Dong-Yul; Kim, Tae-Houn; Komives, Elizabeth A; Mendoza-Cózatl, David G; Schroeder, Julian I

    2009-09-01

    A forward-genetic screen in Arabidopsis led to the isolation of several arsenic tolerance mutants. ars5 was the strongest arsenate- and arsenite-resistant mutant identified in this genetic screen. Here, we report the characterization and cloning of the ars5 mutant gene. ars5 is shown to exhibit an increased accumulation of arsenic and thiol compounds during arsenic stress. Rough mapping together with microarray-based expression mapping identified the ars5 mutation in the alpha subunit F (PAF1) of the 26S proteasome complex. Characterization of an independent paf1 T-DNA insertion allele and complementation by PAF1 confirmed that paf1 mutation is responsible for the enhanced thiol accumulation and arsenic tolerance phenotypes. Arsenic tolerance was not observed in a knock-out mutant of the highly homologous PAF2 gene. However, genetic complementation of ars5 by the overexpression of PAF2 suggests that the PAF2 protein is functionally equivalent to PAF1 when expressed at high levels. No detectible difference was observed in total ubiquitinylated protein profiles between ars5 and wild-type (WT) Arabidopsis, suggesting that the arsenic tolerance observed in ars5 is not derived from a general impairment in proteasome-mediated protein degradation. Quantitative RT-PCR showed that arsenic induces the enhanced transcriptional activation of several key genes that function in glutathione and phytochelatin biosynthesis in the WT, and this arsenic induction of gene expression is more dramatic in ars5. The enhanced transcriptional response to arsenic and the increased accumulation of thiol compounds in ars5, compared with WT, suggest the presence of a positive regulation pathway for thiol biosynthesis that is enhanced in the ars5 background. PMID:19453443

  18. A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40*

    OpenAIRE

    Singh, Sandeep K.; Bhardwaj, Reetika; Wilczynska, Katarzyna M.; Dumur, Catherine I.; Kordula, Tomasz

    2011-01-01

    Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expressio...

  19. Mass spectrometric analysis and mutagenesis predict involvement of multiple cysteines in redox regulation of the skeletal muscle ryanodine receptor ion channel complex

    Directory of Open Access Journals (Sweden)

    Evgeniy V Petrotchenko

    2011-01-01

    Full Text Available Evgeniy V Petrotchenko1,2,4, Naohiro Yamaguchi1,3,4, Daniel A Pasek1, Christoph H Borchers1,2, Gerhard Meissner11Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA; 2University of Victoria, Genome BC Proteomics Centre, Victoria, British Columbia, Canada; 3Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA 4Contributed equally to the workAbstract: The tetrameric skeletal muscle ryanodine receptor ion channel complex (RyR1 contains a large number of free cysteines that are potential targets for redox-active molecules. Here, we report the mass spectrometric analysis of free thiols in RyR1 using the lipophilic, thiol-specific probe monobromobimane (MBB. In the presence of reduced glutathione, MBB labeled 14 cysteines per RyR1 subunit in tryptic peptides in five of five experiments. Forty-six additional MBB-labeled cysteines per RyR1 subunit were detected with lower frequency in tryptic peptides, bringing the total number of MBB-labeled cysteines to 60 per RyR1 subunit. A combination of fluorescence detection and mass spectrometry of RyR1, labeled in the presence of reduced and oxidized glutathione, identified two redox-sensitive cysteines (C1040 and C1303. Regulation of RyR activity by reduced and oxidized glutathione was investigated in skeletal muscle mutant RyR1s in which 18 cysteines were substituted with serine or alanine, using a [3H]ryanodine ligand binding assay. Three single-site RyR1 mutants (C1781S, C2436S, and C2606S and two multisite mutants with five and seven substituted cysteines exhibited a reduced redox response compared with wild-type RyR1. The results suggest that multiple cysteines determine the redox state and activity of RyR1.Keywords: mass spectrometry, mutagenesis, ryanodine receptor, redox modification of cysteines

  20. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.

    Directory of Open Access Journals (Sweden)

    Silvia Naitza

    2012-01-01

    results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.

  1. A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation

    Science.gov (United States)

    Naitza, Silvia; Porcu, Eleonora; Steri, Maristella; Taub, Dennis D.; Mulas, Antonella; Xiao, Xiang; Strait, James; Dei, Mariano; Lai, Sandra; Busonero, Fabio; Maschio, Andrea; Usala, Gianluca; Zoledziewska, Magdalena; Sidore, Carlo; Zara, Ilenia; Pitzalis, Maristella; Loi, Alessia; Virdis, Francesca; Piras, Roberta; Deidda, Francesca; Whalen, Michael B.; Crisponi, Laura; Concas, Antonio; Podda, Carlo; Uzzau, Sergio; Scheet, Paul; Longo, Dan L.; Lakatta, Edward; Abecasis, Gonçalo R.; Cao, Antonio; Schlessinger, David; Uda, Manuela

    2012-01-01

    4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process. PMID:22291609

  2. Fusel Alcohols Regulate Translation Initiation by Inhibiting eIF2B to Reduce Ternary Complex in a Mechanism That May Involve Altering the Integrity and Dynamics of the eIF2B Body

    OpenAIRE

    Taylor, Eleanor J.; Campbell, Susan G.; Griffiths, Christian D.; Reid, Peter J.; Slaven, John W.; Harrison, Richard J.; Sims, Paul F G; Pavitt, Graham D.; Delneri, Daniela; Ashe, Mark P.

    2010-01-01

    Recycling of eIF2-GDP to the GTP-bound form constitutes a core essential, regulated step in eukaryotic translation. This reaction is mediated by eIF2B, a heteropentameric factor with important links to human disease. eIF2 in the GTP-bound form binds to methionyl initiator tRNA to form a ternary complex, and the levels of this ternary complex can be a critical determinant of the rate of protein synthesis. Here we show that eIF2B serves as the target for translation inhibition by various fusel ...

  3. Do Different Goal-Setting Conditions Facilitate Students' Ability to Regulate Their Learning of Complex Science Topics with RiverWeb?

    Science.gov (United States)

    Azevedo, Roger; Ragan, Susan; Cromley, Jennifer G.; Pritchett, Stacy

    This study examined the role of different goal setting instructional interventions in facilitating high school students' regulation of their conceptual understanding of ecological systems while using a Web-based water quality simulation environment. Building on the information processing theory of self-regulated learning (SRL) of P. Winne and…

  4. Dynamic Modeling as a Cognitive Regulation Scaffold for Developing Complex Problem-Solving Skills in an Educational Massively Multiplayer Online Game Environment

    Science.gov (United States)

    Eseryel, Deniz; Ge, Xun; Ifenthaler, Dirk; Law, Victor

    2011-01-01

    Following a design-based research framework, this article reports two empirical studies with an educational MMOG, called "McLarin's Adventures," on facilitating 9th-grade students' complex problem-solving skill acquisition in interdisciplinary STEM education. The article discusses the nature of complex and ill-structured problem solving and,…

  5. G Protein-coupled Receptors and Resistance to Inhibitors of Cholinesterase-8A (Ric-8A) Both Regulate the Regulator of G Protein Signaling 14 (RGS14)·Gαi1 Complex in Live Cells*

    OpenAIRE

    Vellano, Christopher P.; Maher, Ellen M.; Hepler, John R.; Blumer, Joe B.

    2011-01-01

    Background: Regulator of G protein signaling 14 (RGS14) is a G protein regulatory (GPR) protein that participates in unconventional G protein signaling independent of G protein-coupled receptors (GPCRs).

  6. Molecular Mechanism Governing Heme Signaling in Yeast: a Higher-Order Complex Mediates Heme Regulation of the Transcriptional Activator HAP1

    OpenAIRE

    Zhang, Li; Hach, Angela; Wang, Cheng

    1998-01-01

    Apart from serving as a prosthetic group in globins and enzymes, heme is a key regulator controlling a wide range of molecular and cellular processes involved in oxygen sensing and utilization. To gain insights into molecular mechanisms of heme signaling and oxygen sensing in eukaryotes, we investigated the yeast heme-responsive transcriptional activator HAP1. HAP1 activity is regulated precisely and tightly by heme. Here we show that in the absence of heme, HAP1 forms a biochemically distinc...

  7. A Complex Genetic Switch Involving Overlapping Divergent Promoters and DNA Looping Regulates Expression of Conjugation Genes of a Gram-positive Plasmid

    OpenAIRE

    2014-01-01

    Plasmid conjugation plays a significant role in the dissemination of antibiotic resistance and pathogenicity determinants. Understanding how conjugation is regulated is important to gain insights into these features. Little is known about regulation of conjugation systems present on plasmids from Gram-positive bacteria. pLS20 is a native conjugative plasmid from the Gram-positive bacterium Bacillus subtilis. Recently the key players that repress and activate pLS20 conjugation have been identi...

  8. The cAMP-CRP/CytR nucleoprotein complex in Escherichia coli: two pairs of closely linked binding sites for the cAMP-CRP activator complex are involved in combinatorial regulation of the cdd promoter.

    OpenAIRE

    Holst, B.; Søgaard-Andersen, L; Pedersen, H; Valentin-Hansen, P

    1992-01-01

    Transcription initiation at CytR regulated promoters in Escherichia coli is controlled by a combinatorial regulatory system in which the cAMP receptor protein (CRP) functions as both an activator and a co-repressor. By combining genetic studies and footprinting analyses, we demonstrate that regulated expression of the CytR controlled cdd promoter requires three CRP-binding sites: a high affinity site (CRP-1) and two overlapping low affinity sites (CRP-2 and CRP-3) centred at positions -41, -9...

  9. Crystal structure of the CaV2 IQ domain in complex with Ca2+/calmodulin: High-resolution mechanistic implications for channel regulation by Ca2+

    OpenAIRE

    Mori, Masayuki X.; Vander Kooi, Craig W.; Leahy, Daniel J.; Yue, David T.

    2008-01-01

    Calmodulin (CaM) regulation of Ca2+ channels is central to Ca2+ signaling. CaV1 versus CaV2 classes of these channels exhibit divergent forms of regulation, potentially relating to customized CaM/IQ interactions among different channels. Here, we report the crystal structures for the Ca2+/CaM—IQ domains of both CaV2.1 and CaV2.3 channels. These highly similar structures emphasize that major CaM contacts with the IQ domain extend well upstream of traditional consensus residues. Surprisingly, u...

  10. DEAD-box helicase DDX27 regulates 3′ end formation of ribosomal 47S RNA and stably associates with the PeBoW-complex

    Energy Technology Data Exchange (ETDEWEB)

    Kellner, Markus; Rohrmoser, Michaela [Department of Molecular Epigenetics, Helmholtz Center Munich, Center for Integrated Protein Science Munich (CIPSM), Marchioninistr. 25, Munich 81377 (Germany); Forné, Ignasi [Adolf Butenandt Institute, Ludwig Maximilians University of Munich, Center for Integrated Protein Science Munich (CIPSM), Schillerstr. 44, Munich 80336 (Germany); Voss, Kirsten; Burger, Kaspar; Mühl, Bastian; Gruber-Eber, Anita [Department of Molecular Epigenetics, Helmholtz Center Munich, Center for Integrated Protein Science Munich (CIPSM), Marchioninistr. 25, Munich 81377 (Germany); Kremmer, Elisabeth [Institute of Molecular Immunology, Helmholtz Center Munich, Marchioninistr. 25, Munich 81377 (Germany); Imhof, Axel [Adolf Butenandt Institute, Ludwig Maximilians University of Munich, Center for Integrated Protein Science Munich (CIPSM), Schillerstr. 44, Munich 80336 (Germany); Eick, Dirk, E-mail: eick@helmholtz-muenchen.de [Department of Molecular Epigenetics, Helmholtz Center Munich, Center for Integrated Protein Science Munich (CIPSM), Marchioninistr. 25, Munich 81377 (Germany)

    2015-05-15

    PeBoW, a trimeric complex consisting of pescadillo (Pes1), block of proliferation (Bop1), and the WD repeat protein 12 (WDR12), is essential for processing and maturation of mammalian 5.8S and 28S ribosomal RNAs. Applying a mass spectrometric analysis, we identified the DEAD-box helicase DDX27 as stably associated factor of the PeBoW-complex. DDX27 interacts with the PeBoW-complex via an evolutionary conserved F×F motif in the N-terminal domain and is recruited to the nucleolus via its basic C-terminal domain. This recruitment is RNA-dependent and occurs independently of the PeBoW-complex. Interestingly, knockdown of DDX27, but not of Pes1, induces the accumulation of an extended form of the primary 47S rRNA. We conclude that DDX27 can interact specifically with the Pes1 and Bop1 but fulfils critical function(s) for proper 3′ end formation of 47S rRNA independently of the PeBoW-complex. - Highlights: • DEAD-box helicase DDX27 is a new constituent of the PeBoW-complex. • The N-terminal F×F motif of DDX27 interacts with the PeBoW components Pes1 and Bop1. • Nucleolar anchoring of DDX27 via its basic C-terminal domain is RNA dependent. • Knockdown of DDX27 induces a specific defect in 3′ end formation of 47S rRNA.

  11. Binding of the human papillomavirus E1 origin-recognition protein is regulated through complex formation with the E2 enhancer-binding protein.

    OpenAIRE

    Frattini, M G; Laimins, L A

    1994-01-01

    The papillomavirus E1 and E2 proteins form heteromeric complexes and individually bind specific sequences within the viral origin of replication. The mechanism by which these proteins are recruited to the origin and the role of the E1/E2 complex in replication remain undefined. To examine the interplay of these replication proteins, we have analyzed the binding of human papillomavirus (HPV) type 31b E1 and E2 proteins to the origin of replication. Binding of E1 to the origin was increased by ...

  12. Regulator Interface Strategies Implemented at the Y-12 National Security Complex Old Salvage Yard Soils Remediation Project, Oak Ridge, TN - 12162

    International Nuclear Information System (INIS)

    The Oak Ridge Y-12 National Security Complex housed an area known as the Old Salvage Yard (OSY) that was approximately 7 acres. The OSY was used as an area for the accumulation, processing and storage of scrap metal and equipment from Y-12 operations extending from 1968 until 2009. Areas in the northern sections of OSY also have been used for the storage of used oils containing solvents and the accumulation and recycling or de-heading and crushing of 55-gal metal drums. Scrap metal operations historically involved the accumulation, sorting, storage, public sale or disposal of scrap metal and equipment. Non-containerised storage of scrap metal was routine until 1995 when scrap metal received at OSY was placed in B-24 and B-25 boxes. Under the American Recovery and Reinvestment Act (ARRA), approximately 26,759 cubic meters of scrap metal and debris were removed and disposed at both on and off-site disposal facilities including the on-site, Oak Ridge Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) landfill in 2010 and 2011. This removal action was performed in accordance with a CERCLA Record of Decision (ROD) and a close working relationship with both the U.S. Environmental Protection Agency (EPA) Region IV and Tennessee Department of Environment and Conservation (TDEC). Due to efficiencies and the excellent cooperative relationship forged with EPA Region IV and TDEC for Y-12 ARRA Cleanup Projects, a surplus of funding was available for additional remediation work that was completed in fiscal year (FY) 2011. The underlying OSY soils were targeted for characterization and potential remediation. To expedite these important activities, the U.S. Department of Energy Oak Ridge Environmental Management partnered with the regulators during detailed planning sessions through a variety of means to quickly and efficiently characterize and pinpoint areas requiring remediation according to previous ROD commitments. Data Quality Objectives (DQOs

  13. Managing Complexity

    Energy Technology Data Exchange (ETDEWEB)

    Chassin, David P.; Posse, Christian; Malard, Joel M.

    2004-08-01

    Physical analogs have shown considerable promise for understanding the behavior of complex adaptive systems, including macroeconomics, biological systems, social networks, and electric power markets. Many of today’s most challenging technical and policy questions can be reduced to a distributed economic control problem. Indeed, economically-based control of large-scale systems is founded on the conjecture that the price-based regulation (e.g., auctions, markets) results in an optimal allocation of resources and emergent optimal system control. This paper explores the state of the art in the use physical analogs for understanding the behavior of some econophysical systems and to deriving stable and robust control strategies for them. In particular we review and discussion applications of some analytic methods based on the thermodynamic metaphor according to which the interplay between system entropy and conservation laws gives rise to intuitive and governing global properties of complex systems that cannot be otherwise understood.

  14. Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

    Czech Academy of Sciences Publication Activity Database

    Ralph, S.J.; Moreno-Sanchez, R.; Neužil, Jiří; Rodriguez-Enriquez, S.

    2011-01-01

    Roč. 28, č. 11 (2011), s. 2695-2730. ISSN 0724-8741 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mitocans * SDH/Complex II * mitochondrial ROS production Subject RIV: CE - Biochemistry Impact factor: 4.093, year: 2011

  15. MBL-associated serine protease-3 circulates in high serum concentrations predominantly in complex with Ficolin-3 and regulates Ficolin-3 mediated complement activation

    DEFF Research Database (Denmark)

    Skjoedt, Mikkel-Ole; Palarasah, Yaseelan; Munthe-Fog, Lea;

    2010-01-01

    The human lectin complement pathway (LCP) involves circulating complexes consisting of mannose-binding lectin (MBL) or ficolins in association with serine proteases named MASP-1, -2 and -3 and a non-enzymatic protein, sMAP. MASP-3 originates from the MASP1 gene through differential splicing and...

  16. A Mutation in cnot8, Component of the Ccr4-Not Complex Regulating Transcript Stability, Affects Expression Levels of Developmental Regulators and Reveals a Role of Fgf3 in Development of Caudal Hypothalamic Dopaminergic Neurons

    OpenAIRE

    Koch, Peter; Löhr, Heiko B.; Driever, Wolfgang

    2014-01-01

    While regulation of the activity of developmental control genes at the transcriptional level as well as by specific miRNA-based degradation are intensively studied, little is known whether general cellular mechanisms controlling mRNA decay may contribute to differential stability of mRNAs of developmental control genes. Here, we investigate whether a mutation in the deadenylation dependent mRNA decay pathway may reveal differential effects on developmental mechanisms, using dopaminergic diffe...

  17. Activated Rac1 regulates the degradation of IκBα and the nuclear translocation of STAT3–NFκB complexes in starved cancer cells

    Science.gov (United States)

    Kim, Sung Joo; Yoon, Sarah

    2016-01-01

    In several human tumors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NFκB) are activated and interact; how these STAT3–NFκB complexes are transported to the nucleus is not fully understood. In this study, we found that Rac1 was activated in starved cancer cells and that activated Rac1 coexisted with STAT3 and NFκB. Rac1 knockdown and overexpression of the dominant-negative mutant Rac1N19 inhibited the degradation of IκBα, an inhibitor of NFκB. MG132, an inhibitor of the ubiquitin proteasome pathway, increased the amount of non-phosphorylated IκBα, but not serine-phosphorylated IκBα, indicating that IκBα degradation by Rac1 in starved cancer cells is independent of IκBα serine phosphorylation by IKK. Rac1 knockdown also inhibited the nuclear translocation of STAT3–NFκB complexes, indicating that this translocation requires activated Rac1. We also demonstrated that the mutant STAT3 Y705F could form complexes with NFκB, and these unphosphorylated STAT3–NFκB complexes translocated into the nucleus and upregulated the activity of NFκB in starved cancer cells, suggesting that phosphorylation of STAT3 is not essential for its translocation. To our knowledge, this is the first study demonstrating the crucial role of Rac1 in the function of STAT3–NFκB complexes in starved cancer cells and implies that targeting Rac1 may have future therapeutic significance in cancer therapy. PMID:27151455

  18. Crystal Structure of the Response Regulator 02 Receiver Domain, the Essential YycF Two-Component System of Streptococcus pneumoniae in both Complexed and Native States†

    OpenAIRE

    Bent, Colin J.; Isaacs, Neil W.; Mitchell, Timothy J.; Riboldi-Tunnicliffe, Alan

    2004-01-01

    A variety of bacterial cellular responses to environmental signals are mediated by two-component signal transduction systems comprising a membrane-associated histidine protein kinase and a cytoplasmic response regulator (RR), which interpret specific stimuli and produce a measured physiological response. In RR activation, transient phosphorylation of a highly conserved aspartic acid residue drives the conformation changes needed for full activation of the protein. Sequence homology reveals th...

  19. FLP-4 neuropeptide and its receptor in a neuronal circuit regulate preference choice through functions of ASH-2 trithorax complex in Caenorhabditis elegans

    OpenAIRE

    Yonglin Yu; Lingtong Zhi; Xiangmin Guan; Daoyong Wang; Dayong Wang

    2016-01-01

    Preference choice on food is an important response strategy for animals living in the environment. Using assay system of preference choice on bacterial foods, OP50 and PA14, we identified the involvement of ADL sensory neurons in the control of preference choice in Caenorhabditis elegans. Both genetically silencing and ChR2-mediated activation of ADL sensory neurons significantly affected preference choice. ADL regulated preference choice by inhibiting function of G protein-coupled receptor (...

  20. The EZH1-SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT.

    Science.gov (United States)

    Su, Shuai-Kun; Li, Chun-Yuan; Lei, Pin-Ji; Wang, Xiang; Zhao, Quan-Yi; Cai, Yang; Wang, Zhen; Li, Lianyun; Wu, Min

    2016-06-15

    Unlike other members of the polycomb group protein family, EZH1 has been shown to positively associate with active transcription on a genome-wide scale. However, the underlying mechanism for this behavior still remains elusive. Here, we report that EZH1 physically interacts with UXT, a small chaperon-like transcription co-activator. UXT specifically interacts with EZH1 and SUZ12, but not EED. Similar to upon knockdown of UXT, knockdown of EZH1 or SUZ12 through RNA interference in the cell impairs the transcriptional activation of nuclear factor (NF)-κB target genes induced by TNFα. EZH1 deficiency also increases TNFα-induced cell death. Interestingly, chromatin immunoprecipitation and the following next-generation sequencing analysis show that H3K27 mono-, di- and tri-methylation on NF-κB target genes are not affected in EZH1- or UXT-deficient cells. EZH1 also does not affect the translocation of the p65 subunit of NF-κB (also known as RELA) from the cytosol to the nucleus. Instead, EZH1 and SUZ12 regulate the recruitment of p65 and RNA Pol II to target genes. Taken together, our study shows that EZH1 and SUZ12 act as positive regulators for NF-κB signaling and demonstrates that EZH1, SUZ12 and UXT work synergistically to regulate pathway activation in the nucleus. PMID:27127229

  1. Glucose depletion inhibits translation initiation via eIF4A loss and subsequent 48S preinitiation complex accumulation, while the pentose phosphate pathway is coordinately up-regulated

    OpenAIRE

    Castelli, Lydia M.; Lui, Jennifer; Campbell, Susan G.; Rowe, William; Zeef, Leo A. H.; Holmes, Leah E.A.; Hoyle, Nathaniel P.; Bone, Jonathon; Selley, Julian N.; Sims, Paul F. G.; Ashe, Mark P.

    2011-01-01

    Cellular stress can globally inhibit translation initiation, and glucose removal from yeast causes one of the most dramatic effects in terms of rapidity and scale. Here we show that the same rapid inhibition occurs during yeast growth as glucose levels diminish. We characterize this novel regulation showing that it involves alterations within the 48S preinitiation complex. In particular, the interaction between eIF4A and eIF4G is destabilized, leading to a temporary stabilization of the eIF3–...

  2. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease

    OpenAIRE

    Ward, Lucas D.; Kellis, Manolis

    2015-01-01

    More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. This has increased the urgency of understanding the regulatory genome as a key component for translating genetic results into mechanistic insights and ultimately therapeutics. To address this challenge, we developed HaploReg (http://compbio.mit.edu/HaploReg) to aid the functional dissection of genome-wide association study (GWAS) results, the ...

  3. Reactive oxygen species production in cardiac mitochondria after complex I inhibition: Modulation by substrate-dependent regulation of the NADH/NAD(+) ratio.

    Science.gov (United States)

    Korge, Paavo; Calmettes, Guillaume; Weiss, James N

    2016-07-01

    Reactive oxygen species (ROS) production by isolated complex I is steeply dependent on the NADH/NAD(+) ratio. We used alamethicin-permeabilized mitochondria to study the substrate-dependence of matrix NADH and ROS production when complex I is inhibited by piericidin or rotenone. When complex I was inhibited in the presence of malate/glutamate, membrane permeabilization accelerated O2 consumption and ROS production due to a rapid increase in NADH generation that was not limited by matrix NAD(H) efflux. In the presence of inhibitor, both malate and glutamate were required to generate a high enough NADH/NAD(+) ratio to support ROS production through the coordinated activity of malate dehydrogenase (MDH) and aspartate aminotransferase (AST). With malate and glutamate present, the rate of ROS production was closely related to local NADH generation, whereas in the absence of substrates, ROS production was accelerated by increase in added [NADH]. With malate alone, oxaloacetate accumulation limited NADH production by MDH unless glutamate was also added to promote oxaloacetate removal via AST. α-ketoglutarate (KG) as well as AST inhibition also reversed NADH generation and inhibited ROS production. If malate and glutamate were provided before rather than after piericidin or rotenone, ROS generation was markedly reduced due to time-dependent efflux of CoA. CoA depletion decreased KG oxidation by α-ketoglutarate dehydrogenase (KGDH), such that the resulting increase in [KG] inhibited oxaloacetate removal by AST and NADH generation by MDH. These findings were largely obscured in intact mitochondria due to robust H2O2 scavenging and limited ability to control substrate concentrations in the matrix. We conclude that in mitochondria with inhibited complex I, malate/glutamate-stimulated ROS generation depends strongly on oxaloacetate removal and on the ability of KGDH to oxidize KG generated by AST. PMID:27068062

  4. Coligand-regulated assembly, fluorescence, and magnetic properties of Co(II) and Cd(II) complexes with a non-coplanar dicarboxylate

    International Nuclear Information System (INIS)

    A non-coplanar dicarboxylate ndca (H2ndca=5-norbornene-2,3-dicarboxylic acid), combining with various dipyridyl-typed tectons, constructs six Cd(II)/Co(II) coordination polymers under hydrothermal conditions, namely [Co(ndca)(H2O)]n (1), ([Co(ndca)(bpe)(H2O)]·H2O)n (2), [Co(ndca)(bpa)0.5(H2O)]n (3), [Cd(ndca)(bpe)(H2O)]n (4), ([Cd(ndca)(bpa)(H2O)]·0.5H2O)n (5), and ([Cd(ndca)(bpp) (H2O)]·H2O)n (6) (bpe=1,2-di(4-pyridyl)ethylene, bpa=1,2-bi(4-pyridyl)ethane, and bpp=1,3-bis(4-pyridyl)propane). All these compounds contain various metal(II)–carboxylate motifs, including carboxylate binuclear (2, 4, 5), carboxylate chain (1, 6) and carboxylate layer (3), which are further extended by dipyridyl-typed coligands to afford a vast diversity of the structures with 2D pyknotic layers (1, 6), 2D open layer (5), 2D→3D interpenetrated networks (2,4), and 3D pillared-layer framework (3), respectively. In addition, fluorescent spectra of Cd(II) complexes and magnetic properties of Co(II) complexes are also given. - Graphical abstract: Six various cadmium(II)/cobalt(II)–organic frameworks were constructed by 5-norbornene-2,3-dicarboxylic acid and different bis(pyridine) rod-like tectons, and Cd (II) complexes exhibit blue–violet emissions, whereas Co (II) complexes show antiferromagnetic behaviours. Display Omitted

  5. The Choice of Alternative 5' Splice Sites in Influenza Virus M1 mRNA is Regulated by the Viral Polymerase Complex

    Science.gov (United States)

    Shih, Shin-Ru; Nemeroff, Martin E.; Krug, Robert M.

    1995-07-01

    The influenza virus M1 mRNA has two alternative 5' splice sites: a distal 5' splice site producing mRNA_3 that has the coding potential for 9 amino acids and a proximal 5' splice site producing M2 mRNA encoding the essential M2 ion-channel protein. Only mRNA_3 was made in uninfected cells transfected with DNA expressing M1 mRNA. Similarly, using nuclear extracts from uninfected cells, in vitro splicing of M1 mRNA yielded only mRNA_3. Only when the mRNA_3 5' splice site was inactivated by mutation was M2 mRNA made in uninfected cells and in uninfected cell extracts. In influenza virus-infected cells, M2 mRNA was made, but only after a delay, suggesting that newly synthesized viral gene product(s) were needed to activate the M2 5' splice site. We present strong evidence that these gene products are the complex of the three polymerase proteins, the same complex that functions in the transcription and replication of the viral genome. Gel shift experiments showed that the viral polymerase complex bound to the 5' end of the viral M1 mRNA in a sequence-specific and cap-dependent manner. During in vitro splicing catalyzed by uninfected cell extracts, the binding of the viral polymerase complex blocked the mRNA_3 5' splice site, resulting in the switch to the M2 mRNA 5' splice site and the production of M2 mRNA.

  6. Complexity for Artificial Substrates (

    NARCIS (Netherlands)

    Loke, L.H.L.; Jachowski, N.R.; Bouma, T.J.; Ladle, R.J.; Todd, P.A.

    2014-01-01

    Physical habitat complexity regulates the structure and function of biological communities, although the mechanisms underlying this relationship remain unclear. Urbanisation, pollution, unsustainable resource exploitation and climate change have resulted in the widespread simplification (and loss) o

  7. The Isy1p component of the NineTeen Complex interacts with the ATPase Prp16p to regulate the fidelity of pre-mRNA splicing

    OpenAIRE

    Villa, Tommaso; Guthrie, Christine

    2005-01-01

    Prp16p is a DEAH-box ATPase that transiently associates with the spliceosome to promote the structural transition required for the second chemical step. Yeast strains carrying the cold-sensitive allele prp16-302 stall the release of Prp16p at low temperatures, yet splice precursors with aberrant branchpoints at increased frequency. To identify new factors involved in the regulation of splicing fidelity, we sought suppressors of the prp16-302 growth phenotype. Deletion of the nonessential ISY1...

  8. PIAS1 regulates CP2c localization and active promoter complex formation in erythroid cell-specific α-globin expression

    OpenAIRE

    Chul Kang, Ho; Hyung Chae, Ji; Jeon, Jinseon; Kim, Won; Hyun Ha, Dae; Ho Shin, June; Gil Kim, Chan; Geun Kim, Chul

    2010-01-01

    Data presented here extends our previous observations on α-globin transcriptional regulation by the CP2 and PIAS1 proteins. Using RNAi knockdown, we have now shown that CP2b, CP2c and PIAS1 are each necessary for synergistic activation of endogenous α-globin gene expression in differentiating MEL cells. In this system, truncated PIAS1 mutants lacking the ring finger domain recruited CP2c to the nucleus, as did wild-type PIAS1, demonstrating that this is a sumoylation-independent process. In v...

  9. Regulating Rho GTPases and their regulators.

    Science.gov (United States)

    Hodge, Richard G; Ridley, Anne J

    2016-08-01

    Rho GTPases regulate cytoskeletal and cell adhesion dynamics and thereby coordinate a wide range of cellular processes, including cell migration, cell polarity and cell cycle progression. Most Rho GTPases cycle between a GTP-bound active conformation and a GDP-bound inactive conformation to regulate their ability to activate effector proteins and to elicit cellular responses. However, it has become apparent that Rho GTPases are regulated by post-translational modifications and the formation of specific protein complexes, in addition to GTP-GDP cycling. The canonical regulators of Rho GTPases - guanine nucleotide exchange factors, GTPase-activating proteins and guanine nucleotide dissociation inhibitors - are regulated similarly, creating a complex network of interactions to determine the precise spatiotemporal activation of Rho GTPases. PMID:27301673

  10. SOCIAL DEVELOPMENT OF RURAL AREAS AS A MAIN DIRECTION OF GOVERNMENT REGULATION OF AGRO-INDUSTRIAL COMPLEX IN THE KRASNODAR REGION

    Directory of Open Access Journals (Sweden)

    Burkovskiy P. V.

    2015-10-01

    Full Text Available This article is devoted to evaluation and analysis of basic trends, that revealing modern situation and current level of the development of social sphere in rural areas in the Krasnodar region. We have carried out a theoretical view to current problems in gasification, water supply, and development infrastructure objects in rural areas of the region. The authors have considered main attention is a social standards when developing targeted programs for the social development of rural areas. The article provides a specific list of normative values still indicators as the presence of a central gas supply, the central and the local water supply (hot and cold, the length of the street and objects known telephone. We have explained the mechanism of government regulations aimed at social infrastructure in rural areas of the Krasnodar region and the organization work of municipal institutions to protect and maintenance local roads. Based on the above authors’ suggestions, it is planned to achieve more definable and justifiable opinion in the implementation of municipal regulation social development rural areas designed on the basis targeted programs in the subject area. Actual and significant to readers are measures of gap consumer budget and the level of monetary income between urban and rural areas presented in the article

  11. EGF-stimulated activation of Rab35 regulates RUSC2-GIT2 complex formation to stabilize GIT2 during directional lung cancer cell migration.

    Science.gov (United States)

    Duan, Biao; Cui, Jie; Sun, Shixiu; Zheng, Jianchao; Zhang, Yujie; Ye, Bixing; Chen, Yan; Deng, Wenjie; Du, Jun; Zhu, Yichao; Chen, Yongchang; Gu, Luo

    2016-08-28

    Non-small cell lung cancer (NSCLC) remains one of the most metastasizing tumors, and directional cell migration is critical for targeting tumor metastasis. GIT2 has been known to bind to Paxillin to control cell polarization and directional migration. However, the molecular mechanisms underlying roles of GIT2 in controlling cell polarization and directional migration remain elusive. Here we demonstrated GIT2 control cell polarization and direction dependent on the regulation of Golgi through RUSC2. RUSC2 interacts with SHD of GIT2 in various lung cancer cells, and stabilizes GIT2 (Mazaki et al., 2006; Yu et al., 2009) by decreasing degradation and increasing its phosphorylation. Silencing of RUSC2 showed reduced stability of GIT2, defective Golgi reorientation toward the wound edge and decreased directional migration. Moreover, short-term EGF stimulation can increase the interaction between RUSC2 and GIT2, prolonged stimulation leads to a decrease of their interaction through activating Rab35. Silencing of Rab35 also reduced stability and phosphorylation of GIT2 and decreased cell migration. Taken together, our study indicated that RUSC2 participates in EGFR signaling and regulates lung cancer progression, and may be a new therapeutic target against lung cancer metastasis. PMID:27238570

  12. Radiological evaluation of an industrial complex of phosphate fertilizer production in response to the current regulations on health protection against ionizing radiation; Evaluacion radiologica de un complejo industrial de produccion de fertilizantes fosfatado al actual reglamento sobre proteccion sanitaria contra radiaciones ionizantes

    Energy Technology Data Exchange (ETDEWEB)

    Mosqueda Pena, F.; Bolivar Raya, J. P.

    2011-07-01

    We performed a comprehensive study of the radioactive and radiological follow NORM industrial complex, in addition to that regulation, the Criteria for radiological protection against exposure to natural radiation issued by the Nuclear Safety Council (CSN).

  13. Nucleolar protein PinX1p regulates telomerase by sequestering its protein catalytic subunit in an inactive complex lacking telomerase RNA

    OpenAIRE

    Lin, Jue; Elizabeth H. Blackburn

    2004-01-01

    Human TRF1-binding protein PinX1 inhibits telomerase activity. Here we report that overexpression of yeast PinX1p (yPinX1p) results in shortened telomeres and decreased in vitro telomerase activity. yPinX1p coimmunoprecipitated withyeast telomerase protein Est2p even in cells lacking the telomerase RNA TLC1, or the telomerase-associated proteins Est1p and Est3p. Est2p regions required for binding to yPinX1p or TLC1 were similar. Furthermore, we found two distinct Est2p complexes exist, contai...

  14. 3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase

    OpenAIRE

    Torreira, Eva; Tortajada, Agustín; Montes, Tamara; de Córdoba, Santiago Rodríguez; Llorca, Oscar

    2009-01-01

    Generation of the alternative pathway C3-convertase, the central amplification enzyme of the complement cascade, initiates by the binding of factor B (fB) to C3b to form the proconvertase, C3bB. C3bB is subsequently cleaved by factor D (fD) at a single site in fB, producing Ba and Bb fragments. Ba dissociates from the complex, while Bb remains bound to C3b, forming the active alternative pathway convertase, C3bBb. Using single-particle electron microscopy we have determined the 3-dimensional ...

  15. On the Complexity of the Tragedy of Anti-commons Caused by Government Regulation%论政府管制的反公地悲剧的复杂性

    Institute of Scientific and Technical Information of China (English)

    高洁

    2012-01-01

    政府管制造成的反公地悲剧比公地悲剧更为复杂:一是反公地悲剧可能看不见从而难以发现;二是腐败的存在将使反公地悲剧更难以克服和解决;三是政府管制既可能造成资源利用不足的反公地悲剧,也可能造成资源利用过度的悲剧,此时调整交易成本可能比整合产权更为重要。因此,政府在实施管制时要尽量避免制造出反公地悲剧。%The tragedy of anti-commons caused by government regulation is more complex than the tragedy of commons for three reasons.First,the tragedy of anti-commons may be invisible,therefore,hard to detect.Second,the existence of corruption makes such tragedy difficult to tackle.And thirdly,government regulation may lead to both underuse and overuse of resources,under this circumstance,it may be more appropriate to lower transaction cost than to delineate property rights.Due to the complexity of the tragedy of anti-commons,the best way to avoid the tragedy is not to create it.

  16. Can the financialized atmosphere be effectively regulated? A critical analysis of the proposed Australian carbon pollution reduction scheme as a complex market solution to global warming

    Energy Technology Data Exchange (ETDEWEB)

    Windsor, C. [Bond Univ. (Australia); McNicholas, P. [Monash Univ. (Australia)

    2009-07-01

    A large body of scientific evidence indicates that global warming from human induced greenhouse gases (GHG) emissions is producing harmful climate change that will lead to global environmental and economic catastrophe within 10 years. The threat of human induced global warming has been on the international and public policy agenda for several years; for example on 11 December 1998, government representatives of 108 countries signed the United Nations Framework Convention on Climate Change (UNFCCC) an international agreement to reduce global warming or the Kyoto Protocol, with the then exception of the Australian and the United States (U.S.) governments. International action on GHG emissions reduction was thwarted by U.S. and Australian goverments. The then Australian government (1996-2007) surreptitiously funding by vested interests such as the coal industry, had no intention to act even though scientific evidence reported that Australia had begun to experience the detrimental effects of global warming. To fulfil an electoral promise, the center left Labor government signed the Kyoto Protocol on 3 December 2007. To deal with the global warming crisis, the Australian government has proposed an emissions trading scheme now officially called the 'Carbon Pollution Reduction Scheme' or CPRS. The proposed scheme is a cap and trade market mechanism that purportedly encourages businesses to operate more efficiently, thus reducing GHG emissions through price signalling in a government instigated market. Hence credible, transparent and efficient information underpins such a market in a post-Keynes deregulated world. The purpose of this paper is to critically examine the integrity of using current financial and reporting regulation that will oversee and monitor the veracity of newly commoditized carbon financial products, particularly since the global financial crisis has exposed significant financial regulatory weaknesses. Further we contend that current corporate

  17. REGULATION OF VASCULOGENESIS AND ANGIOGENESIS

    Science.gov (United States)

    Regulation of vasculogenesis and angiogenesis.B.D. AbbottReproductive Toxicology Division, Environmental Protection Agency, Research Triangle Park, North Carolina, USA Vasculogenesis and angiogenesis are regulated by a complex, interactive family of receptors and lig...

  18. An investigation of the role of metacognitive behavior in self-regulated learning when learning a complex science topic with a hypermedia learning environment

    Science.gov (United States)

    Binbasaran Tuysuzoglu, Banu

    Studies have shown that learners need to use self-regulated learning (SRL) skills when learning with Hypermedia Learning Environments (HLEs) to reach a conceptual understanding of science. SRL theory suggests that metacognition plays a key role in learning. The aim of this study was to investigate the relationship between metacognitive monitoring (e.g., judgment of learning [JOL]) and metacognitive control and their effects upon learning about the circulatory system with an HLE. I examined the frequencies of learners' use of negative JOL with and without a change in strategy use, which indicates the quality (i.e., static or adaptive) of metacognitive behavior. The results showed that adaptive metacognitive behavior positively related to learning, and static metacognitive behavior negatively related to learning, above and beyond the effect of prior knowledge. Findings provided valuable implications for the benefits of using JOL followed by control over strategy use when learning with HLEs.

  19. Autoregulation of PhoP/PhoQ and positive regulation of the cyclic AMP receptor protein-cyclic AMP complex by PhoP in Yersinia pestis.

    Science.gov (United States)

    Zhang, Yiquan; Wang, Li; Han, Yanping; Yan, Yanfeng; Tan, Yafang; Zhou, Lei; Cui, Yujun; Du, Zongmin; Wang, Xiaoyi; Bi, Yujing; Yang, Huiying; Song, Yajun; Zhang, Pingping; Zhou, Dongsheng; Yang, Ruifu

    2013-03-01

    Yersinia pestis is one of the most dangerous bacterial pathogens. PhoP and cyclic AMP receptor protein (CRP) are global regulators of Y. pestis, and they control two distinct regulons that contain multiple virulence-related genes. The PhoP regulator and its cognate sensor PhoQ constitute a two-component regulatory system. The regulatory activity of CRP is triggered only by binding to its cofactor cAMP, which is synthesized from ATP by adenylyl cyclase (encoded by cyaA). However, the association between the two regulatory systems PhoP/PhoQ and CRP-cAMP is still not understood for Y. pestis. In the present work, the four consecutive genes YPO1635, phoP, phoQ, and YPO1632 were found to constitute an operon, YPO1635-phoPQ-YPO1632, transcribed as a single primary RNA, whereas the last three genes comprised another operon, phoPQ-YPO1632, transcribed with two adjacent transcriptional starts. Through direct PhoP-target promoter association, the transcription of these two operons was stimulated and repressed by PhoP, respectively; thus, both positive autoregulation and negative autoregulation of PhoP/PhoQ were detected. In addition, PhoP acted as a direct transcriptional activator of crp and cyaA. The translational/transcriptional start sites, promoter -10 and -35 elements, PhoP sites, and PhoP box-like sequences were determined for these PhoP-dependent genes, providing a map of the PhoP-target promoter interaction. The CRP and PhoP regulons have evolved to merge into a single regulatory cascade in Y. pestis because of the direct regulatory association between PhoP/PhoQ and CRP-cAMP. PMID:23264579

  20. mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy

    Science.gov (United States)

    Taneike, Manabu; Nishida, Kazuhiko; Omiya, Shigemiki; Zarrinpashneh, Elham; Misaka, Tomofumi; Kitazume-Taneike, Rika; Austin, Ruth; Takaoka, Minoru; Yamaguchi, Osamu; Gambello, Michael J.; Shah, Ajay M.; Otsu, Kinya

    2016-01-01

    Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts. PMID:27023784

  1. Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases.

    Science.gov (United States)

    Fruci, D; Romania, P; D'Alicandro, V; Locatelli, F

    2014-08-01

    Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8(+) T cells for the presence of abnormal intracellular events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N-terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I-associated autoimmune diseases. PMID:25066018

  2. Nucleotide sequence of psbQ gene for 16-kDa protein of oxygen-evolving complex from Arabidopsis thaliana and regulation of its expression.

    Science.gov (United States)

    Grover, M; Gaur, T; Kochhar, A; Maheshwari, S C; Tyagi, A K

    1999-06-30

    The psbQ gene encoding a 16-kDa polypeptide of the oxygen-evolving complex of photosystem II has been isolated from Arabidopsis thaliana and characterized. The gene consists of a 28 nucleotide long leader sequence, two introns and three exons encoding a 223-amino-acid precursor polypeptide. The first 75 amino acids act as a transit peptide for the translocation of the polypeptide into the thylakoid lumen. Expression studies show that the gene is light-inducible and expresses only in green tissues with high steady-state mRNA levels in leaves. Using this gene as a probe, restriction fragment length polymorphism between two ecotypes, Columbia and Estland, has also been detected. PMID:10470848

  3. Complex regulation of the DnaJ homolog CbpA by the global regulators sigmaS and Lrp, by the specific inhibitor CbpM, and by the proteolytic degradation of CbpM.

    Science.gov (United States)

    Chenoweth, Matthew R; Wickner, Sue

    2008-08-01

    CbpA is a DnaJ homolog that functions as a DnaK cochaperone. Several cellular processes, including growth at low and high temperatures and septum formation during cell division, require either CbpA or DnaJ. CbpA is encoded in an operon with the gene for CbpM, which is a specific in vivo and in vitro inhibitor of CbpA. Here, we have cooverexpressed CbpA with CbpM in a DeltacbpAM DeltadnaJ strain and examined the resulting phenotypes. Under these conditions, sufficient free CbpA activity was present to support growth at low temperatures, but not at high temperatures. Defects in cell division and in lambda replication were also partially complemented by CbpA when cooverexpressed with CbpM. Utilizing reporter fusions, we demonstrated that the cbpAM operon was maximally transcribed at the transition from exponential growth to stationary phase. Transcription was controlled by the sigma(S) and Lrp global regulators, and both leucine availability and growth temperature influenced transcription. CbpA and CbpM accumulated to similar levels in stationary phase, approximately 2,300 monomers per cell. When not bound to CbpA, CbpM was unstable and was degraded by the Lon and ClpAP proteases. These data demonstrate that CbpA activity is controlled at multiple levels. PMID:18502857

  4. Regulator of G protein signaling 8 inhibits protease-activated receptor 1/Gi/o signaling by forming a distinct G protein-dependent complex in live cells.

    Science.gov (United States)

    Lee, Jinyong; Ghil, Sungho

    2016-05-01

    Activation of seven-transmembrane-domain-possessing G protein-coupled receptors (GPCRs) by extracellular stimuli elicits intracellular responses. One class of GPCRs-protease-activated receptors (PARs)-is activated by endogenous proteases, such as thrombin and trypsin. Members of the regulator of G protein signaling (RGS) family stimulate GTP hydrolysis of G protein alpha (Gα) subunits, thereby inhibiting GPCR/Gα-mediated signaling. We previously reported that RGS2 and RGS4 inhibit PAR1/Gα-mediated signaling by interacting with PAR1 in a Gα-dependent manner. Here, employing the bioluminescence resonance energy transfer (BRET) technique, we identified RGS8 as a novel PAR1-interacting protein. Very little BRET activity was observed between PAR1-Venus (PAR1-Ven) and RGS8-Luciferase (RGS8-Luc) in the absence of Gα. However, in the presence of Gαo, BRET activity was specifically and significantly increased. This interaction was confirmed by biochemical and immunofluorescence assays. Notably, RGS8 inhibited PAR1/Gαi/o-mediated adenylyl cyclase and ERK activation, and prevented Gαo-induced neurite outgrowth and activation of Necdin protein, a downstream target of Gαo. Our findings suggest a novel function of RGS8 and reveal cellular mechanisms by which RGS8 mediates PAR1 inhibition. PMID:26829215

  5. SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter

    Science.gov (United States)

    Smith, Jennifer A.; Haberstroh, Friederike S.; White, Elizabeth A.; Livingston, David M.; DeCaprio, James A.; Howley, Peter M.

    2014-01-01

    An important step in the malignant progression of HPV-associated lesions is the dysregulation of expression of the viral E6 and E7 oncogenes. This is often achieved through the loss of expression of E2, which represses the HPV LCR promoter and E6/E7 expression. Our previous studies confirmed a role for Brd4 in mediating the E2 transcriptional repression function, and identified JARID1C/SMCX and EP400 as contributors to E2-mediated repression. Here we show that TIP60, a component of the TIP60/TRRAP histone acetyltransferase complex, also contributes to the E2 repression function, and we extend our studies on SMCX. Di- and tri-methyl marks on histone H3K4 are reduced in the presence of E2 and SMCX, suggesting a mechanism by which SMCX contributes to E2-mediated repression of the HPV LCR. Together, these findings lead us to hypothesize that E2 recruits histone-modifying cellular proteins to the HPV LCR, resulting in transcriptional repression of E6 and E7. PMID:25222147

  6. SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter.

    Science.gov (United States)

    Smith, Jennifer A; Haberstroh, Friederike S; White, Elizabeth A; Livingston, David M; DeCaprio, James A; Howley, Peter M

    2014-11-01

    An important step in the malignant progression of HPV-associated lesions is the dysregulation of expression of the viral E6 and E7 oncogenes. This is often achieved through the loss of expression of E2, which represses the HPV LCR promoter and E6/E7 expression. Our previous studies confirmed a role for Brd4 in mediating the E2 transcriptional repression function, and identified JARID1C/SMCX and EP400 as contributors to E2-mediated repression. Here we show that TIP60, a component of the TIP60/TRRAP histone acetyltransferase complex, also contributes to the E2 repression function, and we extend our studies on SMCX. Di- and tri-methyl marks on histone H3K4 are reduced in the presence of E2 and SMCX, suggesting a mechanism by which SMCX contributes to E2-mediated repression of the HPV LCR. Together, these findings lead us to hypothesize that E2 recruits histone-modifying cellular proteins to the HPV LCR, resulting in transcriptional repression of E6 and E7. PMID:25222147

  7. The β-propeller gene Rv1057 of Mycobacterium tuberculosis has a complex promoter directly regulated by both the MprAB and TrcRS two-component systems

    Science.gov (United States)

    Pang, Xiuhua; Cao, Guangxiang; Neuenschwander, Pierre F.; Haydel, Shelley E.; Hou, Guihua; Howard, Susan T.

    2011-01-01

    SUMMARY The β-propeller gene Rv1057 of Mycobacterium tuberculosis is activated by envelope stress and was first characterized as a regulatory target of the TrcRS two-component system (TCS). Rv1057 expression is repressed by TrcRS, and the Rv1057 proximal promoter contains a TrcR binding site. In this study, we determined that Rv1057 is also directly regulated by MprAB, a TCS associated with envelope stress. Multiple potential MprA binding sites (MprA boxes) were identified in the 1 kb intergenic region upstream of Rv1057, and four sites were shown to bind MprA. Although MprA boxes were found in the proximal promoter, analyses suggest that MprA and TrcR do not compete for binding in this region. An MprAB-dependent, detergent-inducible transcriptional start point for Rv1057 was identified downstream of the MprA boxes, and a second TrcR binding site and small ORF of the 13E12 family were discovered in the distal promoter. MprAB was required for activation of Rv1057 during growth in macrophages and under detergent stress, and lacZ promoter constructs suggest the entire intergenic region is utilized during MprAB-dependent activation of Rv1057. These findings indicate that Rv1057 has an extensive and complex promoter, and provide evidence for coordinated regulation of stress response genes by TCSs. PMID:22099420

  8. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    Science.gov (United States)

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  9. Complex Beauty

    OpenAIRE

    Franceschet, Massimo

    2014-01-01

    Complex systems and their underlying convoluted networks are ubiquitous, all we need is an eye for them. They pose problems of organized complexity which cannot be approached with a reductionist method. Complexity science and its emergent sister network science both come to grips with the inherent complexity of complex systems with an holistic strategy. The relevance of complexity, however, transcends the sciences. Complex systems and networks are the focal point of a philosophical, cultural ...

  10. Market, Regulation, Market, Regulation

    DEFF Research Database (Denmark)

    Frankel, Christian; Galland, Jean-Pierre

    2015-01-01

    This paper focuses on the European Regulatory system which was settled both for opening the Single Market for products and ensuring the consumers' safety. It claims that the New Approach and Standardization, and the Global Approach to conformity assessment, which suppressed the last technical...... barriers to trade in Europe, realized the free movement of products by organizing progressively several orders of markets and regulation. Based on historical and institutional documents, on technical publications, and on interviews, this article relates how the European Commission and the Member States had...... alternatively recourse to markets and to regulations, at the three main levels of the New Approach Directives implementation. The article focuses also more specifically on the Medical Devices sector, not only because this New Approach sector has long been controversial in Europe, and has recently been concerned...

  11. Complex chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Bong Gon; Kim, Jae Sang; Kim, Jin Eun; Lee, Boo Yeon

    2006-06-15

    This book introduces complex chemistry with ten chapters, which include development of complex chemistry on history coordination theory and Warner's coordination theory and new development of complex chemistry, nomenclature on complex with conception and define, chemical formula on coordination compound, symbol of stereochemistry, stereo structure and isomerism, electron structure and bond theory on complex, structure of complex like NMR and XAFS, balance and reaction on solution, an organo-metallic chemistry, biology inorganic chemistry, material chemistry of complex, design of complex and calculation chemistry.

  12. Complex chemistry

    International Nuclear Information System (INIS)

    This book introduces complex chemistry with ten chapters, which include development of complex chemistry on history coordination theory and Warner's coordination theory and new development of complex chemistry, nomenclature on complex with conception and define, chemical formula on coordination compound, symbol of stereochemistry, stereo structure and isomerism, electron structure and bond theory on complex, structure of complex like NMR and XAFS, balance and reaction on solution, an organo-metallic chemistry, biology inorganic chemistry, material chemistry of complex, design of complex and calculation chemistry.

  13. Advances in network complexity

    CERN Document Server

    Dehmer, Matthias; Emmert-Streib, Frank

    2013-01-01

    A well-balanced overview of mathematical approaches to describe complex systems, ranging from chemical reactions to gene regulation networks, from ecological systems to examples from social sciences. Matthias Dehmer and Abbe Mowshowitz, a well-known pioneer in the field, co-edit this volume and are careful to include not only classical but also non-classical approaches so as to ensure topicality. Overall, a valuable addition to the literature and a must-have for anyone dealing with complex systems.

  14. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures.

    Science.gov (United States)

    van Scheppingen, J; Iyer, A M; Prabowo, A S; Mühlebner, A; Anink, J J; Scholl, T; Feucht, M; Jansen, F E; Spliet, W G; Krsek, P; Zamecnik, J; Buccoliero, A M; Giordano, F; Genitori, L; Kotulska, K; Jozwiak, S; Jaworski, J; Liszewska, E; van Vliet, E A; Aronica, E

    2016-06-01

    Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1β expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1β and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1β stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1β signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate. GLIA 2016;64:1066-1082. PMID:27014996

  15. Bucolic Complexes

    CERN Document Server

    Brešar, Bostjan; Chepoi, Victor; Gologranc, Tanja; Osajda, Damian

    2012-01-01

    In this article, we introduce and investigate bucolic complexes, a common generalization of systolic complexes and of CAT(0) cubical complexes. This class of complexes is closed under Cartesian products and amalgamations over some convex subcomplexes. We study various approaches to bucolic complexes: from graph-theoretic and topological viewpoints, as well as from the point of view of geometric group theory. Bucolic complexes can be defined as locally-finite simply connected prism complexes satisfying some local combinatorial conditions. We show that bucolic complexes are contractible, and satisfy some nonpositive-curvature-like properties. In particular, we prove a version of the Cartan-Hadamard theorem, the fixed point theorem for finite group actions, and establish some results on groups acting geometrically on such complexes. We also characterize the 1-skeletons (which we call bucolic graphs) and the 2-skeletons of bucolic complexes. In particular, we prove that bucolic graphs are precisely retracts of Ca...

  16. Bisthienylethene Th2im and its complex (Th2imH)2[ReCl6]: crystalline-phase photochromism, and photochemical regulation of luminescence and magnetic properties.

    Science.gov (United States)

    Gong, Dan-Ping; Chen, Jun-Feng; Zhao, Yue; Cao, Deng-Ke

    2016-02-16

    Molecular assembly of bisthienylethene Th2im () and [ReCl6](2-) anions leads to the complex (Th2imH)2[ReCl6] (), in which a [ReCl6](2-) anion connects two equivalent Th2imH(+) cations through ClN/C hydrogen bonds. Crystal structures of and indicate that two thiophene groups of each Th2im/Th2imH(+) molecule adopt a photoactive antiparallel conformation. Thus, two compounds show crystalline-phase photochromism (CPP), i.e. reversible structural transformation between the open form and the closed form upon alternately irradiating the sample with UV light (365 nm) and visible light (574 nm for , 624 nm for ). It was found that the CPP behaviors of and could regulate their luminescence and/or magnetic properties. Their solid-state emissions (433, 448, 482, 531 and 570 nm for , and 460, 489, 535 and 593 nm for ) exhibited weaker intensities after UV irradiation with 365 nm light. Besides CPP and luminescence, compound shows field-induced slow magnetic relaxation. Before and after UV irradiation, this compound revealed different magnetic behaviors, including the differences in the shape of the χMT vs. T plot, D parameter, and the values of the relaxation barrier Ueff and the preexponential factor τ0. PMID:26790478

  17. Proteasomes: a complex story

    DEFF Research Database (Denmark)

    Hendil, Klavs B; Hartmann-Petersen, Rasmus

    2004-01-01

    Protein degradation in eukaryotic cells is important for regulation of metabolism, progression through the division cycle, in cell signalling pathways, and in mammals also for generation of antigen fragments for presentation on the major histocompatibility complex (MHC) class I. Most cell proteins...

  18. Regulation of cholesterol homeostasis

    NARCIS (Netherlands)

    van der Wulp, Mariette Y. M.; Verkade, Henkjan J.; Groen, Albert K.

    2013-01-01

    Hypercholesterolemia is an important risk factor for cardiovascular disease. It is caused by a disturbed balance between cholesterol secretion into the blood versus uptake. The pathways involved are regulated via a complex interplay of enzymes, transport proteins, transcription factors and non-codin

  19. Tropical complexes

    OpenAIRE

    Cartwright, Dustin

    2013-01-01

    We introduce tropical complexes, which are Delta-complexes together with additional numerical data. On a tropical complex, we define divisors and linear equivalence between divisors, analogous to the notions for algebraic varieties, and generalizing previous work for graphs. We prove a comparison theorem showing that divisor-curve intersection numbers agree under certain conditions.

  20. Medical Complex

    OpenAIRE

    Kumaraswamy, Mohan

    2002-01-01

    One element of the CIVCAL project Web-based resources containing images, tables, texts and associated data on the construction of the Medical Complex. This project covers the construction of a new Hong Kong University Medical Complex on Sassoon Road, Pokfulam. The complex will comprise two buildings, one will house laboratories and a car park, while the other will contain lecture halls

  1. Dictyostelium possesses highly diverged presenilin/γ-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/γ-secretase complex

    Science.gov (United States)

    McMains, Vanessa C.; Myre, Michael; Kreppel, Lisa; Kimmel, Alan R.

    2010-01-01

    SUMMARY Presenilin (PS) is the catalytic moiety of the γ-secretase complex. PS and other γ-secretase components are well conserved among metazoa, but their presence and function in more-distant species are not resolved. Because inappropriate γ-secretase processing of amyloid precursor protein (APP) in humans is associated with familial Alzheimer’s disease, understanding essential elements within each γ-secretase component is crucial to functional studies. Diverged proteins have been identified in primitive plants but experiments have failed to demonstrate γ-secretase activity. We have identified highly diverged orthologs for each γ-secretase component in the ancient eukaryote Dictyostelium, which lacks equivalents of APP, Notch and other characterized PS/γ-secretase substrates. We show that wild-type (WT) Dictyostelium is capable of amyloidogenic processing of ectopically expressed human APP to generate amyloid-β peptides Aβ40 and Aβ42; strains deficient in γ-secretase cannot produce Aβ peptides but accumulate processed intermediates of APP that co-migrate with the C-terminal fragments α- and β-CTF of APP that are found in mammalian cells. We further demonstrate that Dictyostelium requires PS for phagocytosis and cell-fate specification in a cell-autonomous manner, and show that regulation of phagocytosis requires an active γ-secretase, a pathway suggested, but not proven, to occur in mammalian and Drosophila cells. Our results indicate that PS signaling is an ancient process that arose prior to metazoan radiation, perhaps independently of Notch. Dictyostelium might serve to identify novel PS/γ-secretase signaling targets and provide a unique system for high-throughput screening of small-molecule libraries to select new therapeutic targets for diseases associated with this pathway. PMID:20699477

  2. Dictyostelium possesses highly diverged presenilin/gamma-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/gamma-secretase complex.

    Science.gov (United States)

    McMains, Vanessa C; Myre, Michael; Kreppel, Lisa; Kimmel, Alan R

    2010-01-01

    Presenilin (PS) is the catalytic moiety of the gamma-secretase complex. PS and other gamma-secretase components are well conserved among metazoa, but their presence and function in more-distant species are not resolved. Because inappropriate gamma-secretase processing of amyloid precursor protein (APP) in humans is associated with familial Alzheimer's disease, understanding essential elements within each gamma-secretase component is crucial to functional studies. Diverged proteins have been identified in primitive plants but experiments have failed to demonstrate gamma-secretase activity. We have identified highly diverged orthologs for each gamma-secretase component in the ancient eukaryote Dictyostelium, which lacks equivalents of APP, Notch and other characterized PS/gamma-secretase substrates. We show that wild-type (WT) Dictyostelium is capable of amyloidogenic processing of ectopically expressed human APP to generate amyloid-beta peptides Abeta(40) and Abeta(42); strains deficient in gamma-secretase cannot produce Abeta peptides but accumulate processed intermediates of APP that co-migrate with the C-terminal fragments alpha- and beta-CTF of APP that are found in mammalian cells. We further demonstrate that Dictyostelium requires PS for phagocytosis and cell-fate specification in a cell-autonomous manner, and show that regulation of phagocytosis requires an active gamma-secretase, a pathway suggested, but not proven, to occur in mammalian and Drosophila cells. Our results indicate that PS signaling is an ancient process that arose prior to metazoan radiation, perhaps independently of Notch. Dictyostelium might serve to identify novel PS/gamma-secretase signaling targets and provide a unique system for high-throughput screening of small-molecule libraries to select new therapeutic targets for diseases associated with this pathway. PMID:20699477

  3. Taming Dynamical Complexity and Managing High Technology

    Institute of Scientific and Technical Information of China (English)

    FANGJin-qing; CHENGuan-rong; ZHAOGeng

    2003-01-01

    Variability is one of the most important features of complexity m complex networks anu systems,which usually depends sensitively on small perturbations. Various possible competing behaviours in a system may provide great flexibility in regulating or taming dynamical complexity, through which the designer may be able to better select and manage a desired behaviour for a specific application. In many high-tech fields, how to regulate or manage complexity is a very important but challenge issue.

  4. Communication complexity and information complexity

    Science.gov (United States)

    Pankratov, Denis

    Information complexity enables the use of information-theoretic tools in communication complexity theory. Prior to the results presented in this thesis, information complexity was mainly used for proving lower bounds and direct-sum theorems in the setting of communication complexity. We present three results that demonstrate new connections between information complexity and communication complexity. In the first contribution we thoroughly study the information complexity of the smallest nontrivial two-party function: the AND function. While computing the communication complexity of AND is trivial, computing its exact information complexity presents a major technical challenge. In overcoming this challenge, we reveal that information complexity gives rise to rich geometrical structures. Our analysis of information complexity relies on new analytic techniques and new characterizations of communication protocols. We also uncover a connection of information complexity to the theory of elliptic partial differential equations. Once we compute the exact information complexity of AND, we can compute exact communication complexity of several related functions on n-bit inputs with some additional technical work. Previous combinatorial and algebraic techniques could only prove bounds of the form theta( n). Interestingly, this level of precision is typical in the area of information theory, so our result demonstrates that this meta-property of precise bounds carries over to information complexity and in certain cases even to communication complexity. Our result does not only strengthen the lower bound on communication complexity of disjointness by making it more exact, but it also shows that information complexity provides the exact upper bound on communication complexity. In fact, this result is more general and applies to a whole class of communication problems. In the second contribution, we use self-reduction methods to prove strong lower bounds on the information

  5. Splicing regulators: targets and drugs

    OpenAIRE

    Yeo, Gene Wei-Ming

    2005-01-01

    Silencing of splicing regulators by RNA interference, combined with splicing-specific microarrays, has revealed a complex network of distinct alternative splicing events in Drosophila, while a high-throughput screen of more than 6,000 compounds has identified drugs that interfere specifically and directly with one class of splicing regulators in human cells.

  6. Complexity Plots

    KAUST Repository

    Thiyagalingam, Jeyarajan

    2013-06-01

    In this paper, we present a novel visualization technique for assisting the observation and analysis of algorithmic complexity. In comparison with conventional line graphs, this new technique is not sensitive to the units of measurement, allowing multivariate data series of different physical qualities (e.g., time, space and energy) to be juxtaposed together conveniently and consistently. It supports multivariate visualization as well as uncertainty visualization. It enables users to focus on algorithm categorization by complexity classes, while reducing visual impact caused by constants and algorithmic components that are insignificant to complexity analysis. It provides an effective means for observing the algorithmic complexity of programs with a mixture of algorithms and black-box software through visualization. Through two case studies, we demonstrate the effectiveness of complexity plots in complexity analysis in research, education and application. © 2013 The Author(s) Computer Graphics Forum © 2013 The Eurographics Association and Blackwell Publishing Ltd.

  7. Engaging complexity

    Directory of Open Access Journals (Sweden)

    Gys M. Loubser

    2014-01-01

    Full Text Available In this article, I discuss studies in complexity and its epistemological implications for systematic and practical theology. I argue that engagement with complexity does not necessarily assurea non-reductionist approach. However, if complexity is engaged transversally, it becomes possible to transcend reductionist approaches. Moreover, systematic and practical the ologians can draw on complexity in developing new ways of understanding and, therefore, new ways of describing the focus, epistemic scope and heuristic structures of systematic and practical theology. Firstly, Edgar Morin draws a distinction between restricted and general complexity based on the epistemology drawn upon in studies in complexity. Moving away from foundationalist approaches to epistemology, Morin argues for a paradigm of systems. Secondly,I discuss Kees van Kooten Niekerk�s distinction between epistemology, methodology andontology in studies in complexity and offer an example of a theological argument that drawson complexity. Thirdly, I argue for the importance of transversality in engaging complexity by drawing on the work of Wentzel van Huyssteen and Paul Cilliers. In conclusion, I argue that theologians have to be conscious of the epistemic foundations of each study in complexity, and these studies illuminate the heart of Reformed theology.Intradisciplinary and/or interdisciplinary implications: Therefore, this article has both intradisciplinary and interdisciplinary implications. When theologians engage studies incomplexity, the epistemological roots of these studies need to be considered seeing thatresearchers in complexity draw on different epistemologies. Drawing on transversality wouldenhance such considerations. Furthermore, Edgar Morin�s and Paul Cilliers� approach tocomplexity will inform practical and theoretical considerations in church polity and unity.

  8. Carney Complex

    Science.gov (United States)

    ... of Carney complex are Cushing’s syndrome and multiple thyroid nodules (tumors). Cushing’s syndrome features a combination of weight gain, ... with Carney complex include adrenocortical carcinoma , pituitary gland tumors , thyroid , colorectal , liver and pancreatic cancers . Ovarian cancer in ...

  9. Simplifying complexity

    NARCIS (Netherlands)

    Leemput, van de I.A.

    2016-01-01

    In this thesis I use mathematical models to explore the properties of complex systems ranging from microbial nitrogen pathways and coral reefs to the human state of mind. All are examples of complex systems, defined as systems composed of a number of interconnected parts, where the systemic behavior

  10. Hamiltonian complexity

    International Nuclear Information System (INIS)

    In recent years we have seen the birth of a new field known as Hamiltonian complexity lying at the crossroads between computer science and theoretical physics. Hamiltonian complexity is directly concerned with the question: how hard is it to simulate a physical system? Here I review the foundational results, guiding problems, and future directions of this emergent field.

  11. Radiation regulation

    International Nuclear Information System (INIS)

    The five main areas of radiation regulation considered are radiation exposure in the mining of uranium and other minerals, exposure in the use of uranium in nuclear reactors, risks in the transport of radioactive materials and hazards associated with the disposal of used materials. In Australia these problems are regulated by mines departments, the Australian Atomic Energy Commission and radiation control branches in state health departments. Each of these instutional areas of regulation is examined

  12. Managing Complexity

    DEFF Research Database (Denmark)

    Maylath, Bruce; Vandepitte, Sonia; Minacori, Patricia;

    2013-01-01

    and into French. The complexity of the undertaking proved to be a central element in the students' learning, as the collaboration closely resembles the complexity of international documentation workplaces of language service providers. © Association of Teachers of Technical Writing.......This article discusses the largest and most complex international learning-by-doing project to date- a project involving translation from Danish and Dutch into English and editing into American English alongside a project involving writing, usability testing, and translation from English into Dutch...

  13. Complex variables

    CERN Document Server

    Fisher, Stephen D

    1999-01-01

    The most important topics in the theory and application of complex variables receive a thorough, coherent treatment in this introductory text. Intended for undergraduates or graduate students in science, mathematics, and engineering, this volume features hundreds of solved examples, exercises, and applications designed to foster a complete understanding of complex variables as well as an appreciation of their mathematical beauty and elegance. Prerequisites are minimal; a three-semester course in calculus will suffice to prepare students for discussions of these topics: the complex plane, basic

  14. Complexity a very short introduction

    CERN Document Server

    Holland, John H

    2014-01-01

    The importance of complexity is well-captured by Hawking's comment: "Complexity is the science of the 21st century". From the movement of flocks of birds to the Internet, environmental sustainability, and market regulation, the study and understanding of complex non-linear systems has become highly influential over the last 30 years. In this Very Short Introduction, one of the leading figures in the field, John Holland, introduces the key elements and conceptual framework of complexity. From complex physical systems such as fluid flow and the difficulties of predicting weather, to complex adaptive systems such as the highly diverse and interdependent ecosystems of rainforests, he combines simple, well-known examples - Adam Smith's pin factory, Darwin's comet orchid, and Simon's 'watchmaker' - with an account of the approaches, involving agents and urn models, taken by complexity theory. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost eve...

  15. Modeling Complex Time Limits

    Directory of Open Access Journals (Sweden)

    Oleg Svatos

    2013-01-01

    Full Text Available In this paper we analyze complexity of time limits we can find especially in regulated processes of public administration. First we review the most popular process modeling languages. There is defined an example scenario based on the current Czech legislature which is then captured in discussed process modeling languages. Analysis shows that the contemporary process modeling languages support capturing of the time limit only partially. This causes troubles to analysts and unnecessary complexity of the models. Upon unsatisfying results of the contemporary process modeling languages we analyze the complexity of the time limits in greater detail and outline lifecycles of a time limit using the multiple dynamic generalizations pattern. As an alternative to the popular process modeling languages there is presented PSD process modeling language, which supports the defined lifecycles of a time limit natively and therefore allows keeping the models simple and easy to understand.

  16. Complex Covariance

    Directory of Open Access Journals (Sweden)

    Frieder Kleefeld

    2013-01-01

    Full Text Available According to some generalized correspondence principle the classical limit of a non-Hermitian quantum theory describing quantum degrees of freedom is expected to be the well known classical mechanics of classical degrees of freedom in the complex phase space, i.e., some phase space spanned by complex-valued space and momentum coordinates. As special relativity was developed by Einstein merely for real-valued space-time and four-momentum, we will try to understand how special relativity and covariance can be extended to complex-valued space-time and four-momentum. Our considerations will lead us not only to some unconventional derivation of Lorentz transformations for complex-valued velocities, but also to the non-Hermitian Klein-Gordon and Dirac equations, which are to lay the foundations of a non-Hermitian quantum theory.

  17. Simplifying complexity

    OpenAIRE

    Leemput, van de, J.C.H.

    2016-01-01

    In this thesis I use mathematical models to explore the properties of complex systems ranging from microbial nitrogen pathways and coral reefs to the human state of mind. All are examples of complex systems, defined as systems composed of a number of interconnected parts, where the systemic behavior leads to the emergence of properties that would not be expected from behavior or properties of the individual parts of the system. Although the full behavior of the systems I address will probably...

  18. Human telomerase activity regulation

    OpenAIRE

    Wojtyla, Aneta; Gladych, Marta; Rubis, Blazej

    2010-01-01

    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 b...

  19. Regulating hate speech online

    OpenAIRE

    Banks, James

    2010-01-01

    The exponential growth in the Internet as a means of communication has been emulated by an increase in far-right and extremist web sites and hate based activity in cyberspace. The anonymity and mobility afforded by the Internet has made harassment and expressions of hate effortless in a landscape that is abstract and beyond the realms of traditional law enforcement. This paper examines the complexities of regulating hate speech on the Internet through legal and technological frameworks. It ex...

  20. Iron regulation by hepcidin

    OpenAIRE

    Zhao, Ningning; Zhang, An-Sheng; Enns, Caroline A

    2013-01-01

    Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulati...

  1. Bcl-2与IP3R相互作用调控肿瘤细胞程序性死亡的研究进展%IP3R/Bcl-2-channel complexes regulates programmed cell death

    Institute of Scientific and Technical Information of China (English)

    顾文文; 施韬; 顾一骅; 杨军

    2013-01-01

    由1,4,5-三磷酸肌醇受体(inositol 1,4,5-trisphosphate receptor,IP3R)介导的细胞内钙离子释放在细胞生理学过程中具有中枢性作用,其通道活性受到复杂信号网络的精细调节.近来有研究发现,IP3R是抗凋亡分子B细胞性淋巴瘤-2(B cell lymphoma-2,Bcl-2)家族蛋白的一个作用靶点,而抗凋亡Bcl-2蛋白作为IP3R的内源性调节分子,具有控制内质网中IP3R活性和抑制促凋亡钙信号的功能.已有研究证实,基于干扰Bcl-2家族成员与IP3R相互作用功能区域的多肽分子具有一定的抗肿瘤作用,因此,根据Bcl-2蛋白分子的结构特征及其与IP3R的相互作用机制而设计的靶向药物,已成为抗肿瘤新药的一个重要发展方向,并且部分药物已进入临床研究阶段.这些处于研发中的新药有望为慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)等Bcl-2依赖性肿瘤的治疗及对抗Bcl-2介导的化疗放疗耐药现象带来新希望.本文旨在对上述研究的进展作一综述,以期为肿瘤细胞程序性死亡的调控机制的研究提供一些有价值的参考依据.%The Ca2+ release through IP3R (inositol 1,4,5-trisphosphate receptor) channels mediates the essential procedure of cellular functions.The process of Ca2+ release is elaborately regulated by the complex network system of signal transduction pathway.Recently,anti-apoptotic Bcl-2 proteins were reported to modulate Ca2+ gating of IP3R in ER (endoplasmic reticular) resulting in enhanced cellular bioenergetics and death resistance.Targeting Bcl-2-IP3R interaction was found to be able to induce apoptosis in vitro and in vivo.In addition,the natural or chemically synthesized compounds depending on the molecular structure of anti-apoptotic Bcl-2 proteins,have been tested in several clinical trials of chronic lymphocytic leukemia to verify their anti-tumor effect.Overall,current studies have provided some novel strategies of anti-tumor therapy involved in the

  2. ANTICIPATING AND REGULATING BIOSYSTEM

    Directory of Open Access Journals (Sweden)

    Ion Iorga Siman

    2010-06-01

    Full Text Available Regulating biosystems closely related to human beings are structures still difficult to understand.Numerous intimate processes taking place in these systems, even their actual constitution, are insufficiently decoded, and that they have populated the world long before man invented the first regulator, appears not to have contributed much to their knowledge. This work is intended to highlight what regulating biosystems are.There is no secret that somatic muscles perform control operations which no act of moving would be possible without. All actions are the result of dynamic controlled processes adjusted to strict control laws. By treating them very seriously may lead to knowledge of processes occurring in complex systems

  3. Complex networks: Patterns of complexity

    Science.gov (United States)

    Pastor-Satorras, Romualdo; Vespignani, Alessandro

    2010-07-01

    The Turing mechanism provides a paradigm for the spontaneous generation of patterns in reaction-diffusion systems. A framework that describes Turing-pattern formation in the context of complex networks should provide a new basis for studying the phenomenon.

  4. NOISE REGULATION

    OpenAIRE

    Cristina Voican; Constantin Stanescu

    2012-01-01

    Noise regulation includes statutes or guidelines relating to sound transmission established by national, state or provincial and municipal levels of government. After the watershed passage of the United States Noise Control Act of 1972, other local and state governments passed further regulations. Although the UK and Japan enacted national laws in 1960 and 1967 respectively, these laws were not at all comprehensive or fully enforceable as to address generally rising ambient noise, enforceable...

  5. Complex analysis

    CERN Document Server

    Freitag, Eberhard

    2005-01-01

    The guiding principle of this presentation of ``Classical Complex Analysis'' is to proceed as quickly as possible to the central results while using a small number of notions and concepts from other fields. Thus the prerequisites for understanding this book are minimal; only elementary facts of calculus and algebra are required. The first four chapters cover the essential core of complex analysis: - differentiation in C (including elementary facts about conformal mappings) - integration in C (including complex line integrals, Cauchy's Integral Theorem, and the Integral Formulas) - sequences and series of analytic functions, (isolated) singularities, Laurent series, calculus of residues - construction of analytic functions: the gamma function, Weierstrass' Factorization Theorem, Mittag-Leffler Partial Fraction Decomposition, and -as a particular highlight- the Riemann Mapping Theorem, which characterizes the simply connected domains in C. Further topics included are: - the theory of elliptic functions based on...

  6. Regulation of the power sector

    CERN Document Server

    2013-01-01

    Regulation of the Power Sector is a unified, consistent and comprehensive treatment of the theories and practicalities of regulation in modern power-supply systems. The need for generation to occur at the time of use occasioned by the impracticality of large-scale electricity storage coupled with constant and often unpredictable changes in demand make electricity-supply systems large, dynamic and complex and their regulation a daunting task. Conceptually arranged in four parts, this book addresses both traditional regulatory frameworks and also liberalized and re-regulated environments. First, an introduction gives a full characterization of power supply including engineering, economic and regulatory viewpoints. The second part presents the fundamentals of regulation and the third looks at the regulation of particular components of the power sector in detail. Advanced topics and subjects still open or subject to dispute form the content of the fourth part. In a sector where regulatory design is the key driver...

  7. Complex Networks

    CERN Document Server

    Evsukoff, Alexandre; González, Marta

    2013-01-01

    In the last decade we have seen the emergence of a new inter-disciplinary field focusing on the understanding of networks which are dynamic, large, open, and have a structure sometimes called random-biased. The field of Complex Networks is helping us better understand many complex phenomena such as the spread of  deseases, protein interactions, social relationships, to name but a few. Studies in Complex Networks are gaining attention due to some major scientific breakthroughs proposed by network scientists helping us understand and model interactions contained in large datasets. In fact, if we could point to one event leading to the widespread use of complex network analysis is the availability of online databases. Theories of Random Graphs from Erdös and Rényi from the late 1950s led us to believe that most networks had random characteristics. The work on large online datasets told us otherwise. Starting with the work of Barabási and Albert as well as Watts and Strogatz in the late 1990s, we now know th...

  8. NORM regulations

    Energy Technology Data Exchange (ETDEWEB)

    Gray, P. [ed.

    1997-02-01

    The author reviews the question of regulation for naturally occuring radioactive material (NORM), and the factors that have made this a more prominent concern today. Past practices have been very relaxed, and have often involved very poor records, the involvment of contractors, and the disposition of contaminated equipment back into commercial service. The rationale behind the establishment of regulations is to provide worker protection, to exempt low risk materials, to aid in scrap recycling, to provide direction for remediation and to examine disposal options. The author reviews existing regulations at federal and state levels, impending legislation, and touches on the issue of site remediation and potential liabilities affecting the release of sites contaminated by NORM.

  9. Histamine and the regulation of body weight

    DEFF Research Database (Denmark)

    Jørgensen, Emilie A; Knigge, Ulrich; Warberg, Jørgen;

    2007-01-01

    Energy intake and expenditure is regulated by a complex interplay between peripheral and central factors. An exhaustive list of peptides and neurotransmitters taking part in this complex regulation of body weight exists. Among these is histamine, which acts as a central neurotransmitter. In the p......Energy intake and expenditure is regulated by a complex interplay between peripheral and central factors. An exhaustive list of peptides and neurotransmitters taking part in this complex regulation of body weight exists. Among these is histamine, which acts as a central neurotransmitter...... lipolysis. Based on the current evidence of the involvement of histamine in the regulation of body weight, the histaminergic system is an obvious target for the development of pharmacological agents to control obesity. At present, H(3) receptor antagonists that stimulate the histaminergic system may...

  10. The Complex of Ciliary Neurotrophic Factor-Ciliary Neurotrophic Factor Receptor α Up-Regulates Connexin43 and Intercellular Coupling in Astrocytes via the Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription PathwayD⃞

    OpenAIRE

    Ozog, Mark A.; Bernier, Suzanne M; Bates, Dave C.; Chatterjee, Bishwanath; Lo, Cecilia W.; Naus, Christian C.G.

    2004-01-01

    Cytokines regulate numerous cell processes, including connexin expression and gap junctional coupling. In this study, we examined the effect of ciliary neurotrophic factor (CNTF) on connexin43 (Cx43) expression and intercellular coupling in astrocytes. Murine cortical astrocytes matured in vitro were treated with CNTF (20 ng/ml), soluble ciliary neurotrophic factor receptor α (CNTFRα) (200 ng/ml), or CNTF-CNTFRα. Although CNTF and CNTFRα alone had no effect on Cx43 expression, the heterodimer...

  11. Structural insights into transcription complexes

    NARCIS (Netherlands)

    Berger, I.; Blanco, A.G.; Boelens, R.; Cavarelli, J.; Coll, M.; Folkers, G.E.; Nie, Y.; Pogenberg, V.; Schultz, P.; Wilmanns, M.; Moras, D.; Poterszman, A.

    2011-01-01

    Control of transcription allows the regulation of cell activity in response to external stimuli and research in the field has greatly benefited from efforts in structural biology. In this review, based on specific examples from the European SPINE2-COMPLEXES initiative, we illustrate the impact of st

  12. Environmentally regulated aerospace coatings

    Science.gov (United States)

    Morris, Virginia L.

    1995-01-01

    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.

  13. Complex dynamics

    CERN Document Server

    Carleson, Lennart

    1993-01-01

    Complex dynamics is today very much a focus of interest. Though several fine expository articles were available, by P. Blanchard and by M. Yu. Lyubich in particular, until recently there was no single source where students could find the material with proofs. For anyone in our position, gathering and organizing the material required a great deal of work going through preprints and papers and in some cases even finding a proof. We hope that the results of our efforts will be of help to others who plan to learn about complex dynamics and perhaps even lecture. Meanwhile books in the field a. re beginning to appear. The Stony Brook course notes of J. Milnor were particularly welcome and useful. Still we hope that our special emphasis on the analytic side will satisfy a need. This book is a revised and expanded version of notes based on lectures of the first author at UCLA over several \\Vinter Quarters, particularly 1986 and 1990. We owe Chris Bishop a great deal of gratitude for supervising the production of cour...

  14. Complex Systems

    Directory of Open Access Journals (Sweden)

    Yi Zhao

    2012-01-01

    Full Text Available Quantum instanton (QI approximation is recently proposed for the evaluations of the chemical reaction rate constants with use of full dimensional potential energy surfaces. Its strategy is to use the instanton mechanism and to approximate time-dependent quantum dynamics to the imaginary time propagation of the quantities of partition function. It thus incorporates the properties of the instanton idea and the quantum effect of partition function and can be applied to chemical reactions of complex systems. In this paper, we present the QI approach and its applications to several complex systems mainly done by us. The concrete systems include, (1 the reaction of H+CH4→H2+CH3, (2 the reaction of H+SiH4→H2+SiH3, (3 H diffusion on Ni(100 surface; and (4 surface-subsurface transport and interior migration for H/Ni. Available experimental and other theoretical data are also presented for the purpose of comparison.

  15. Supra-optimal expression of the cold-regulated OsMyb4 transcription factor in transgenic rice changes the complexity of transcriptional network with major effects on stress tolerance and panicle development

    KAUST Repository

    Park, Myoungryoul

    2010-09-28

    The R2R3-type OsMyb4 transcription factor of rice has been shown to play a role in the regulation of osmotic adjustment in heterologous overexpression studies. However, the exact composition and organization of its underlying transcriptional network has not been established to be a robust tool for stress tolerance enhancement by regulon engineering. OsMyb4 network was dissected based on commonalities between the global chilling stress transcriptome and the transcriptome configured by OsMyb4 overexpression. OsMyb4 controls a hierarchical network comprised of several regulatory sub-clusters associated with cellular defense and rescue, metabolism and development. It regulates target genes either directly or indirectly through intermediary MYB, ERF, bZIP, NAC, ARF and CCAAT-HAP transcription factors. Regulatory sub-clusters have different combinations of MYB-like, GCC-box-like, ERD1-box-like, ABRE-like, G-box-like, as1/ocs/TGA-like, AuxRE-like, gibberellic acid response element (GARE)-like and JAre-like cis-elements. Cold-dependent network activity enhanced cellular antioxidant capacity through radical scavenging mechanisms and increased activities of phenylpropanoid and isoprenoid metabolic processes involving various abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), ethylene and reactive oxygen species (ROS) responsive genes. OsMyb4 network is independent of drought response element binding protein/C-repeat binding factor (DREB/CBF) and its sub-regulons operate with possible co-regulators including nuclear factor-Y. Because of its upstream position in the network hierarchy, OsMyb4 functions quantitatively and pleiotrophically. Supra-optimal expression causes misexpression of alternative targets with costly trade-offs to panicle development. © 2010 Blackwell Publishing Ltd.

  16. Complex regulation of the global regulatory gene csrA: CsrA-mediated translational repression, transcription from five promoters by Eσ70 and EσS, and indirect transcriptional activation by CsrA

    OpenAIRE

    Yakhnin, Helen; Yakhnin, Alexander V.; Baker, Carol S.; Sineva, Elena; Berezin, Igor; Romeo, Tony; Babitzke, Paul

    2011-01-01

    CsrA of Escherichia coli is an RNA binding protein that globally regulates gene expression by repressing translation and/or altering the stability of target transcripts. Here we explored mechanisms that control csrA expression. Four CsrA binding sites were predicted upstream of the csrA initiation codon, one of which overlapped its Shine-Dalgarno sequence. Results from gel shift, footprint, toeprint and in vitro translation experiments indicate that CsrA binds to these four sites and represse...

  17. Efficiency of complex production in changing environment

    Directory of Open Access Journals (Sweden)

    Levanon Erez Y

    2009-01-01

    Full Text Available Abstract Background Cell function necessitates the assemblage of proteins into complexes, a process which requires further regulation on top of the fairly understood mechanisms used to control the transcription and translation of a single protein. However, not much is known about how protein levels are controlled to realize that regulation. Results We integrated data on the composition of yeast protein complexes and the dynamics of their protein building-blocks concentrations to show how the cell regulates protein levels to optimize complex formation. We find that proteins which are subunits of the same complex tend to have similar levels which change similarly following a change in growth conditions, and that abundant proteins undergo larger decrease in their copy number when grown in minimal media. We also study the fluctuations in protein levels and find them to be significantly smaller in large complexes, and in the least abundant subunit of each complex. We use a mathematical model of complex synthesis to explain how all these observations increase the efficiency of complex synthesis, in terms of better utilization of the available molecules and better resilience to stochastic variations. Conclusion In conclusion, these results indicate an intricate regulation at all levels of protein production for the purpose of optimizing complex formation.

  18. Cosmic Complexity

    Science.gov (United States)

    Mather, John C.

    2012-01-01

    What explains the extraordinary complexity of the observed universe, on all scales from quarks to the accelerating universe? My favorite explanation (which I certainty did not invent) ls that the fundamental laws of physics produce natural instability, energy flows, and chaos. Some call the result the Life Force, some note that the Earth is a living system itself (Gaia, a "tough bitch" according to Margulis), and some conclude that the observed complexity requires a supernatural explanation (of which we have many). But my dad was a statistician (of dairy cows) and he told me about cells and genes and evolution and chance when I was very small. So a scientist must look for me explanation of how nature's laws and statistics brought us into conscious existence. And how is that seemll"!gly Improbable events are actually happening a!1 the time? Well, the physicists have countless examples of natural instability, in which energy is released to power change from simplicity to complexity. One of the most common to see is that cooling water vapor below the freezing point produces snowflakes, no two alike, and all complex and beautiful. We see it often so we are not amazed. But physlc!sts have observed so many kinds of these changes from one structure to another (we call them phase transitions) that the Nobel Prize in 1992 could be awarded for understanding the mathematics of their common features. Now for a few examples of how the laws of nature produce the instabilities that lead to our own existence. First, the Big Bang (what an insufficient name!) apparently came from an instability, in which the "false vacuum" eventually decayed into the ordinary vacuum we have today, plus the most fundamental particles we know, the quarks and leptons. So the universe as a whole started with an instability. Then, a great expansion and cooling happened, and the loose quarks, finding themselves unstable too, bound themselves together into today's less elementary particles like protons and

  19. Complex silumins

    Directory of Open Access Journals (Sweden)

    S. Pietrowski

    2007-09-01

    Full Text Available Purpose: The study presents the results of investigations carried out on silumins with additions of Mg, Ni, Cu, Cr, Mo and W. The silumins containing Mg, Cu and Ni are well-known and commonly used in construction of machines and equipment.Design/methodology/approach: Additions of Cr, Mo and W have not been thoroughly investigated yet. They are considered a new family of innovative cast aluminium alloys.Findings: In Al-Si systems they form silicides, like Cr3Si, Mo3Si, W3Si and intermetallic phases of Al13Cr4Si4, Al12Mo, Al12W and AlWSi. The silicides crystallise in cubic lattice of parameters similar to aluminium and silicon.Research limitations/implications: Therefore they can act as crystallisation substrates and occur as separate phases. The examinations under the microscope and X-ray microanalysis of the linear and point distribution of elements confirmed the presence of the above mentioned phases. A combination of two elements, e.g. Cr and Mo, or Cr and W, was observed to cause the formation of complex silicide layers of Mo3Si and (Cr, Mo3Si, or Cr3Si as well as (W, Cr3Si.Originality/value: The presence of the silicides has been indicated as a possible source of the refinement of α(Al and β(Si phases. The precipitations of these phases and of the intermetallic phases favour a high degree of the silumins hardening. A characteristic feature is the fact that nucleation and crystallisation of the successive phases takes place at the phase boundaries formed between the previously precipitated phase and solid solution α. The studies carried out so far have indicated that in complex silumins at high temperatures crystallise the silicides and peritectic phases of Al12W, AlWSi, Al12Mo and Al13Cr4Si4. Phases α or β are the next ones to crystallise, followed by complex eutectic α + β +Al(Si, Cr, Mo, W, Fe. Further crystallise the phases of Mg2Si, Al3Ni and Al2Cu. The silumins presented here are characterised by high mechanical properties: Rp0

  20. Regulation of microtubule dynamic instability

    NARCIS (Netherlands)

    B. van der Vaart (Babet); A.S. Akhmanova (Anna); A. Straube (Anne)

    2009-01-01

    textabstractProper regulation of MT (microtubule) dynamics is essential for various vital processes, including the segregation of chromosomes, directional cell migration and differentiation. MT assembly and disassembly is modulated by a complex network of intracellular factors that co-operate or ant

  1. RegulatING chromatin regulators

    DEFF Research Database (Denmark)

    Satpathy, Shankha; Nabbi, Arash; Riabowol, Karl

    2013-01-01

    The five human ING genes encode at least 15 splicing isoforms, most of which affect cell growth, differentiation and apoptosis through their ability to alter gene expression by epigenetic mechanisms. Since their discovery in 1996, ING proteins have been classified as type II tumour suppressors on...... the basis of reports describing their down-regulation and mislocalization in a variety of cancer types. In addition to their regulation by transcriptional mechanisms, understanding the range of PTMs (post-translational modifications) of INGs is important in understanding how ING functions are fine...... stresses. We also describe the ING PTMs that have been identified by several unbiased MS-based PTM enrichment techniques and subsequent proteomic analysis. Among the ING PTMs identified to date, a subset has been characterized for their biological significance and have been shown to affect processes...

  2. Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms

    DEFF Research Database (Denmark)

    Nestoras, Konstantinos; Mohammed, Asma Hadi; Schreurs, Ann-Sofie; Fleck, Oliver; Watson, Adam T; Poitelea, Marius; O'Shea, Charlotte; Chahwan, Charly; Holmberg, Christian; Kragelund, Birthe B; Nielsen, Olaf; Osborne, Mark; Carr, Antony M; Liu, Cong

    2010-01-01

    The correct levels of deoxyribonucleotide triphosphates and their relative abundance are important to maintain genomic integrity. Ribonucleotide reductase (RNR) regulation is complex and multifaceted. RNR is regulated allosterically by two nucleotide-binding sites, by transcriptional control, and...

  3. Regulator of G protein signaling 2 (RGS2 and RGS4 form distinct G protein-dependent complexes with protease activated-receptor 1 (PAR1 in live cells.

    Directory of Open Access Journals (Sweden)

    Sungho Ghil

    Full Text Available Protease-activated receptor 1 (PAR1 is a G-protein coupled receptor (GPCR that is activated by natural proteases to regulate many physiological actions. We previously reported that PAR1 couples to Gi, Gq and G12 to activate linked signaling pathways. Regulators of G protein signaling (RGS proteins serve as GTPase activating proteins to inhibit GPCR/G protein signaling. Some RGS proteins interact directly with certain GPCRs to modulate their signals, though cellular mechanisms dictating selective RGS/GPCR coupling are poorly understood. Here, using bioluminescence resonance energy transfer (BRET, we tested whether RGS2 and RGS4 bind to PAR1 in live COS-7 cells to regulate PAR1/Gα-mediated signaling. We report that PAR1 selectively interacts with either RGS2 or RGS4 in a G protein-dependent manner. Very little BRET activity is observed between PAR1-Venus (PAR1-Ven and either RGS2-Luciferase (RGS2-Luc or RGS4-Luc in the absence of Gα. However, in the presence of specific Gα subunits, BRET activity was markedly enhanced between PAR1-RGS2 by Gαq/11, and PAR1-RGS4 by Gαo, but not by other Gα subunits. Gαq/11-YFP/RGS2-Luc BRET activity is promoted by PAR1 and is markedly enhanced by agonist (TFLLR stimulation. However, PAR1-Ven/RGS-Luc BRET activity was blocked by a PAR1 mutant (R205A that eliminates PAR1-Gq/11 coupling. The purified intracellular third loop of PAR1 binds directly to purified His-RGS2 or His-RGS4. In cells, RGS2 and RGS4 inhibited PAR1/Gα-mediated calcium and MAPK/ERK signaling, respectively, but not RhoA signaling. Our findings indicate that RGS2 and RGS4 interact directly with PAR1 in Gα-dependent manner to modulate PAR1/Gα-mediated signaling, and highlight a cellular mechanism for selective GPCR/G protein/RGS coupling.

  4. Nuclear regulation

    International Nuclear Information System (INIS)

    Today, 112 nuclear power plants, 22 facilities that support these plants, 54 reactors used in research, and approximately 23,000 organizations hold licenses from either the Nuclear Regulator Commission or various states to use radioactive material; other facilities are operated by various government agencies. Eventually most of these facilities will be decommissioned, which involves removing the radioactive material and terminating the license. NRC needs to ensure that licensees appropriately decontaminate their facilities because, under current regulations, NRC cannot specifically require additional cleanup once it terminates a license. This paper presents a GAO report on NRC's decommissioning procedures. In two of eight cases GAO reviewed, NRC fully or partially released sites for unrestricted use where radioactive contamination was higher than its guidelines allowed; in the other cases, NRC's information was inadequate or incomplete. Further, NRC lacks information on the types and amounts of radioactive waste buried on-site. At five sites reviewed by GAO, groundwater has been found to be contaminated by radioactive waste

  5. SchA-p85-FAK complex dictates isoform-specific activation of Akt2 and subsequent PCBP1-mediated post-transcriptional regulation of TGFβ-mediated epithelial to mesenchymal transition in human lung cancer cell line A549.

    Science.gov (United States)

    Xue, Xinying; Wang, Xin; Liu, Yuxia; Teng, Guigen; Wang, Yong; Zang, Xuefeng; Wang, Kaifei; Zhang, Jinghui; Xu, Yali; Wang, Jianxin; Pan, Lei

    2014-08-01

    A post-transcriptional pathway by which TGF-β modulates expression of specific proteins, Disabled-2 (Dab2) and Interleukin-like EMT Inducer (ILEI), inherent to epithelial to mesenchymal transition (EMT) in murine epithelial cells through Akt2-mediated phosphorylation of poly r(C) binding protein (PCBP1), has been previously elucidated. The aims of the current study were to determine if the same mechanism is operative in the non-small cell lung cancer (NSCLC) cell line, A549, and to delineate the underlying mechanism. Steady-state transcript and protein expression levels of Dab2 and ILEI were examined in A549 cells treated with TGF-β for up to 48 h. Induction of translational de-repression in this model was quantified by polysomal fractionation followed by qRT-PCR. The underlying mechanism of isoform-specific activation of Akt2 was elucidated through a combination of co-immunoprecipitation studies. TGF-β induced EMT in A549 cells concomitant with translational upregulation of Dab2 and ILEI proteins through isoform-specific activation of Akt2 followed by phosphorylation of PCBP1 at serine-43. Our experiments further elucidated that the adaptor protein SchA is phosphorylated at tyrosine residues following TGF-β treatment, which initiated a signaling cascade resulting in the sequential recruitment of p85 subunit of PI3K and focal adhesion kinase (FAK). The SchA-FAK-p85 complex subsequently selectively recruited and activated Akt2, not Akt1. Inhibition of the p85 subunit through phosphorylated 1257 peptide completely attenuated EMT in these cells. We have defined the underlying mechanism responsible for isoform-specific recruitment and activation of Akt2, not Akt1, during TGF-β-mediated EMT in A549 cells. Inhibition of the formation of this complex thus represents an important and novel therapeutic target in metastatic lung carcinoma. PMID:24819169

  6. Altered Pattern of Major Histocompatibility Complex Expression in Renal Carcinoma : Tumor-Specific Expression of the Nonclassical Human Leukocyte Antigen-G Molecule Is Restricted to Clear Cell Carcinoma While Up-Regulation of Other Major Histocompatibility Complex Antigens Is Primarily Distributed in All Subtypes of Renal Carcinoma

    OpenAIRE

    Ibrahim, El Chérif; Allory, Yves; Commo, Frédéric; Gattegno, Bernard; Callard, Patrice; Paul, Pascale

    2003-01-01

    Renal epithelial cancers represent a heterogeneous group of neoplasms arising from the malignant transformation of presumed diverse cell lineages. We recently demonstrated that tumor-specific up-regulation of human leukocyte antigen (HLA)-G, a nonclassical HLA class Ib molecule that might be involved in immune evasion by tumor cells, frequently occurs in conventional (clear cell) renal carcinoma. We here examined whether HLA-G activation is a common process affecting all types of renal epithe...

  7. Understanding Homeschooling: A Better Approach to Regulation

    Science.gov (United States)

    Kunzman, Robert

    2009-01-01

    Drawing from six years of qualitative research, this article analyzes the broad range of proposed and existing homeschool regulations throughout the United States. It argues that current homeschool regulations--and most proposals for how to improve them--misjudge the complexity of such an endeavor; state resources are misused and the basic…

  8. Polycomb complexes and silencing mechanisms

    DEFF Research Database (Denmark)

    Lund, Anders H; van Lohuizen, Maarten

    2004-01-01

    Advances in the past couple of years have brought important new knowledge on the mechanisms by which Polycomb-group proteins regulate gene expression and on the consequences of their actions. The discovery of histone methylation imprints specific for Polycomb and Trithorax complexes has provided...... mechanistic insight on how this ancient epigenetic memory system acts to repress and indicates that it may share mechanistic aspects with other silencing and genome-protective processes, such as RNA interference....

  9. Tuberous sclerosis complex.

    Science.gov (United States)

    Henske, Elizabeth P; Jóźwiak, Sergiusz; Kingswood, J Christopher; Sampson, Julian R; Thiele, Elizabeth A

    2016-01-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure. PMID:27226234

  10. Measuring Tax Complexity

    OpenAIRE

    David Ulph

    2014-01-01

    This paper critically examines a number of issues relating to the measurement of tax complexity. It starts with an analysis of the concept of tax complexity, distinguishing tax design complexity and operational complexity. It considers the consequences/costs of complexity, and then examines the rationale for measuring complexity. Finally it applies the analysis to an examination of an index of complexity developed by the UK Office of Tax Simplification (OTS). Postprint

  11. On State Complexes and Special Cube Complexes

    Science.gov (United States)

    Peterson, Valerie J.

    2009-01-01

    This thesis presents the first steps toward a classification of non-positively curved cube complexes called state complexes. A "state complex" is a configuration space for a "reconfigurable system," i.e., an abstract system in which local movements occur in some discrete manner. Reconfigurable systems can be used to describe, for example,…

  12. Fatty acids and the regulation of pyruvate dehydrogenase interconversion

    OpenAIRE

    Stewart, Melanie Ann.

    1997-01-01

    This thesis presents evidence for a novel mechanism of regulation of pyruvate dehydrogenase (PDH) kinase by fatty acids and also results of a study of muscle triacylglycerol concentration. In animals regulation of PDH complex activity is central to the selection of respiratory fuels and to the conservation of glucose during carbohydrate deprivation. The principal means of regulation of PDH complex is interconversion of phosphorylated (inactive) and dephosphorylated (active) fo...

  13. The regulated firm: Effects of regulation on competence development and sustainable competitive advantage

    OpenAIRE

    Frohwein, Torsten

    2015-01-01

    Sustainable competitive advantage (SCA) is a central tenet in strategic management theory. The effect of regulation on sustaining competitive advantages is widely neglected in literature. The impact on competence development and SCA of the firm can be significant, if regulatory requirements and regulatory prohibitions as types of specific industry regulation are considered. In arguing that resource-based theory can be modeled analogous to complex system theory, the effect of regulation on com...

  14. Babies' Self-Regulation: Taking a Broad Perspective

    Science.gov (United States)

    Elliot, Enid; Gonzalez-Mena, Janet

    2011-01-01

    Self-regulation is a complex process that involves coordinating various systems of the body and mind, including feelings. It's not only about emotions but also about cognition. Self-regulation has an impact on social development, influencing how babies and toddlers get along with others. Through self-regulation, babies and toddlers learn to pay…

  15. Transcriptional regulation by Polycomb group proteins

    DEFF Research Database (Denmark)

    Di Croce, Luciano; Helin, Kristian

    2013-01-01

    Polycomb group (PcG) proteins are epigenetic regulators of transcription that have key roles in stem-cell identity, differentiation and disease. Mechanistically, they function within multiprotein complexes, called Polycomb repressive complexes (PRCs), which modify histones (and other proteins) and...... silence target genes. The dynamics of PRC1 and PRC2 components has been the focus of recent research. Here we discuss our current knowledge of the PRC complexes, how they are targeted to chromatin and how the high diversity of the PcG proteins allows these complexes to influence cell identity....

  16. Pricing complexity options

    OpenAIRE

    Malihe Alikhani; Bj{\\o}rn Kjos-Hanssen; Amirarsalan Pakravan; Babak Saadat

    2015-01-01

    We consider options that pay the complexity deficiency of a sequence of up and down ticks of a stock upon exercise. We study the price of European and American versions of this option numerically for automatic complexity, and theoretically for Kolmogorov complexity. We also consider run complexity, which is a restricted form of automatic complexity.

  17. Apico-basal polarity complex and cancer

    Indian Academy of Sciences (India)

    Mohammed Khursheed; Murali Dharan Bashyam

    2014-03-01

    Apico-basal polarity is a cardinal molecular feature of adult eukaryotic epithelial cells and appears to be involved in several key cellular processes including polarized cell migration and maintenance of tissue architecture. Epithelial cell polarity is maintained by three well-conserved polarity complexes, namely, PAR, Crumbs and SCRIB. The location and interaction between the components of these complexes defines distinct structural domains of epithelial cells. Establishment and maintenance of apico-basal polarity is regulated through various conserved cell signalling pathways including TGF, Integrin and WNT signalling. Loss of cell polarity is a hallmark for carcinoma, and its underlying molecular mechanism is beginning to emerge from studies on model organisms and cancer cell lines. Moreover, deregulated expression of apico-basal polarity complex components has been reported in human tumours. In this review, we provide an overview of the apico-basal polarity complexes and their regulation, their role in cell migration, and finally their involvement in carcinogenesis.

  18. Regulation of Autophagy by Kinases

    International Nuclear Information System (INIS)

    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

  19. Complex Regulation of Prolyl-4-Hydroxylases Impacts Root Hair Expansion

    DEFF Research Database (Denmark)

    Velasquez, Silvia M; Ricardi, Martiniano M; Poulsen, Christian Peter;

    2015-01-01

    Root hairs are single cells that develop by tip growth, a process shared with pollen tubes, axons, and fungal hyphae. However, structural plant cell walls impose constraints to accomplish tip growth. In addition to polysaccharides, plant cell walls are composed of hydroxyproline-rich glycoprotein...

  20. GMO Regulations, International Trade and the Imperialism of Standards

    OpenAIRE

    Vigani, Mauro; Raimondi, Valentina; Olper, Alessandro

    2010-01-01

    This paper deals with the quantification of GMO regulations on bilateral trade flows. A composite index of the complexity of such regulations for sixty countries as well as an objective score for six GMO regulatory sub-dimensions has been developed. Using a gravity model, we show how bilateral similarity?in GMO regulations, affect trade flows for the composite index and its components. Results show that bilateral distance in GMO regulations negatively affect trade flows, especially as an effe...

  1. National Regulations on Local Public Administration

    OpenAIRE

    Apostolache, Mihai

    2014-01-01

    The local public administration, like any other field of activity, knows a certain regulation determined by the specificity of this field and by its importance within the global social system. The norms governing local public administration are included in the fundamental act, as well as other legal acts inferior to the Constitution, that are meant to develop the rules as principles from the Constitution. Given its importance and complexity, local public administration has a vast regulation ...

  2. Regulation of myostatin activity and muscle growth

    OpenAIRE

    Lee, Se-Jin; McPherron, Alexandra C.

    2001-01-01

    Myostatin is a transforming growth factor-β family member that acts as a negative regulator of skeletal muscle mass. To identify possible myostatin inhibitors that may have applications for promoting muscle growth, we investigated the regulation of myostatin signaling. Myostatin protein purified from mammalian cells consisted of a noncovalently held complex of the N-terminal propeptide and a disulfide-linked dimer of C-terminal fragments. The purified C-terminal myostatin dimer was capable of...

  3. Regulation of phospholipid synthesis in yeast

    OpenAIRE

    Carman, George M.; Han, Gil-Soo

    2009-01-01

    Phospholipid synthesis in the yeast Saccharomyces cerevisiae is a complex process that involves regulation by both genetic and biochemical mechanisms. The activity levels of phospholipid synthesis enzymes are controlled by gene expression (e.g., transcription) and by factors (lipids, water-soluble phospholipid precursors and products, and covalent modification of phosphorylation) that modulate catalysis. Phosphatidic acid, whose levels are controlled by the biochemical regulation of key phosp...

  4. Fucose Sensing Regulates Bacterial Intestinal Colonization

    OpenAIRE

    Pacheco, Alline R.; Curtis, Meredith M.; Ritchie, Jennifer M; Munera, Diana; Matthew K Waldor; Moreira, Cristiano G.; Sperandio, Vanessa

    2012-01-01

    The mammalian gastrointestinal (GI) tract provides a complex and competitive environment for the microbiota 1 . Successful colonization by pathogens depends on scavenging nutrients, sensing chemical signals, competing with the resident bacteria, and precisely regulating expression of virulence genes 2 . The GI pathogen enterohemorrhagic E.coli (EHEC) relies on inter-kingdom chemical sensing systems to regulate virulence gene expression 3–4 . Here we show that these systems control the express...

  5. Mechano-Regulation of Alternative Splicing

    OpenAIRE

    Liu, Huan; Tang, Liling

    2013-01-01

    Alternative splicing contributes to the complexity of proteome by producing multiple mRNAs from a single gene. Affymetrix exon arrays and experiments in vivo or in vitro demonstrated that alternative splicing was regulated by mechanical stress. Expression of mechano-growth factor (MGF) which is the splicing isoform of insulin-like growth factor 1(IGF-1) and vascular endothelial growth factor (VEGF) splicing variants such as VEGF121, VEGF165, VEGF206, VEGF189, VEGF165 and VEGF145 are regulated...

  6. Polycomb complexes and epigenetic states.

    Science.gov (United States)

    Schwartz, Yuri B; Pirrotta, Vincenzo

    2008-06-01

    Important advances in the study of Polycomb Group (PcG) complexes in the past two years have focused on the role of this repressive system in programing the genome. Genome-wide analyses have shown that PcG mechanisms control a large number of genes regulating many cellular functions and all developmental pathways. Current evidence shows that, contrary to the classical picture of their role, PcG complexes do not set a repressed chromatin state that is maintained throughout development but have a much more dynamic role. PcG target genes can become repressed or be reactivated or exist in intermediate states. What controls the balance between repression and derepression is a crucial question in understanding development and differentiation in higher organisms. PMID:18439810

  7. Regulation of Communication Policy of Modern Banks

    OpenAIRE

    Ketova Natalia, P.; Ovchinnikov Victor, .N.

    2016-01-01

    The paper shows the need for effective communication commercial banks, revealed the possibility of interaction with customers through advertising, sponsorship, philanthropy, sales promotion, lobbying of interests of banking institutions. The principles for the regulation of communications to ensure consistency of communication complex, which cause a complex effect on the external environment, the creation of adaptive system of marketing communications. It is proved that the possibilities of i...

  8. Regulation of Adiponectin Multimerization, Signaling and Function

    OpenAIRE

    Liu, Meilian; Liu, Feng

    2013-01-01

    Adiponectin, which exists in serum in three major complexes including trimer, hexamer, and the high molecular weight (HMW) form, has strong insulin sensitizing, antiinflammatory and anti-diabetic functions. Different adiponectin complexes exert tissue-specific biological functions and activate distinct signaling pathways. In this review, we summarize our current understanding on the mechanisms regulating adiponectin multimerization. We also describe the major target tissues in which distinct ...

  9. Regulations and instructions

    International Nuclear Information System (INIS)

    Regulations and instructions for operating the RA reactor consist of the following chapters: general regulations with the fundamental RA reactor characteristics, operating regulations and instructions for the personnel on duty, regulations for accidental conditions, training program for the staff of the Laboratory for reactor operation

  10. Second Quantized Kolmogorov Complexity

    OpenAIRE

    Rogers, Caroline; Vedral, Vlatko; Nagarajan, Rajagopal

    2008-01-01

    The Kolmogorov complexity of a string is the length of its shortest description. We define a second quantised Kolmogorov complexity where the length of a description is defined to be the average length of its superposition. We discuss this complexity's basic properties. We define the corresponding prefix complexity and show that the inequalities obeyed by this prefix complexity are also obeyed by von Neumann entropy.

  11. Complex Multiplicative Calculus

    OpenAIRE

    Bashirov, Agamirza; Riza, Mustafa

    2011-01-01

    In the present paper we extend the concepts of multiplicative de- rivative and integral to complex-valued functions of complex variable. Some drawbacks, arising with these concepts in the real case, are explained satis- factorily. Properties of complex multiplicative derivatives and integrals are studied. In particular, the fundamental theorem of complex multiplicative calculus, relating these concepts, is proved. It is shown that complex multi- plicative calculus is not just another realizat...

  12. Complex networks analysis of language complexity

    CERN Document Server

    Amancio, Diego R; Oliveira, Osvaldo N; Costa, Luciano da F; 10.1209/0295-5075/100/58002

    2013-01-01

    Methods from statistical physics, such as those involving complex networks, have been increasingly used in quantitative analysis of linguistic phenomena. In this paper, we represented pieces of text with different levels of simplification in co-occurrence networks and found that topological regularity correlated negatively with textual complexity. Furthermore, in less complex texts the distance between concepts, represented as nodes, tended to decrease. The complex networks metrics were treated with multivariate pattern recognition techniques, which allowed us to distinguish between original texts and their simplified versions. For each original text, two simplified versions were generated manually with increasing number of simplification operations. As expected, distinction was easier for the strongly simplified versions, where the most relevant metrics were node strength, shortest paths and diversity. Also, the discrimination of complex texts was improved with higher hierarchical network metrics, thus point...

  13. Social Regulation of Emotion: Messy Layers

    Directory of Open Access Journals (Sweden)

    ArvidKappas

    2013-02-01

    Full Text Available Emotions are evolved systems of intra- and interpersonal processes that are regulatory in nature, dealing mostly with issues of personal or social concern. They regulate social interaction and in extension, the social sphere. In turn, processes in the social sphere regulate emotions of individuals and groups. In other words, intrapersonal processes project in the interpersonal space, and inversely, interpersonal experiences deeply influence intrapersonal processes. Thus, I argue that the concepts of emotion generation and regulation should not be artificially separated. Similarly, interpersonal emotions should not be reduced to interacting systems of intraindividual processes. Instead, we can consider emotions at different social levels, ranging from dyads to large scale e-communities. The interaction between these levels is complex and does not only involve influences from one level to the next. In this sense the levels of emotion/regulation are messy and a challenge for empirical study. In this article, I discuss the concepts of emotions and regulation at different intra- and interpersonal levels. I extend the concept of auto-regulation of emotions (Kappas, 2008. 2011a, 2011b to social processes. Furthermore, I argue for the necessity of including mediated communication, particularly in cyberspace in contemporary models of emotion/regulation. Lastly, I suggest the use of concepts from systems dynamics and complex systems to tackle the challenge of the “messy layers.”

  14. Nongenomic Mechanisms of PTEN Regulation

    Directory of Open Access Journals (Sweden)

    Jimmie E. Fata

    2012-01-01

    Full Text Available A large amount of data supports the view that PTEN is a bona fide tumor suppressor gene. However, recent evidence suggests that derailment of cellular localization and expression levels of functional nonmutated PTEN is a determining force in inducing abnormal cellular and tissue outcomes. As the cellular mechanisms that regulate normal PTEN enzymatic activity resolve, it is evident that deregulation of these mechanisms can alter cellular processes and tissue architecture and ultimately lead to oncogenic transformation. Here we discuss PTEN ubiquitination, PTEN complex formation with components of the adherens junction, PTEN nuclear localization, and microRNA regulation of PTEN as essential regulatory mechanisms that determine PTEN function independent of gene mutations and epigenetic events.

  15. Phytochrome-regulated Gene Expression

    Institute of Scientific and Technical Information of China (English)

    Peter H. Quail

    2007-01-01

    Identification of all genes involved in the phytochrome (phy)-mediated responses of plants to their light environment is an important goal in providing an overall understanding of light-regulated growth and development. This article highlights and integrates the central findings of two recent comprehensive studies in Arabidopsis that have identified the genome-wide set of phy-regulated genes that respond rapidly to red-light signals upon first exposure of dark-grown seedlings, and have tested the functional relevance to normal seedling photomorphogenesis of an initial subset of these genes. The data: (a) reveal considerable complexity in the channeling of the light signals through the different phy-family members (phyA to phyE) to responsive genes; (b) identify a diversity of transcription-factor-encoding genes as major early, if not primary, targets of phy signaling, and, therefore, as potentially important regulators in the transcriptional-network hierarchy; and (c) identify auxin-related genes as the dominant class among rapidly-regulated, hormone-related genes. However, reverse-genetic functional profiling of a selected subset of these genes reveals that only a limited fraction are necessary for optimal phy-induced seedling deetiolation.

  16. Regulating anxiety with extrasynaptic inhibition.

    Science.gov (United States)

    Botta, Paolo; Demmou, Lynda; Kasugai, Yu; Markovic, Milica; Xu, Chun; Fadok, Jonathan P; Lu, Tingjia; Poe, Michael M; Xu, Li; Cook, James M; Rudolph, Uwe; Sah, Pankaj; Ferraguti, Francesco; Lüthi, Andreas

    2015-10-01

    Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ(+) neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes. PMID:26322928

  17. Food-web complexity, meta-community complexity and community stability.

    Science.gov (United States)

    Mougi, A; Kondoh, M

    2016-01-01

    What allows interacting, diverse species to coexist in nature has been a central question in ecology, ever since the theoretical prediction that a complex community should be inherently unstable. Although the role of spatiality in species coexistence has been recognized, its application to more complex systems has been less explored. Here, using a meta-community model of food web, we show that meta-community complexity, measured by the number of local food webs and their connectedness, elicits a self-regulating, negative-feedback mechanism and thus stabilizes food-web dynamics. Moreover, the presence of meta-community complexity can give rise to a positive food-web complexity-stability effect. Spatiality may play a more important role in stabilizing dynamics of complex, real food webs than expected from ecological theory based on the models of simpler food webs. PMID:27071716

  18. 44 CFR 1.8 - Regulations review.

    Science.gov (United States)

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Regulations review. 1.8 Section 1.8 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF... the rule from the public; (3) The complexity of the rule, including need for review of language...

  19. MicroRNA regulation in mammalian adipogenesis

    Science.gov (United States)

    Adipogenesis, the complex fat cell development from preadipocyte or mesenchymal stem cell to mature adipocytes, is essential for fat formation and metabolism of adipose tissues in mammals. It has been reported to be regulated by hormones and various adipogenic transcription factors which are express...

  20. Vincristine Lipid Complex Injection

    Science.gov (United States)

    Vincristine lipid complex is used to treat a certain type of acute lymphoblastic leukemia (ALL; a type ... at least two different treatments with other medications. Vincristine lipid complex is in a class of medications ...

  1. Curve complexes are rigid

    OpenAIRE

    Rafi, Kasra; Schleimer, Saul

    2007-01-01

    Any quasi-isometry of the complex of curves is bounded distance from a simplicial automorphism. As a consequence, the quasi-isometry type of the curve complex determines the homeomorphism type of the surface.

  2. Complexity An Introduction

    CERN Document Server

    Parwani, R R

    2002-01-01

    This article summarises a Web-book on "Complexity" that was developed to introduce undergraduate students to interesting complex systems in the biological, physical and social sciences, and the common tools, principles and concepts used for their study.

  3. Oligocyclopentadienyl transition metal complexes

    Energy Technology Data Exchange (ETDEWEB)

    de Azevedo, Cristina G.; Vollhardt, K. Peter C.

    2002-01-18

    Synthesis, characterization, and reactivity studies of oligocyclopentadienyl transition metal complexes, namely those of fulvalene, tercyclopentadienyl, quatercyclopentadienyl, and pentacyclopentadienyl(cyclopentadienyl) are the subject of this account. Thermal-, photo-, and redox chemistries of homo- and heteropolynuclear complexes are described.

  4. Quantum Communication Complexity

    OpenAIRE

    Klauck, Hartmut

    2000-01-01

    This paper surveys the field of quantum communication complexity. Some interesting recent results are collected concerning relations to classical communication, lower bound methods, one-way communication, and applications of quantum communication complexity.

  5. Irinotecan Lipid Complex Injection

    Science.gov (United States)

    Irinotecan lipid complex is used in combination with other medications to treat pancreatic cancer that has spread to other parts of ... after treatment with other chemotherapy medications. Irinotecan lipid complex is in a class of antineoplastic medications called ...

  6. Vincristine Lipid Complex Injection

    Science.gov (United States)

    Vincristine lipid complex is used to treat a certain type of acute lymphoblastic leukemia (ALL; a type of cancer of the ... two different treatments with other medications. Vincristine lipid complex is in a class of medications called vinca ...

  7. Doxorubicin Lipid Complex Injection

    Science.gov (United States)

    Doxorubicin lipid complex is used to treat ovarian cancer that has not improved or that has worsened after treatment with other medications. Doxorubicin lipid complex is also used to treat Kaposi's sarcoma (a ...

  8. Mycobacterium Avium Complex (MAC)

    Science.gov (United States)

    ... Select a Language: Fact Sheet 514 Mycobacterium Avium Complex (MAC) WHAT IS MAC? HOW DO I KNOW ... THE BOTTOM LINE WHAT IS MAC? Mycobacterium Avium Complex (MAC) is a serious illness caused by common ...

  9. Cytarabine Lipid Complex Injection

    Science.gov (United States)

    Cytarabine lipid complex is used to treat lymphomatous meningitis (a type of cancer in the covering of the spinal cord and brain). Cytarabine lipid complex is in a class of medications called antimetabolites. ...

  10. Evolution of biological complexity

    OpenAIRE

    Adami, Christoph; Ofria, Charles; Collier, Travis C.

    2000-01-01

    In order to make a case for or against a trend in the evolution of complexity in biological evolution, complexity needs to be both rigorously defined and measurable. A recent information-theoretic (but intuitively evident) definition identifies genomic complexity with the amount of information a sequence stores about its environment. We investigate the evolution of genomic complexity in populations of digital organisms and monitor in detail the evolutionary transitions that increase complexit...

  11. Complexity Near Horizons

    CERN Document Server

    Halyo, Edi

    2015-01-01

    We generalize the concept of complexity near horizons to all nondegenerate black holes. For Schwarzschild black holes, we show that Rindler observers see a complexity change of $S$ during proper time $1/\\kappa$ which corresponds to the creation of a causal patch with proper length $1/\\kappa$ inside the horizon. We attempt to describe complexity in the horizon CFT and the Euclidean picture.

  12. Ocean Dumping Control Regulations

    International Nuclear Information System (INIS)

    These Regulations were made further to the Ocean Dumping Control Act which provides for restrictions in dumping operations. The Regulations contain model applications for permits to dump or load a series of materials. (NEA)

  13. Trout Stream Special Regulations

    Data.gov (United States)

    Minnesota Department of Natural Resources — This layer shows Minnesota trout streams that have a special regulation as described in the 2006 Minnesota Fishing Regulations. Road crossings were determined using...

  14. Regulation of Genetic Tests

    Science.gov (United States)

    ... advertised. The Commission has the authority to regulate advertising that delivers health-related information to consumers to ensure that it is not false or misleading. Top of page FDA Regulation and ...

  15. Activists versus Captured Regulators

    OpenAIRE

    Daubanes, Julien; Rochet, Jean-Charles

    2013-01-01

    We analyze the consequences of activism in a regulated industry where the regulator has been captured by the industry. Unlike ordinary economic agents, activists are insensitive to monetary incentives. Moreover, they are less well informed than regulators and their actions generate dead-weight costs. Yet we find that activism may increase social welfare because it disciplines captured regulators and reduces the social cost of imperfect regulatory systems.

  16. Hepcidin: regulation of the master iron regulator

    OpenAIRE

    2015-01-01

    Iron, an essential nutrient, is required for many diverse biological processes. The absence of a defined pathway to excrete excess iron makes it essential for the body to regulate the amount of iron absorbed; a deficiency could lead to iron deficiency and an excess to iron overload and associated disorders such as anaemia and haemochromatosis respectively. This regulation is mediated by the iron-regulatory hormone hepcidin. Hepcidin binds to the only known iron export protein, ferroportin (FP...

  17. Detergent zeolite complex "Alusil", Zvornik

    Directory of Open Access Journals (Sweden)

    Stanković Mirjana S.

    2003-01-01

    Full Text Available The IGPC Engineering Department designed the basis technological and machine projects for a detergent zeolite complex, on the basis of which a pilot plant with an initial capacity of 5,000 t/y was constructed in 1983 within Birač-Zvornik production complex. Additional projects were done afterwards and the starting capacity increased to 200,000 t/y in 1988. This plant became the biggest producer of detergent zeolite in the world. These projects were manufactured on the basis of specific technology developed in the laboratories of the IGPC.Several goals were realized by designing a detergent zeolite production complex. This technology was an innovation, because a new approach in detergent zeolite production was developed. The product meets all quality demands, as well as environmental regulations. The detergent production process is fully automatized and the product has uniform quality. There is no waste material in detergent zeolite production, because all products with unsatisfactory quality are returned to the process. The production process can be controlled manually, which is necessary during stanrt-up, and repairs.

  18. Complex variables I essentials

    CERN Document Server

    Solomon, Alan D

    2013-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Complex Variables I includes functions of a complex variable, elementary complex functions, integrals of complex functions in the complex plane, sequences and series, and poles and r

  19. SYSTEMS WITH COMPLEXITY

    Institute of Scientific and Technical Information of China (English)

    WANG Chenghong; ZHANG Lijun

    2004-01-01

    Science of Complexity is a newly emerging branch of natural scienceAlthoughwe still haven't a precise definition, there are some principles for justifying whether a systemis a complex systemThe purpose of this article is to reveal some of such principlesOnthe basis of them, the concept of a system with complexity is proposedThey may helpus to distinguish a real complex system from complicated objects in common senseThenwe propose some fundamental problems faced by the study of systems with complexity.

  20. Randomness, Information, and Complexity

    CERN Document Server

    Grassberger, Peter

    2012-01-01

    We review possible measures of complexity which might in particular be applicable to situations where the complexity seems to arise spontaneously. We point out that not all of them correspond to the intuitive (or "naive") notion, and that one should not expect a unique observable of complexity. One of the main problems is to distinguish complex from disordered systems. This and the fact that complexity is closely related to information requires that we also give a review of information measures. We finally concentrate on quantities which measure in some way or other the difficulty of classifying and forecasting sequences of discrete symbols, and study them in simple examples.

  1. Detailed kinetics and regulation of mammalian 2-oxoglutarate dehydrogenase

    OpenAIRE

    Dash Ranjan K; Pradhan Ranjan K; Qi Feng; Beard Daniel A

    2011-01-01

    Abstract Background Mitochondrial 2-oxoglutarate (α-ketoglutarate) dehydrogenase complex (OGDHC), a key regulatory point of tricarboxylic acid (TCA) cycle, plays vital roles in multiple pathways of energy metabolism and biosynthesis. The catalytic mechanism and allosteric regulation of this large enzyme complex are not fully understood. Here computer simulation is used to test possible catalytic mechanisms and mechanisms of allosteric regulation of the enzyme by nucleotides (ATP, ADP), pH, an...

  2. HIV-1 Vpr: A Novel Role in Regulating RNA Splicing

    OpenAIRE

    Zhang, Xianfeng; Aida, Yoko

    2009-01-01

    Pre-mRNA splicing is a critical step in gene expression for metazoans. Several viral proteins regulate the splicing of pre-mRNAs through complex interactions between the virus and the host cell RNA splicing machinery. Here, we focus on a novel function of HIV-1 Vpr, that selectively inhibit cellular and viral pre-mRNA splicing, via interactions with components of functional spliceosomal complexes. This review discusses our current knowledge of how RNA splicing regulation is accomplished by Vp...

  3. Status of mixed-waste regulation

    International Nuclear Information System (INIS)

    Mixed waste is waste containing radionuclides regulated by the US Nuclear Regulatory Commission (NRC) under the Atomic Energy Act, as well as hazardous waste materials regulated by the Environmental Protection Agency (EPA) under the Resource Conservation and Recovery Act (RCRA). This has led to a situation of dual regulation in which both NRC and EPA regulate the same waste under requirements that at times appear conflicting. The NRC has been working with the EPA to resolve the issues associated with the dual regulation of mixed waste. Discussions between the two agencies indicate that dual regulation of mixed wastes appears technically achievable, although the procedures may be complex and burdensome to the regulated community. The staffs of both agencies have been coordinating their efforts to minimize the burden of dual regulation on state agencies and the industry. Three major issues were identified as sources of potential regulatory conflict: (a) definition and identification of mixed waste, (b) siting guidelines for disposal facilities, and (c) design concepts for disposal units

  4. The Role, Interaction and Regulation of the Velvet Regulator VelB in Aspergillus nidulans

    OpenAIRE

    Park, Hee-Soo; Ni, Min; Jeong, Kwang Cheol; Kim, Young Hwan; Yu, Jae-Hyuk

    2012-01-01

    The multifunctional regulator VelB physically interacts with other velvet regulators and the resulting complexes govern development and secondary metabolism in the filamentous fungus Aspergillus nidulans. Here, we further characterize VelB’s role in governing asexual development and conidiogenesis in A. nidulans. In asexual spore formation, velB deletion strains show reduced number of conidia, and decreased and delayed mRNA accumulation of the key asexual regulatory genes brlA, abaA, and vosA...

  5. Photocytotoxic lanthanide complexes

    Indian Academy of Sciences (India)

    Akhtar Hussain; Akhil R Chakravarty

    2012-11-01

    Lanthanide complexes have recently received considerable attention in the field of therapeutic and diagnostic medicines. Among many applications of lanthanides, gadolinium complexes are used as magnetic resonance imaging (MRI) contrast agents in clinical radiology and luminescent lanthanides for bioanalysis, imaging and sensing. The chemistry of photoactive lanthanide complexes showing biological applications is of recent origin. Photodynamic therapy (PDT) is a non-invasive treatment modality of cancer using a photosensitizer drug and light. This review primarily focuses on different aspects of the chemistry of lanthanide complexes showing photoactivated DNA cleavage activity and cytotoxicity in cancer cells. Macrocyclic texaphyrin-lanthanide complexes are known to show photocytotoxicity with the PDT effect in near-IR light. Very recently, non-macrocyclic lanthanide complexes are reported to show photocytotoxicity in cancer cells. Attempts have been made in this perspective article to review and highlight the photocytotoxic behaviour of various lanthanide complexes for their potential photochemotherapeutic applications.

  6. Radiation Control Regulation 1993

    International Nuclear Information System (INIS)

    This Regulation (No. 434-1993) was made in pursuance of the Radiation Control Act 1990 and replaces the Active Substances Regulations 1959 repealed by the Act. It entered into force on 1 September 1993. The Regulation specifies that the technical radiation protection definitions have the same meaning as in the 1990 recommendations. The Regulation provides for the licensing of persons to use radioactive substances and radiation apparatus. It prescribes activities which may only be carried out by an accredited radiation expert and regulates the use of radiation apparatus and radioactive substances as well as the disposal and transport of radiation apparatus and radioactive substances. (NEA)

  7. Views of the regulators

    International Nuclear Information System (INIS)

    In dealing with a challenging problem in occupational exposure the nuclear regulator in South Africa concluded that the involvement of stake holders was critical. Valuable lessons were learnt in the process. These related to co-operation amongst regulators, the involvement of regulators in addressing occupational exposure problems, the training of workers by the regulator and the need for technical training of the workers. In general, it was also learnt that regulators should establish mechanisms to measure and continuously improve the satisfaction of their stake holders. (author)

  8. Nuclear safety regulations

    International Nuclear Information System (INIS)

    The Nuclear Safety Regulations for Nuclear Installations and Nuclear Safety Codes for Nuclear Pressure Retaining Components were issued by the NNSA in 1995. The Atomic Act and Regulations on the Safety Regulation for Transportation of Radioactive Materials have been finished and submitted to the State Council in 1995. At the same time the NNSA organized a revised collection of regulations on nuclear safety in both Chinese and English, titled 'The Collection of Regulations on Nuclear Safety of the People's Republic of China'. To enhance the implementation of newly issued nuclear safety regulations, the NNSA conducted seven times of propagating activities in relation to the regulations for nuclear pressure retaining components and research reactors design and operating in 1995

  9. Molecular mechanism and regulation of autophagy

    Institute of Scientific and Technical Information of China (English)

    Ya-ping YANG; Zhong-qin LIANG; Zhen-lun GU; Zheng-hong QIN

    2005-01-01

    Autophagy is a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in eukaryotic cells. A large number of intracellular/extracellular stimuli, including amino acid starvation and invasion of microorganisms, are able to induce the autophagic response in cells. The discovery of the ATG genes in yeast has greatly advanced our understanding of the molecular mechanisms participating in autophagy and the genes involved in regulating the autophagic pathway. Many yeast genes have mammalian homologs,suggesting that the basic machinery for autophagy has been evolutionarily conserved along the eukaryotic phylum. The regulation of autophagy is a very complex process. Many signaling pathways, including target of rapamycin (TOR) or mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase-I (PI3K-I)/PKB, GTPases, calcium and protein synthesis all play important roles in regulating autophagy. The molecular mechanisms and regulation of autophagy are discussed in this review.

  10. Physical Module Networks: an integrative approach for reconstructing transcription regulation

    OpenAIRE

    Novershtern, Noa; Regev, Aviv; Friedman, Nir

    2011-01-01

    Motivation: Deciphering the complex mechanisms by which regulatory networks control gene expression remains a major challenge. While some studies infer regulation from dependencies between the expression levels of putative regulators and their targets, others focus on measured physical interactions. Results: Here, we present Physical Module Networks, a unified framework that combines a Bayesian model describing modules of co-expressed genes and their shared regulation programs, and a phys...

  11. Complex networks and computing

    Institute of Scientific and Technical Information of China (English)

    Shuigeng ZHOU; Zhongzhi ZHANG

    2009-01-01

    @@ Nowadays complex networks are pervasive in various areas of science and technology. Popular examples of complex networks include the Internet, social networks of collaboration, citations and co-authoring, as well as biological networks such as gene and protein interactions and others. Complex networks research spans across mathematics, computer science, engineering, biology and the social sciences. Even in computer science area, increasing problems are either found to be related to complex networks or studied from the perspective of complex networks, such as searching on Web and P2P networks, routing in sensor networks, language processing, software engineering etc. The interaction and mergence of complex networks and computing is inspiring new chances and challenges in computer science.

  12. Two giant stellar complexes

    Science.gov (United States)

    Efremov, Yu. N.; Efremov, E. Yu.

    Common star complexes are huge (0.3-1 kpc in diameter) groups of relatively young stars, associations and clusters. The complexes usually form regular chains along spiral arms of grand design galaxies, being evidently formed and supported by magneto- gravitational instability developing along an arm. Special attention is given to a few large complexes which have signatures of gravitational boundness, such as round shape and high central density. Concentrations of stars and clusters in such a complex in M51 galaxy were found in this paper; we concluded it is possible to suggest that the complex is gravitationally bound. It is also stressed that some properties of the giant complex in NGC 6946 (such as its semicircular and sharp Western edge) are still enigmatic.

  13. Simplicial complexes of graphs

    CERN Document Server

    Jonsson, Jakob

    2008-01-01

    A graph complex is a finite family of graphs closed under deletion of edges. Graph complexes show up naturally in many different areas of mathematics, including commutative algebra, geometry, and knot theory. Identifying each graph with its edge set, one may view a graph complex as a simplicial complex and hence interpret it as a geometric object. This volume examines topological properties of graph complexes, focusing on homotopy type and homology. Many of the proofs are based on Robin Forman's discrete version of Morse theory. As a byproduct, this volume also provides a loosely defined toolbox for attacking problems in topological combinatorics via discrete Morse theory. In terms of simplicity and power, arguably the most efficient tool is Forman's divide and conquer approach via decision trees; it is successfully applied to a large number of graph and digraph complexes.

  14. How evolution guides complexity

    OpenAIRE

    LARRY S. YAEGER

    2009-01-01

    Long-standing debates about the role of natural selection in the growth of biological complexity over geological time scales are difficult to resolve from the paleobiological record. Using an evolutionary model—a computational ecosystem subjected to natural selection—we investigate evolutionary trends in an information-theoretic measure of the complexity of the neural dynamics of artificial agents inhabiting the model. Our results suggest that evolution always guides complexity change, just n...

  15. Quantum Computational Complexity

    OpenAIRE

    Watrous, John

    2008-01-01

    This article surveys quantum computational complexity, with a focus on three fundamental notions: polynomial-time quantum computations, the efficient verification of quantum proofs, and quantum interactive proof systems. Properties of quantum complexity classes based on these notions, such as BQP, QMA, and QIP, are presented. Other topics in quantum complexity, including quantum advice, space-bounded quantum computation, and bounded-depth quantum circuits, are also discussed.

  16. Complex Systems and Dependability

    CERN Document Server

    Zamojski, Wojciech; Sugier, Jaroslaw

    2012-01-01

    Typical contemporary complex system is a multifaceted amalgamation of technical, information, organization, software and human (users, administrators and management) resources. Complexity of such a system comes not only from its involved technical and organizational structure but mainly from complexity of information processes that must be implemented in the operational environment (data processing, monitoring, management, etc.). In such case traditional methods of reliability analysis focused mainly on technical level are usually insufficient in performance evaluation and more innovative meth

  17. Engineering Complex Tissues

    OpenAIRE

    Mikos, Antonios G.; Herring, Susan W.; OCHAREON, PANNEE; Elisseeff, Jennifer; Lu, Helen H.; Kandel, Rita; Schoen, Frederick J.; Toner, Mehmet; Mooney, David; ATALA, ANTHONY; VAN DYKE, MARK E.; Kaplan, David; Vunjak-Novakovic, Gordana

    2006-01-01

    This article summarizes the views expressed at the third session of the workshop “Tissue Engineering—The Next Generation,” which was devoted to the engineering of complex tissue structures. Antonios Mikos described the engineering of complex oral and craniofacial tissues as a “guided interplay” between biomaterial scaffolds, growth factors, and local cell populations toward the restoration of the original architecture and function of complex tissues. Susan Herring, reviewing osteogenesis and ...

  18. Berger Engineering Complex

    Data.gov (United States)

    Federal Laboratory Consortium — Description/History: Engineering laboratory The Berger Lab Complex is a multi-purpose building with professional office, 100 seat auditorium, general purpose labs,...

  19. Conducting metal dithiolate complexes

    DEFF Research Database (Denmark)

    Underhill, A. E.; Ahmad, M. M.; Turner, D. J.; Clemenson, P. I.; Carneiro, K.; Yueqiuan, S.; Mortensen, Kell

    Further work on the chemical composition of the one-dimensional metallic metal dithiolene complex Li-Pt(mnt) is reported. The electrical conduction and thermopower properties of the nickel and palladium complexes are reported and compared with those of the platinum compound......Further work on the chemical composition of the one-dimensional metallic metal dithiolene complex Li-Pt(mnt) is reported. The electrical conduction and thermopower properties of the nickel and palladium complexes are reported and compared with those of the platinum compound...

  20. Conducting metal dithiolate complexes

    DEFF Research Database (Denmark)

    Underhill, A. E.; Ahmad, M. M.; Turner, D. J.;

    1985-01-01

    Further work on the chemical composition of the one-dimensional metallic metal dithiolene complex Li-Pt(mnt) is reported. The electrical conduction and thermopower properties of the nickel and palladium complexes are reported and compared with those of the platinum compound......Further work on the chemical composition of the one-dimensional metallic metal dithiolene complex Li-Pt(mnt) is reported. The electrical conduction and thermopower properties of the nickel and palladium complexes are reported and compared with those of the platinum compound...

  1. MULTISCALE COMPLEXITY/ENTROPY

    OpenAIRE

    Y. BAR-YAM

    2004-01-01

    We discuss the role of scale dependence of entropy/complexity and its relationship to component interdependence. The complexity as a function of scale of observation is expressed in terms of subsystem entropies for a system having a description in terms of variables that have the same a priori scale. The sum of the complexity over all scales is the same for any system with the same number of underlying degrees of freedom (variables), even though the complexity at specific scales differs due t...

  2. Phospholyl-uranium complexes

    International Nuclear Information System (INIS)

    After having reported a bibliographical study on penta-methylcyclopentadienyl uranium complexes, and a description of the synthesis and radioactivity of uranium (III) and (IV) boron hydrides compounds, this research thesis reports the study of mono and bis-tetramethyl-phospholyl uranium complexes comprising chloride, boron hydride, alkyl and alkoxide ligands. The third part reports the comparison of structures, stabilities and reactions of homologue complexes in penta-methylcyclopentadienyl and tetramethyl-phospholyl series. The last part addresses the synthesis of tris-phospholyl uranium (III) and (IV) complexes.

  3. Regulation by Blue Light of the fluffy Gene Encoding a Major Regulator of Conidiation in Neurospora crassa

    OpenAIRE

    Olmedo, María; Ruger-Herreros, Carmen; Corrochano, Luis M.

    2010-01-01

    The development of asexual spores, that is, the process of conidiation, in the fungus Neurospora crassa is increased by light. The fluffy (fl) gene, encoding a major regulator of conidiation, is activated by light. We describe here a detailed characterization of the regulation by blue light of fl in vegetative hyphae. This induction requires the white collar complex (WCC) while the FLD protein acts as a dark repressor of fl transcription. We show that the WCC directly regulates fl transcripti...

  4. Structural Features of Caspase-Activating Complexes

    Directory of Open Access Journals (Sweden)

    Hyun Ho Park

    2012-04-01

    Full Text Available Apoptosis, also called programmed cell death, is an orderly cellular suicide program that is critical for the development, immune regulation and homeostasis of a multi-cellular organism. Failure to control this process can lead to serious human diseases, including many types of cancer, neurodegenerative diseases, and autoimmununity. The process of apoptosis is mediated by the sequential activation of caspases, which are cysteine proteases. Initiator caspases, such as caspase-2, -8, -9, and -10, are activated by formation of caspase-activating complexes, which function as a platform to recruit caspases, providing proximity for self-activation. Well-known initiator caspase-activating complexes include (1 DISC (Death Inducing Signaling Complex, which activates caspases-8 and 10; (2 Apoptosome, which activates caspase-9; and (3 PIDDosome, which activates caspase-2. Because of the fundamental biological importance of capases, many structural and biochemical studies to understand the molecular basis of assembly mechanism of caspase-activating complexes have been performed. In this review, we summarize previous studies that have examined the structural and biochemical features of caspase-activating complexes. By analyzing the structural basis for the assembly mechanism of the caspase-activating complex, we hope to provide a comprehensive understanding of caspase activation by these important oligomeric complexes.

  5. The complexity of chloroplast chaperonins.

    Science.gov (United States)

    Vitlin Gruber, Anna; Nisemblat, Shahar; Azem, Abdussalam; Weiss, Celeste

    2013-12-01

    Type I chaperonins are large oligomeric protein ensembles that are involved in the folding and assembly of other proteins. Chloroplast chaperonins and co-chaperonins exist in multiple copies of two distinct isoforms that can combine to form a range of labile oligomeric structures. This complex system increases the potential number of chaperonin substrates and possibilities for regulation. The incorporation of unique subunits into the oligomer can modify substrate specificity. Some subunits are upregulated in response to heat shock and some show organ-specific expression, whereas others possess additional functions that are unrelated to their role in protein folding. Accumulating evidence suggests that specific subunits have distinct roles in biogenesis of ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco). PMID:24035661

  6. TOWARD MORE EFFECTIVE REGULATION

    Energy Technology Data Exchange (ETDEWEB)

    J. GRAF

    2000-06-01

    This paper proposes a model relationship between the operator engaged in a hazardous activity, the regulator of that activity, and the general public. The roles and responsibilities of each entity are described in a way that allows effective communication flow. The role of the regulator is developed using the steam boiler as an example of a hazard subject to regulation; however, the model applies to any regulated activity. In this model the safety analyst has the extremely important role of communicating sometimes difficult technical information to the regulator in a way that the regulator can provide credible assurance to the general public as to the adequacy of the control of the hazardous activity. The conclusion asserts that acceptance of the model, understanding of the roles and responsibilities and definition of who communicates what information to whom will mitigate frustration on the part of each of the three entities.

  7. The development of regulations

    International Nuclear Information System (INIS)

    In October 2002, The Act on Protection Against Ionising Radiation and Nuclear Safety which regulates all aspects of protection against ionising radiation and nuclear safety entered into force in Slovenia. The Slovenian government and its responsible ministries shall issue several governmental and ministerial regulations to support the above - mentioned act. The Slovenian Nuclear Safety Administration (SNSA) which acts within the Ministry of the Environment, Spatial Planing and Energy takes an active part in drafting the regulations which are defined in the act. Due to a very comprehensive and pretentious task, that is to be completed in a relatively short period of time, taking into consideration the involvement of stakeholders and all competent ministries, the SNSA within the Quality Management System developed a special procedure that insures the systematic approach to the preparation of regulations. The article will briefly represent the process that: defines the preparation, development, harmonisation, review, approval and issue of regulations and uniforms the format of developed regulations. (author)

  8. Nuclear safety regulations

    International Nuclear Information System (INIS)

    The enactment of nuclear safety regulations in 1996 is mainly focused on the preparation of related regulations, and safety guides for nuclear materials control, the reprocessing installations of spent fuels, the treatment and disposal for radioactive waste. The NNSA also assists the departments concerned of the State Council for modification on the 'Atomic Energy Act' (draft) and the' Regulations on the Safety Supervision and Control of Radioactive Materials Transportation' (draft)

  9. Attention in emotion regulation

    OpenAIRE

    Gelow, Stefan

    2013-01-01

    The concept of emotion and how to regulate it is a central aspect of modern psychology. Within the process model of emotion regulation (Gross, 1998), one issue is how attentional deployment affects emotion regulation and how this can be measured. In task 1, pictures of positive or negative valence were showed in two conditions, either attend or decrease emotional reaction, while participants’ eye movements were followed with an eye tracker. Ratings of arousal and valence were significantly af...

  10. Accounting Regulation in Ukraine

    OpenAIRE

    Hora, Michal; Chyzevska, Ludmila

    2013-01-01

    The aim of the paper is to evaluate the regulation and organization of accounting in Ukraine under the changes in the national economic system development and impact of IFRS implementation. The system of legal regulation of accounting in Ukraine is presented by five levels, each comprised of a number of corresponding subjects of regulation and documents. Typical Chart of Accounts is evidence of the continental accounting model in Ukraine. The accounting standards provide freedom of choice as ...

  11. Emotional regulation and friendship

    OpenAIRE

    Zaccagnini, J.L.; Ruiz-Aranda, D.

    2013-01-01

    Previous literature has been shown that emotional regulation facilitates the establishment and maintenance of social relations (Dodge Garber, 1991; Saarni, 1999). The objective of the present study was to analyze the influence of emotional regulation (Gross y John, 2003) in positive friendship (Berscheid, 2003), specifically at the level of intimacy with friends. In addition, we examined the mediating role of positive emotions in the relationship between the emotional regulation and the leve...

  12. Benchmarking and regulation

    OpenAIRE

    Agrell, Per Joakim; Bogetoft, Peter

    2013-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The application of benchmarking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publication...

  13. Better Regulation in Europe

    OpenAIRE

    Wiener, Jonathan B.

    2006-01-01

    "Better Regulation" is afoot in Europe. After several transatlantic conflicts over regulatory topics such as the precautionary principle, genetically modified foods, and climate change, Europe and America now appear to be converging on the analytic basis for regulation. In a process of hybridization, European institutions are borrowing "Better Regulation" reforms from both the US approach to regulatory review using benefit-cost analysis and from European member states' initiatives on administ...

  14. Introductory complex analysis

    CERN Document Server

    Silverman, Richard A

    1984-01-01

    A shorter version of A. I. Markushevich's masterly three-volume Theory of Functions of a Complex Variable, this edition is appropriate for advanced undergraduate and graduate courses in complex analysis. Numerous worked-out examples and more than 300 problems, some with hints and answers, make it suitable for independent study. 1967 edition.

  15. Complexity dimensions and learnability

    NARCIS (Netherlands)

    S-H. Nienhuys-Cheng (Shan-Hwei); M. Polman

    1992-01-01

    textabstractA stochastic model of learning from examples has been introduced by Valiant [1984]. This PAC-learning model (PAC = probably approximately correct) reflects differences in complexity of concept classes, i.e. very complex classes are not efficiently PAC-learnable. Blumer et al. [1989] foun

  16. The complexity of science

    Directory of Open Access Journals (Sweden)

    H.P.P. (Hennie Lótter

    1999-03-01

    Full Text Available In this article an alternative philosophy of science based on ideas drawn from the study of complex adaptive systems is presented. As a result of the enormous expansion in scientific disciplines, and the number of scientists and scientific institutions in the twentieth century, I believe science can be characterised as a complex system. I want to interpret the processes of science through which scientists themselves determine what is regarded as good science. This characterisation of science as a complex system can supply an answer to the question why the sciences have been so successful in solving growing numbers of problems and correcting their own mistakes. I utilise components of complexity theory to explain and interpret science as a complex system. I first explain the concept of complexity in ordinary language. The explanation of science as a complex system starts with a definition of the basic rules guiding the behaviour of science as a complex system. Next, I indicate how various sciences have resulted through the implementation of these rules in the study of a specific aspect of reality. The explanation of the growth of science through evolutionary adaptation and learning forms the core o f the article.

  17. Complexity in Picture Books

    Science.gov (United States)

    Sierschynski, Jarek; Louie, Belinda; Pughe, Bronwyn

    2015-01-01

    One of the key requirements of Common Core State Standards (CCSS) in English Language Arts is that students are able to read and access complex texts across all grade levels. The CCSS authors emphasize both the limitations and lack of accuracy in the current CCSS model of text complexity, calling for the development of new frameworks. In response…

  18. Freestanding Complex Optical Scanners.

    Science.gov (United States)

    Frisbie, David A.

    A complex freestanding optical mark recognition (OMR) scanner is one which is not on-line to an external processor; it has intelligence stemming from an internal processor located within the unit or system. The advantages and disadvantages of a complex OMR can best be assessed after identifying the scanning needs and constraints of the potential…

  19. Visual Complexity: A Review

    Science.gov (United States)

    Donderi, Don C.

    2006-01-01

    The idea of visual complexity, the history of its measurement, and its implications for behavior are reviewed, starting with structuralism and Gestalt psychology at the beginning of the 20th century and ending with visual complexity theory, perceptual learning theory, and neural circuit theory at the beginning of the 21st. Evidence is drawn from…

  20. Urban geography and complexity

    OpenAIRE

    Denise Pumain

    2004-01-01

    The contemporary approach of complex systems raises common questions that could be handled by a transdisciplinary theory. We demonstrate how the main concepts of urban geography could be integrated in such a theory ofcomplexity. We illustrate the complexity approach by a short presentationof the SIMPOP model that uses a multi-agents formalism for the simulationof the evolutionary properties of systems of cities.

  1. Gold trifluoromethyl complexes.

    Science.gov (United States)

    Gil-Rubio, Juan; Vicente, José

    2015-12-01

    This article reviews the synthesis, reactivity and applications of gold trifluoromethyl complexes, which are the only isolated perfluoroalkyl complexes of gold. The most reported examples are neutral Au(i) complexes of the type [Au(CF3)L], whereas only two Au(ii) trifluoromethyl complexes have been reported, both being diamagnetic and containing a strong Au-Au bond. A number of Au(iii) trifluoromethyl complexes have been prepared by oxidative addition of halogens or iodotrifluoromethane to Au(i) complexes or, in a few cases, by transmetallation reactions. Owing to the limitations of the available synthetic methods, a lower number of examples is known, particularly for the oxidation states (ii) and (iii). Gold trifluoromethyl complexes present singular characteristics, such as thermal stability, strong Au-C bonds and, in some cases, reactive α-C-F bonds. Some of the Au(iii) complexes reported, show unusually easy reductive elimination reactions of trifluoromethylated products which could be applied in the development of gold-catalyzed processes for the trifluoromethylation of organic compounds. PMID:26169553

  2. [Complexity: an introduction].

    Science.gov (United States)

    Gómez, Carlos Alberto Palacio; Jaramillo, Francisco Luis Ochoa

    2011-01-01

    Complexity appears in the twentieth century as a way to understand many phenomena that are perceived as chaotic and complex from classical thought, which still persist in our way of explaining the world. Its purpose is to study the complex and adaptive systems that are sensitive to initial conditions. Some of the characteristics of complex thought are systemic perspective, autopoiesis, self-organization, emergent properties, unpredictability of the systems, analogic thought, and the complementarity of the phenomena, among others. Living systems respond to a complex logic, and in that sense, our vision of human populations and patients, and how we try to solve problems and human diseases, should be open to the possibilities that arise from this form of understand the world. PMID:21503430

  3. Improving Urban Mobility by Understanding its Complexity

    OpenAIRE

    Gershenson, Carlos

    2016-01-01

    Urban mobility systems are composed multiple elements with strong interactions, i.e. their future is co-determined by the state of other elements. Thus, studying components in isolation, i.e. using a reductionist approach, is inappropriate. I propose five recommendations to improve urban mobility based on insights from the scientific study of complex systems: use adaptation over prediction, regulate interactions to avoid friction, use sensors to recover real time information, develop adaptive...

  4. Complex Evaluation Model of Corporate Energy Management

    OpenAIRE

    Ágnes Kádár Horváth

    2014-01-01

    With the ever increasing energy problems at the doorstep alongside with political, economic, social and environmental challenges, conscious energy management has become of increasing importance in corporate resource management. Rising energy costs, stricter environmental and climate regulations as well as considerable changes in the energy market require companies to rationalise their energy consumption and cut energy costs. This study presents a complex evaluation model of corporate energy m...

  5. Emotion-regulation choice

    NARCIS (Netherlands)

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

    2011-01-01

    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 hypothesiz

  6. Benchmarking and Regulation

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    nchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The applica...

  7. Reset Complexity of Ideal Languages

    OpenAIRE

    Maslennikova, Marina

    2014-01-01

    We present a new characteristic of a regular ideal language called reset complexity. We find some bounds on the reset complexity in terms of the state complexity of a given language. We also compare the reset complexity and the state complexity for languages related to slowly synchronizing automata and study uniqueness question for automata yielding the minimum of reset complexity.

  8. Structure and function of mitochondrial complex I.

    Science.gov (United States)

    Wirth, Christophe; Brandt, Ulrich; Hunte, Carola; Zickermann, Volker

    2016-07-01

    Proton-pumping NADH:ubiquinone oxidoreductase (complex I) is the largest and most complicated enzyme of the respiratory chain. Fourteen central subunits represent the minimal form of complex I and can be assigned to functional modules for NADH oxidation, ubiquinone reduction, and proton pumping. In addition, the mitochondrial enzyme comprises some 30 accessory subunits surrounding the central subunits that are not directly associated with energy conservation. Complex I is known to release deleterious oxygen radicals (ROS) and its dysfunction has been linked to a number of hereditary and degenerative diseases. We here review recent progress in structure determination, and in understanding the role of accessory subunits and functional analysis of mitochondrial complex I. For the central subunits, structures provide insight into the arrangement of functional modules including the substrate binding sites, redox-centers and putative proton channels and pump sites. Only for two of the accessory subunits, detailed structures are available. Nevertheless, many of them could be localized in the overall structure of complex I, but most of these assignments have to be considered tentative. Strikingly, redox reactions and proton pumping machinery are spatially completely separated and the site of reduction for the hydrophobic substrate ubiquinone is found deeply buried in the hydrophilic domain of the complex. The X-ray structure of complex I from Yarrowia lipolytica provides clues supporting the previously proposed two-state stabilization change mechanism, in which ubiquinone redox chemistry induces conformational states and thereby drives proton pumping. The same structural rearrangements may explain the active/deactive transition of complex I implying an integrated mechanistic model for energy conversion and regulation. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt. PMID:26921811

  9. Reconceptualizing Civil Regulation

    DEFF Research Database (Denmark)

    Galang, Roberto Martin; Castello, Itziar

    2011-01-01

    This article re-conceptualizes the notion of civil regulation, through an analysis of 775 projects by firms located in 21 Asian countries, wherein we map the state of civil regulation initiatives in the region. We challenge two established assumptions in the Corporate Social Responsibility...... literature. First, contrary to what is commonly argued, we claim that strong states in Asia promote civil regulation in what we call the “paradox of the weak state”. Second, we not only argue that civil regulation is mainly enforced by multinational enterprises willing to promote international social and...... environmental standards; but also that local, small and medium companies play a key role in the development of Asian civil regulation. We call this second finding the “CSR importation trap”. Our findings are supported by evidence on the limitations in the interchangeable properties of business and governments...

  10. Lignification: Flexibility, Biosynthesis and Regulation.

    Science.gov (United States)

    Zhao, Qiao

    2016-08-01

    Lignin is a complex phenolic polymer that is deposited in the secondary cell wall of all vascular plants. The evolution of lignin is considered to be a critical event during vascular plant development, because lignin provides mechanical strength, rigidity, and hydrophobicity to secondary cell walls to allow plants to grow tall and transport water and nutrients over a long distance. In recent years, great research efforts have been made to genetically alter lignin biosynthesis to improve biomass degradability for the production of second-generation biofuels. This global focus on lignin research has significantly advanced our understanding of the lignification process. Based on these advances, here I provide an overview of lignin composition, the biosynthesis pathway and its regulation. PMID:27131502

  11. Proteomics-Based Analysis of Protein Complexes in Pluripotent Stem Cells and Cancer Biology

    OpenAIRE

    Putty-Reddy Sudhir; Chung-Hsuan Chen

    2016-01-01

    A protein complex consists of two or more proteins that are linked together through protein–protein interactions. The proteins show stable/transient and direct/indirect interactions within the protein complex or between the protein complexes. Protein complexes are involved in regulation of most of the cellular processes and molecular functions. The delineation of protein complexes is important to expand our knowledge on proteins functional roles in physiological and pathological conditions. T...

  12. Stable Spirocyclic Meisenheimer Complexes

    Directory of Open Access Journals (Sweden)

    Gonzalo Guirado

    2008-06-01

    Full Text Available Meisenheimer complexes are important intermediates in Nucleophilic Aromatic Substitution Reactions (SNAr. They are formed by the addition of electron rich species to polynitro aromatic compounds or aromatic compounds with strong electron withdrawing groups. It is possible to distinguish two types of Meisenheimer or σ-complexes, the σHcomplex or σX-complex (also named ipso, depending on the aromatic ring position attacked by the nucleophile (a non-substituted or substituted one, respectively. Special examples of σX- or ipso-complexes are formed through intermediate spiro adducts, via intramolecular SNAr. Some of these spirocyclic Meisenheimer complexes, a type of σXcomplex, are exceptionally stable in solution and/or as solids. They can be isolated and characterized using X-ray, and various spectroscopic techniques such as NMR, UV-Vis, IR, and fluorescence. A few of these stable spirocyclic Meisenheimer complexes are zwitterionic and exhibit interesting photophysical and redox properties. We will review recent advances, synthesis and potential applications of these stable spirocyclic Meisenheimer complexes.

  13. Complex intuitionistic fuzzy sets

    Science.gov (United States)

    Alkouri, Abdulazeez (Moh'd. Jumah) S.; Salleh, Abdul Razak

    2012-09-01

    This paper presents a new concept of complex intuitionistic fuzzy set (CIFS) which is generalized from the innovative concept of a complex fuzzy set (CFS) by adding the non-membership term to the definition of CFS. The novelty of CIFS lies in its ability for membership and non-membership functions to achieve more range of values. The ranges of values are extended to the unit circle in complex plane for both membership and non-membership functions instead of [0, 1] as in the conventional intuitionistic fuzzy functions. We define basic operations namely complement, union, and intersection on CIFSs. Properties of these operations are derived.

  14. Query complexity in expectation

    OpenAIRE

    Kaniewski, J.; Lee, Troy; Wolf,

    2014-01-01

    We study the query complexity of computing a function f:{0,1}^n-->R_+ in expectation. This requires the algorithm on input x to output a nonnegative random variable whose expectation equals f(x), using as few queries to the input x as possible. We exactly characterize both the randomized and the quantum query complexity by two polynomial degrees, the nonnegative literal degree and the sum-of-squares degree, respectively. We observe that the quantum complexity can be unboundedly smaller than t...

  15. Complexity and forensic pathology.

    Science.gov (United States)

    Jones, Richard Martin

    2015-12-01

    It has become increasingly apparent that nonlinearity and complexity are the norm in human physiological systems, the relevance of which is informing an enhanced understanding of basic pathological processes such as inflammation, the host response to severe trauma, and critical illness. This article will explore how an understanding of nonlinear systems and complexity might inform the study of the pathophysiology of deaths of medicolegal interest, and how 'complexity thinking' might usefully be incorporated into modern forensic medicine and forensic pathology research, education and practice. PMID:26372537

  16. Complexity for artificial substrates (CASU: software for creating and visualising habitat complexity.

    Directory of Open Access Journals (Sweden)

    Lynette H L Loke

    Full Text Available Physical habitat complexity regulates the structure and function of biological communities, although the mechanisms underlying this relationship remain unclear. Urbanisation, pollution, unsustainable resource exploitation and climate change have resulted in the widespread simplification (and loss of habitats worldwide. One way to restore physical complexity to anthropogenically simplified habitats is through the use of artificial substrates, which also offer excellent opportunities to explore the effects of different components (variables of complexity on biodiversity and community structure that would be difficult to separate in natural systems. Here, we describe a software program (CASU that enables users to visualise static, physical complexity. CASU also provides output files that can be used to create artificial substrates for experimental and/or restoration studies. It has two different operational modes: simple and advanced. In simple mode, users can adjust the five main variables of informational complexity (i.e. the number of object types, relative abundance of object types, density of objects, variability and range in the objects' dimensions, and their spatial arrangement and visualise the changes as they do so. The advanced mode allows users to design artificial substrates by fine-tuning the complexity variables as well as alter object-specific parameters. We illustrate how CASU can be used to create tiles of different designs for application in a marine environment. Such an ability to systematically influence physical complexity could greatly facilitate ecological restoration by allowing conservationists to rebuild complexity in degraded and simplified habitats.

  17. Cancer initiation and progression: an unsimplifiable complexity

    Directory of Open Access Journals (Sweden)

    Frezza Eldo E

    2006-10-01

    Full Text Available Abstract Background Cancer remains one of the most complex diseases affecting humans and, despite the impressive advances that have been made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still widely debated. Conclusion There is no doubt that human carcinogenesis is a dynamic process that depends on a large number of variables and is regulated at multiple spatial and temporal scales. Viewing cancer as a system that is dynamically complex in time and space will, however, probably reveal more about its underlying behavioural characteristics. It is encouraging that mathematicians, biologists and clinicians continue to contribute together towards a common quantitative understanding of cancer complexity. This way of thinking may further help to clarify concepts, interpret new and old experimental data, indicate alternative experiments and categorize the acquired knowledge on the basis of the similarities and/or shared behaviours of very different tumours.

  18. Complex Pharmacology of Free Fatty Acid Receptors

    DEFF Research Database (Denmark)

    Milligan, Graeme; Shimpukade, Bharat; Ulven, Trond;

    2016-01-01

    G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond...... pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for...... the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential....

  19. A quantitative approach to wireless spectrum regulation

    OpenAIRE

    Harrison, Kate

    2015-01-01

    Wireless spectrum regulation is an area of increasing interest, complexity, and importance. After decades of single-purpose, exclusive spectrum allocations, the Federal Communications Commission (FCC) brought about the era of dynamically shared spectrum with their landmark ruling in 2008. Although unlicensed spectrum—“free for all” spectrum such as the 2.4 GHz band—is universally agreed to be critical to economic development, there is scarcely enough to meet current demands. WiFi could never ...

  20. Translation regulation gets its 'omics' moment.

    Science.gov (United States)

    Kuersten, Scott; Radek, Agnes; Vogel, Christine; Penalva, Luiz O F

    2013-01-01

    The fate of cellular RNA is largely determined by complex networks of protein-RNA interactions through ribonucleoprotein (RNP) complexes. Despite their relatively short half-life, transcripts associate with many different proteins that process, modify, translate, and degrade the RNA. Following biogenesis some mRNPs are immediately directed to translation and produce proteins, but many are diverted and regulated by processes including miRNA-mediated mechanisms, transport and localization, as well as turnover. Because of this complex interplay estimates of steady-state expression by methods such as RNAseq alone cannot capture critical aspects of cellular fate, environmental response, tumorigenesis, or gene expression regulation. More selective and integrative tools are needed to measure protein-RNA complexes and the regulatory processes involved. One focus area is measurements of the transcriptome associated with ribosomes and translation. These so-called polysome or ribosome profiling techniques can evaluate translation efficiency as well as the interplay between translation initiation, elongation, and termination-subject areas not well understood at a systems biology level. Ribosome profiling is a highly promising technique that provides mRNA positional information of ribosome occupancy, potentially bridging the gap between gene expression (i.e., RNAseq and microarray analysis) and protein quantification (i.e., mass spectrometry). In combination with methods such as RNA immunoprecipitation, miRNA profiling, or proteomics, we obtain a fresh view of global post-transcriptional and translational gene regulation. In addition, these techniques also provide new insight into new regulatory elements, such as alternative open reading frames, and translation regulation under different conditions. PMID:23677826