Science.gov

Sample records for non-canonical dimension

  1. Refining inflation using non-canonical scalars

    SciTech Connect

    Unnikrishnan, Sanil; Sahni, Varun; Toporensky, Aleksey E-mail: varun@iucaa.ernet.in

    2012-08-01

    This paper revisits the Inflationary scenario within the framework of scalar field models possessing a non-canonical kinetic term. We obtain closed form solutions for all essential quantities associated with chaotic inflation including slow roll parameters, scalar and tensor power spectra, spectral indices, the tensor-to-scalar ratio, etc. We also examine the Hamilton-Jacobi equation and demonstrate the existence of an inflationary attractor. Our results highlight the fact that non-canonical scalars can significantly improve the viability of inflationary models. They accomplish this by decreasing the tensor-to-scalar ratio while simultaneously increasing the value of the scalar spectral index, thereby redeeming models which are incompatible with the cosmic microwave background (CMB) in their canonical version. For instance, the non-canonical version of the chaotic inflationary potential, V(φ) ∼ λφ{sup 4}, is found to agree with observations for values of λ as large as unity! The exponential potential can also provide a reasonable fit to CMB observations. A central result of this paper is that steep potentials (such as V∝φ{sup −n}) usually associated with dark energy, can drive inflation in the non-canonical setting. Interestingly, non-canonical scalars violate the consistency relation r = −8n{sub T}, which emerges as a smoking gun test for this class of models.

  2. Lessons from non-canonical splicing

    PubMed Central

    Ule, Jernej

    2016-01-01

    Recent improvements in experimental and computational techniques used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons, and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimises their potential to disrupt gene expression. While non-canonical splicing can lead to aberrant transcripts that cause many diseases, we also explain how it can be exploited for new therapeutic strategies. PMID:27240813

  3. Non-canonical actions of mismatch repair

    PubMed Central

    Crouse, Gray F.

    2015-01-01

    At the heart of the mismatch repair (MMR) system are proteins that recognize mismatches in DNA. Such mismatches can be mispairs involving normal or damaged bases or insertion/deletion loops due to strand misalignment. When such mispairs are generated during replication or recombination, MMR will direct removal of an incorrectly paired base or block recombination between nonidentical sequences. However, when mispairs are recognized outside the context of replication, proper strand discrimination between old and new DNA is lost, and MMR can act randomly and mutagenically on mispaired DNA. Such non-canonical actions of MMR are important in somatic hypermutation and class switch recombination, expansion of triplet repeats, and potentially in mutations arising in nondividing cells. MMR involvement in damage recognition and signaling is complex, with the end result likely dependent on the amount of DNA damage in a cell. PMID:26698648

  4. Non-canonical modulators of nuclear receptors.

    PubMed

    Tice, Colin M; Zheng, Ya-Jun

    2016-09-01

    Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research.

  5. Relations between canonical and non-canonical inflation

    SciTech Connect

    Gwyn, Rhiannon; Rummel, Markus; Westphal, Alexander E-mail: markus.rummel@physics.ox.ac.uk

    2013-12-01

    We look for potential observational degeneracies between canonical and non-canonical models of inflation of a single field φ. Non-canonical inflationary models are characterized by higher than linear powers of the standard kinetic term X in the effective Lagrangian p(X,φ) and arise for instance in the context of the Dirac-Born-Infeld (DBI) action in string theory. An on-shell transformation is introduced that transforms non-canonical inflationary theories to theories with a canonical kinetic term. The 2-point function observables of the original non-canonical theory and its canonical transform are found to match in the case of DBI inflation.

  6. Non-canonical inflation coupled to matter

    SciTech Connect

    Céspedes, Sebastián; Davis, Anne-Christine E-mail: a.c.davis@damtp.cam.ac.uk

    2015-11-01

    We compute corrections to the inflationary potential due to conformally coupled non-relativistic matter. We find that under certain conditions of the matter coupling, inflation may be interrupted abruptly. We display this in the superconformal Starobinsky model, where matter is conformally coupled to the Einstein frame metric. These corrections may easily stop inflation provided that there is an initial density of non-relativistic matter. Since these additional heavy degrees of freedom generically occur in higher dimension theories, for example as Kaluza-Klein modes, this effect can arise in multiple scenarios.

  7. Non-canonical WNT signalling in the lung.

    PubMed

    Li, Changgong; Bellusci, Saverio; Borok, Zea; Minoo, Parviz

    2015-11-01

    The role of WNT signalling in metazoan organogenesis has been a topic of widespread interest. In the lung, while the role of canonical WNT signalling has been examined in some detail by multiple studies, the non-canonical WNT signalling has received limited attention. Reliable evidence shows that this important signalling mechanism constitutes a major regulatory pathway in lung development. In addition, accumulating evidence has also shown that the non-canonical WNT pathway is critical for maintaining lung homeostasis and that aberrant activation of this pathway may underlie several debilitating lung diseases. Functional analyses have further revealed that the non-canonical WNT pathway regulates multiple cellular activities in the lung that are dependent on the specific cellular context. In most cell types, non-canonical WNT signalling regulates canonical WNT activity, which is also critical for many aspects of lung biology. This review will summarize what is currently known about the role of non-canonical WNT signalling in lung development, homeostasis and pathogenesis of disease.

  8. Non-canonical WNT signalling in the lung

    PubMed Central

    Li, Changgong; Bellusci, Saverio; Borok, Zea; Minoo, Parviz

    2015-01-01

    The role of WNT signalling in metazoan organogenesis has been a topic of widespread interest. In the lung, while the role of canonical WNT signalling has been examined in some detail by multiple studies, the non-canonical WNT signalling has received limited attention. Reliable evidence shows that this important signalling mechanism constitutes a major regulatory pathway in lung development. In addition, accumulating evidence has also shown that the non-canonical WNT pathway is critical for maintaining lung homeostasis and that aberrant activation of this pathway may underlie several debilitating lung diseases. Functional analyses have further revealed that the non-canonical WNT pathway regulates multiple cellular activities in the lung that are dependent on the specific cellular context. In most cell types, non-canonical WNT signalling regulates canonical WNT activity, which is also critical for many aspects of lung biology. This review will summarize what is currently known about the role of non-canonical WNT signalling in lung development, homeostasis and pathogenesis of disease. PMID:26261051

  9. Accretion of the Moon from non-canonical discs.

    PubMed

    Salmon, J; Canup, R M

    2014-09-13

    Impacts that leave the Earth-Moon system with a large excess in angular momentum have recently been advocated as a means of generating a protolunar disc with a composition that is nearly identical to that of the Earth's mantle. We here investigate the accretion of the Moon from discs generated by such 'non-canonical' impacts, which are typically more compact than discs produced by canonical impacts and have a higher fraction of their mass initially located inside the Roche limit. Our model predicts a similar overall accretional history for both canonical and non-canonical discs, with the Moon forming in three consecutive steps over hundreds of years. However, we find that, to yield a lunar-mass Moon, the more compact non-canonical discs must initially be more massive than implied by prior estimates, and only a few of the discs produced by impact simulations to date appear to meet this condition. Non-canonical impacts require that capture of the Moon into the evection resonance with the Sun reduced the Earth-Moon angular momentum by a factor of 2 or more. We find that the Moon's semi-major axis at the end of its accretion is approximately 7R⊕, which is comparable to the location of the evection resonance for a post-impact Earth with a 2.5 h rotation period in the absence of a disc. Thus, the dynamics of the Moon's assembly may directly affect its ability to be captured into the resonance.

  10. Intermediate inflation from a non-canonical scalar field

    SciTech Connect

    Rezazadeh, K.; Karami, K.; Karimi, P. E-mail: KKarami@uok.ac.ir

    2015-09-01

    We study the intermediate inflation in a non-canonical scalar field framework with a power-like Lagrangian. We show that in contrast with the standard canonical intermediate inflation, our non-canonical model is compatible with the observational results of Planck 2015. Also, we estimate the equilateral non-Gaussianity parameter which is in well agreement with the prediction of Planck 2015. Then, we obtain an approximation for the energy scale at the initial time of inflation and show that it can be of order of the Planck energy scale, i.e. M{sub P} ∼ 10{sup 18}GeV. We will see that after a short period of time, inflation enters in the slow-roll regime that its energy scale is of order M{sub P}/100 ∼ 10{sup 16}GeV and the horizon exit takes place in this energy scale. We also examine an idea in our non-canonical model to overcome the central drawback of intermediate inflation which is the fact that inflation never ends. We solve this problem without disturbing significantly the nature of the intermediate inflation until the time of horizon exit.

  11. Non-Canonical Cell Death Induced by p53

    PubMed Central

    Ranjan, Atul; Iwakuma, Tomoo

    2016-01-01

    Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA), ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells. PMID:27941671

  12. Non-Canonical Cell Death Induced by p53.

    PubMed

    Ranjan, Atul; Iwakuma, Tomoo

    2016-12-09

    Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA), ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells.

  13. Intermediate inflation from a non-canonical scalar field

    NASA Astrophysics Data System (ADS)

    Rezazadeh, K.; Karami, K.; Karimi, P.

    2015-09-01

    We study the intermediate inflation in a non-canonical scalar field framework with a power-like Lagrangian. We show that in contrast with the standard canonical intermediate inflation, our non-canonical model is compatible with the observational results of Planck 2015. Also, we estimate the equilateral non-Gaussianity parameter which is in well agreement with the prediction of Planck 2015. Then, we obtain an approximation for the energy scale at the initial time of inflation and show that it can be of order of the Planck energy scale, i.e. MP ~ 1018GeV. We will see that after a short period of time, inflation enters in the slow-roll regime that its energy scale is of order MP/100 ~ 1016GeV and the horizon exit takes place in this energy scale. We also examine an idea in our non-canonical model to overcome the central drawback of intermediate inflation which is the fact that inflation never ends. We solve this problem without disturbing significantly the nature of the intermediate inflation until the time of horizon exit.

  14. Accretion of the Moon from non-canonical discs

    PubMed Central

    Salmon, J.; Canup, R. M

    2014-01-01

    Impacts that leave the Earth–Moon system with a large excess in angular momentum have recently been advocated as a means of generating a protolunar disc with a composition that is nearly identical to that of the Earth's mantle. We here investigate the accretion of the Moon from discs generated by such ‘non-canonical’ impacts, which are typically more compact than discs produced by canonical impacts and have a higher fraction of their mass initially located inside the Roche limit. Our model predicts a similar overall accretional history for both canonical and non-canonical discs, with the Moon forming in three consecutive steps over hundreds of years. However, we find that, to yield a lunar-mass Moon, the more compact non-canonical discs must initially be more massive than implied by prior estimates, and only a few of the discs produced by impact simulations to date appear to meet this condition. Non-canonical impacts require that capture of the Moon into the evection resonance with the Sun reduced the Earth–Moon angular momentum by a factor of 2 or more. We find that the Moon's semi-major axis at the end of its accretion is approximately 7R⊕, which is comparable to the location of the evection resonance for a post-impact Earth with a 2.5 h rotation period in the absence of a disc. Thus, the dynamics of the Moon's assembly may directly affect its ability to be captured into the resonance. PMID:25114307

  15. Novel perspectives on non-canonical inflammasome activation

    PubMed Central

    Diamond, Catherine Emma; Khameneh, Hanif Javanmard; Brough, David; Mortellaro, Alessandra

    2015-01-01

    Inflammasomes are cytosolic multi-protein complexes that regulate the secretion of the proinflammatory cytokines, IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. The NLRP3 inflammasome is the most well-characterized member of this family and functions by sensing intracellular pathogen- and damage-associated molecular patterns and activating caspase-1, which processes the biologically inactive IL-1β and IL-18 precursors into active cytokines. Recent studies have identified an alternative mechanism of inflammasome activation, termed the non-canonical inflammasome, which is triggered by cytosolic sensing of lipopolysaccharide (LPS) derived from bacteria that have escaped phagolysosomes. This pathway is independent of Toll-like receptor 4 (TLR4), the well-known extracellular receptor for LPS, but instead depends on the inflammatory protease, caspase-11. Although our understanding of caspase-11 activation is still in its infancy, it appears to be an essential mediator of septic shock and attenuates intestinal inflammation. In this review, we bring together the latest data on the roles of caspase-11 and the mechanisms underlying caspase-11-mediated activation of the non-canonical inflammasome, and consider the implications of this pathway on TLR4-independent immune responses to LPS. PMID:27471719

  16. Non-Canonical Replication Initiation: You're Fired!

    PubMed

    Ravoitytė, Bazilė; Wellinger, Ralf Erik

    2017-01-27

    The division of prokaryotic and eukaryotic cells produces two cells that inherit a perfect copy of the genetic material originally derived from the mother cell. The initiation of canonical DNA replication must be coordinated to the cell cycle to ensure the accuracy of genome duplication. Controlled replication initiation depends on a complex interplay of cis-acting DNA sequences, the so-called origins of replication (ori), with trans-acting factors involved in the onset of DNA synthesis. The interplay of cis-acting elements and trans-acting factors ensures that cells initiate replication at sequence-specific sites only once, and in a timely order, to avoid chromosomal endoreplication. However, chromosome breakage and excessive RNA:DNA hybrid formation can cause breakinduced (BIR) or transcription-initiated replication (TIR), respectively. These non-canonical replication events are expected to affect eukaryotic genome function and maintenance, and could be important for genome evolution and disease development. In this review, we describe the difference between canonical and non-canonical DNA replication, and focus on mechanistic differences and common features between BIR and TIR. Finally, we discuss open issues on the factors and molecular mechanisms involved in TIR.

  17. Non-Canonical Replication Initiation: You’re Fired!

    PubMed Central

    Ravoitytė, Bazilė; Wellinger, Ralf Erik

    2017-01-01

    The division of prokaryotic and eukaryotic cells produces two cells that inherit a perfect copy of the genetic material originally derived from the mother cell. The initiation of canonical DNA replication must be coordinated to the cell cycle to ensure the accuracy of genome duplication. Controlled replication initiation depends on a complex interplay of cis-acting DNA sequences, the so-called origins of replication (ori), with trans-acting factors involved in the onset of DNA synthesis. The interplay of cis-acting elements and trans-acting factors ensures that cells initiate replication at sequence-specific sites only once, and in a timely order, to avoid chromosomal endoreplication. However, chromosome breakage and excessive RNA:DNA hybrid formation can cause break-induced (BIR) or transcription-initiated replication (TIR), respectively. These non-canonical replication events are expected to affect eukaryotic genome function and maintenance, and could be important for genome evolution and disease development. In this review, we describe the difference between canonical and non-canonical DNA replication, and focus on mechanistic differences and common features between BIR and TIR. Finally, we discuss open issues on the factors and molecular mechanisms involved in TIR. PMID:28134821

  18. The non-canonical functions of the heme oxygenases.

    PubMed

    Vanella, Luca; Barbagallo, Ignazio; Tibullo, Daniele; Forte, Stefano; Zappalà, Agata; Li Volti, Giovanni

    2016-10-18

    Heme oxygenase (HO) isoforms catalyze the conversion of heme to carbon monoxide (CO) and biliverdin with a concurrent release of iron, which can drive the synthesis of ferritin for iron sequestration. Most of the studies so far were directed at evaluating the protective effect of these enzymes because of their ability to generate antioxidant and antiapoptotic molecules such as CO and bilirubin. Recent evidences are suggesting that HO may possess other important physiological functions, which are not related to its enzymatic activity and for which we would like to introduce for the first time the term "non canonical functions". Recent evidence suggest that both HO isoforms may form protein-protein interactions (i.e. cytochrome P450, adiponectin, CD91) thus serving as chaperone-like protein. In addition, truncated HO-1 isoform was localized in the nuclear compartment under certain experimental conditions (i.e. excitotoxicity, hypoxia) regulating the activity of important nuclear transcription factors (i.e. Nrf2) and DNA repair. In the present review, we discuss three potential signaling mechanisms that we refer to as the non-canonical functions of the HO isoforms: protein-protein interaction, intracellular compartmentalization, and extracellular secretion. The aim of the present review is to describe each of this mechanism and all the aspects warranting additional studies in order to unravel all the functions of the HO system.

  19. Unsaturated fatty acids induce non-canonical autophagy

    PubMed Central

    Niso-Santano, Mireia; Malik, Shoaib Ahmad; Pietrocola, Federico; Bravo-San Pedro, José Manuel; Mariño, Guillermo; Cianfanelli, Valentina; Ben-Younès, Amena; Troncoso, Rodrigo; Markaki, Maria; Sica, Valentina; Izzo, Valentina; Chaba, Kariman; Bauvy, Chantal; Dupont, Nicolas; Kepp, Oliver; Rockenfeller, Patrick; Wolinski, Heimo; Madeo, Frank; Lavandero, Sergio; Codogno, Patrice; Harper, Francis; Pierron, Gérard; Tavernarakis, Nektarios; Cecconi, Francesco; Maiuri, Maria Chiara; Galluzzi, Lorenzo; Kroemer, Guido

    2015-01-01

    To obtain mechanistic insights into the cross talk between lipolysis and autophagy, two key metabolic responses to starvation, we screened the autophagy-inducing potential of a panel of fatty acids in human cancer cells. Both saturated and unsaturated fatty acids such as palmitate and oleate, respectively, triggered autophagy, but the underlying molecular mechanisms differed. Oleate, but not palmitate, stimulated an autophagic response that required an intact Golgi apparatus. Conversely, autophagy triggered by palmitate, but not oleate, required AMPK, PKR and JNK1 and involved the activation of the BECN1/PIK3C3 lipid kinase complex. Accordingly, the downregulation of BECN1 and PIK3C3 abolished palmitate-induced, but not oleate-induced, autophagy in human cancer cells. Moreover, Becn1+/− mice as well as yeast cells and nematodes lacking the ortholog of human BECN1 mounted an autophagic response to oleate, but not palmitate. Thus, unsaturated fatty acids induce a non-canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus. PMID:25586377

  20. A comprehensive survey of non-canonical splice sites in the human transcriptome

    PubMed Central

    Parada, Guillermo E.; Munita, Roberto; Cerda, Cledi A.; Gysling, Katia

    2014-01-01

    We uncovered the diversity of non-canonical splice sites at the human transcriptome using deep transcriptome profiling. We mapped a total of 3.7 billion human RNA-seq reads and developed a set of stringent filters to avoid false non-canonical splice site detections. We identified 184 splice sites with non-canonical dinucleotides and U2/U12-like consensus sequences. We selected 10 of the herein identified U2/U12-like non-canonical splice site events and successfully validated 9 of them via reverse transcriptase-polymerase chain reaction and Sanger sequencing. Analyses of the 184 U2/U12-like non-canonical splice sites indicate that 51% of them are not annotated in GENCODE. In addition, 28% of them are conserved in mouse and 76% are involved in alternative splicing events, some of them with tissue-specific alternative splicing patterns. Interestingly, our analysis identified some U2/U12-like non-canonical splice sites that are converted into canonical splice sites by RNA A-to-I editing. Moreover, the U2/U12-like non-canonical splice sites have a differential distribution of splicing regulatory sequences, which may contribute to their recognition and regulation. Our analysis provides a high-confidence group of U2/U12-like non-canonical splice sites, which exhibit distinctive features among the total human splice sites. PMID:25123659

  1. Complete Hamiltonian analysis of cosmological perturbations at all orders II: non-canonical scalar field

    NASA Astrophysics Data System (ADS)

    Nandi, Debottam; Shankaranarayanan, S.

    2016-10-01

    In this work, we present a consistent Hamiltonian analysis of cosmological perturbations for generalized non-canonical scalar fields. In order to do so, we introduce a new phase-space variable that is uniquely defined for different non-canonical scalar fields. We also show that this is the simplest and efficient way of expressing the Hamiltonian. We extend the Hamiltonian approach of [1] to non-canonical scalar field and obtain an unique expression of speed of sound in terms of phase-space variable. In order to invert generalized phase-space Hamilton's equations to Euler-Lagrange equations of motion, we prescribe a general inversion formulae and show that our approach for non-canonical scalar field is consistent. We also obtain the third and fourth order interaction Hamiltonian for generalized non-canonical scalar fields and briefly discuss the extension of our method to generalized Galilean scalar fields.

  2. Accretion of the Moon from non-canonical impacts

    NASA Astrophysics Data System (ADS)

    Salmon, Julien; Canup, R. M.

    2013-10-01

    The generally accepted scenario for the formation of the Moon involves the impact of a Mars-size object into the proto-Earth, resulting in the formation of a disk from which the Moon accretes (Cameron and Ward 1976). In a first paper (Salmon & Canup 2012), we showed that the disks resulting from these “canonical” impacts can lead to the accretion of a 1 lunar mass object on a timescale of order 10^2 yr. Recent works have focused on alternative impact configurations: bigger impactors (Canup 2012) or higher speed impacts into a fast spinning Earth (Cuk & Stewart 2012). These impacts leave the Earth-Moon system with an angular momentum about twice that in the current system. This quantity can be made consistent with its current value if the newly formed Moon is captured for a prolonged period in the evection resonance with the Sun (Cuk & Stewart 2012). The protolunar disks that are formed from these “non-canonical” impacts are generally more massive and more compact, containing a much greater fraction of their total disk mass in the Roche-interior portion of the disk, compared to canonical impacts. We have investigated the dynamics of the accretion of the Moon from such disks. While the overall accretion process is similar to that found from disks typical of canonical impacts, the more massive, compact disks typically produce a final moon with a much larger initial eccentricity, i.e. > 0.1 vs. 10^-3 to 10^-2 in canonical disks. Such high initial eccentricities may substantially reduce the probability of capture of the Moon into the evection resonance (e.g., Touma & Wisdom 1998), which is required to lower the angular momentum of the system in the non-canonical impacts. We will discuss which disk configurations can lead to the successful formation of the Moon, and how the Moon’s initial orbital properties vary for different impact scenarios.

  3. Unbiased Mitoproteome Analyses Confirm Non-canonical RNA, Expanded Codon Translations.

    PubMed

    Seligmann, Hervé

    2016-01-01

    Proteomic MS/MS mass spectrometry detections are usually biased towards peptides cleaved by experimentally added digestion enzyme(s). Hence peptides resulting from spontaneous degradation and natural proteolysis usually remain undetected. Previous analyses of tryptic human proteome data (cleavage after K, R) detected non-canonical tryptic peptides translated according to tetra- and pentacodons (codons expanded by silent mono- and dinucleotides), and from transcripts systematically (a) deleting mono-, dinucleotides after trinucleotides (delRNAs), (b) exchanging nucleotides according to 23 bijective transformations. Nine symmetric and fourteen asymmetric nucleotide exchanges (X ↔ Y, e.g. A ↔ C; and X → Y → Z → X, e.g. A → C → G → A) produce swinger RNAs. Here unbiased reanalyses of these proteomic data detect preferentially non-canonical tryptic peptides despite assuming random cleavage. Unbiased analyses couldn't reconstruct experimental tryptic digestion if most detected non-canonical peptides were false positives. Detected non-tryptic non-canonical peptides map preferentially on corresponding, previously described non-canonical transcripts, as for tryptic non-canonical peptides. Hence unbiased analyses independently confirm previous trypsin-biased analyses that showed translations of del- and swinger RNA and expanded codons. Accounting for natural proteolysis completes trypsin-biased mitopeptidome analyses, independently confirms non-canonical transcriptions and translations.

  4. The Plasmodium falciparum exportome contains non-canonical PEXEL/HT proteins.

    PubMed

    Schulze, Jana; Kwiatkowski, Marcel; Borner, Janus; Schlüter, Hartmut; Bruchhaus, Iris; Burmester, Thorsten; Spielmann, Tobias; Pick, Christian

    2015-07-01

    The pathogenicity of Plasmodium falciparum is partly due to parasite-induced host cell modifications. These modifications are facilitated by exported P. falciparum proteins, collectively referred to as the exportome. Export of several hundred proteins is mediated by the PEXEL/HT, a protease cleavage site. The PEXEL/HT is usually comprised of five amino acids, of which R at position 1, L at position 3 and E, D or Q at position 5 are conserved and important for export. Non-canonical PEXEL/HTs with K or H at position 1 and/or I at position 3 are presently considered non-functional. Here, we show that non-canonical PEXEL/HT proteins are overrepresented in P. falciparum and other Plasmodium species. Furthermore, we show that non-canonical PEXEL/HTs can be cleaved and can promote export in both a REX3 and a GBP reporter, but not in a KAHRP reporter, indicating that non-canonical PEXEL/HTs are functional in concert with a supportive sequence environment. We then selected P. falciparum proteins with a non-canonical PEXEL/HT and show that some of these proteins are exported and that their export depends on non-canonical PEXEL/HTs. We conclude that PEXEL/HT plasticity is higher than appreciated and that non-canonical PEXEL/HT proteins cannot categorically be excluded from Plasmodium exportome predictions.

  5. Splitting K-symplectic methods for non-canonical separable Hamiltonian problems

    NASA Astrophysics Data System (ADS)

    Zhu, Beibei; Zhang, Ruili; Tang, Yifa; Tu, Xiongbiao; Zhao, Yue

    2016-10-01

    Non-canonical Hamiltonian systems have K-symplectic structures which are preserved by K-symplectic numerical integrators. There is no universal method to construct K-symplectic integrators for arbitrary non-canonical Hamiltonian systems. However, in many cases of interest, by using splitting, we can construct explicit K-symplectic methods for separable non-canonical systems. In this paper, we identify situations where splitting K-symplectic methods can be constructed. Comparative numerical experiments in three non-canonical Hamiltonian problems show that symmetric/non-symmetric splitting K-symplectic methods applied to the non-canonical systems are more efficient than the same-order Gauss' methods/non-symmetric symplectic methods applied to the corresponding canonicalized systems; for the non-canonical Lotka-Volterra model, the splitting algorithms behave better in efficiency and energy conservation than the K-symplectic method we construct via generating function technique. In our numerical experiments, the favorable energy conservation property of the splitting K-symplectic methods is apparent.

  6. Natural chymotrypsin-like-cleaved human mitochondrial peptides confirm tetra-, pentacodon, non-canonical RNA translations.

    PubMed

    Seligmann, Hervé

    2016-09-01

    Mass spectra of human mitochondrial peptides match non-canonical transcripts systematically (a) deleting mono/dinucleotides after trinucleotides (delRNA), (b) exchanging nucleotides (swinger RNA), translated according to tri, (c) tetra- and pentacodons (codons expanded by a 4th (and 5th) silent nucleotide(s)). Swinger transcriptions are 23 bijective transformations, nine symmetric (X<->Y, e.g. A<->C) and fourteen asymmetric exchanges (X->Y->Z->X, e.g. A->C->G->A). Here, proteomic analyses assuming cleavage after W,Y, F (chymotrypsin-like, for trypsinized samples) detect fewer chymotrypsinized than trypsinized peptides. Detected non-canonical peptides map preferentially on detected non-canonical RNAs for chymotrypsinized peptides, as previously found for trypsinized peptides. This suggests residual natural chymotrypsin-like digestion detectable within experimentally trypsinized peptide data. Some trypsinized peptides are detected twice, by analyses assuming trypsin, and those assuming chymotrypsin cleavages. They have higher spectra counts than peptides detected only once, meaning that abundant peptides are more frequently detected, but detection certainties resemble those for peptides detected only once. Analyses assuming 'incorrect' digestions are inadequate negative controls for digestion enzymes naturally active in biological samples. Chymotrypsin-analyses confirm non-canonical transcriptions/translations independently of results obtained assuming trypsinization, increase non-canonical peptidome coverage, indicating mitogenome-encoding of yet undetected proteins.

  7. Non-Canonical Hh Signaling in Cancer-Current Understanding and Future Directions.

    PubMed

    Gu, Dongsheng; Xie, Jingwu

    2015-08-27

    As a major regulatory pathway for embryonic development and tissue patterning, hedgehog signaling is not active in most adult tissues, but is reactivated in a number of human cancer types. A major milestone in hedgehog signaling in cancer is the Food and Drug Administration (FDA) approval of a smoothened inhibitor Vismodegib for treatment of basal cell carcinomas. Vismodegib can block ligand-mediated hedgehog signaling, but numerous additional clinical trials have failed to show significant improvements in cancer patients. Amounting evidence indicate that ligand-independent hedgehog signaling plays an essential role in cancer. Ligand-independent hedgehog signaling, also named non-canonical hedgehog signaling, generally is not sensitive to smoothened inhibitors. What we know about non-canonical hedgehog signaling in cancer, and how should we prevent its activation? In this review, we will summarize recent development of non-canonical hedgehog signaling in cancer, and will discuss potential ways to prevent this type of hedgehog signaling.

  8. Teaching old NCATs new tricks: using non-canonical amino acid tagging to study neuronal plasticity.

    PubMed

    Hinz, F I; Dieterich, D C; Schuman, E M

    2013-10-01

    The non-canonical amino acid labeling techniques BONCAT (bioorthogonal non-canonical amino acid tagging) and FUNCAT (fluorescent non-canonical amino acid tagging) enable the specific identification and visualization of newly synthesized proteins. Recently, these techniques have been applied to neuronal systems to elucidate protein synthesis dynamics during plasticity, identify stimulation-induced proteomes and subproteomes and to investigate local protein synthesis in specific subcellular compartments. The next generation of tools and applications, reviewed here, includes the development of new tags, the quantitative identification of newly synthesized proteins, the application of NCAT to whole animals, and the ability to genetically restrict NCAT labeling. These techniques will enable not only improved detection but also allow new scientific questions to be tackled.

  9. Teaching old NCATs new tricks: using non-canonical amino acid tagging to study neuronal plasticity

    PubMed Central

    Hinz, FI; Dieterich, DC; Schuman, EM

    2016-01-01

    The non-canonical amino acid labeling techniques BONCAT (bioorthogonal non-canonical amino acid tagging) and FUNCAT (fluorescent non-canonical amino acid tagging) enable the specific identification and visualization of newly synthesized proteins. Recently, these techniques have been applied to neuronal systems to elucidate protein synthesis dynamics during plasticity, identify stimulation-induced proteomes and subproteomes and to investigate local protein synthesis in specific subcellular compartments. The next generation of tools and applications, reviewed here, includes the development of new tags, the quantitative identification of newly synthesized proteins, the application of NCAT to whole animals, and the ability to genetically restrict NCAT labeling. These techniques will enable not only improved detection but also allow new scientific questions to be tackled. PMID:23938204

  10. Generalized second law of thermodynamics for non-canonical scalar field model with corrected-entropy

    NASA Astrophysics Data System (ADS)

    Das, Sudipta; Debnath, Ujjal; Mamon, Abdulla Al

    2015-10-01

    In this work, we have considered a non-canonical scalar field dark energy model in the framework of flat FRW background. It has also been assumed that the dark matter sector interacts with the non-canonical dark energy sector through some interaction term. Using the solutions for this interacting non-canonical scalar field dark energy model, we have investigated the validity of generalized second law (GSL) of thermodynamics in various scenarios using first law and area law of thermodynamics. For this purpose, we have assumed two types of horizons viz apparent horizon and event horizon for the universe and using first law of thermodynamics, we have examined the validity of GSL on both apparent and event horizons. Next, we have considered two types of entropy-corrections on apparent and event horizons. Using the modified area law, we have examined the validity of GSL of thermodynamics on apparent and event horizons under some restrictions of model parameters.

  11. Non-canonical NFκB activation promotes chemokine expression in podocytes

    PubMed Central

    Valiño-Rivas, Lara; Gonzalez-Lafuente, Laura; Sanz, Ana B.; Ruiz-Ortega, Marta; Ortiz, Alberto; Sanchez-Niño, Maria D.

    2016-01-01

    TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is expressed by podocytes and Fn14 deficiency protects from experimental proteinuric kidney disease. However, the downstream effectors of TWEAK/Fn14 in podocytes are poorly characterized. We have explored TWEAK activation of non-canonical NFκB signaling in cultured podocytes. In cultured podocytes, TWEAK increased the expression of the chemokines CCL21, CCL19 and RANTES in a time-dependent manner. The inhibitor of canonical NFκB activation parthenolide inhibited the CCL19 and the early RANTES responses, but not the CCL21 or late RANTES responses. In this regard, TWEAK induced non-canonical NFκB activation in podocytes, characterized by NFκB2/p100 processing to NFκB2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NFκB pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NFκB target in podocytes. Increased kidney Fn14 and CCL21 expression was also observed in rat proteinuric kidney disease induced by puromycin, and was localized to podocytes. In conclusion, TWEAK activates the non-canonical NFκB pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NFκB pathway should be explored as a potential therapeutic target in proteinuric kidney disease. PMID:27353019

  12. Signature and Pathophysiology of Non-canonical Pores in Voltage-Dependent Cation Channels.

    PubMed

    Held, Katharina; Voets, Thomas; Vriens, Joris

    2016-01-01

    Opening and closing of voltage-gated cation channels allows the regulated flow of cations such as Na(+), K(+), and Ca(2+) across cell membranes, which steers essential physiological processes including shaping of action potentials and triggering Ca(2+)-dependent processes. Classical textbooks describe the voltage-gated cation channels as membrane proteins with a single, central aqueous pore. In recent years, however, evidence has accumulated for the existence of additional ion permeation pathways in this group of cation channels, distinct from the central pore, which here we collectively name non-canonical pores. Whereas the first non-canonical pores were unveiled only after making specific point mutations in the voltage-sensor region of voltage-gated Na(+) and K(+) channels, recent evidence indicates that they may also be functional in non-mutated channels. Moreover, several channelopathies have been linked to mutations that cause the appearance of a non-canonical ion permeation pathway as a new pathological mechanism. This review provides an integrated overview of the biophysical properties of non-canonical pores described in voltage-dependent cation channels (KV, NaV, Cav, Hv1, and TRPM3) and of the (patho)physiological impact of opening of such pores.

  13. Multiple site-selective insertions of non-canonical amino acids into sequence-repetitive polypeptides

    PubMed Central

    Wu, I-Lin; Patterson, Melissa A.; Carpenter Desai, Holly E.; Mehl, Ryan A.; Giorgi, Gianluca

    2013-01-01

    A simple and efficient method is described for introduction of non-canonical amino acids at multiple, structurally defined sites within recombinant polypeptide sequences. E. coli MRA30, a bacterial host strain with attenuated activity for release factor 1 (RF1), is assessed for its ability to support the incorporation of a diverse range of non-canonical amino acids in response to multiple encoded amber (TAG) codons within genetic templates derived from superfolder GFP and an elastin-mimetic protein polymer. Suppression efficiency and isolated protein yield were observed to depend on the identity of the orthogonal aminoacyl-tRNA synthetase/tRNACUA pair and the non-canonical amino acid substrate. This approach afforded elastin-mimetic protein polymers containing non-canonical amino acid derivatives at up to twenty-two positions within the repeat sequence with high levels of substitution. The identity and position of the variant residues was confirmed by mass spectrometric analysis of the full-length polypeptides and proteolytic cleavage fragments resulting from thermolysin digestion. The accumulated data suggest that this multi-site suppression approach permits the preparation of protein-based materials in which novel chemical functionality can be introduced at precisely defined positions within the polypeptide sequence. PMID:23625817

  14. Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.

    PubMed

    Franco, Claudio A; Jones, Martin L; Bernabeu, Miguel O; Vion, Anne-Clemence; Barbacena, Pedro; Fan, Jieqing; Mathivet, Thomas; Fonseca, Catarina G; Ragab, Anan; Yamaguchi, Terry P; Coveney, Peter V; Lang, Richard A; Gerhardt, Holger

    2016-02-04

    Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

  15. Non-Canonical Roles of Dengue Virus Non-Structural Proteins.

    PubMed

    Zeidler, Julianna D; Fernandes-Siqueira, Lorena O; Barbosa, Glauce M; Da Poian, Andrea T

    2017-03-13

    The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. These non-canonical functions probably have evolved independently and may serve as the base to the development of specific therapies for each of those diseases. Here it is discussed what is currently known about the non-canonical roles of dengue virus (DENV) non-structural proteins (NSPs), which may account for some of the effects specifically observed in DENV infection, but not in other members of the Flaviviridae family. This review explores how DENV NSPs contributes to the physiopathology of dengue, evasion from host immunity, metabolic changes, and redistribution of cellular components during infection.

  16. Non-Canonical Roles of Dengue Virus Non-Structural Proteins

    PubMed Central

    Zeidler, Julianna D.; Fernandes-Siqueira, Lorena O.; Barbosa, Glauce M.; Da Poian, Andrea T.

    2017-01-01

    The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. These non-canonical functions probably have evolved independently and may serve as the base to the development of specific therapies for each of those diseases. Here it is discussed what is currently known about the non-canonical roles of dengue virus (DENV) non-structural proteins (NSPs), which may account for some of the effects specifically observed in DENV infection, but not in other members of the Flaviviridae family. This review explores how DENV NSPs contributes to the physiopathology of dengue, evasion from host immunity, metabolic changes, and redistribution of cellular components during infection. PMID:28335410

  17. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells.

    PubMed

    Stefater, James A; Lewkowich, Ian; Rao, Sujata; Mariggi, Giovanni; Carpenter, April C; Burr, Adam R; Fan, Jieqing; Ajima, Rieko; Molkentin, Jeffery D; Williams, Bart O; Wills-Karp, Marsha; Pollard, Jeffrey W; Yamaguchi, Terry; Ferrara, Napoleone; Gerhardt, Holger; Lang, Richard A

    2011-05-29

    Myeloid cells are a feature of most tissues. Here we show that during development, retinal myeloid cells (RMCs) produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in RMCs of the Wnt ligand transporter Wntless results in increased angiogenesis in the deeper layers. We also show that mutation of Wnt5a and Wnt11 results in increased angiogenesis and that these ligands elicit RMC responses via a non-canonical Wnt pathway. Using cultured myeloid-like cells and RMC somatic deletion of Flt1, we show that an effector of Wnt-dependent suppression of angiogenesis by RMCs is Flt1, a naturally occurring inhibitor of vascular endothelial growth factor (VEGF). These findings indicate that resident myeloid cells can use a non-canonical, Wnt-Flt1 pathway to suppress angiogenic branching.

  18. Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer

    PubMed Central

    Lawrence, Cortney L.; Baldwin, Albert S.

    2016-01-01

    Enhancer of zeste homology 2 (EZH2) is the methyltransferase component of the polycomb repressive complex (PRC2) which represses gene transcription via histone H3 trimethylation at lysine 23 (H3K27me3). EZH2 activity has been linked with oncogenesis where it is thought to block expression of certain tumor suppressors. Relative to a role in cancer, EZH2 functions to promote self-renewal and has been shown to be important for the tumor-initiating cell (TIC) phenotype in breast cancer. Recently a non-canonical role for EZH2 has been identified where it promotes transcriptional activation of certain genes. Here we show that EZH2, through a methyltransferase-independent mechanism, promotes the transcriptional activation of the non-canonical NF-κB subunit RelB to drive self-renewal and the TIC phenotype of triple-negative breast cancer cells. PMID:27764181

  19. Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis.

    PubMed

    Neuman, Nicole A; Henske, Elizabeth Petri

    2011-04-01

    The protein products of the tuberous sclerosis complex (TSC) genes, TSC1 and TSC2, form a complex, which inhibits the small G-protein, Ras homolog enriched in brain (Rheb). The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb. Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR. We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

  20. Swiss army knives: non-canonical functions of nuclear Drosha and Dicer.

    PubMed

    Burger, Kaspar; Gullerova, Monika

    2015-07-01

    The RNase III enzymes Drosha and Dicer are essential for the production of small non-coding RNAs (ncRNAs). In canonical RNAi, microRNAs (miRNAs) regulate gene expression by post-transcriptional gene silencing. In non-canonical RNAi, nuclear RNAi factors generate small ncRNAs that are essential for transcriptional gene silencing. Recent evidence points to the existence of additional non-canonical nuclear RNAi functions in various organisms, including in genome maintenance and editing, as well as in DNA repair. Drosha and Dicer directly regulate gene expression and RNA metabolism at different stages, such as transcriptional initiation and termination, and the processing of various RNA species, including pre-mRNAs. Furthermore, Dicer isoforms were recently discovered and attributed with roles in apoptosis, development and disease.

  1. Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation.

    PubMed

    Yuan, Xue; Cao, Jay; He, Xiaoning; Serra, Rosa; Qu, Jun; Cao, Xu; Yang, Shuying

    2016-03-21

    Intraflagellar transport proteins (IFT) are required for hedgehog (Hh) signalling transduction that is essential for bone development, however, how IFT proteins regulate Hh signalling in osteoblasts (OBs) remains unclear. Here we show that deletion of ciliary IFT80 in OB precursor cells (OPC) in mice results in growth retardation and markedly decreased bone mass with impaired OB differentiation. Loss of IFT80 blocks canonical Hh-Gli signalling via disrupting Smo ciliary localization, but elevates non-canonical Hh-Gαi-RhoA-stress fibre signalling by increasing Smo and Gαi binding. Inhibition of RhoA and ROCK activity partially restores osteogenic differentiation of IFT80-deficient OPCs by inhibiting non-canonical Hh-RhoA-Cofilin/MLC2 signalling. Cytochalasin D, an actin destabilizer, dramatically restores OB differentiation of IFT80-deficient OPCs by disrupting actin stress fibres and promoting cilia formation and Hh-Gli signalling. These findings reveal that IFT80 is required for OB differentiation by balancing between canonical Hh-Gli and non-canonical Hh-Gαi-RhoA pathways and highlight IFT80 as a therapeutic target for craniofacial and skeletal abnormalities.

  2. Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation

    PubMed Central

    Yuan, Xue; Cao, Jay; He, Xiaoning; Serra, Rosa; Qu, Jun; Cao, Xu; Yang, Shuying

    2016-01-01

    Intraflagellar transport proteins (IFT) are required for hedgehog (Hh) signalling transduction that is essential for bone development, however, how IFT proteins regulate Hh signalling in osteoblasts (OBs) remains unclear. Here we show that deletion of ciliary IFT80 in OB precursor cells (OPC) in mice results in growth retardation and markedly decreased bone mass with impaired OB differentiation. Loss of IFT80 blocks canonical Hh–Gli signalling via disrupting Smo ciliary localization, but elevates non-canonical Hh–Gαi–RhoA–stress fibre signalling by increasing Smo and Gαi binding. Inhibition of RhoA and ROCK activity partially restores osteogenic differentiation of IFT80-deficient OPCs by inhibiting non-canonical Hh–RhoA–Cofilin/MLC2 signalling. Cytochalasin D, an actin destabilizer, dramatically restores OB differentiation of IFT80-deficient OPCs by disrupting actin stress fibres and promoting cilia formation and Hh–Gli signalling. These findings reveal that IFT80 is required for OB differentiation by balancing between canonical Hh–Gli and non-canonical Hh–Gαi–RhoA pathways and highlight IFT80 as a therapeutic target for craniofacial and skeletal abnormalities. PMID:26996322

  3. Drosophila melanogaster Hedgehog cooperates with Frazzled to guide axons through a non-canonical signalling pathway.

    PubMed

    Ricolo, Delia; Butí, Elisenda; Araújo, Sofia J

    2015-08-01

    We report that the morphogen Hedgehog (Hh) is an axonal chemoattractant in the midline of Drosophila melanogaster embryos. Hh is present in the ventral nerve cord during axonal guidance and overexpression of hh in the midline causes ectopic midline crossing of FasII-positive axonal tracts. In addition, we show that Hh influences axonal guidance via a non-canonical signalling pathway dependent on Ptc. Our results reveal that the Hh pathway cooperates with the Netrin/Frazzled pathway to guide axons through the midline in invertebrates.

  4. Dynamical Characteristics of a Non-canonical Scalar-Torsion Model of Dark Energy

    NASA Astrophysics Data System (ADS)

    Banijamali, A.; Ghasemi, E.

    2016-08-01

    In this paper, we analyze the phase-space of a model of dark energy in which a non-canonical scalar field (tachyon) non-minimally coupled to torsion scalar in the framework of teleparallelism. Scalar field potential and non-minimal coupling function are chosen as V( ϕ) = V 0 ϕ n and f( ϕ) = ϕ N , respectively. We obtain a critical point that behaves like a stable or saddle point depending on the values of N and n. Additionally we find an unstable critical line. We have shown such a behavior of critical points using numerical computations and phase-space trajectories explicitly.

  5. Sodium tungstate activates glycogen synthesis through a non-canonical mechanism involving G-proteins.

    PubMed

    Zafra, Delia; Nocito, Laura; Domínguez, Jorge; Guinovart, Joan J

    2013-01-31

    Tungstate treatment ameliorates experimental diabetes by increasing liver glycogen deposition through an as yet unidentified mechanism. The signalling mechanism of tungstate was studied in CHOIR cells and primary cultured hepatocytes. This compound exerted its pro-glycogenic effects through a new G-protein-dependent and Tyr-Kinase Receptor-independent mechanism. Chemical or genetic disruption of G-protein signalling prevented the activation of the Ras/ERK cascade and the downstream induction of glycogen synthesis caused by tungstate. Thus, these findings unveil a novel non-canonical signalling pathway that leads to the activation of glycogen synthesis and that could be exploited as an approach to treat diabetes.

  6. Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

    PubMed Central

    Hydbring, Per; Malumbres, Marcos; Sicinski, Piotr

    2016-01-01

    The role of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression is well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important roles in other cellular processes such as transcription, DNA damage repair, the control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or by CDKs, independent of their respective cell cycle partners, suggesting a substantial divergence in the function of these proteins during evolution. PMID:27033256

  7. Rational design of a non-canonical "sticky-ended" collagen triple helix.

    PubMed

    Jalan, Abhishek A; Jochim, Katherine A; Hartgerink, Jeffrey D

    2014-05-28

    In a canonical collagen triple helix, three peptides self-assemble into a supercoiled motif with a one-amino-acid offset between the peptide chains. Design of triple helices that contain more than one residue offset is lucrative, as it leaves the non-covalent interactions unsatisfied at the termini and renders the termini "sticky" to further self-assemble into collagen-like nanofibers. Here we use lysine-glutamate axial salt-bridges to design a heterotrimeric collagen triple helix, ABC-1, containing a non-canonical offset of four residues between the peptide chains. The four-residue offset is necessary to prevent aggregation, which would prevent characterization of the non-canonical chain arrangement at the molecular level by NMR spectroscopy. A second heterotrimer, ABC-2, also stabilized by axial salt-bridges, is designed containing a canonical one-amino-acid offset to facilitate comparison of structure and stability by CD and NMR. ABC-1 and ABC-2 demonstrate our ability to modulate chain offset in a collagen triple helix. This lays the groundwork to design longer, and therefore stickier, offsets allowing access to a new class of collagen-related nanostructures.

  8. Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling

    PubMed Central

    Franco, Claudio A; Jones, Martin L; Bernabeu, Miguel O; Vion, Anne-Clemence; Barbacena, Pedro; Fan, Jieqing; Mathivet, Thomas; Fonseca, Catarina G; Ragab, Anan; Yamaguchi, Terry P; Coveney, Peter V; Lang, Richard A; Gerhardt, Holger

    2016-01-01

    Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus. DOI: http://dx.doi.org/10.7554/eLife.07727.001 PMID:26845523

  9. Unambiguous generalization effects after treatment of non-canonical sentence production in German agrammatism.

    PubMed

    Stadie, Nicole; Schröder, Astrid; Postler, Jenny; Lorenz, Antje; Swoboda-Moll, Maria; Burchert, Frank; De Bleser, Ria

    2008-03-01

    Agrammatism is-among others, characterized by a deficit in producing grammatical structures. Of specific difficulty is the utilization of complex, non-canonical sentence structures (e.g. object-questions, passives, object-clefts). Several studies have documented positive effects when applying a specific treatment protocol in terms of increasingly correct production of target complex sentence structures with some variance in generalization patterns noted across individuals. The objective of this intervention study was to evaluate an intervention program focussing on the production of non-canonical sentences. Hypotheses about the occurrence of treatment effects were formulated on the basis of syntactic complexity, referring to the amount of syntactic phrase structures necessary to generate specific German sentence structures. A multiple single case study with seven agrammatic participants was applied, each participant receiving training in the production of object-relative-clauses and who-questions. The investigation was designed to unambiguously evaluate for each individual, structure specific and generalized learning effects with respect to the production of object-relative-clauses, who-questions and passive sentences. Results showed significant improvements for all sentences types. This outcome is considered within methodological issues of treatment studies. Theoretical and clinical implications are discussed.

  10. Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway

    PubMed Central

    Fleury, Audrey; Hoch, Lucile; Martinez, M. Carmen; Faure, Hélène; Taddei, Maurizio; Petricci, Elena; Manetti, Fabrizio; Girard, Nicolas; Mann, André; Jacques, Caroline; Larghero, Jérôme; Ruat, Martial; Andriantsitohaina, Ramaroson; Le Lay, Soazig

    2016-01-01

    Hedgehog (Hh) is a critical regulator of adipogenesis. Extracellular vesicles are natural Hh carriers, as illustrated by activated/apoptotic lymphocytes specifically shedding microparticles (MP) bearing the morphogen (MPHh+). We show that MPHh+ inhibit adipocyte differentiation and orientate mesenchymal stem cells towards a pro-osteogenic program. Despite a Smoothened (Smo)-dependency, MPHh+ anti-adipogenic effects do not activate a canonical Hh signalling pathway in contrast to those elicited either by the Smo agonist SAG or recombinant Sonic Hedgehog. The Smo agonist GSA-10 recapitulates many of the hallmarks of MPHh+ anti-adipogenic effects. The adipogenesis blockade induced by MPHh+ and GSA-10 was abolished by the Smo antagonist LDE225. We further elucidate a Smo/Lkb1/Ampk axis as the non-canonical Hh pathway used by MPHh+ and GSA-10 to inhibit adipocyte differentiation. Our results highlight for the first time the ability of Hh-enriched MP to signal via a non-canonical pathway opening new perspectives to modulate fat development. PMID:27010359

  11. Translocation of Non-Canonical Polypeptides into Cells Using Protective Antigen

    PubMed Central

    Rabideau, Amy E.; Liao, Xiaoli; Akçay, Gizem; Pentelute, Bradley L.

    2015-01-01

    A variety of pathogenic bacteria infect host eukaryotic cells using protein toxins, which enter the cytosol and exert their cytotoxic effects. Anthrax lethal toxin, for example, utilizes the membrane-spanning translocase, protective antigen (PA) pore, to deliver the protein toxin lethal factor (LF) from the endosome into the cytosol of cells. Previous work has investigated the delivery of natural peptides and enzymatic domains appended to the C-terminus of the PA-binding domain of lethal factor (LFN) into the cytosol via PA pore. Here, we move beyond natural amino acids and systematically investigate the translocation of polypeptide cargo containing non-canonical amino acids and functionalities through PA pore. Our results indicate translocation is not perturbed with alterations to the peptide backbone or side-chain. Moreover, despite their structural complexity, we found that the small molecule drugs, doxorubicin and monomethyl auristatin F (MMAF) translocated efficiently through PA pore. However, we found cyclic peptides and the small molecule drug docetaxel abrogated translocation due to their large size and structural rigidity. For cargos that reached the cytosol, we demonstrated that each remained intact after translocation. These studies show PA is capable of translocating non-canonical cargo provided it is in a conformational state conducive for passage through the narrow pore. PMID:26178180

  12. Ptk7 and Mcc, Unfancied Components in Non-Canonical Wnt Signaling and Cancer

    PubMed Central

    Dunn, Norris Ray; Tolwinski, Nicholas S.

    2016-01-01

    Human development uses a remarkably small number of signal transduction pathways to organize vastly complicated tissues. These pathways are commonly associated with disease in adults if activated inappropriately. One such signaling pathway, Wnt, solves the too few pathways conundrum by having many alternate pathways within the Wnt network. The main or “canonical” Wnt pathway has been studied in great detail, and among its numerous downstream components, several have been identified as drug targets that have led to cancer treatments currently in clinical trials. In contrast, the non-canonical Wnt pathways are less well characterized, and few if any possible drug targets exist to tackle cancers caused by dysregulation of these Wnt offshoots. In this review, we focus on two molecules—Protein Tyrosine Kinase 7 (Ptk7) and Mutated in Colorectal Cancer (Mcc)—that do not fit perfectly into the non-canonical pathways described to date and whose roles in cancer are ill defined. We will summarize work from our laboratories as well as many others revealing unexpected links between these two proteins and Wnt signaling both in cancer progression and during vertebrate and invertebrate embryonic development. We propose that future studies focused on delineating the signaling machinery downstream of Ptk7 and Mcc will provide new, hitherto unanticipated drug targets to combat cancer metastasis. PMID:27438854

  13. Incorporation of non-canonical amino acids into the developing murine proteome

    PubMed Central

    Calve, Sarah; Witten, Andrew J.; Ocken, Alexander R.; Kinzer-Ursem, Tamara L.

    2016-01-01

    Analysis of the developing proteome has been complicated by a lack of tools that can be easily employed to label and identify newly synthesized proteins within complex biological mixtures. Here, we demonstrate that the methionine analogs azidohomoalanine and homopropargylglycine can be globally incorporated into the proteome of mice through facile intraperitoneal injections. These analogs contain bio-orthogonal chemical handles to which fluorescent tags can be conjugated to identify newly synthesized proteins. We show these non-canonical amino acids are incorporated into various tissues in juvenile mice and in a concentration dependent manner. Furthermore, administration of these methionine analogs to pregnant dams during a critical stage of murine development, E10.5–12.5 when many tissues are assembling, does not overtly disrupt development as assessed by proteomic analysis and normal parturition and growth of pups. This successful demonstration that non-canonical amino acids can be directly administered in vivo will enable future studies that seek to characterize the murine proteome during growth, disease and repair. PMID:27572480

  14. Canonical and non-canonical VEGF pathways: New developments in biology and signal transduction

    PubMed Central

    Domigan, Courtney K.; Ziyad, Safiyyah; Iruela-Arispe, M. Luisa

    2014-01-01

    The last five years have witnessed a significant expansion in our understanding of VEGF signaling. In particular, the process of canonical activation of VEGFR tyrosine kinases by homodimeric VEGF molecules have now been broadened by the realization that heterodimeric ligands and receptors are also active participants in the signaling process. While heterodimer receptors were described two decades ago, their impact, along with the effect of additional cell surface partners and novel autocrine VEGF signaling pathways, are only now starting to be clarified. Furthermore, ligand-independent signaling (non-canonical) has been identified which occurs through galectin and gremlin binding, and upon rise of intracellular levels of reactive oxygen species. Activation of the VEGF receptors in the absence of ligand holds immediate implications for therapeutic approaches that exclusively target VEGF. The present review provides a concise summary of the recent developments in both canonical and non-canonical VEGF signaling and places these findings in perspective to their potential clinical and biological ramifications. PMID:25278287

  15. Hedgehog Signaling Non-Canonical Activated by Pro-Inflammatory Cytokines in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Wang, Yuqiong; Jin, Gang; Li, Quanjiang; Wang, Zhiping; Hu, Weimin; Li, Ping; Li, Shude; Wu, Hongyu; Kong, Xiangyu; Gao, Jun; Li, Zhaoshen

    2016-01-01

    Hedgehog(HH) pathway is found to be activated through a manner of canonical, or the non-canonical HH pathways. Distinct hyperplasia stroma around tumor cells is supposed to express pro-inflammatory cytokines abundantly, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), etc. in pancreatic ductal adenocarcinoma (PDAC) tissues. In this study we observed the effects of TNF-α and IL-1β on HH pathway activation in PDAC cells, and explored their activation manners. Our results showed that pro-inflammatory cytokines, TNF-α and IL-1β, could up-regulate the expression of GLI1 gene, increase its nuclear protein expression and promote malignant cell behaviors including migration, invasion, epithelial-mesenchymal transition (EMT) and drug resistance as well. Moreover, GLI1 promoter-reporter assay in combination with blocking either NF-κB or Smoothened (SMO) suggested that TNF-α and IL-1β could transcriptionally up-regulate expression of GLI1 completely via NF-κB, whereas ablation of SMO could not completely attenuate the regulation effects of TNF-α and IL-1β on GLI1 expression. Collectively, our results indicated that TNF-α and IL-1β in hyperplasia stroma can promote the PDAC cell development by activating HH pathway, through both the canonical and non-canonical HH activation ways. PMID:27877222

  16. Canonical and non-canonical Hedgehog signalling and the control of metabolism

    PubMed Central

    Teperino, Raffaele; Aberger, Fritz; Esterbauer, Harald; Riobo, Natalia; Pospisilik, John Andrew

    2014-01-01

    Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease. PMID:24862854

  17. A non-canonical landscape of the microRNA system

    PubMed Central

    Cipolla, Gabriel A.

    2014-01-01

    Microribonucleic acids, best known as microRNAs or miRNAs, are small, non-coding RNAs with important regulatory roles in eukaryotic cells. Here, I present a broad review on highly relevant but generally non-depicted features of miRNAs, among which stand out the non-conventional miRNA seed sites, the unusual messenger RNA (mRNA) target regions, the non-canonical miRNA-guided mechanisms of gene expression regulation, and the recently identified new class of miRNA ligands. Furthermore, I address the miRNA uncommon genomic location, transcription, and subcellular localization. Altogether, these unusual features and roles place the miRNA system as a very diverse, complex, and intriguing biological mechanism. PMID:25295056

  18. Expanding the genetic code of Salmonella with non-canonical amino acids

    PubMed Central

    Gan, Qinglei; Lehman, Brent P.; Bobik, Thomas A.; Fan, Chenguang

    2016-01-01

    The diversity of non-canonical amino acids (ncAAs) endows proteins with new features for a variety of biological studies and biotechnological applications. The genetic code expansion strategy, which co-translationally incorporates ncAAs into specific sites of target proteins, has been applied in many organisms. However, there have been only few studies on pathogens using genetic code expansion. Here, we introduce this technique into the human pathogen Salmonella by incorporating p-azido-phenylalanine, benzoyl-phenylalanine, acetyl-lysine, and phosphoserine into selected Salmonella proteins including a microcompartment shell protein (PduA), a type III secretion effector protein (SteA), and a metabolic enzyme (malate dehydrogenase), and demonstrate practical applications of genetic code expansion in protein labeling, photocrosslinking, and post-translational modification studies in Salmonella. This work will provide powerful tools for a wide range of studies on Salmonella. PMID:28008993

  19. Insider trading: Extracellular matrix proteins and their non-canonical intracellular roles.

    PubMed

    Hellewell, Andrew L; Adams, Josephine C

    2016-01-01

    In metazoans, the extracellular matrix (ECM) provides a dynamic, heterogeneous microenvironment that has important supportive and instructive roles. Although the primary site of action of ECM proteins is extracellular, evidence is emerging for non-canonical intracellular roles. Examples include osteopontin, thrombospondins, IGF-binding protein 3 and biglycan, and relate to roles in transcription, cell-stress responses, autophagy and cancer. These findings pose conceptual problems on how proteins signalled for secretion can be routed to the cytosol or nucleus, or can function in environments with diverse redox, pH and ionic conditions. We review evidence for intracellular locations and functions of ECM proteins, and current knowledge of the mechanisms by which they may enter intracellular compartments. We evaluate the experimental methods that are appropriate to obtain rigorous evidence for intracellular localisation and function. Better insight into this under-researched topic is needed to decipher the complete spectrum of physiological and pathological roles of ECM proteins.

  20. Promiscuous Mutations Activate the Non-Canonical NF-kB Pathway in Multiple Myeloma

    PubMed Central

    Keats, Jonathan J.; Fonseca, Rafael; Chesi, Marta; Schop, Roelandt; Baker, Angela; Chng, Wee-Joo; Van Wier, Scott; Tiedemann, Rodger; Shi, Chang-Xin; Sebag, Michael; Braggio, Esteban; Henry, Travis; Zhu, Yuan-Xiao; Fogle, Homer; Price-Troska, Tammy; Ahmann, Gregory; Mancini, Catherine; Brents, Leslie A.; Kumar, Shaji; Greipp, Philip; Dispenzieri, Angela; Bryant, Barb; Mulligan, George; Bruhn, Laurakay; Barrett, Michael; Valdez, Riccardo; Trent, Jeff; Stewart, A. Keith; Carpten, John; Bergsagel, P. Leif

    2007-01-01

    Summary Activation of NF-kB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the non-canonical NF-kB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kB pathway in the pathogenesis of multiple myeloma. PMID:17692805

  1. A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish

    NASA Astrophysics Data System (ADS)

    Alcaraz-Pérez, Francisca; García-Castillo, Jesús; García-Moreno, Diana; López-Muñoz, Azucena; Anchelin, Monique; Angosto, Diego; Zon, Leonard I.; Mulero, Victoriano; Cayuela, María L.

    2014-02-01

    Dyskeratosis congenita (DC) is an inherited disorder with mutations affecting telomerase or telomeric proteins. DC patients usually die of bone marrow failure. Here we show that genetic depletion of the telomerase RNA component (TR) in the zebrafish results in impaired myelopoiesis, despite normal development of haematopoietic stem cells (HSCs). The neutropenia caused by TR depletion is independent of telomere length and telomerase activity. Genetic analysis shows that TR modulates the myeloid-erythroid fate decision by controlling the levels of the master myeloid and erythroid transcription factors spi1 and gata1, respectively. The alteration in spi1 and gata1 levels occurs through stimulation of gcsf and mcsf. Our model of TR deficiency in the zebrafish illuminates the non-canonical roles of TR, and could establish therapeutic targets for DC.

  2. XEDAR activates the non-canonical NF-κB pathway

    SciTech Connect

    Verhelst, Kelly; Gardam, Sandra; Borghi, Alice; Kreike, Marja; Carpentier, Isabelle; Beyaert, Rudi

    2015-09-18

    Members of the tumor necrosis factor receptor (TNFR) superfamily are involved in a number of physiological and pathological responses by activating a wide variety of intracellular signaling pathways. The X-linked ectodermal dysplasia receptor (XEDAR; also known as EDA2R or TNFRSF27) is a member of the TNFR superfamily that is highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2), a member of the TNF family that is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Although XEDAR was first described in the year 2000, its function and molecular mechanism of action is still largely unclear. XEDAR has been reported to activate canonical nuclear factor κB (NF-κB) signaling and mitogen-activated protein (MAP) kinases. Here we report that XEDAR is also able to trigger the non-canonical NF-κB pathway, characterized by the processing of p100 (NF-κB2) into p52, followed by nuclear translocation of p52 and RelB. We provide evidence that XEDAR-induced p100 processing relies on the binding of XEDAR to TRAF3 and TRAF6, and requires the kinase activity of NIK and IKKα. We also show that XEDAR stimulation results in NIK accumulation and that p100 processing is negatively regulated by TRAF3, cIAP1 and A20. - Highlights: • XEDAR activates the non-canonical NF-κB pathway. • XEDAR-induced processing of p100 depends on XEDAR interaction with TRAF3 and TRAF6. • XEDAR-induced processing of p100 depends on NIK and IKKα activity. • Overexpression of XEDAR leads to NIK accumulation. • XEDAR-induced processing of p100 is negatively regulated by TRAF3 cIAP1 and A20.

  3. Linkage-specific conformational ensembles of non-canonical polyubiquitin chains

    PubMed Central

    Castañeda, Carlos A.; Chaturvedi, Apurva; Camara, Christina M.; Curtis, Joseph E.; Krueger, Susan; Fushman, David

    2015-01-01

    Polyubiquitination is a critical protein post-translational modification involved in a variety of processes in eukaryotic cells. The molecular basis for selective recognition of the polyubiquitin signals by cellular receptors is determined by the conformations polyubiquitin chains adopt; this has been demonstrated for K48- and K63-linked chains. Recent studies of the so-called non-canonical chains (linked via K6, K11, K27, K29, or K33) suggest they play important regulatory roles in growth, development, and immune system pathways, but biophysical studies are needed to elucidate the physical/structural basis of their interactions with receptors. A first step towards this goal is characterization of the conformations these chains adopt in solution. We assembled diubiquitins (Ub2) comprised of every lysine linkage. Using solution NMR measurements, small-angle neutron scattering (SANS), and in silico ensemble generation, we determined population-weighted conformational ensembles that shed light on the structure and dynamics of the non-canonical polyubiquitin chains. We found that polyubiquitin is conformationally heterogeneous, and each chain type exhibits unique conformational ensembles. For example, K6-Ub2 and K11-Ub2 (at physiological salt concentration) are in dynamic equilibrium between at least two conformers, where one exhibits a unique Ub/Ub interface, distinct from that observed in K48-Ub2 but similar to crystal structures of these chains. Conformers for K29-Ub2 and K33-Ub2 resemble recent crystal structures in the ligand-bound state. Remarkably, a number of diubiquitins adopt conformers similar to K48-Ub2 or K63-Ub2, suggesting potential overlap of biological function among different lysine linkages. These studies highlight the potential power of determining function from elucidation of conformational states. PMID:26422168

  4. Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications in In Vivo Imaging

    PubMed Central

    Grinstead, Kristen M.; Rowe, Laura; Ensor, Charles M.; Joel, Smita; Daftarian, Pirouz; Dikici, Emre; Zingg, Jean-Marc; Daunert, Sylvia

    2016-01-01

    The increased importance of in vivo diagnostics has posed new demands for imaging technologies. In that regard, there is a need for imaging molecules capable of expanding the applications of current state-of-the-art imaging in vivo diagnostics. To that end, there is a desire for new reporter molecules capable of providing strong signals, are non-toxic, and can be tailored to diagnose or monitor the progression of a number of diseases. Aequorin is a non-toxic photoprotein that can be used as a sensitive marker for bioluminescence in vivo imaging. The sensitivity of aequorin is due to the fact that bioluminescence is a rare phenomenon in nature and, therefore, it does not suffer from autofluorescence, which contributes to background emission. Emission of bioluminescence in the blue-region of the spectrum by aequorin only occurs when calcium, and its luciferin coelenterazine, are bound to the protein and trigger a biochemical reaction that results in light generation. It is this reaction that endows aequorin with unique characteristics, making it ideally suited for a number of applications in bioanalysis and imaging. Herein we report the site-specific incorporation of non-canonical or non-natural amino acids and several coelenterazine analogues, resulting in a catalog of 72 cysteine-free, aequorin variants which expand the potential applications of these photoproteins by providing several red-shifted mutants better suited to use in vivo. In vivo studies in mouse models using the transparent tissue of the eye confirmed the activity of the aequorin variants incorporating L-4-iodophehylalanine and L-4-methoxyphenylalanine after injection into the eye and topical addition of coelenterazine. The signal also remained localized within the eye. This is the first time that aequorin variants incorporating non-canonical amino acids have shown to be active in vivo and useful as reporters in bioluminescence imaging. PMID:27367859

  5. The non-canonical BMP and Wnt/β-catenin signaling pathways orchestrate early tooth development.

    PubMed

    Yuan, Guohua; Yang, Guobin; Zheng, Yuqian; Zhu, Xiaojing; Chen, Zhi; Zhang, Zunyi; Chen, YiPing

    2015-01-01

    BMP and Wnt signaling pathways play a crucial role in organogenesis, including tooth development. Despite extensive studies, the exact functions, as well as if and how these two pathways act coordinately in regulating early tooth development, remain elusive. In this study, we dissected regulatory functions of BMP and Wnt pathways in early tooth development using a transgenic noggin (Nog) overexpression model (K14Cre;pNog). It exhibits early arrested tooth development, accompanied by reduced cell proliferation and loss of odontogenic fate marker Pitx2 expression in the dental epithelium. We demonstrated that overexpression of Nog disrupted BMP non-canonical activity, which led to a dramatic reduction of cell proliferation rate but did not affect Pitx2 expression. We further identified a novel function of Nog by inhibiting Wnt/β-catenin signaling, causing loss of Pitx2 expression. Co-immunoprecipitation and TOPflash assays revealed direct binding of Nog to Wnts to functionally prevent Wnt/β-catenin signaling. In situ PLA and immunohistochemistry on Nog mutants confirmed in vivo interaction between endogenous Nog and Wnts and modulation of Wnt signaling by Nog in tooth germs. Genetic rescue experiments presented evidence that both BMP and Wnt signaling pathways contribute to cell proliferation regulation in the dental epithelium, with Wnt signaling also controlling the odontogenic fate. Reactivation of both BMP and Wnt signaling pathways, but not of only one of them, rescued tooth developmental defects in K14Cre;pNog mice, in which Wnt signaling can be substituted by transgenic activation of Pitx2. Our results reveal the orchestration of non-canonical BMP and Wnt/β-catenin signaling pathways in the regulation of early tooth development.

  6. The non-canonical Wnt receptor Ryk regulates hematopoietic stem cell repopulation in part by controlling proliferation and apoptosis

    PubMed Central

    Famili, Farbod; Perez, Laura Garcia; Naber, Brigitta AE; Noordermeer, Jasprina N; Fradkin, Lee G; Staal, Frank JT

    2016-01-01

    The development of blood and immune cells requires strict control by various signaling pathways in order to regulate self-renewal, differentiation and apoptosis in stem and progenitor cells. Recent evidence indicates critical roles for the canonical and non-canonical Wnt pathways in hematopoiesis. The non-canonical Wnt pathway is important for establishment of cell polarity and cell migration and regulates apoptosis in the thymus. We here investigate the role of the non-canonical Wnt receptor Ryk in hematopoiesis and lymphoid development. We show that there are dynamic changes in Ryk expression during development and in different hematopoietic tissues. Functionally, Ryk regulates NK cell development in a temporal fashion. Moreover, Ryk-deficient mice show diminished, but not absent self-renewal of hematopoietic stem cells (HSC), via effects on mildly increased proliferation and apoptosis. Thus, Ryk deficiency in HSCs from fetal liver reduces their quiescence, leading to proliferation-induced apoptosis and decreased self-renewal. PMID:27882948

  7. Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells

    PubMed Central

    Hartlerode, Andrea J.; Rajendran, Anbazhagan; Manis, John P.

    2016-01-01

    A proportion of homologous recombination (HR) events in mammalian cells resolve by “long tract” gene conversion, reflecting copying of several kilobases from the donor sister chromatid prior to termination. Cells lacking the major hereditary breast/ovarian cancer predisposition genes, BRCA1 or BRCA2, or certain other HR-defective cells, reveal a bias in favor of long tract gene conversion, suggesting that this aberrant HR outcome might be connected with genomic instability. If termination of gene conversion occurs in regions lacking homology with the second end of the break, the normal mechanism of HR termination by annealing (i.e., homologous pairing) is not available and termination must occur by as yet poorly defined non-canonical mechanisms. Here we use a previously described HR reporter to analyze mechanisms of non-canonical termination of long tract gene conversion in mammalian cells. We find that non-canonical HR termination can occur in the absence of the classical non-homologous end joining gene XRCC4. We observe obligatory use of microhomology (MH)-mediated end joining and/or nucleotide addition during rejoining with the second end of the break. Notably, non-canonical HR termination is associated with complex breakpoints. We identify roles for homology-mediated template switching and, potentially, MH-mediated template switching/microhomology-mediated break-induced replication, in the formation of complex breakpoints at sites of non-canonical HR termination. This work identifies non-canonical HR termination as a potential contributor to genomic instability and to the formation of complex breakpoints in cancer. PMID:27832076

  8. Markedness and Salience in Language Contact and Second-Language Acquisition: Evidence from a Non-Canonical Contact Language.

    ERIC Educational Resources Information Center

    Deumert, Ana

    2003-01-01

    Argues that the study of contact varieties of a language are relevant to understanding of second language acquisition and use, because non-canonical contact languages are often situated on a continuum between pidginization and the more general processes of untutored second language acquisition. Data on participle regularization in Namibian Black…

  9. Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis.

    PubMed

    Chung, Chi-Yeh; Sun, Zhen; Mullokandov, Gavriel; Bosch, Almudena; Qadeer, Zulekha A; Cihan, Esma; Rapp, Zachary; Parsons, Ramon; Aguirre-Ghiso, Julio A; Farias, Eduardo F; Brown, Brian D; Gaspar-Maia, Alexandre; Bernstein, Emily

    2016-07-12

    Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.

  10. A non-canonical mechanism for Crm1-export cargo complex assembly.

    PubMed

    Fischer, Ute; Schäuble, Nico; Schütz, Sabina; Altvater, Martin; Chang, Yiming; Faza, Marius Boulos; Panse, Vikram Govind

    2015-04-21

    The transport receptor Crm1 mediates the export of diverse cargos containing leucine-rich nuclear export signals (NESs) through complex formation with RanGTP. To ensure efficient cargo release in the cytoplasm, NESs have evolved to display low affinity for Crm1. However, mechanisms that overcome low affinity to assemble Crm1-export complexes in the nucleus remain poorly understood. In this study, we reveal a new type of RanGTP-binding protein, Slx9, which facilitates Crm1 recruitment to the 40S pre-ribosome-associated NES-containing adaptor Rio2. In vitro, Slx9 binds Rio2 and RanGTP, forming a complex. This complex directly loads Crm1, unveiling a non-canonical stepwise mechanism to assemble a Crm1-export complex. A mutation in Slx9 that impairs Crm1-export complex assembly inhibits 40S pre-ribosome export. Thus, Slx9 functions as a scaffold to optimally present RanGTP and the NES to Crm1, therefore, triggering 40S pre-ribosome export. This mechanism could represent one solution to the paradox of weak binding events underlying rapid Crm1-mediated export.

  11. Non-Canonical Role of IKKα in the Regulation of STAT1 Phosphorylation in Antiviral Signaling

    PubMed Central

    Xing, Fei; Matsumiya, Tomoh; Shiba, Yuko; Hayakari, Ryo; Yoshida, Hidemi; Imaizumi, Tadaatsu

    2016-01-01

    Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addition to the well-known type I IFN-dependent pathway. IκB kinase α (IKKα) is involved in antiviral signaling induced by dsRNA; however, its role is incompletely understood. Here, we explored the function of IKKα in RLR-mediated STAT1 phosphorylation. Silencing of IKKα markedly decreased the level of IFN-β and STAT1 phosphorylation inHeH response to dsRNA. However, the inhibition of IKKα did not alter the RLR signaling-mediated dimerization of interferon responsive factor 3 (IRF3) or the nuclear translocation of nuclear factor-κB (NFκB). These results suggest a non-canonical role of IKKα in RLR signaling. Furthermore, phosphorylation of STAT1 was suppressed by IKKα knockdown in cells treated with a specific neutralizing antibody for the type I IFN receptor (IFNAR) and in IFNAR-deficient cells. Collectively, the dual regulation of STAT1 by IKKα in antiviral signaling suggests a role for IKKα in the fine-tuning of antiviral signaling in response to non-self RNA. PMID:27992555

  12. 20-hydroxyecdysone mediates non-canonical regulation of mosquito vitellogenins through alternative splicing.

    PubMed

    Provost-Javier, K N; Rasgon, J L

    2014-08-01

    Vitellogenesis is one of the most well-studied physiological processes in mosquitoes. Expression of mosquito vitellogenin genes is classically described as being restricted to female adult reproduction. We report premature vitellogenin transcript expression in three vector mosquitoes: Culex tarsalis, Aedes aegypti and Anopheles gambiae. Vitellogenins expressed during non-reproductive stages are alternatively spliced to retain their first intron and encode premature termination codons. We show that intron retention results in transcript degradation by translation-dependent nonsense-mediated mRNA decay. This is probably an example of regulated unproductive splicing and translation (RUST), a mechanism known to regulate gene expression in numerous organisms but which has never been described in mosquitoes. We demonstrate that the hormone 20-hydroxyecdysone (20E) is responsible for regulating post-transcriptional splicing of vitellogenin. After exposure of previtellogenic fat bodies to 20E, vitellogenin expression switches from a non-productive intron-retaining transcript to a spliced protein-coding transcript. This effect is independent of factors classically known to influence transcription, such as juvenile hormone-mediated competence and amino acid signalling through the target of rapamycin pathway. Non-canonical regulation of vitellogenesis through RUST is a novel role for the multifunctional hormone 20E, and may have important implications for general patterns of gene regulation in mosquitoes.

  13. TRIM24 Links a Non-canonical Histone Signature to Breast Cancer

    SciTech Connect

    W Tsai; Z Wang; T Yiu; K Akdemir; W Xia; S Winter; C Tsai; X Shi; D Schwarzer; et al.

    2011-12-31

    Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.

  14. Non-Canonical and Sexually Dimorphic X Dosage Compensation States in the Mouse and Human Germline.

    PubMed

    Sangrithi, Mahesh N; Royo, Helene; Mahadevaiah, Shantha K; Ojarikre, Obah; Bhaw, Leena; Sesay, Abdul; Peters, Antoine H F M; Stadler, Michael; Turner, James M A

    2017-02-06

    Somatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a "sex-reversed" X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility.

  15. A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons

    PubMed Central

    Hayashi, Yukari; Nishimune, Hiroshi; Hozumi, Katsuto; Saga, Yumiko; Harada, Akihiro; Yuzaki, Michisuke; Iwatsubo, Takeshi; Kopan, Raphael; Tomita, Taisuke

    2016-01-01

    Notch signaling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not γ-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but γ-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons. PMID:27040987

  16. FAM46 proteins are novel eukaryotic non-canonical poly(A) polymerases

    PubMed Central

    Kuchta, Krzysztof; Muszewska, Anna; Knizewski, Lukasz; Steczkiewicz, Kamil; Wyrwicz, Lucjan S.; Pawlowski, Krzysztof; Rychlewski, Leszek; Ginalski, Krzysztof

    2016-01-01

    FAM46 proteins, encoded in all known animal genomes, belong to the nucleotidyltransferase (NTase) fold superfamily. All four human FAM46 paralogs (FAM46A, FAM46B, FAM46C, FAM46D) are thought to be involved in several diseases, with FAM46C reported as a causal driver of multiple myeloma; however, their exact functions remain unknown. By using a combination of various bioinformatics analyses (e.g. domain architecture, cellular localization) and exhaustive literature and database searches (e.g. expression profiles, protein interactors), we classified FAM46 proteins as active non-canonical poly(A) polymerases, which modify cytosolic and/or nuclear RNA 3′ ends. These proteins may thus regulate gene expression and probably play a critical role during cell differentiation. A detailed analysis of sequence and structure diversity of known NTases possessing PAP/OAS1 SBD domain, combined with state-of-the-art comparative modelling, allowed us to identify potential active site residues responsible for catalysis and substrate binding. We also explored the role of single point mutations found in human cancers and propose that FAM46 genes may be involved in the development of other major malignancies including lung, colorectal, hepatocellular, head and neck, urothelial, endometrial and renal papillary carcinomas and melanoma. Identification of these novel enzymes taking part in RNA metabolism in eukaryotes may guide their further functional studies. PMID:27060136

  17. Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site

    NASA Astrophysics Data System (ADS)

    Liu, Chuang; Perilla, Juan R.; Ning, Jiying; Lu, Manman; Hou, Guangjin; Ramalho, Ruben; Himes, Benjamin A.; Zhao, Gongpu; Bedwell, Gregory J.; Byeon, In-Ja; Ahn, Jinwoo; Gronenborn, Angela M.; Prevelige, Peter E.; Rousso, Itay; Aiken, Christopher; Polenova, Tatyana; Schulten, Klaus; Zhang, Peijun

    2016-03-01

    The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.

  18. IL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells

    PubMed Central

    Wan, Chi-Keung; Li, Peng; Spolski, Rosanne; Oh, Jangsuk; Andraski, Allison B.; Du, Ning; Yu, Zu-Xi; Dillon, Christopher P.; Green, Douglas R.; Leonard, Warren J.

    2015-01-01

    The canonical pathway for IL-1β production requires TLR-mediated NF-κB-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1β. Here we show that IL-21 unexpectedly induces IL-1β production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-κB-independent pathway. IL-21 does not induce Il1b expression in CD4+ T cells, with differential histone marks present in these cells versus cDCs. IL-21-induced IL-1β processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1β expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with pneumonia virus of mice. These results demonstrate lineage-restricted IL-21-induced IL-1β via a non-canonical pathway and provide evidence for its importance in vivo. PMID:26269257

  19. Swinger RNA self-hybridization and mitochondrial non-canonical swinger transcription, transcription systematically exchanging nucleotides.

    PubMed

    Seligmann, Hervé

    2016-06-21

    Stem-loop hairpins punctuate mitochondrial post-transcriptional processing. Regulation of mitochondrial swinger transcription, transcription producing RNAs matching the mitogenome only assuming systematic exchanges between nucleotides (23 bijective transformations along 9 symmetric exchanges X<>Y, e.g. A<>G, and 14 asymmetric exchanges X>Y>Z>X, e.g. A>G>C>A) remains unknown. Does swinger RNA self-hybridization regulate swinger, as regular, transcription? Groups of 8 swinger transformations share canonical self-hybridization properties within each group, group 0 includes identity (regular) transcription. The human mitogenome has more stem-loop hairpins than randomized sequences for all groups. Group 2 transformations reveal complementarity of the light strand replication origin (OL) loop and a neighboring tRNA gene, detecting the longtime presumed OL/tRNA homology. Non-canonical G=U pairings in hairpins increases with swinger RNA detection. These results confirm biological relevancy of swinger-transformed DNA/RNA, independently of, and in combination with, previously detected swinger DNA/RNA and swinger peptides. Swinger-transformed mitogenomes include unsuspected multilayered information.

  20. Thickness Mismatch of Coexisting Liquid Phases in Non-Canonical Lipid Bilayers

    PubMed Central

    Bleecker, Joan V.; Cox, Phillip A.; Foster, Rami N.; Litz, Jonathan P.; Blosser, Matthew C.; Castner, David G.; Keller, Sarah L.

    2016-01-01

    Lipid composition dictates membrane thickness, which in turn can influence membrane protein activity. Lipid composition also determines whether a membrane demixes into coexisting liquid-crystalline phases. Previous direct measurements of demixed lipid membranes have always found a liquid-ordered phase that is thicker than the liquid-disordered phase. Here we investigated non-canonical ternary lipid mixtures designed to produce bilayers with thicker disordered phases than ordered phases. The membranes were comprised of short, saturated (ordered) lipids; long, unsaturated (disordered) lipids; and cholesterol. We found that few of these systems yield coexisting liquid phases above 10 °C. For membranes that do demix into two liquid phases, we measured the thickness mismatch between the phases by atomic force microscopy and found that not one of the systems yields thicker disordered than ordered phases under standard experimental conditions. We found no monotonic relationship between demixing temperatures of these ternary systems and either estimated thickness mismatches between the liquid phases or the physical parameters of single-component membranes comprised of the individual lipids. These results highlight the robustness of a membrane’s liquid-ordered phase to be thicker than the liquid-disordered phase, regardless of the membrane’s lipid composition. PMID:26890258

  1. Database of non-canonical base pairs found in known RNA structures

    NASA Technical Reports Server (NTRS)

    Nagaswamy, U.; Voss, N.; Zhang, Z.; Fox, G. E.

    2000-01-01

    Atomic resolution RNA structures are being published at an increasing rate. It is common to find a modest number of non-canonical base pairs in these structures in addition to the usual Watson-Crick pairs. This database summarizes the occurrence of these rare base pairs in accordance with standard nomenclature. The database, http://prion.bchs.uh.edu/, contains information such as sequence context, sugar pucker conformation, anti / syn base conformations, chemical shift, p K (a)values, melting temperature and free energy. Of the 29 anticipated pairs with two or more hydrogen bonds, 20 have been encountered to date. In addition, four unexpected pairs with two hydrogen bonds have been reported bringing the total to 24. Single hydrogen bond versions of five of the expected geometries have been encountered among the single hydrogen bond interactions. In addition, 18 different types of base triplets have been encountered, each of which involves three to six hydrogen bonds. The vast majority of the rare base pairs are antiparallel with the bases in the anti configuration relative to the ribose. The most common are the GU wobble, the Sheared GA pair, the Reverse Hoogsteen pair and the GA imino pair.

  2. A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

    PubMed Central

    Braga, Daniel; Hoffmeister, Dirk

    2016-01-01

    Auriculamide is the first natural product known from the predatory bacterium Herpetosiphon aurantiacus. It is composed of three unusual building blocks, including the non-proteinogenic amino acid 3-chloro-L-tyrosine, the α-hydroxy acid L-isoleucic acid, and a methylmalonyl-CoA-derived ethane unit. A candidate genetic locus for auriculamide biosynthesis was identified and encodes four enzymes. Among them, the non-canonical 199 kDa four-domain nonribosomal peptide synthetase, AulA, is extraordinary in that it features two consecutive adenylation domains. Here, we describe the functional characterization of the recombinantly produced AulA. The observed activation of 3-methyl-2-oxovaleric acid by the enzyme supports the hypothesis that it participates in the biosynthesis of auriculamide. An artificially truncated version of AulA that lacks the first adenylation domain activated this substrate like the full-length enzyme which shows that the first adenylation domain is dispensable. Additionally, we provide evidence that the enzyme tolerates structural variation of the substrate. α-Carbon substituents significantly affected the substrate turnover. While all tested aliphatic α-keto acids were accepted by the enzyme and minor differences in chain size and branches did not interfere with the enzymatic activity, molecules with methylene α-carbons led to low turnover. Such enzymatic plasticity is an important attribute to help in the perpetual search for novel molecules and to access a greater structural diversity by mutasynthesis. PMID:28144348

  3. Canonical and Non-Canonical Barriers Facing AntimiR Cancer Therapeutics

    PubMed Central

    Cheng, Christopher J.; Saltzman, W. Mark; Slack, Frank J.

    2013-01-01

    Once considered genetic “oddities”, microRNAs (miRNAs) are now recognized as key epigenetic regulators of numerous biological processes, including some with a causal link to the pathogenesis, maintenance, and treatment of cancer. The crux of small RNA-based therapeutics lies in the antagonism of potent cellular targets; the main shortcoming of the field in general, lies in ineffective delivery. Inhibition of oncogenic miRNAs is a relatively nascent therapeutic concept, but as with predecessor RNA-based therapies, success hinges on delivery efficacy. This review will describe the canonical (e.g. pharmacokinetics and clearance, cellular uptake, endosome escape, etc.) and non-canonical (e.g. spatial localization and accessibility of miRNA, technical limitations of miRNA inhibition, off-target impacts, etc.) challenges to the delivery of antisense-based anti-miRNA therapeutics (i.e. antimiRs) for the treatment of cancer. Emphasis will be placed on how the current leading antimiR platforms—ranging from naked chemically modified oligonucleotides to nanoscale delivery vehicles—are affected by and overcome these barriers. The perplexity of antimiR delivery presents both engineering and biological hurdles that must be overcome in order to capitalize on the extensive pharmacological benefits of antagonizing tumor-associated miRNAs PMID:23745563

  4. Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

    PubMed Central

    Olivos, David J.; Mayo, Lindsey D.

    2016-01-01

    Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research. PMID:27898034

  5. NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis.

    PubMed

    Chung, H; Vilaysane, A; Lau, A; Stahl, M; Morampudi, V; Bondzi-Simpson, A; Platnich, J M; Bracey, N A; French, M-C; Beck, P L; Chun, J; Vallance, B A; Muruve, D A

    2016-08-01

    Nod-like receptor, pyrin containing 3 (NLRP3) is characterized primarily as a canonical caspase-1 activating inflammasome in macrophages. NLRP3 is also expressed in the epithelium of the kidney and gut; however, its function remains largely undefined. Primary mouse tubular epithelial cells (TEC) lacking Nlrp3 displayed reduced apoptosis downstream of the tumor necrosis factor (TNF) receptor and CD95. TECs were identified as type II apoptotic cells that activated caspase-8, tBid and mitochondrial apoptosis via caspase-9, responses that were reduced in Nlrp3-/- cells. The activation of caspase-8 during extrinsic apoptosis induced by TNFα/cycloheximide (TNFα/CHX) was dependent on adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and completely independent of caspase-1 or caspase-11. TECs and primary human proximal tubular epithelial cells (HPTC) did not activate a canonical inflammasome, caspase-1, or IL-1β secretion in response to TNFα/CHX or NLRP3-dependent triggers, such as ATP or nigericin. In cell fractionation studies and by confocal microscopy, NLRP3 colocalized with ASC and caspase-8 in speck-like complexes at the mitochondria during apoptosis. The formation of NLRP3/ASC/caspase-8 specks in response to TNFα/CHX was downstream of TNFR signaling and dependent on potassium efflux. Epithelial ASC specks were present in enteroids undergoing apoptosis and in the injured tubules of wild-type but not Nlrp3-/- or ASC-/- mice following ureteric unilateral obstruction in vivo. These data show that NLRP3 and ASC form a conserved non-canonical platform for caspase-8 activation, independent of the inflammasome that regulates apoptosis within epithelial cells.

  6. A non-canonical start codon in the Drosophila fragile X gene yields two functional isoforms

    PubMed Central

    Beerman, Rebecca W.; Jongens, Thomas A.

    2011-01-01

    Fragile X syndrome is caused by the loss of expression of the fragile X mental retardation protein (FMRP). As a RNA binding protein, FMRP functions in translational regulation, localization, and stability of its neuronal target transcripts. The Drosophila homologue, dFMR1, is well conserved in sequence and function with respect to human FMRP. Although dFMR1 is known to express two main isoforms, the mechanism behind production of the second, more slowly migrating isoform has remained elusive. Furthermore, it remains unknown whether the two isoforms may also contribute differentially to dFMR1 function. We have found that this second dFMR1 isoform is generated through an alternative translational start site in the dfmr1 5’UTR. This 5'UTR coding sequence is well conserved in the melanogaster group. Translation of the predominant, smaller form of dFMR1 (dFMR1-SN) begins at a canonical start codon (ATG), whereas translation of the minor, larger form (dFMR1-LN) begins upstream at a non-canonical start codon (CTG). To assess the contribution of the N-terminal extension toward dFMR1 activity, we generated transgenic flies that exclusively express either dFMR1-SN or dFMR1-LN. Expression analyses throughout development revealed that dFMR1-SN is required for normal dFMR1-LN expression levels in adult brains. In situ expression analyses showed that either dFMR1-SN or dFMR1-LN is individually sufficient for proper dFMR1 localization in the nervous system. Functional studies demonstrated that both dFMR1-SN and dFMR1-LN can function independently to rescue dfmr1 null defects in synaptogenesis and axon guidance. Thus, dfmr1 encodes two functional isoforms with respect to expression and activity throughout neuronal development. PMID:21333716

  7. A novel non-canonical Wnt signature for prostate cancer aggressiveness.

    PubMed

    Sandsmark, Elise; Hansen, Ailin Falkmo; Selnæs, Kirsten M; Bertilsson, Helena; Bofin, Anna M; Wright, Alan J; Viset, Trond; Richardsen, Elin; Drabløs, Finn; Bathen, Tone F; Tessem, May-Britt; Rye, Morten B

    2017-02-07

    Activation of the Canonical Wnt pathway (CWP) has been linked to advanced and metastatic prostate cancer, whereas the Wnt5a-induced non-canonical Wnt pathway (NCWP) has been associated with both good and poor prognosis. A newly discovered NCWP, Wnt5/Fzd2, has been shown to induce epithelial-to-mesenchymal transition (EMT) in cancers, but has not been investigated in prostate cancer. The aim of this study was to investigate if the CWP and NCWP, in combination with EMT, are associated with metabolic alterations, aggressive disease and biochemical recurrence in prostate cancer. An initial analysis was performed using integrated transcriptomics, ex vivo and in vivo metabolomics, and histopathology of prostatectomy samples (n=129), combined with at least five-year follow-up. This analysis detected increased activation of NCWP through Wnt5a/ Fzd2 as the most common mode of Wnt activation in prostate cancer. This activation was associated with increased expression of EMT markers and higher Gleason score. The transcriptional association between NCWP and EMT was confirmed in five other publicly available patient cohorts (1519 samples in total). A novel gene expression signature of concordant activation of NCWP and EMT (NCWP-EMT) was developed, and this signature was significantly associated with metastasis and shown to be a significant predictor of biochemical recurrence. The NCWP-EMT signature was also associated with decreased concentrations of the metabolites citrate and spermine, which have previously been linked to aggressive prostate cancer. Our results demonstrate the importance of NCWP and EMT in prostate cancer aggressiveness, suggest a novel gene signature for improved risk stratification, and give new molecular insight.

  8. Multireference M[oslash]ller Plesset perturbation theory with non-canonical and non-orthogonal orbitals

    NASA Astrophysics Data System (ADS)

    Finley, James P.; Hirao, Kimihiko

    2000-09-01

    Using non-orthogonal secondary orbitals and non-canonical (localized) inactive and active orbitals, a second-order multireference perturbation theory is formulated, based on a complete active space self-consistent field (CASSCF) wavefunction. The equations of interest are derived from the first-order Bloch equation by using an approach based on a bi-orthogonal basis and operators expressed in second-quantization.

  9. Explicit high-order non-canonical symplectic particle-in-cell algorithms for Vlasov-Maxwell systems

    SciTech Connect

    Xiao, Jianyuan; Liu, Jian; He, Yang; Zhang, Ruili; Qin, Hong; Sun, Yajuan

    2015-11-15

    Explicit high-order non-canonical symplectic particle-in-cell algorithms for classical particle-field systems governed by the Vlasov-Maxwell equations are developed. The algorithms conserve a discrete non-canonical symplectic structure derived from the Lagrangian of the particle-field system, which is naturally discrete in particles. The electromagnetic field is spatially discretized using the method of discrete exterior calculus with high-order interpolating differential forms for a cubic grid. The resulting time-domain Lagrangian assumes a non-canonical symplectic structure. It is also gauge invariant and conserves charge. The system is then solved using a structure-preserving splitting method discovered by He et al. [preprint http://arxiv.org/abs/arXiv:1505.06076 (2015)], which produces five exactly soluble sub-systems, and high-order structure-preserving algorithms follow by combinations. The explicit, high-order, and conservative nature of the algorithms is especially suitable for long-term simulations of particle-field systems with extremely large number of degrees of freedom on massively parallel supercomputers. The algorithms have been tested and verified by the two physics problems, i.e., the nonlinear Landau damping and the electron Bernstein wave.

  10. Explicit high-order non-canonical symplectic particle-in-cell algorithms for Vlasov-Maxwell systems

    SciTech Connect

    Xiao, Jianyuan; Qin, Hong; Liu, Jian; He, Yang; Zhang, Ruili; Sun, Yajuan

    2015-11-01

    Explicit high-order non-canonical symplectic particle-in-cell algorithms for classical particle-field systems governed by the Vlasov-Maxwell equations are developed. The algorithms conserve a discrete non-canonical symplectic structure derived from the Lagrangian of the particle-field system, which is naturally discrete in particles. The electromagnetic field is spatially discretized using the method of discrete exterior calculus with high-order interpolating differential forms for a cubic grid. The resulting time-domain Lagrangian assumes a non-canonical symplectic structure. It is also gauge invariant and conserves charge. The system is then solved using a structure-preserving splitting method discovered by He et al. [preprint arXiv: 1505.06076 (2015)], which produces five exactly soluble sub-systems, and high-order structure-preserving algorithms follow by combinations. The explicit, high-order, and conservative nature of the algorithms is especially suitable for long-term simulations of particle-field systems with extremely large number of degrees of freedom on massively parallel supercomputers. The algorithms have been tested and verified by the two physics problems, i.e., the nonlinear Landau damping and the electron Bernstein wave. (C) 2015 AIP Publishing LLC.

  11. Discrimination by Escherichia coli initiation factor IF3 against initiation on non-canonical codons relies on complementarity rules.

    PubMed

    Meinnel, T; Sacerdot, C; Graffe, M; Blanquet, S; Springer, M

    1999-07-23

    Translation initiation factor IF3, one of three factors specifically required for translation initiation in Escherichia coli, inhibits initiation on any codon other than the three canonical initiation codons, AUG, GUG, or UUG. This discrimination against initiation on non-canonical codons could be due to either direct recognition of the two last bases of the codon and their cognate bases on the anticodon or to some ability to "feel" codon-anticodon complementarity. To investigate the importance of codon-anticodon complementarity in the discriminatory role of IF3, we constructed a derivative of tRNALeuthat has all the known characteristics of an initiator tRNA except the CAU anticodon. This tRNA is efficiently formylated by methionyl-tRNAfMettransformylase and charged by leucyl-tRNA synthetase irrespective of the sequence of its anticodon. These initiator tRNALeuderivatives (called tRNALI) allow initiation at all the non-canonical codons tested, provided that the complementarity between the codon and the anticodon of the initiator tRNALeuis respected. More remarkably, the discrimination by IF3, normally observed with non-canonical codons, is neutralised if a tRNALIcarrying a complementary anticodon is used for initiation. This suggests that IF3 somehow recognises codon-anticodon complementarity, at least at the second and third position of the codon, rather than some specific bases in either the codon or the anticodon.

  12. Non-canonical Wnt signaling regulates cell polarity in female reproductive tract development via van gogh-like 2

    PubMed Central

    vandenBerg, Alysia L.; Sassoon, David A.

    2009-01-01

    Summary Wnt signaling effectors direct the development and adult remodeling of the female reproductive tract (FRT); however, the role of non-canonical Wnt signaling has not been explored in this tissue. The non-canonical Wnt signaling protein van gogh-like 2 is mutated in loop-tail (Lp) mutant mice (Vangl2Lp), which display defects in multiple tissues. We find that Vangl2Lp mutant uterine epithelium displays altered cell polarity, concommitant with changes in cytoskeletal actin and scribble (scribbled, Scrb1) localization. The postnatal mutant phenotype is an exacerbation of that seen at birth, exhibiting more smooth muscle and reduced stromal mesenchyme. These data suggest that early changes in cell polarity have lasting consequences for FRT development. Furthermore, Vangl2 is required to restrict Scrb1 protein to the basolateral epithelial membrane in the neonatal uterus, and an accumulation of fibrillar-like structures observed by electron microscopy in Vangl2Lp mutant epithelium suggests that mislocalization of Scrb1 in mutants alters the composition of the apical face of the epithelium. Heterozygous and homozygous Vangl2Lp mutant postnatal tissues exhibit similar phenotypes and polarity defects and display a 50% reduction in Wnt7a levels, suggesting that the Vangl2Lp mutation acts dominantly in the FRT. These studies demonstrate that the establishment and maintenance of cell polarity through non-canonical Wnt signaling are required for FRT development. PMID:19363157

  13. Comparison of non-canonical PAMs for CRISPR/Cas9-mediated DNA cleavage in human cells.

    PubMed

    Zhang, Yilan; Ge, Xianglian; Yang, Fayu; Zhang, Liping; Zheng, Jiayong; Tan, Xuefang; Jin, Zi-Bing; Qu, Jia; Gu, Feng

    2014-06-23

    CRISPR/Cas9-mediated DNA cleavage (CCMDC) is becoming increasingly used for efficient genome engineering. Proto-spacer adjacent motif (PAM) adjacent to target sequence is one of the key components in the design of CCMDC strategies. It has been reported that NAG sequences are the predominant non-canonical PAM for CCMDC at the human EMX locus, but it is not clear whether it is universal at other loci. In the present study, we attempted to use a GFP-reporter system to comprehensively and quantitatively test the efficiency of CCMDC with non-canonical PAMs in human cells. The initial results indicated that the effectiveness of NGA PAM for CCMDC is much higher than that of other 14 PAMs including NAG. Then we further designed another three pairs of NGG, NGA and NAG PAMs at different locations in the GFP gene and investigated the corresponding DNA cleavage efficiency. We observed that one group of NGA PAMs have a relatively higher DNA cleavage efficiency, while the other groups have lower efficiency, compared with the corresponding NAG PAMs. Our study clearly demonstrates that NAG may not be the universally predominant non-canonical PAM for CCMDC in human cells. These findings raise more concerns over off-target effects in CRISPR/Cas9-mediated genome engineering.

  14. Explicit high-order non-canonical symplectic particle-in-cell algorithms for Vlasov-Maxwell systems

    NASA Astrophysics Data System (ADS)

    Xiao, Jianyuan; Qin, Hong; Liu, Jian; He, Yang; Zhang, Ruili; Sun, Yajuan

    2015-11-01

    Explicit high-order non-canonical symplectic particle-in-cell algorithms for classical particle-field systems governed by the Vlasov-Maxwell equations are developed. The algorithms conserve a discrete non-canonical symplectic structure derived from the Lagrangian of the particle-field system, which is naturally discrete in particles. The electromagnetic field is spatially discretized using the method of discrete exterior calculus with high-order interpolating differential forms for a cubic grid. The resulting time-domain Lagrangian assumes a non-canonical symplectic structure. It is also gauge invariant and conserves charge. The system is then solved using a structure-preserving splitting method discovered by He et al. [preprint arXiv:1505.06076 (2015)], which produces five exactly soluble sub-systems, and high-order structure-preserving algorithms follow by combinations. The explicit, high-order, and conservative nature of the algorithms is especially suitable for long-term simulations of particle-field systems with extremely large number of degrees of freedom on massively parallel supercomputers. The algorithms have been tested and verified by the two physics problems, i.e., the nonlinear Landau damping and the electron Bernstein wave.

  15. FZD6, targeted by miR-21, represses gastric cancer cell proliferation and migration via activating non-canonical wnt pathway.

    PubMed

    Yan, Jin; Liu, Tingyu; Zhou, Xiaoying; Dang, Yini; Yin, Chengqiang; Zhang, Guoxin

    2016-01-01

    FZD6 plays crucial roles in human tumorigenesis. However, its mechanism in regulating cancers has not been fully elucidated. In the study, we found that FZD6 repressed gastric cancer cell proliferation and migration via activating non-canonical wnt pathway. In addition, non-canonical wnt pathway ameliorated expression of canonical wnt pathway. We also demonstrated that the FZD6 was involved in miR-21-dependent effects in the canonical and non-canonical wnt pathways in gastric cancer. These findings provide a better understanding of the development and progression of gastric cancer and may be an important implication for future therapy.

  16. A non-canonical NRPS is involved in the synthesis of fungisporin and related hydrophobic cyclic tetrapeptides in Penicillium chrysogenum.

    PubMed

    Ali, Hazrat; Ries, Marco I; Lankhorst, Peter P; van der Hoeven, Rob A M; Schouten, Olaf L; Noga, Marek; Hankemeier, Thomas; van Peij, Noël N M E; Bovenberg, Roel A L; Vreeken, Rob J; Driessen, Arnold J M

    2014-01-01

    The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a 'trans-acting' adenylation domain.

  17. A Non-Canonical NRPS Is Involved in the Synthesis of Fungisporin and Related Hydrophobic Cyclic Tetrapeptides in Penicillium chrysogenum

    PubMed Central

    Lankhorst, Peter P.; van der Hoeven, Rob A. M.; Schouten, Olaf L.; Noga, Marek; Hankemeier, Thomas; van Peij, Noël N. M. E.; Bovenberg, Roel A. L.; Vreeken, Rob J.; Driessen, Arnold J. M.

    2014-01-01

    The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a ‘trans-acting’ adenylation domain. PMID:24887561

  18. RNAHelix: computational modeling of nucleic acid structures with Watson-Crick and non-canonical base pairs

    NASA Astrophysics Data System (ADS)

    Bhattacharyya, Dhananjay; Halder, Sukanya; Basu, Sankar; Mukherjee, Debasish; Kumar, Prasun; Bansal, Manju

    2017-02-01

    Comprehensive analyses of structural features of non-canonical base pairs within a nucleic acid double helix are limited by the availability of a small number of three dimensional structures. Therefore, a procedure for model building of double helices containing any given nucleotide sequence and base pairing information, either canonical or non-canonical, is seriously needed. Here we describe a program RNAHelix, which is an updated version of our widely used software, NUCGEN. The program can regenerate duplexes using the dinucleotide step and base pair orientation parameters for a given double helical DNA or RNA sequence with defined Watson-Crick or non-Watson-Crick base pairs. The original structure and the corresponding regenerated structure of double helices were found to be very close, as indicated by the small RMSD values between positions of the corresponding atoms. Structures of several usual and unusual double helices have been regenerated and compared with their original structures in terms of base pair RMSD, torsion angles and electrostatic potentials and very high agreements have been noted. RNAHelix can also be used to generate a structure with a sequence completely different from an experimentally determined one or to introduce single to multiple mutation, but with the same set of parameters and hence can also be an important tool in homology modeling and study of mutation induced structural changes.

  19. Canonical and Non-Canonical Activation of NLRP3 Inflammasome at the Crossroad between Immune Tolerance and Intestinal Inflammation

    PubMed Central

    Pellegrini, Carolina; Antonioli, Luca; Lopez-Castejon, Gloria; Blandizzi, Corrado; Fornai, Matteo

    2017-01-01

    Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in regulating the integrity of intestinal homeostasis and shaping innate immune responses during bowel inflammation. Intensive research efforts are being made to achieve an integrated view about the protective/detrimental role of canonical and non-canonical NLRP3 inflammasome activation in the maintenance of intestinal microenvironment integrity. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome could represent a promising molecular target for the therapeutic management of inflammatory immune-mediated gut diseases. The present review has been intended to provide a critical appraisal of the available knowledge about the role of canonical and non-canonical NLRP3 inflammasome activation in the dynamic interplay between microbiota, intestinal epithelium, and innate immune system, taken together as a whole integrated network regulating the maintenance/breakdown of intestinal homeostasis. Moreover, special attention has been paid to the pharmacological modulation of NLRP3 inflammasome, emphasizing the concept that this multiprotein complex could represent a suitable target for the management of inflammatory bowel diseases. PMID:28179906

  20. RNAHelix: computational modeling of nucleic acid structures with Watson-Crick and non-canonical base pairs.

    PubMed

    Bhattacharyya, Dhananjay; Halder, Sukanya; Basu, Sankar; Mukherjee, Debasish; Kumar, Prasun; Bansal, Manju

    2017-02-01

    Comprehensive analyses of structural features of non-canonical base pairs within a nucleic acid double helix are limited by the availability of a small number of three dimensional structures. Therefore, a procedure for model building of double helices containing any given nucleotide sequence and base pairing information, either canonical or non-canonical, is seriously needed. Here we describe a program RNAHelix, which is an updated version of our widely used software, NUCGEN. The program can regenerate duplexes using the dinucleotide step and base pair orientation parameters for a given double helical DNA or RNA sequence with defined Watson-Crick or non-Watson-Crick base pairs. The original structure and the corresponding regenerated structure of double helices were found to be very close, as indicated by the small RMSD values between positions of the corresponding atoms. Structures of several usual and unusual double helices have been regenerated and compared with their original structures in terms of base pair RMSD, torsion angles and electrostatic potentials and very high agreements have been noted. RNAHelix can also be used to generate a structure with a sequence completely different from an experimentally determined one or to introduce single to multiple mutation, but with the same set of parameters and hence can also be an important tool in homology modeling and study of mutation induced structural changes.

  1. Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures.

    PubMed

    Chattopadhyay, Indranil; Wang, Jianmin; Qin, Maochun; Gao, Lingqiu; Holtz, Renae; Vessella, Robert L; Leach, Robert W; Gelman, Irwin H

    2017-02-07

    Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells. Src induces additional gene signatures unique to CRPC cell lines, LNCaP-C4-2 and CWR22Rv1, and to CRPC LuCaP35.1 xenografts. By comparing the Src-induced AR-cistrome and/or transcriptome in LNCaP to those in CRPC and LuCaP35.1 tumors, we identified an 11-gene Src-regulated CRPC signature consisting of AR-dependent, AR binding site (ARBS)-associated genes whose expression is altered by DHT in LNCaP[Src527F] but not in LNCaP cells. The differential expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival, with the expression of BCAT1 required for Src-induced androgen-independent proliferation. Lastly, Src enhances AR binding to non-canonical ARBS enriched for FOXO1, TOP2B and ZNF217 binding motifs; cooperative AR/TOP2B binding to a non-canonical ARBS was both Src- and DHT-sensitive and correlated with increased levels of Src-induced phosphotyrosyl-TOP2B. These data suggest that CRPC progression is facilitated via Src-induced sensitization of AR to intracrine androgen levels, resulting in the engagement of canonical and non-canonical ARBS-dependent gene signatures.

  2. Crystal structures of the human elongation factor eEFSec suggest a non-canonical mechanism for selenocysteine incorporation

    PubMed Central

    Dobosz-Bartoszek, Malgorzata; Pinkerton, Mark H.; Otwinowski, Zbyszek; Chakravarthy, Srinivas; Söll, Dieter; Copeland, Paul R.; Simonović, Miljan

    2016-01-01

    Selenocysteine is the only proteinogenic amino acid encoded by a recoded in-frame UGA codon that does not operate as the canonical opal stop codon. A specialized translation elongation factor, eEFSec in eukaryotes and SelB in prokaryotes, promotes selenocysteine incorporation into selenoproteins by a still poorly understood mechanism. Our structural and biochemical results reveal that four domains of human eEFSec fold into a chalice-like structure that has similar binding affinities for GDP, GTP and other guanine nucleotides. Surprisingly, unlike in eEF1A and EF-Tu, the guanine nucleotide exchange does not cause a major conformational change in domain 1 of eEFSec, but instead induces a swing of domain 4. We propose that eEFSec employs a non-canonical mechanism involving the distinct C-terminal domain 4 for the release of the selenocysteinyl-tRNA during decoding on the ribosome. PMID:27708257

  3. Vasohibins: new transglutaminase-like cysteine proteases possessing a non-canonical Cys-His-Ser catalytic triad

    PubMed Central

    Sanchez-Pulido, Luis; Ponting, Chris P.

    2016-01-01

    Summary: Vasohibin-1 and Vasohibin-2 regulate angiogenesis, tumour growth and metastasis. Their molecular functions, however, were previously unknown, in large part owing to their perceived lack of homology to proteins of known structure and function. To identify their functional amino acids and domains, their molecular activity and their evolutionary history, we undertook an in-depth analysis of Vasohibin sequences. We find that Vasohibin proteins are previously undetected members of the transglutaminase-like cysteine protease superfamily, and all possess a non-canonical Cys-His-Ser catalytic triad. We further propose a calcium-dependent activation mechanism for Vasohibin proteins. These findings can now be used to design constructs for protein structure determination and to develop enzyme inhibitors as angiogenic regulators to treat metastasis and tumour growth. Contact: luis.sanchezpulido@dpag.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26794318

  4. Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination.

    PubMed

    Yousif, Ashraf S; Stanlie, Andre; Begum, Nasim A; Honjo, Tasuku

    2014-10-01

    Activation-induced cytidine deaminase (AID) is essential to class switch recombination (CSR) and somatic hypermutation (SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair complex, is required for CSR. The role of UNG in CSR and SHM is extremely controversial. AID deficiency in mice abolishes both CSR and SHM, while UNG-deficient mice have drastically reduced CSR but augmented SHM raising a possibility of differential functions of UNG in CSR and SHM. Interestingly, UNG has been associated with a CSR-specific repair adapter protein Brd4, which interacts with acetyl histone 4, γH2AX and 53BP1 to promote non-homologous end joining during CSR. A non-canonical scaffold function of UNG, but not the catalytic activity, can be attributed to the recruitment of essential repair proteins associated with the error-free repair during SHM, and the end joining during CSR.

  5. A non-canonical secondary structure stabilizes mitochondrial tRNASer(UCN) by reducing the entropic cost of tertiary folding

    PubMed Central

    Mustoe, Anthony M.; Liu, Xin; Lin, Paul J.; Al-Hashimi, Hashim M.; Fierke, Carol A.; Brooks, Charles L.

    2015-01-01

    Mammalian mitochondrial tRNASer(UCN) (mt-tRNASer) and pyrrolysine tRNA (tRNAPyl) fold to near-canonical three-dimensional structures despite having non-canonical secondary structures with shortened interhelical loops that disrupt the conserved tRNA tertiary interaction network. How these non-canonical tRNAs compensate for their loss of tertiary interactions remains unclear. Furthermore, in human mt-tRNASer, lengthening the variable-loop by the 7472insC mutation reduces mt-tRNASer concentration in vivo through poorly understood mechanisms, and is strongly associated with diseases such as deafness and epilepsy. Using simulations of the TOPRNA coarse-grained model, we show that increased topological constraints encoded by the unique secondary structure of wild-type mt-tRNASer decrease the entropic cost of folding by ~2.5 kcal/mol compared to canonical tRNA, offsetting its loss of tertiary interactions. Further simulations show that the pathogenic 7472insC mutation disrupts topological constraints and hence destabilizes the mutant mt-tRNASer by ~0.6 kcal/mol relative to wild-type. UV melting experiments confirm that insertion mutations lower mt-tRNASer melting temperature by 6–9°C and increase the folding free energy by 0.8–1.7 kcal/mol in a largely sequence- and salt-independent manner, in quantitative agreement with our simulation predictions. Our results show that topological constraints provide a quantitative framework for describing key aspects of RNA folding behavior and also provide the first evidence of a pathogenic mutation that is due to disruption of topological constraints. PMID:25705930

  6. Canonical and non-canonical EcfG sigma factors control the general stress response in Rhizobium etli.

    PubMed

    Jans, Ann; Vercruysse, Maarten; Gao, Shanjun; Engelen, Kristof; Lambrichts, Ivo; Fauvart, Maarten; Michiels, Jan

    2013-12-01

    A core component of the α-proteobacterial general stress response (GSR) is the extracytoplasmic function (ECF) sigma factor EcfG, exclusively present in this taxonomic class. Half of the completed α-proteobacterial genome sequences contain two or more copies of genes encoding σ(EcfG) -like sigma factors, with the primary copy typically located adjacent to genes coding for a cognate anti-sigma factor (NepR) and two-component response regulator (PhyR). So far, the widespread occurrence of additional, non-canonical σ(EcfG) copies has not satisfactorily been explained. This study explores the hierarchical relation between Rhizobium etli σ(EcfG1) and σ(EcfG2) , canonical and non-canonical σ(EcfG) proteins, respectively. Contrary to reports in other species, we find that σ(EcfG1) and σ(EcfG2) act in parallel, as nodes of a complex regulatory network, rather than in series, as elements of a linear regulatory cascade. We demonstrate that both sigma factors control unique yet also shared target genes, corroborating phenotypic evidence. σ(EcfG1) drives expression of rpoH2, explaining the increased heat sensitivity of an ecfG1 mutant, while katG is under control of σ(EcfG2) , accounting for reduced oxidative stress resistance of an ecfG2 mutant. We also identify non-coding RNA genes as novel σ(EcfG) targets. We propose a modified model for GSR regulation in R. etli, in which σ(EcfG1) and σ(EcfG2) function largely independently. Based on a phylogenetic analysis and considering the prevalence of α-proteobacterial genomes with multiple σ(EcfG) copies, this model may also be applicable to numerous other species.

  7. New insights into transcription fidelity: thermal stability of non-canonical structures in template DNA regulates transcriptional arrest, pause, and slippage.

    PubMed

    Tateishi-Karimata, Hisae; Isono, Noburu; Sugimoto, Naoki

    2014-01-01

    The thermal stability and topology of non-canonical structures of G-quadruplexes and hairpins in template DNA were investigated, and the effect of non-canonical structures on transcription fidelity was evaluated quantitatively. We designed ten template DNAs: A linear sequence that does not have significant higher-order structure, three sequences that form hairpin structures, and six sequences that form G-quadruplex structures with different stabilities. Templates with non-canonical structures induced the production of an arrested, a slipped, and a full-length transcript, whereas the linear sequence produced only a full-length transcript. The efficiency of production for run-off transcripts (full-length and slipped transcripts) from templates that formed the non-canonical structures was lower than that from the linear. G-quadruplex structures were more effective inhibitors of full-length product formation than were hairpin structure even when the stability of the G-quadruplex in an aqueous solution was the same as that of the hairpin. We considered that intra-polymerase conditions may differentially affect the stability of non-canonical structures. The values of transcription efficiencies of run-off or arrest transcripts were correlated with stabilities of non-canonical structures in the intra-polymerase condition mimicked by 20 wt% polyethylene glycol (PEG). Transcriptional arrest was induced when the stability of the G-quadruplex structure (-ΔG°37) in the presence of 20 wt% PEG was more than 8.2 kcal mol(-1). Thus, values of stability in the presence of 20 wt% PEG are an important indicator of transcription perturbation. Our results further our understanding of the impact of template structure on the transcription process and may guide logical design of transcription-regulating drugs.

  8. Non-canonical microRNAs miR-320 and miR-702 promote proliferation in Dgcr8-deficient embryonic stem cells

    SciTech Connect

    Kim, Byeong-Moo; Choi, Michael Y.

    2012-09-21

    Highlights: Black-Right-Pointing-Pointer Embryonic stem cells (ESCs) lacking non-canonical miRNAs proliferate slower. Black-Right-Pointing-Pointer miR-320 and miR-702 are two non-canonical miRNAs expressed in ESCs. Black-Right-Pointing-Pointer miR-320 and miR-702 promote proliferation of Dgcr8-deficient ESCs. Black-Right-Pointing-Pointer miR-320 targets p57 and helps to release Dgcr8-deficient ESCs from G1 arrest. Black-Right-Pointing-Pointer miR-702 targets p21 and helps to release Dgcr8-deficient ESCs from G1 arrest. -- Abstract: MicroRNAs are known to contribute significantly to stem cell phenotype by post-transcriptionally regulating gene expression. Most of our knowledge of microRNAs comes from the study of canonical microRNAs that require two sequential cleavages by the Drosha/Dgcr8 heterodimer and Dicer to generate mature products. In contrast, non-canonical microRNAs bypass the cleavage by the Drosha/Dgcr8 heterodimer within the nucleus but still require cytoplasmic cleavage by Dicer. The function of non-canonical microRNAs in embryonic stem cells (ESCs) remains obscure. It has been hypothesized that non-canonical microRNAs have important roles in ESCs based upon the phenotypes of ESC lines that lack these specific classes of microRNAs; Dicer-deficient ESCs lacking both canonical and non-canonical microRNAs have much more severe proliferation defect than Dgcr8-deficient ESCs lacking only canonical microRNAs. Using these cell lines, we identified two non-canonical microRNAs, miR-320 and miR-702, that promote proliferation of Dgcr8-deficient ESCs by releasing them from G1 arrest. This is accomplished by targeting the 3 Prime -untranslated regions of the cell cycle inhibitors p57 and p21 and thereby inhibiting their expression. This is the first report of the crucial role of non-canonical microRNAs in ESCs.

  9. A Putative Non-Canonical Ras-Like GTPase from P. falciparum: Chemical Properties and Characterization of the Protein

    PubMed Central

    Przyborski, Jude; Kersting, David; Krüger, Mirko

    2015-01-01

    During its development the malaria parasite P. falciparum has to adapt to various different environmental contexts. Key cellular mechanisms involving G-protein coupled signal transduction chains are assumed to act at these interfaces. Heterotrimeric G-proteins are absent in Plasmodium. We here describe the first cloning and expression of a putative, non-canonical Ras-like G protein (acronym PfG) from Plasmodium. PfG reveals an open reading frame of 2736 bp encoding a protein of 912 amino acids with a theoretical pI of 8.68 and a molecular weight of 108.57 kDa. Transcript levels and expression are significantly increased in the erythrocytic phase in particular during schizont and gametocyte formation. Most notably, PfG has GTP binding capacity and GTPase activity due to an EngA2 domain present in small Ras-like GTPases in a variety of Bacillus species and Mycobacteria. By contrast, plasmodial PfG is divergent from any human alpha-subunit. PfG was expressed in E. coli as a histidine-tagged fusion protein and was stable only for 3.5 hours. Purification was only possible under native conditions by Nickel-chelate chromatography and subsequent separation by Blue Native PAGE. Binding of a fluorescent GTP analogue BODIPY® FL guanosine 5’O-(thiotriphosphate) was determined by fluorescence emission. Mastoparan stimulated GTP binding in the presence of Mg2+. GTPase activity was determined colorimetrically. Activity expressed as absolute fluorescence was 50% higher for the human paralogue than the activity of the parasitic enzyme. The PfG protein is expressed in the erythrocytic stages and binds GTP after immunoprecipitation. Immunofluorescence using specific antiserum suggests that PfG localizes to the parasite cytosol. The current data suggest that the putitative, Ras-like G-protein might be involved in a non-canonical signaling pathway in Plasmodium. Research on the function of PfG with respect to pathogenesis and antimalarial chemotherapy is currently under way. PMID

  10. Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension.

    PubMed

    Uschner, Frank E; Ranabhat, Ganesh; Choi, Steve S; Granzow, Michaela; Klein, Sabine; Schierwagen, Robert; Raskopf, Esther; Gautsch, Sebastian; van der Ven, Peter F M; Fürst, Dieter O; Strassburg, Christian P; Sauerbruch, Tilman; Diehl, Anna Mae; Trebicka, Jonel

    2015-09-28

    Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.

  11. The Processing of Non-Canonically Ordered Constituents in Long Distance Dependencies by Pre-School Children: A Real-Time Investigation

    ERIC Educational Resources Information Center

    Love, Tracy E.

    2007-01-01

    Four experiments were performed which had the goal of determining how and when young children acquire the ability to understand long distance dependencies. These studies examined the operations underlying the auditory processing of non-canonically ordered constituents in object-relative sentences. Children 4-6 years of age and an adult population…

  12. Zinc-finger protein 91 plays a key role in LIGHT-induced activation of non-canonical NF-{kappa}B pathway

    SciTech Connect

    Jin, Hong Ri; Jin, Xuejun; Lee, Jung Joon

    2010-10-01

    Research highlights: {yields} LIGHT induces ZFP91expression and nuclear translocation of p65, p52, and RelB in LT{beta}R signaling. {yields} ZFP91 knock-down abolishes DNA-binding activity of p52 and RelB but not of p65. {yields} ZFP91 regulates LIGHT-induced stabilization and activation of NIK. {yields} ZFP91 is required for the expression of non-canonical NF-{kappa}B target genes. -- Abstract: LIGHT is a member of tumor necrosis factor (TNF) superfamily, and its function is mediated through lymphotoxin-{beta} receptor (LT{beta}R), which is known to play important roles in inflammatory and immune responses through activation of NF-{kappa}B signaling pathways. However, molecular mechanism of LT{beta}R ligation-induced NF-{kappa}B signaling remains incompletely understood. In this report we demonstrate that a novel zinc-finger protein 91 (ZFP91) is a critical regulator in LIGHT-induced activation of non-canonical NF-{kappa}B pathway. ZFP91 appears to be required for NF-{kappa}B2 (p100) processing to p52, nuclear translocation of p52 and RelB, and DNA-binding activity of NF-{kappa}B in LIGHT-induced activation of non-canonical NF-{kappa}B pathway. Furthermore, ZFP91 knock-down by RNA interference blocks the LIGHT-induced accumulation of NIK and p100 processing, as well as the expression of non-canonical NF-{kappa}B target genes. These data clearly indicate that ZFP91 is a key regulator in LIGHT-induced activation of non-canonical NF-{kappa}B pathway in LT{beta}R signaling.

  13. Lipopolysaccharide-induced activation of NF-{kappa}B non-canonical pathway requires BCL10 serine 138 and NIK phosphorylations

    SciTech Connect

    Bhattacharyya, Sumit; Borthakur, Alip; Dudeja, Pradeep K.; Tobacman, Joanne K.

    2010-11-15

    Background and aims: B-cell lymphoma/leukemia (BCL)-10 and reactive oxygen species mediate two pathways of NF-{kappa}B (RelA) activation by lipopolysaccharide (LPS) in human colonic epithelial cells. The pathway for LPS activation of RelB by the non-canonical pathway (RelB) in non-myeloid cells was not yet reported, but important for understanding the range of potential microbial LPS-induced effects in inflammatory bowel disease. Methods: Experiments were performed in human colonic epithelial cells and in mouse embryonic fibroblasts deficient in components of the IkappaB kinase (IKK) signalosome, in order to detect mediators of the non-canonical pathway of NF-{kappa}B activation, including nuclear RelB and p52 and phospho- and total NF-{kappa}B inducing kinase (NIK). BCL10 was silenced by siRNA and effects of mutations of specific phosphorylation sites of BCL10 (Ser138Gly and Ser218Gly) were determined. Results: By the non-canonical pathway, LPS exposure increased nuclear RelB and p52, and phospho-NIK, with no change in total NIK. Phosphorylation of BCL10 serine 138 was required for NIK phosphorylation, since mutation of this residue eliminated the increases in phospho-NIK and nuclear RelB and p52. Mutations of either serine 138 or serine 218 reduced RelA, p50, and phospho-I{kappa}B{alpha} of the canonical pathway. Effects of LPS stimulation and BCL10 silencing on NIK phosphorylation were demonstrated in confocal images. Conclusions: LPS induces activation of both canonical and non-canonical pathways of NF-{kappa}B in human colonic epithelial cells, and the non-canonical pathway requires phosphorylations of BCL10 (serine 138) and NIK. These findings demonstrate the important role of BCL10 in mediating LPS-induced inflammation in human colonic epithelial cells and may open new avenues for therapeutic interventions.

  14. Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin.

    PubMed

    Wang, Yuxiao; Pascoe, Heath G; Brautigam, Chad A; He, Huawei; Zhang, Xuewu

    2013-10-01

    Plexins are cell surface receptors that bind semaphorins and transduce signals for regulating neuronal axon guidance and other processes. Plexin signaling depends on their cytoplasmic GTPase activating protein (GAP) domain, which specifically inactivates the Ras homolog Rap through an ill-defined non-canonical catalytic mechanism. The plexin GAP is activated by semaphorin-induced dimerization, the structural basis for which remained unknown. Here we present the crystal structures of the active dimer of zebrafish PlexinC1 cytoplasmic region in the apo state and in complex with Rap. The structures show that the dimerization induces a large-scale conformational change in plexin, which opens the GAP active site to allow Rap binding. Plexin stabilizes the switch II region of Rap in an unprecedented conformation, bringing Gln63 in Rap into the active site for catalyzing GTP hydrolysis. The structures also explain the unique Rap-specificity of plexins. Mutational analyses support that these mechanisms underlie plexin activation and signaling. DOI:http://dx.doi.org/10.7554/eLife.01279.001.

  15. Non-canonical 3'-5' extension of RNA with prebiotically plausible ribonucleoside 2',3'-cyclic phosphates.

    PubMed

    Mutschler, Hannes; Holliger, Philipp

    2014-04-09

    Ribonucleoside 2',3'-cyclic phosphates (N>p's) are generated by multiple prebiotically plausible processes and are credible building blocks for the assembly of early RNA oligomers. While N>p's can be polymerized into short RNAs by non-enzymatic processes with variable efficiency and regioselectivity, no enzymatic route for RNA synthesis had been described. Here we report such a non-canonical 3'-5' nucleotidyl transferase activity. We engineered a variant of the hairpin ribozyme to catalyze addition of all four N>p's (2',3'-cyclic A-, G-, U-, and CMP) to the 5'-hydroxyl termini of RNA strands with 5' nucleotide addition enhanced in all cases by eutectic ice phase formation at -7 °C. We also observed 5' addition of 2',3'-cyclic phosphate-activated β-nicotinamide adenine dinucleotide (NAD>p) and ACA>p RNA trinucleotide, and multiple additions of GUCCA>p RNA pentamers. Our results establish a new mode of RNA 3'-5' extension with implications for RNA oligomer synthesis from prebiotic nucleotide pools.

  16. Distinct pathways for modification of the bacterial cell wall by non-canonical D-amino acids.

    PubMed

    Cava, Felipe; de Pedro, Miguel A; Lam, Hubert; Davis, Brigid M; Waldor, Matthew K

    2011-07-26

    Production of non-canonical D-amino acids (NCDAAs) in stationary phase promotes remodelling of peptidoglycan (PG), the polymer that comprises the bacterial cell wall. Impairment of NCDAAs production leads to excessive accumulation of PG and hypersensitivity to osmotic shock; however, the mechanistic bases for these phenotypes were not previously determined. Here, we show that incorporation of NCDAAs into PG is a critical means by which NCDAAs control PG abundance and strength. We identified and reconstituted in vitro two (of at least three) distinct processes that mediate NCDAA incorporation. Diverse bacterial phyla incorporate NCDAAs into their cell walls, either through periplasmic editing of the mature PG or via incorporation into PG precursor subunits in the cytosol. Production of NCDAAs in Vibrio cholerae requires the stress response sigma factor RpoS, suggesting that NCDAAs may aid bacteria in responding to varied environmental challenges. The widespread capacity of diverse bacteria, including non-producers, to incorporate NCDAAs suggests that these amino acids may serve as both autocrine- and paracrine-like regulators of chemical and physical properties of the cell wall in microbial communities.

  17. DRB2, DRB3 and DRB5 function in a non-canonical microRNA pathway in Arabidopsis thaliana.

    PubMed

    Eamens, Andrew L; Wook Kim, Ki; Waterhouse, Peter M

    2012-10-01

    DOUBLE-STRANDED RNA BINDING (DRB) proteins have been functionally characterized in viruses, prokaryotes and eukaryotes and are involved in all aspects of RNA biology. Arabidopsis thaliana (Arabidopsis) encodes five closely related DRB proteins, DRB1 to DRB5. DRB1 and DRB4 are required by DICER-LIKE (DCL) proteins DCL1 and DCL4 to accurately and efficiently process structurally distinct double-stranded RNA (dsRNA) precursor substrates in the microRNA (miRNA) and trans-acting small-interfering RNA (tasiRNA) biogenesis pathways respectively. We recently reported that DRB2 is also involved in the biogenesis of specific miRNA subsets. ( 1) Furthermore, the severity of the developmental phenotype displayed by the drb235 triple mutant plant, compared with those expressed by either drb2, drb3 and drb5 single mutants, or double mutant combinations thereof, indicates that DRB3 and DRB5 function in the same non-canonical miRNA pathway as DRB2. Through the use of our artificial miRNA (amiRNA) plant expression vector, pBlueGreen ( 2) (,) ( 3) we demonstrate here that unlike DRB2, DRB3 and DRB5 are not involved in the dsRNA processing stages of the miRNA biogenesis pathway, but are required to mediate RNA silencing of target genes of DRB2-associated miRNAs.

  18. Deoxycholic acid mediates non-canonical EGFR-MAPK activation through the induction of calcium signaling in colon cancer cells.

    PubMed

    Centuori, Sara M; Gomes, Cecil J; Trujillo, Jesse; Borg, Jamie; Brownlee, Joshua; Putnam, Charles W; Martinez, Jesse D

    2016-07-01

    Obesity and a western diet have been linked to high levels of bile acids and the development of colon cancer. Specifically, increased levels of the bile acid deoxycholic acid (DCA), an established tumor promoter, has been shown to correlate with increased development of colorectal adenomas and progression to carcinoma. Herein we investigate the mechanism by which DCA leads to EGFR-MAPK activation, a candidate mechanism by which DCA may promote colorectal tumorigenesis. DCA treated colon cancer cells exhibited strong and prolonged activation of ERK1/2 when compared to EGF treatment alone. We also showed that DCA treatment prevents EGFR degradation as opposed to the canonical EGFR recycling observed with EGF treatment. Moreover, the combination of DCA and EGF treatment displayed synergistic activity, suggesting DCA activates MAPK signaling in a non-canonical manner. Further evaluation showed that DCA treatment increased intracellular calcium levels and CAMKII phosphorylation, and that blocking calcium with BAPTA-AM abrogated MAPK activation induced by DCA, but not by EGF. Finally we showed that DCA-induced CAMKII leads to MAPK activation through the recruitment of c-Src. Taken together, we demonstrated that DCA regulates MAPK activation through calcium signaling, an alternative mechanism not previously recognized in human colon cancer cells. Importantly, this mechanism allows for EGFR to escape degradation and thus achieve a constitutively active state, which may explain its tumor promoting effects.

  19. Wnt3a regulates proliferation and migration of HUVEC via canonical and non-canonical Wnt signaling pathways

    SciTech Connect

    Samarzija, Ivana; Sini, Patrizia; Schlange, Thomas; MacDonald, Gwen; Hynes, Nancy E.

    2009-08-28

    Untangling the signaling pathways involved in endothelial cell biology is of central interest for the development of antiangiogenesis based therapies. Here we report that Wnt3a induces the proliferation and migration of HUVECs, but does not affect their survival. Wnt3a-induced proliferation was VEGFR signaling independent, but reduced upon CamKII inhibition. In a search for the downstream mediators of Wnt3a's effects on HUVEC biology, we found that Wnt3a treatment leads to phosphorylation of DVL3 and stabilization of {beta}-catenin. Moreover, under the same conditions we observed an upregulation in c-MYC, TIE-2 and GJA1 mRNA transcripts. Although treatment of HUVECs with Wnt5a induced DVL3 phosphorylation, we did not observe any of the other effects seen upon Wnt3a stimulation. Taken together, our data indicate that Wnt3a induces canonical and non-canonical Wnt signaling in HUVECs, and stimulates their proliferation and migration.

  20. A non-canonical function of eukaryotic elongation factor 1A1: regulation of interleukin-6 expression.

    PubMed

    Schulz, Ingo; Engel, Claudia; Niestroj, André J; Kehlen, Astrid; Rahfeld, Jens-Ulrich; Kleinschmidt, Martin; Lehmann, Karola; Roßner, Steffen; Demuth, Hans-Ulrich

    2014-05-01

    Interleukin-6 is one of the most prominent triggers of inflammatory processes. We have shown recently that heteroarylketones (HAKs) interfere with stimulated interleukin-6 expression in astrocytes by suppression of STAT3 phosphorylation at serine 727. Surprisingly, this effect is not based on the inhibition of STAT3-relevant kinases. Therefore, we here used the structurally modified HAK compound biotin-HAK-3 in a reverse chemical approach to identify the relevant molecular target in UV-mediated cross-linking experiments. Employing streptavidin-specific 2D-immunoblotting followed by mass spectrometry we identified nine proteins putatively interacting with biotin-HAK-3. After co-immunoprecipitation, co-immunofluorescence, surface plasmon resonance analyses and RNAi-mediated knock-down, the eukaryotic elongation factor 1A1 (eEF1A1) was verified as the relevant target of HAK bioactivity. eEF1A1 forms complexes with STAT3 and PKCδ, which are crucial for STAT3(S727) phosphorylation and for NF-κB/STAT3-enhanced interleukin-6 expression. Furthermore, the intracellular HAK accumulation is strongly dependent on eEF1A1 expression. Taken together, the results reveal a novel molecular mechanism for a non-canonical role of eEF1A1 in signal transduction via direct modulation of kinase-dependent phosphorylation events.

  1. Canonical and Non-Canonical Aspects of JAK–STAT Signaling: Lessons from Interferons for Cytokine Responses

    PubMed Central

    Majoros, Andrea; Platanitis, Ekaterini; Kernbauer-Hölzl, Elisabeth; Rosebrock, Felix; Müller, Mathias; Decker, Thomas

    2017-01-01

    Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported. These include kinase-independent JAK functions as well as extra- and intranuclear activities of U-STATs without phosphotyrosines. Additionally, transcriptional control by STAT complexes resembling neither GAF nor ISGF3 contributes to transcriptome changes in IFN-treated cells. Our review summarizes the contribution of non-canonical JAK–STAT signaling to the innate antimicrobial immunity imparted by IFN. Moreover, we touch upon functions of IFN pathway proteins beyond the IFN response. These include metabolic functions of IRF9 as well as the regulation of natural killer cell activity by kinase-dead TYK2 and different phosphorylation isoforms of STAT1. PMID:28184222

  2. A Novel, Non-canonical Splice Variant of the Ikaros Gene Is Aberrantly Expressed in B-cell Lymphoproliferative Disorders

    PubMed Central

    Mancarelli, Maria Michela; Verzella, Daniela; Fischietti, Mariafausta; Di Tommaso, Ambra; Maccarone, Rita; Plebani, Sara; Di Ianni, Mauro; Gulino, Alberto; Alesse, Edoardo

    2013-01-01

    The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders. PMID:23874502

  3. The non-canonical mitochondrial inner membrane presequence translocase of trypanosomatids contains two essential rhomboid-like proteins

    PubMed Central

    Harsman, Anke; Oeljeklaus, Silke; Wenger, Christoph; Huot, Jonathan L.; Warscheid, Bettina; Schneider, André

    2016-01-01

    Mitochondrial protein import is essential for all eukaryotes. Here we show that the early diverging eukaryote Trypanosoma brucei has a non-canonical inner membrane (IM) protein translocation machinery. Besides TbTim17, the single member of the Tim17/22/23 family in trypanosomes, the presequence translocase contains nine subunits that co-purify in reciprocal immunoprecipitations and with a presequence-containing substrate that is trapped in the translocation channel. Two of the newly discovered subunits are rhomboid-like proteins, which are essential for growth and mitochondrial protein import. Rhomboid-like proteins were proposed to form the protein translocation pore of the ER-associated degradation system, suggesting that they may contribute to pore formation in the presequence translocase of T. brucei. Pulldown of import-arrested mitochondrial carrier protein shows that the carrier translocase shares eight subunits with the presequence translocase. This indicates that T. brucei may have a single IM translocase that with compositional variations mediates import of presequence-containing and carrier proteins. PMID:27991487

  4. The non-canonical NOTCH1 ligand Delta-like 1 homolog (DLK1) self interacts in mammals.

    PubMed

    Traustadóttir, Gunnhildur Ásta; Jensen, Charlotte Harken; Garcia Ramirez, Jose Javier; Beck, Hans Christian; Sheikh, Søren Paludan; Andersen, Ditte Caroline

    2017-04-01

    Delta-like 1 homolog (DLK1) is an imprinted gene, which is widely expressed during mammalian development and plays a pivotal role in differentiation of various tissue types. Most recently, we have shown that DLK1 interacts with NOTCH1, yet several Notch independent mechanisms have previously been suggested as well, but only poorly confirmed in a mammalian context. In the present study, we employed the mammalian two-hybrid (MTH) system, a genetic in vivo protein-protein interaction system, to show robust DLK1-DLK1, DLK1-FnI (Fibronectin) and DLK1-CFR (cysteine-rich FGF receptor) interactions, whereas the proposed DLK1-IGFBP1 interaction was not supported by MTH. Very little has previously been described on the DLK1 self-interaction. Herein, we showed by immunoprecipitation as well as Sulfo-SBED label transfer that the DLK1-DLK1 interaction likely is part of Dlk1's function in preadipocytes. Furthermore our data suggest that DLK1 interacts with itself through EGF domain 4 and 5, which is distinct from the recently described NOTCH1-DLK1 interaction, which occurs between EGF domain 5 and 6. This opens up the possibility that Notch independent mechanisms like the DLK1-DLK1 interaction may modulate the non-canonical NOTCH1-DLK1 interaction further complexing this system.

  5. Evidence for a non-canonical role of HDAC5 in regulation of the cardiac Ncx1 and Bnp genes

    PubMed Central

    Harris, Lillianne G.; Wang, Sabina H.; Mani, Santhosh K.; Kasiganesan, Harinath; Chou, C. James; Menick, Donald R.

    2016-01-01

    Class IIa histone deacetylases (HDACs) are very important for tissue specific gene regulation in development and pathology. Because class IIa HDAC catalytic activity is low, their exact molecular roles have not been fully elucidated. Studies have suggested that class IIa HDACs may serve as a scaffold to recruit the catalytically active class I HDAC complexes to their substrate. Here we directly address whether the class IIa HDAC, HDAC5 may function as a scaffold to recruit co-repressor complexes to promoters. We examined two well-characterized cardiac promoters, the sodium calcium exchanger (Ncx1) and the brain natriuretic peptide (Bnp) whose hypertrophic upregulation is mediated by both class I and IIa HDACs. Selective inhibition of class IIa HDACs did not prevent adrenergic stimulated Ncx1 upregulation, however HDAC5 knockout prevented pressure overload induced Ncx1 upregulation. Using the HDAC5(-/-) mouse we show that HDAC5 is required for the interaction of the HDAC1/2/Sin3a co-repressor complexes with the Nkx2.5 and YY1 transcription factors and critical for recruitment of the HDAC1/Sin3a co-repressor complex to either the Ncx1 or Bnp promoter. Our novel findings support a non-canonical role of class IIa HDACs in the scaffolding of transcriptional regulatory complexes, which may be relevant for therapeutic intervention for pathologies. PMID:26704971

  6. Structure-based non-canonical amino acid design to covalently crosslink an antibody-antigen complex.

    PubMed

    Xu, Jianqing; Tack, Drew; Hughes, Randall A; Ellington, Andrew D; Gray, Jeffrey J

    2014-02-01

    Engineering antibodies to utilize non-canonical amino acids (NCAA) should greatly expand the utility of an already important biological reagent. In particular, introducing crosslinking reagents into antibody complementarity determining regions (CDRs) should provide a means to covalently crosslink residues at the antibody-antigen interface. Unfortunately, finding the optimum position for crosslinking two proteins is often a matter of iterative guessing, even when the interface is known in atomic detail. Computer-aided antibody design can potentially greatly restrict the number of variants that must be explored in order to identify successful crosslinking sites. We have therefore used Rosetta to guide the introduction of an oxidizable crosslinking NCAA, l-3,4-dihydroxyphenylalanine (l-DOPA), into the CDRs of the anti-protective antigen scFv antibody M18, and have measured crosslinking to its cognate antigen, domain 4 of the anthrax protective antigen. Computed crosslinking distance, solvent accessibility, and interface energetics were three factors considered that could impact the efficiency of l-DOPA-mediated crosslinking. In the end, 10 variants were synthesized, and crosslinking efficiencies were generally 10% or higher, with the best variant crosslinking to 52% of the available antigen. The results suggest that computational analysis can be used in a pipeline for engineering crosslinking antibodies. The rules learned from l-DOPA crosslinking of antibodies may also be generalizable to the formation of other crosslinked interfaces and complexes.

  7. Non-canonical Cajal bodies form in the nucleus of late stage avian oocytes lacking functional nucleolus.

    PubMed

    Khodyuchenko, Tatiana; Gaginskaya, Elena; Krasikova, Alla

    2012-07-01

    In the somatic cell nucleus, there are several universal domains such as nucleolus, SC35-domains, Cajal bodies (CBs) and histone locus bodies (HLBs). Among them, CBs were described more than 100 years ago; however, we still do not have a final understanding of their nature and biological significance. The giant nucleus of avian and amphibian growing oocytes represents an advantageous model for analysis of functions and biogenesis of various nuclear domains. Nevertheless, in large-sized avian oocytes that contain transcriptionally active lampbrush chromosomes, CB-like organelles have not been identified yet. Here we demonstrate that in the pigeon (Columba livia) oocyte nucleus, characterized by absence of any functional nucleoli, extrachromosomal spherical bodies contain TMG-capped spliceosomal snRNAs, core proteins of Sm snRNPs and the protein coilin typical for CBs, but not splicing factor SC35 nor the histone pre-mRNA 3'-end processing factor symplekin. The results establish that coilin-rich nuclear organelles in pigeon late-stage oocyte are not the equivalents of HLBs but belong to a group of CBs. At the same time, they do not contain the snoRNP/scaRNP protein fibrillarin involved in 2'-O-methylation of snoRNAs and snRNAs. Thus, the nucleus of late-stage pigeon oocytes houses CB-like organelles that have an unusual molecular composition and are implicated in the snRNP biogenesis pathway. These data demonstrate that snRNP-rich non-canonical CBs can form in the absence of nucleolus. We argue that pigeon oocytes represent a new promising model to investigate CB modular organization, functions and formation mechanism.

  8. CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling

    PubMed Central

    Rodríguez-Nieves, José A.; Patalano, Susan C.; Almanza, Diego; Gharaee-Kermani, Mehrnaz; Macoska, Jill A.

    2016-01-01

    Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis. PMID:27434301

  9. Loss of a membrane trafficking protein αSNAP induces non-canonical autophagy in human epithelia

    PubMed Central

    Naydenov, Nayden G.; Harris, Gianni; Morales, Victor; Ivanov, Andrei I.

    2012-01-01

    Autophagy is a catabolic process that sequesters intracellular proteins and organelles within membrane vesicles called autophagosomes with their subsequent delivery to lyzosomes for degradation. This process involves multiple fusions of autophagosomal membranes with different vesicular compartments; however, the role of vesicle fusion in autophagosomal biogenesis remains poorly understood. This study addresses the role of a key vesicle fusion regulator, soluble N-ethylmaleimide-sensitive factor attachment protein α (αSNAP), in autophagy. Small interfering RNA-mediated downregulation of αSNAP expression in cultured epithelial cells stimulated the autophagic flux, which was manifested by increased conjugation of microtubule-associated protein light chain 3 (LC3-II) and accumulation of LC3-positive autophagosomes. This enhanced autophagy developed via a non-canonical mechanism that did not require beclin1-p150-dependent nucleation, but involved Atg5 and Atg7-mediated elongation of autophagosomal membranes. Induction of autophagy in αSNAP-depleted cells was accompanied by decreased mTOR signaling but appeared to be independent of αSNAP-binding partners, N-ethylmaleimide-sensitive factor and BNIP1. Loss of αSNAP caused fragmentation of the Golgi and downregulation of the Golgi-specific GTP exchange factors, GBF1, BIG1 and BIG2. Pharmacological disruption of the Golgi and genetic inhibition of GBF1 recreated the effects of αSNAP depletion on the autophagic flux. Our study revealed a novel role for αSNAP as a negative regulator of autophagy that acts by enhancing mTOR signaling and regulating the integrity of the Golgi complex. PMID:23187805

  10. CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling.

    PubMed

    Rodríguez-Nieves, José A; Patalano, Susan C; Almanza, Diego; Gharaee-Kermani, Mehrnaz; Macoska, Jill A

    2016-01-01

    Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis.

  11. Structure of human cytomegalovirus UL141 binding to TRAIL-R2 reveals novel, non-canonical death receptor interactions.

    PubMed

    Nemčovičová, Ivana; Benedict, Chris A; Zajonc, Dirk M

    2013-03-01

    The TRAIL (TNF-related apoptosis inducing ligand) death receptors (DRs) of the tumor necrosis factor receptor superfamily (TNFRSF) can promote apoptosis and regulate antiviral immunity by maintaining immune homeostasis during infection. In turn, human cytomegalovirus (HCMV) expresses immunomodulatory proteins that down-regulate cell surface expression of TNFRSF members as well as poliovirus receptor-related proteins in an effort to inhibit host immune effector pathways that would lead to viral clearance. The UL141 glycoprotein of human cytomegalovirus inhibits host defenses by blocking cell surface expression of TRAIL DRs (by retention in ER) and poliovirus receptor CD155, a nectin-like Ig-fold molecule. Here we show that the immunomodulatory function of HCMV UL141 is associated with its ability to bind diverse proteins, while utilizing at least two distinct binding sites to selectively engage TRAIL DRs or CD155. Binding studies revealed high affinity interaction of UL141 with both TRAIL-R2 and CD155 and low affinity binding to TRAIL-R1. We determined the crystal structure of UL141 bound to TRAIL-R2 at 2.1 Å resolution, which revealed that UL141 forms a homodimer that engages two TRAIL-R2 monomers 90° apart to form a heterotetrameric complex. Our structural and biochemical data reveal that UL141 utilizes its Ig-domain to facilitate non-canonical death receptor interactions while UL141 partially mimics the binding site of TRAIL on TRAIL-R2, which we found to be distinct from that of CD155. Moreover, UL141 also binds to an additional surface patch on TRAIL-R2 that is distinct from the TRAIL binding site. Therefore, the breadth of UL141-mediated effects indicates that HCMV has evolved sophisticated strategies to evade the immune system by modulating multiple effector pathways.

  12. Prospects of In vivo Incorporation of Non-canonical Amino Acids for the Chemical Diversification of Antimicrobial Peptides

    PubMed Central

    Baumann, Tobias; Nickling, Jessica H.; Bartholomae, Maike; Buivydas, Andrius; Kuipers, Oscar P.; Budisa, Nediljko

    2017-01-01

    The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life. Although the primary focus of this report is on ribosomally synthesized and post-translationally modified peptides (RiPPs), we have included selected cases of peptides produced by solid phase peptide synthesis to comparatively show the potential and impact of ncAA introduction. Generally speaking, the introduction of ncAAs in recombinant AMPs delivers novel levels of chemical diversification. Cotranslationally incorporated, they can take part in AMP biogenesis either through direction interaction with elements of the post-translational modification (PTM) machinery or as untargeted sites with unique physicochemical properties and chemical handles for further modification. Together with genetic libraries, genome mining and processing by PTM machineries, ncAAs present not a mere addition to this process, but a highly diverse pool of building blocks to significantly broaden the chemical space of this valuable class of molecules. This perspective summarizes new developments of ncAA containing peptides. Challenges to be resolved in order to reach large-scale pharmaceutical production of these promising compounds and prospects for future developments are discussed. PMID:28210246

  13. Non-canonical Smads phosphorylation induced by the glutamate release inhibitor, riluzole, through GSK3 activation in melanoma.

    PubMed

    Abushahba, Walid; Olabisi, Oyenike O; Jeong, Byeong-Seon; Boregowda, Rajeev K; Wen, Yu; Liu, Fang; Goydos, James S; Lasfar, Ahmed; Cohen-Solal, Karine A

    2012-01-01

    Riluzole, an inhibitor of glutamate release, has shown the ability to inhibit melanoma cell xenograft growth. A phase 0 clinical trial of riluzole as a single agent in patients with melanoma resulted in involution of tumors associated with inhibition of both the mitogen-activated protein kinase (MAPK) and phophoinositide-3-kinase/AKT (PI3K/AKT) pathways in 34% of patients. In the present study, we demonstrate that riluzole inhibits AKT-mediated glycogen synthase kinase 3 (GSK3) phosphorylation in melanoma cell lines. Because we have demonstrated that GSK3 is involved in the phosphorylation of two downstream effectors of transforming growth factor beta (TGFβ), Smad2 and Smad3, at their linker domain, our aim was to determine whether riluzole could induce GSK3β-mediated linker phosphorylation of Smad2 and Smad3. We present evidence that riluzole increases Smad2 and Smad3 linker phosphorylation at the cluster of serines 245/250/255 and serine 204 respectively. Using GSK3 inhibitors and siRNA knock-down, we demonstrate that the mechanism of riluzole-induced Smad phosphorylation involved GSK3β. In addition, GSK3β could phosphorylate the same linker sites in vitro. The riluzole-induced Smad linker phosphorylation is mechanistically different from the Smad linker phosphorylation induced by TGFβ. We also demonstrate that riluzole-induced Smad linker phosphorylation is independent of the expression of the metabotropic glutamate receptor 1 (GRM1), which is one of the glutamate receptors whose involvement in human melanoma has been documented. We further show that riluzole upregulates the expression of INHBB and PLAU, two genes associated with the TGFβ signaling pathway. The non-canonical increase in Smad linker phosphorylation induced by riluzole could contribute to the modulation of the pro-oncogenic functions of Smads in late stage melanomas.

  14. Molecular cloning and characterization of a novel isoform of the non-canonical poly(A) polymerase PAPD7

    SciTech Connect

    Ogami, Koichi; Cho, Rihe; Hoshino, Shin-ichi

    2013-03-01

    Highlights: ► So far, only an enzymatically inactive isoform of PAPD7 was reported. ► The novel isoform: PAPD7 l shows robust nucleotidyl transferase activity. ► The newly identified amino terminal region is required for the activity. ► PAPD7 l localizes to the nucleoplasm. ► The N terminal region identified is also required for the nuclear localization. - Abstract: Non-canonical poly(A) polymerases (ncPAPs) catalyze the addition of poly(A) tail to the 3′ end of RNA to play pivotal roles in the regulation of gene expression and also in quality control. Here we identified a novel isoform of the 7th member of ncPAPs: PAPD7 (PAPD7 l), which contains 230 extra amino acids at the amino terminus of the previously identified PAPD7 (PAPD7 s). In sharp contrast to the inactive PAPD7 s, PAPD7 l showed robust nucleotidyl transferase activity when tethered to an RNA. A region required for the activity was localized to 187–219 aa, and this region was also required for the nuclear retention of PAPD7 l. Western blot analysis revealed that 94 kDa band (corresponding to PAPD7 l) but not 62 kDa band (corresponding to PAPD7 s) detected by PAPD7 antibody was specifically depleted by treatment with PAPD7 siRNA in both HeLa and U2OS cells. These results suggest that PAPD7 l is the major and active isoform of PAPD7 expressed in cells.

  15. Puerarin Attenuates Cardiac Hypertrophy Partly Through Increasing Mir-15b/195 Expression and Suppressing Non-Canonical Transforming Growth Factor Beta (Tgfβ) Signal Pathway

    PubMed Central

    Zhang, Xiuzhou; Liu, Yuxiang; Han, Qingliang

    2016-01-01

    Background Previous studies demonstrated that puerarin has therapeutic effects on cardiac hypertrophy. This study aimed to explore whether the effect of puerarin on attenuating cardiac hypertrophy is related to regulation of microRNAs (miRNAs) and the transforming growth factor beta (TGFβ) signal pathway. Material/Methods The therapeutic effect of puerarin was assessed using an angiotensin (Ang) II-induced heart hypertrophy model in mice. The primary cardiomyocytes were used as an in vitro model. MiR-15 family expression was quantified using qRT-PCR analysis. The expression of the genes involved in canonical and non-canonical TGFβ signal pathways was measured using qRT-PCR and Western blot analysis. In vitro cardiac hypertrophic features were assessed by quantifying cardiac hypertrophic genes and measurement of cell surface, protein synthesis, and total protein content. Results Puerarin attenuated cardiac hypertrophy and increased miR-15b and miR-195 expression in the mouse cardiac hypertrophy model and in primary cardiomyocytes. It suppressed both canonical and non-canonical TGFβ signal pathways, partially through miR-15b and miR-195. Puerarin reduced mRNA expression of cardiac hypertrophic genes, reduced cell surface area, and lowered the rate of protein synthesis and the total protein content induced by Ang II. Knockdown of endogenous miR-15b and miR-195 partly abrogated these effects. Knockdown of endogenous p38, but not Smad2/3/4, presented similar effects as miR-15b. Conclusions Puerarin administration enhances miR-15b and miR-195 expression in an Ang II-induced cardiac hypertrophy model, through which it suppresses both canonical and non-canonical TGFβ signal pathways at the same time. However, the effect of puerarin on attenuating cardiac hypertrophy is mainly through the non-canonical TGFβ pathway. PMID:27145790

  16. A novel non-canonical forkhead-associated (FHA) domain-binding interface mediates the interaction between Rad53 and Dbf4 proteins.

    PubMed

    Matthews, Lindsay A; Selvaratnam, Rajeevan; Jones, Darryl R; Akimoto, Madoka; McConkey, Brendan J; Melacini, Giuseppe; Duncker, Bernard P; Guarné, Alba

    2014-01-31

    Forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains are overrepresented in DNA damage and replication stress response proteins. They function primarily as phosphoepitope recognition modules but can also mediate non-canonical interactions. The latter are rare, and only a few have been studied at a molecular level. We have identified a crucial non-canonical interaction between the N-terminal FHA1 domain of the checkpoint effector kinase Rad53 and the BRCT domain of the regulatory subunit of the Dbf4-dependent kinase that is critical to suppress late origin firing and to stabilize stalled forks during replication stress. The Rad53-Dbf4 interaction is phosphorylation-independent and involves a novel non-canonical interface on the FHA1 domain. Mutations within this surface result in hypersensitivity to genotoxic stress. Importantly, this surface is not conserved in the FHA2 domain of Rad53, suggesting that the FHA domains of Rad53 gain specificity by engaging additional interaction interfaces beyond their phosphoepitope-binding site. In general, our results point to FHA domains functioning as complex logic gates rather than mere phosphoepitope-targeting modules.

  17. Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation

    PubMed Central

    Li, Yinghui; Zhou, Qi-Ling; Sun, Wenjie; Chandrasekharan, Prashant; Cheng, Hui Shan; Ying, Zhe; Lakshmanan, Manikandan; Raju, Anandhkumar; Tenen, Daniel G.; Cheng, Shi-Yuan; Chuang, Kai-Hsiang; Li, Jun; Prabhakar, Shyam; Li, Mengfeng; Tergaonkar, Vinay

    2016-01-01

    Transcriptional reactivation of TERT, the catalytic subunit of telomerase, is necessary for cancer progression in about 90% of human cancers. The recent discovery of two prevalent somatic mutations—C250T and C228T—in the TERT promoter in various cancers has provided insight into a plausible mechanism of TERT reactivation. Although the two hotspot mutations create a similar binding motif for E-twenty-six (ETS) transcription factors, we show that they are functionally distinct, in that the C250T unlike the C228T TERT promoter is driven by non-canonical NF-κB signalling. We demonstrate that binding of ETS to the mutant TERT promoter is insufficient in driving its transcription but this process requires non-canonical NF-κB signalling for stimulus responsiveness, sustained telomerase activity and hence cancer progression. Our findings highlight a previously unrecognized role of non-canonical NF-κB signalling in tumorigenesis and elucidate a fundamental mechanism for TERT reactivation in cancers, which if targeted could have immense therapeutic implications. PMID:26389665

  18. Galectin-1 induces invasion and the epithelial-mesenchymal transition in human gastric cancer cells via non-canonical activation of the hedgehog signaling pathway

    PubMed Central

    Chong, Yang; Tang, Dong; Gao, Jun; Jiang, Xuetong; Xu, Chuanqi; Xiong, Qingquan; Huang, Yuqin; Wang, Jie; Zhou, Huaicheng; Shi, Youquan; Wang, Daorong

    2016-01-01

    Galectin-1 (Gal-1) has been reported to be an independent prognostic indicator of poor survival in gastric cancer and overexpression of Gal-1 enhances the invasiveness of gastric cancer cells. However, the downstream mechanisms by which Gal-1 promotes invasion remains unclear. Moreover, the function of Gal-1 in the epithelial-mesenchymal transition (EMT) in gastric cancer has not yet been elucidated. In this study, we observed Gal-1 expression was upregulated and positively associated with metastasis and EMT markers in 162 human gastric cancer tissue specimens. In vitro studies showed Gal-1 induced invasion, the EMT phenotype and activated the non-canonical hedgehog (Hh) pathway in gastric cancer cell lines. Furthermore, our data revealed that Gal-1 modulated the non-canonical Hh pathway by increasing the transcription of glioma-associated oncogene-1 (Gli-1) via a Smoothened (SMO)-independent manner, and that upregulation of Gal-1 was strongly associated with gastric cancer metastasis. We conclude that Gal-1 promotes invasion and the EMT in gastric cancer cells via activation of the non-canonical Hh pathway, suggesting Gal-1 could represent a promising therapeutic target for the prevention and treatment of gastric cancer metastasis. PMID:27835885

  19. Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation.

    PubMed

    Li, Yinghui; Zhou, Qi-Ling; Sun, Wenjie; Chandrasekharan, Prashant; Cheng, Hui Shan; Ying, Zhe; Lakshmanan, Manikandan; Raju, Anandhkumar; Tenen, Daniel G; Cheng, Shi-Yuan; Chuang, Kai-Hsiang; Li, Jun; Prabhakar, Shyam; Li, Mengfeng; Tergaonkar, Vinay

    2015-10-01

    Transcriptional reactivation of TERT, the catalytic subunit of telomerase, is necessary for cancer progression in about 90% of human cancers. The recent discovery of two prevalent somatic mutations-C250T and C228T-in the TERT promoter in various cancers has provided insight into a plausible mechanism of TERT reactivation. Although the two hotspot mutations create a similar binding motif for E-twenty-six (ETS) transcription factors, we show that they are functionally distinct, in that the C250T unlike the C228T TERT promoter is driven by non-canonical NF-κB signalling. We demonstrate that binding of ETS to the mutant TERT promoter is insufficient in driving its transcription but this process requires non-canonical NF-κB signalling for stimulus responsiveness, sustained telomerase activity and hence cancer progression. Our findings highlight a previously unrecognized role of non-canonical NF-κB signalling in tumorigenesis and elucidate a fundamental mechanism for TERT reactivation in cancers, which if targeted could have immense therapeutic implications.

  20. Prediction of two-photon absorption enhancement in red fluorescent protein chromophores made from non-canonical amino acids.

    PubMed

    Salem, M Alaraby; Twelves, Isaac; Brown, Alex

    2016-09-21

    Two-photon spectroscopy of fluorescent proteins is a powerful bio-imaging tool known for deep tissue penetration and little cellular damage. Being less sensitive than the one-photon microscopy alternatives, a protein with a large two-photon absorption (TPA) cross-section is needed. Here, we use time-dependent density functional theory (TD-DFT) at the B3LYP and CAM-B3LYP/6-31+G(d,p) levels of theory to screen twenty-two possible chromophores that can be formed upon replacing the amino-acid Tyr66 that forms the red fluorescent protein (RFP) chromophore with a non-canonical amino acid. The two-level model for TPA was used to assess the properties (i.e., transition dipole moment, permanent dipole moment difference, and the angle between them) leading to the TPA cross-sections determined via response theory. Computing TPA cross-sections with B3LYP and CAM-B3LYP yields similar overall trends. Results using both functionals agree that the RFP-derived model of the Gold Fluorescent Protein chromophore (Model 20) has the largest intrinsic TPA cross-section at the optimized geometry. TPA was further computed for selected chromophores following conformational changes: variation of both the dihedral angle of the acylimine moiety and the tilt and twist angles between the rings of the chromophore. The TPA cross-section assumed an oscillatory trend with the rotation of the acylimine dihedral, and the TPA is maximized in the planar conformation for almost all models. Model 21 (a hydroxyquinoline derivative) is shown to be comparable to Model 20 in terms of TPA cross-section. The conformational study on Model 21 shows that the acylimine angle has a much stronger effect on the TPA than its tilt and twist angles. Having an intrinsic TPA ability that is more than 7 times that of the native RFP chromophore, Models 20 and 21 appear to be very promising for future experimental investigation.

  1. Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

    PubMed Central

    Sowers, L. P.; Loo, L.; Wu, Y.; Campbell, E.; Ulrich, J. D.; Wu, S.; Paemka, L.; Wassink, T.; Meyer, K.; Bing, X.; El-Shanti, H.; Usachev, Y. M.; Ueno, N.; Manak, R. J.; Shepherd, A. J.; Ferguson, P. J.; Darbro, B. W.; Richerson, G. B.; Mohapatra, D. P.; Wemmie, J. A.; Bassuk, A. G.

    2014-01-01

    Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post synaptic density 95 (PSD-95). Here we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number, and post-synaptic density size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs. PMID:23711981

  2. Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway

    PubMed Central

    Roy, P; Mukherjee, T; Chatterjee, B; Vijayaragavan, B; Banoth, B; Basak, S

    2017-01-01

    Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug

  3. Muscle Fiber Type Specific Activation of the Slow Myosin Heavy Chain 2 Promoter by a Non-canonical E-box

    PubMed Central

    Weimer, Kristina; DiMario, Joseph X.

    2016-01-01

    Different mechanisms control skeletal muscle fiber type gene expression at specific times in vertebrate development. Embryonic myogenesis leading to formation of primary muscle fibers in avian species is largely directed by myoblast cell commitment to the formation of diverse fiber types. In contrast, development of different secondary fiber types during fetal myogenesis is partly determined by neural influences. In both primary and secondary chicken muscle fibers, differential expression of the slow myosin heavy chain 2 (MyHC2) gene distinguishes fast from fast/slow muscle fibers. This study focused on the transcriptional regulation of the slow MyHC2 gene in primary myotubes formed from distinct fast/slow and fast myogenic cell lineages. Promoter deletion analyses identified a discrete 86bp promoter segment that conferred fiber type, lineage-specific gene expression in fast/slow versus fast myoblast derived primary myotubes. Sequence analysis and promoter activity assays determined that this segment contains two functional cis-regulatory elements. One element is a non-canonical E-box, and electromobility shift assays demonstrated that both cis-elements interacted with the E-protein, E47. The results indicate that primary muscle fiber type specific expression of the slow MyHC2 gene is controlled by a novel mechanism involving a transcriptional complex that includes E47 at a non-canonical E-box. PMID:26707643

  4. Canonical Wnt signaling protects hippocampal neurons from Aβ oligomers: role of non-canonical Wnt-5a/Ca(2+) in mitochondrial dynamics.

    PubMed

    Silva-Alvarez, Carmen; Arrázola, Macarena S; Godoy, Juan A; Ordenes, Daniela; Inestrosa, Nibaldo C

    2013-01-01

    Alzheimer's disease (AD) is the most common type of age-related dementia. The disease is characterized by a progressive loss of cognitive abilities, severe neurodegeneration, synaptic loss and mitochondrial dysfunction. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulate the function of the adult nervous system. We report here, that indirect activation of canonical Wnt/β-catenin signaling using Bromoindirubin-30-Oxime (6-BIO), an inhibitor of glycogen synthase kinase-3β, protects hippocampal neurons from amyloid-β (Aβ) oligomers with the concomitant blockade of neuronal apoptosis. More importantly, activation with Wnt-5a, a non-canonical Wnt ligand, results in the modulation of mitochondrial dynamics, preventing the changes induced by Aβ oligomers (Aβo) in mitochondrial fission-fusion dynamics and modulates Bcl-2 increases induced by oligomers. The canonical Wnt-3a ligand neither the secreted Frizzled-Related Protein (sFRP), a Wnt scavenger, did not prevent these effects. In contrast, some of the Aβ oligomer effects were blocked by Ryanodine. We conclude that canonical Wnt/β-catenin signaling controls neuronal survival, and that non-canonical Wnt/Ca(2+)signaling modulates mitochondrial dysfunction. Since mitochondrial dysfunction is present in neurodegenerative diseases, the therapeutic possibilities of the activation of Wnt signaling are evident.

  5. Canonical Wnt signaling protects hippocampal neurons from Aβ oligomers: role of non-canonical Wnt-5a/Ca2+ in mitochondrial dynamics

    PubMed Central

    Silva-Alvarez, Carmen; Arrázola, Macarena S.; Godoy, Juan A.; Ordenes, Daniela; Inestrosa, Nibaldo C.

    2013-01-01

    Alzheimer's disease (AD) is the most common type of age-related dementia. The disease is characterized by a progressive loss of cognitive abilities, severe neurodegeneration, synaptic loss and mitochondrial dysfunction. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulate the function of the adult nervous system. We report here, that indirect activation of canonical Wnt/β-catenin signaling using Bromoindirubin-30-Oxime (6-BIO), an inhibitor of glycogen synthase kinase-3β, protects hippocampal neurons from amyloid-β (Aβ) oligomers with the concomitant blockade of neuronal apoptosis. More importantly, activation with Wnt-5a, a non-canonical Wnt ligand, results in the modulation of mitochondrial dynamics, preventing the changes induced by Aβ oligomers (Aβo) in mitochondrial fission-fusion dynamics and modulates Bcl-2 increases induced by oligomers. The canonical Wnt-3a ligand neither the secreted Frizzled-Related Protein (sFRP), a Wnt scavenger, did not prevent these effects. In contrast, some of the Aβ oligomer effects were blocked by Ryanodine. We conclude that canonical Wnt/β-catenin signaling controls neuronal survival, and that non-canonical Wnt/Ca2+signaling modulates mitochondrial dysfunction. Since mitochondrial dysfunction is present in neurodegenerative diseases, the therapeutic possibilities of the activation of Wnt signaling are evident. PMID:23805073

  6. Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway.

    PubMed

    Kim, Nan-Sun; Mbongue, Jacques C; Nicholas, Dequina A; Esebanmen, Grace E; Unternaehrer, Juli J; Firek, Anthony F; Langridge, William H R

    2016-01-01

    A chimeric protein vaccine composed of the cholera toxin B subunit fused to proinsulin (CTB-INS) was shown to suppress type 1 diabetes onset in NOD mice and upregulate biosynthesis of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in human dendritic cells (DCs). Here we demonstrate siRNA inhibition of the NF-κB-inducing kinase (NIK) suppresses vaccine-induced IDO1 biosynthesis as well as IKKα phosphorylation. Chromatin immunoprecipitation (ChIP) analysis of CTB-INS inoculated DCs showed that RelB bound to NF-κB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-κB pathway activates IDO1 expression in vivo. The addition of Tumor Necrosis Factor Associated Factors (TRAF) TRAF 2, 3 and TRAF6 blocking peptides to vaccine inoculated DCs was shown to inhibit IDO1 biosynthesis. This experimental outcome suggests vaccine activation of the TNFR super-family receptor pathway leads to upregulation of IDO1 biosynthesis in CTB-INS inoculated dendritic cells. Together, our experimental data suggest the CTB-INS vaccine uses a TNFR-dependent signaling pathway of the non-canonical NF-κB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity.

  7. p53 in the mitochondria, as a trans-acting protein, provides error-correction activities during the incorporation of non-canonical dUTP into DNA.

    PubMed

    Bonda, Elad; Rahav, Galia; Kaya, Angelina; Bakhanashvili, Mary

    2016-11-08

    Mutations in mitochondrial DNA is an outcome of errors produced by DNA polymerase γ during replication and failure of the repair mechanism. Misincorporation of non-canonical dUTP leads to mutagenesis or apoptosis, and may contribute to the cytotoxic effects of 5'-fluorouracil chemotherapy. Tumor suppressor p53 protein in the mitochondria displays physical and functional interactions with mitochondrial DNA and polymerase γ, and by its intrinsic 3'→5' exonuclease activity can diminish the polymerization errors. Here we demonstrate the impact of p53 on incorporation of uracil into DNA examined with mitochondrial fractions, as the source of polymerase γ. p53 in mitochondria facilitates DNA damage repair functions resulting from uracil-DNA misincorporation. Our biochemical studies revealed that the procession of U:A and mismatched U:G lesions enhances in the presence of recombinant or endogenous cytoplasmic p53. p53 in mitochondria can function as an exonuclease/proofreader for polymerase γ by either decreasing the incorporation of non-canonical dUTP into DNA or by promoting the excision of incorporated nucleotide from nascent DNA, thus expanding the spectrum of DNA damage sites exploited for proofreading as a trans-acting protein. The data suggest that p53 may contribute to defense of the cells from consequences of dUTP misincorporation in both normal and tumor cells.

  8. Mono and trimethine cyanines Cyan 40 and Cyan 2 as probes for highly selective fluorescent detection of non-canonical DNA structures.

    PubMed

    Kovalska, Vladyslava B; Losytskyy, Mykhaylo Yu; Yarmoluk, Sergiy M; Lubitz, Irit; Kotlyar, Alexander B

    2011-01-01

    Two of earlier reported dsDNA sensitive cyanine dyes-monomethine Cyan 40 and meso-substituted trimethine Cyan 2 were studied for their ability to interact with non-canonical DNA conformations. These dyes were characterized by spectral-luminescent methods in the presence of G-quadruplex, triplex and dsDNA motifs. We have demonstrated that Cyan 2 binds strongly and preferentially to triple- and quadruple-stranded DNA forms that results in a strong enhancement of the dye fluorescence, as compared to dsDNA, while Cyan 40 form fluorescent complexes preferentially only with the triplex form. Highly fluorescent complexes of Cyan 2 with DNA triplexes and G-quadruplexes and Cyan 40 with DNA triplexes are very stable and do not dissociate during gel electrophoresis, leading to preferential staining of the above DNA forms in gels. The data presented point to the intercalation mechanism of the Cyan 2 binding to G4-DNA, while the complexes of Cyan 40 and Cyan 2 with triplex DNA are believed to be formed via groove binding mode. The Cyan dyes can provide a highly sensitive method for detection and quantification of non-canonical structures in genome.

  9. p53 in the mitochondria, as a trans-acting protein, provides error-correction activities during the incorporation of non-canonical dUTP into DNA

    PubMed Central

    Bonda, Elad; Rahav, Galia; Kaya, Angelina; Bakhanashvili, Mary

    2016-01-01

    Mutations in mitochondrial DNA is an outcome of errors produced by DNA polymerase γ during replication and failure of the repair mechanism. Misincorporation of non-canonical dUTP leads to mutagenesis or apoptosis, and may contribute to the cytotoxic effects of 5′-fluorouracil chemotherapy. Tumor suppressor p53 protein in the mitochondria displays physical and functional interactions with mitochondrial DNA and polymerase γ, and by its intrinsic 3′→5′ exonuclease activity can diminish the polymerization errors. Here we demonstrate the impact of p53 on incorporation of uracil into DNA examined with mitochondrial fractions, as the source of polymerase γ. p53 in mitochondria facilitates DNA damage repair functions resulting from uracil–DNA misincorporation. Our biochemical studies revealed that the procession of U:A and mismatched U:G lesions enhances in the presence of recombinant or endogenous cytoplasmic p53. p53 in mitochondria can function as an exonuclease/proofreader for polymerase γ by either decreasing the incorporation of non-canonical dUTP into DNA or by promoting the excision of incorporated nucleotide from nascent DNA, thus expanding the spectrum of DNA damage sites exploited for proofreading as a trans-acting protein. The data suggest that p53 may contribute to defense of the cells from consequences of dUTP misincorporation in both normal and tumor cells. PMID:27689337

  10. Genome-wide mapping of embedded ribonucleotides and other non-canonical nucleotides using emRiboSeq and EndoSeq

    PubMed Central

    Ding, James; Taylor, Martin S.; Jackson, Andrew P.; Reijns, Martin A. M.

    2016-01-01

    Ribonucleotides are the most common non-canonical nucleotides incorporated into the genome of replicating cells. They are efficiently removed by ribonucleotide excision repair initiated by Ribonuclease (RNase) H2 cleavage. In the absence of RNase H2, such embedded ribonucleotides can be used to track DNA polymerase activity in vivo. To determine their precise location in Saccharomyces cerevisiae we developed embedded Ribonucleotide Sequencing (emRiboSeq), which uses recombinant RNase H2 to selectively create ligatable 3’-hydroxyl groups, in contrast to alternative methods that utilize alkaline hydrolysis. EmRiboSeq allows reproducible, strand-specific and potentially quantitative detection of embedded ribonucleotides at single-nucleotide resolution. This protocol can be adapted for the genome-wide mapping of other non-canonical bases by replacing RNase H2 with specific nicking endonucleases, a method we term Endonuclease Sequencing (EndoSeq). With the protocol taking <5 days to complete, these methods allow the in vivo study of DNA replication and repair, including the identification of replication origins and termination regions. PMID:26313479

  11. Interaction between the N-terminal SH3 domain of Nck-alpha and CD3-epsilon-derived peptides: non-canonical and canonical recognition motifs.

    PubMed

    Santiveri, Clara M; Borroto, Aldo; Simón, Luis; Rico, Manuel; Alarcón, Balbino; Jiménez, M Angeles

    2009-01-01

    The first SH3 domain (SH3.1) of Nckalpha specifically recognizes the proline-rich region of CD3varepsilon, a subunit of the T cell receptor complex. We have solved the NMR structure of Nckalpha SH3.1 that shows the characteristic SH3 fold consisting of two antiparallel beta-sheets tightly packed against each other. According to chemical shift mapping analysis, a peptide encompassing residues 150-166 of CD3varepsilon binds at the canonical SH3 binding site. An exhaustive comparison with the structures of other SH3 domains able and unable to bind CD3varepsilon reveals that Nckalpha SH3.1 recognises a non-canonical PxxPxxDY motif that orientates at the binding site as a class II ligand. A positively charged residue (K/R) at position -2 relative to the WW sequence at the beginning of strand beta3 is crucial for PxxDY recognition. A 14-mer optimised Nckalpha SH3.1 ligand was found using a multi-substitution approach. Based on NMR data, this improved ligand binds Nckalpha SH3.1 through a PxxPxRDY motif that combines specific stabilising interactions corresponding to both canonical class II, PxxPx(K/R), and non-canonical PxxPxxDY motifs. This explains its higher capacity for Nckalpha SH3.1 binding relative to the wild type sequence.

  12. Induction of CXC chemokines in human mesenchymal stem cells by stimulation with secreted frizzled-related proteins through non-canonical Wnt signaling

    PubMed Central

    Bischoff, David S; Zhu, Jian-Hua; Makhijani, Nalini S; Yamaguchi, Dean T

    2015-01-01

    AIM: To investigate the effect of secreted frizzled-related proteins (sFRPs) on CXC chemokine expression in human mesenchymal stem cells (hMSCs). METHODS: CXC chemokines such as CXCL5 and CXCL8 are induced in hMSCs during differentiation with osteogenic differentiation medium (OGM) and may be involved in angiogenic stimulation during bone repair. hMSCs were treated with conditioned medium (CM) from L-cells expressing non-canonical Wnt5a protein, or with control CM from wild type L-cells, or directly with sFRPs for up to 10 d in culture. mRNA expression levels of both CXCL5 and CXCL8 were quantitated by real-time reverse transcriptase-polymerase chain reaction and secreted protein levels of these proteins determined by ELISA. Dose- (0-500 ng/mL) and time-response curves were generated for treatment with sFRP1. Signal transduction pathways were explored by western blot analysis with pan- or phosphorylation-specific antibodies, through use of specific pathway inhibitors, and through use of siRNAs targeting specific frizzled receptors (Fzd)-2 and 5 or the receptor tyrosine kinase-like orphan receptor-2 (RoR2) prior to treatment with sFRPs. RESULTS: CM from L-cells expressing Wnt5a, a non-canonical Wnt, stimulated an increase in CXCL5 mRNA expression and protein secretion in comparison to control L-cell CM. sFRP1, which should inhibit both canonical and non-canonical Wnt signaling, surprisingly enhanced the expression of CXCL5 at 7 and 10 d. Dickkopf1, an inhibitor of canonical Wnt signaling prevented the sFRP-stimulated induction of CXCL5 and actually inhibited basal levels of CXCL5 expression at 7 but not at 10 d post treatment. In addition, all four sFRPs isoforms induced CXCL8 expression in a dose- and time-dependent manner with maximum expression at 7 d with treatment at 150 ng/mL. The largest increases in CXCL5 expression were seen from stimulation with sFRP1 or sFRP2. Analysis of mitogen-activated protein kinase signaling pathways in the presence of OGM showed s

  13. The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway

    PubMed Central

    Abdelhamed, Zakia A.; Natarajan, Subaashini; Wheway, Gabrielle; Inglehearn, Christopher F.; Toomes, Carmel; Johnson, Colin A.; Jagger, Daniel J.

    2015-01-01

    ABSTRACT Ciliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67tm1Dgen/H1 knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital

  14. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer.

    PubMed

    Puvirajesinghe, Tania M; Bertucci, François; Jain, Ashish; Scerbo, Pierluigi; Belotti, Edwige; Audebert, Stéphane; Sebbagh, Michael; Lopez, Marc; Brech, Andreas; Finetti, Pascal; Charafe-Jauffret, Emmanuelle; Chaffanet, Max; Castellano, Rémy; Restouin, Audrey; Marchetto, Sylvie; Collette, Yves; Gonçalvès, Anthony; Macara, Ian; Birnbaum, Daniel; Kodjabachian, Laurent; Johansen, Terje; Borg, Jean-Paul

    2016-01-12

    The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2-p62/SQSTM1-JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2-p62/SQSTM1 interaction. VANGL2-JNK signalling is thus a potential target for breast cancer therapy.

  15. Evidence of non-canonical NOTCH signaling: Delta-like 1 homolog (DLK1) directly interacts with the NOTCH1 receptor in mammals.

    PubMed

    Traustadóttir, Gunnhildur Ásta; Jensen, Charlotte H; Thomassen, Mads; Beck, Hans Christian; Mortensen, Sussi B; Laborda, Jorge; Baladrón, Victoriano; Sheikh, Søren P; Andersen, Ditte C

    2016-04-01

    Canonical NOTCH signaling, known to be essential for tissue development, requires the Delta-Serrate-LAG2 (DSL) domain for NOTCH to interact with its ligand. However, despite lacking DSL, Delta-like 1 homolog (DLK1), a protein that plays a significant role in mammalian development, has been suggested to interact with NOTCH1 and act as an antagonist. This non-canonical interaction is, however controversial, and evidence for a direct interaction, still lacking in mammals. In this study, we elucidated the putative DLK1-NOTCH1 interaction in a mammalian context. Taking a global approach and using Dlk1(+/+) and Dlk1(-/-) mouse tissues at E16.5, we demonstrated that several NOTCH signaling pathways indeed are affected by DLK1 during tissue development, and this was supported by a lower activation of NOTCH1 protein in Dlk1(+/+) embryos. Likewise, but using a distinct Dlk1-manipulated (siRNA) setup in a mammalian cell line, NOTCH signaling was substantially inhibited by DLK1. Using a mammalian two-hybrid system, we firmly established that the effect of DLK1 on NOTCH signaling was due to a direct interaction between DLK1 and NOTCH1. By careful dissection of this mechanism, we found this interaction to occur between EGF domains 5 and 6 of DLK1 and EGF domains 10-15 of NOTCH1. Thus, our data provide the first evidence for a direct interaction between DLK1 and NOTCH1 in mammals, and substantiate that non-canonical NOTCH ligands exist, adding to the complexity of NOTCH signaling.

  16. TGF-β1 prevents simulated ischemia/reperfusion-induced cardiac fibroblast apoptosis by activation of both canonical and non-canonical signaling pathways.

    PubMed

    Vivar, Raúl; Humeres, Claudio; Ayala, Pedro; Olmedo, Ivonne; Catalán, Mabel; García, Lorena; Lavandero, Sergio; Díaz-Araya, Guillermo

    2013-06-01

    Ischemia/reperfusion injury is a major cause of myocardial death. In the heart, cardiac fibroblasts play a critical role in healing post myocardial infarction. TGF-β1 has shown cardioprotective effects in cardiac damage; however, if TGF-β1 can prevent cardiac fibroblast death triggered by ischemia/reperfusion is unknown. Therefore, we test this hypothesis, and whether the canonical and/or non-canonical TGF-β1 signaling pathways are involved in this protective effect. Cultured rat cardiac fibroblasts were subjected to simulated ischemia/reperfusion. Cell viability was analyzed by trypan blue exclusion and propidium iodide by flow cytometry. The processing of procaspases 8, 9 and 3 to their active forms was assessed by Western blot, whereas subG1 population was evaluated by flow cytometry. Levels of total and phosphorylated forms of ERK1/2, Akt and Smad2/3 were determined by Western blot. The role of these signaling pathways on the protective effect of TGF-β1 was studied using specific chemical inhibitors. Simulated ischemia over 8h triggers a significant cardiac fibroblast death, which increased by reperfusion, with apoptosis actively involved. These effects were only prevented by the addition of TGF-β1 during reperfusion. TGF-β1 pretreatment increased the levels of phosphorylated forms of ERK1/2, Akt and Smad2/3. The inhibition of ERK1/2, Akt and Smad3 also blocked the preventive effects of TGF-β1 on cardiac fibroblast apoptosis induced by simulated ischemia/reperfusion. Overall, our data suggest that TGF-β1 prevents cardiac fibroblast apoptosis induced by simulated ischemia-reperfusion through the canonical (Smad3) and non canonical (ERK1/2 and Akt) signaling pathways.

  17. A phenotypic screen in zebrafish identifies a novel small-molecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling.

    PubMed

    Gebruers, Evelien; Cordero-Maldonado, María Lorena; Gray, Alexander I; Clements, Carol; Harvey, Alan L; Edrada-Ebel, Ruangelie; de Witte, Peter A M; Crawford, Alexander D; Esguerra, Camila V

    2013-01-01

    Zebrafish have recently emerged as an attractive model for the in vivo bioassay-guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen - Jasminum gilgianum, an Oleaceae species native to Papua New Guinea - induced ectopic tails during zebrafish embryonic development. As ectopic tail formation occurs when BMP or non-canonical Wnt signaling is inhibited during the tail protrusion process, we suspected a constituent of this extract to act as a modulator of these pathways. A bioassay-guided isolation was carried out on the basis of this zebrafish phenotype, identifying para-coumaric acid methyl ester (pCAME) as the active compound. We then performed an in-depth phenotypic analysis of pCAME-treated zebrafish embryos, including a tissue-specific marker analysis of the secondary tails. We found pCAME to synergize with the BMP-inhibitors dorsomorphin and LDN-193189 in inducing ectopic tails, and causing convergence-extension defects in compound-treated embryos. These results indicate that pCAME may interfere with non-canonical Wnt signaling. Inhibition of Jnk, a downstream target of Wnt/PCP signaling (via morpholino antisense knockdown and pharmacological inhibition with the kinase inhibitor SP600125) phenocopied pCAME-treated embryos. However, immunoblotting experiments revealed pCAME to not directly inhibit Jnk-mediated phosphorylation of c-Jun, suggesting additional targets of SP600125, and/or other pathways, as possibly being involved in the ectopic tail formation activity of pCAME. Further investigation of pCAME's mechanism of action will help determine this compound's pharmacological utility.

  18. Estrogen receptor α regulates non-canonical autophagy that provides stress resistance to neuroblastoma and breast cancer cells and involves BAG3 function

    PubMed Central

    Felzen, V; Hiebel, C; Koziollek-Drechsler, I; Reißig, S; Wolfrum, U; Kögel, D; Brandts, C; Behl, C; Morawe, T

    2015-01-01

    Breast cancer is a heterogeneous disease and approximately 70% of newly diagnosed breast cancers are estrogen receptor (ER) positive. Out of the two ER types, α and β, ERα is the only ER that is detectable by immunohistochemistry in breast cancer biopsies and is the predominant subtype expressed in breast tumor tissue. ER-positive tumors are currently treated with anti-hormone therapy to inhibit ER signaling. It is well known that breast cancer cells can develop endocrine resistance and resistance to anti-hormone therapy and this can be facilitated via the autophagy pathway, but so far the description of a detailed autophagy expression profile of ER-positive cancer cells is missing. In the present study, we characterized tumor cell lines ectopically expressing ERα or ERβ as well as the breast cancer-derived MCF-7 cell line endogenously expressing ERα but being ERβ negative. We could show that ERα-expressing cells have a higher autophagic activity than cells expressing ERβ and cells lacking ER expression. Additionally, for autophagy-related gene expression we describe an ERα-specific ‘autophagy-footprint' that is fundamentally different to tumor cells expressing ERβ or lacking ER expression. This newly described ERα-mediated and estrogen response element (ERE)-independent non-canonical autophagy pathway, which involves the function of the co-chaperone Bcl2-associated athanogene 3 (BAG3), is independent of classical mammalian target of rapamycin (mTOR) and phosphatidylinositol 3 kinase (PI3K) signaling networks and provides stress resistance in our model systems. Altogether, our study uncovers a novel non-canonical autophagy pathway that might be an interesting target for personalized medicine and treatment of ERα-positive breast cancer cells that do not respond to anti-hormone therapy and classical autophagy inhibitors. PMID:26158518

  19. TWEAK favors phosphate-induced calcification of vascular smooth muscle cells through canonical and non-canonical activation of NFκB

    PubMed Central

    Hénaut, L; Sanz, A B; Martin-Sanchez, D; Carrasco, S; Villa-Bellosta, R; Aldamiz-Echevarria, G; Massy, Z A; Sanchez-Nino, M D; Ortiz, A

    2016-01-01

    Vascular calcification (VC) is associated with increased cardiovascular mortality in aging, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM) and atherosclerosis. TNF-like weak inducer of apoptosis (TWEAK) recently emerged as a new biomarker for the diagnosis and prognosis of cardiovascular diseases. TWEAK binding to its functional receptor Fn14 was reported to promote several steps of atherosclerotic plaque progression. However, no information is currently available on the role of TWEAK/Fn14 on the development of medial calcification, which is highly prevalent in aging, CKD and T2DM. This study explored the involvement of TWEAK in human vascular smooth muscle cells (h-VSMCs) calcification in vitro. We report that TWEAK binding to Fn14 promotes inorganic phosphate-induced h-VSMCs calcification, favors h-VSMCs osteogenic transition, decreasing acta2 and myh11 and increasing bmp2 mRNA and tissue non-specific alkaline phosphatase (TNAP), and increases MMP9 activity. Blockade of the canonical NFκB pathway reduced by 80% TWEAK pro-calcific properties and decreased osteogenic transition, TNAP and MMP9 activity. Blockade of non-canonical NFκB signaling by a siRNA targeting RelB reduced by 20% TWEAK pro-calcific effects and decreased TWEAK-induced loss of h-VSMCs contractile phenotype and MMP9 activity, without modulating bmp2 mRNA or TNAP activity. Inhibition of ERK1/2 activation by a MAPK kinase inhibitor did not influence TWEAK pro-calcific properties. Our results suggest that TWEAK/Fn14 directly favors inorganic phosphate-induced h-VSMCs calcification by activation of both canonical and non-canonical NFκB pathways. Given the availability of neutralizing anti-TWEAK strategies, our study sheds light on the TWEAK/Fn14 axis as a novel therapeutic target in the prevention of VC. PMID:27441657

  20. The cross-talk between canonical and non-canonical Wnt-dependent pathways regulates P-glycoprotein expression in human blood–brain barrier cells

    PubMed Central

    Pinzón-Daza, Martha L; Salaroglio, Iris C; Kopecka, Joanna; Garzòn, Ruth; Couraud, Pierre-Olivier; Ghigo, Dario; Riganti, Chiara

    2014-01-01

    In this work, we investigate if and how transducers of the ‘canonical' Wnt pathway, i.e., Wnt/glycogen synthase kinase 3 (GSK3)/β-catenin, and transducers of the ‘non-canonical' Wnt pathway, i.e., Wnt/RhoA/RhoA kinase (RhoAK), cooperate to control the expression of P-glycoprotein (Pgp) in blood–brain barrier (BBB) cells. By analyzing human primary brain microvascular endothelial cells constitutively activated for RhoA, silenced for RhoA or treated with the RhoAK inhibitor Y27632, we found that RhoAK phosphorylated and activated the protein tyrosine phosphatase 1B (PTP1B), which dephosphorylated tyrosine 216 of GSK3, decreasing the GSK3-mediated inhibition of β-catenin. By contrast, the inhibition of RhoA/RhoAK axis prevented the activation of PTP1B, enhanced the GSK3-induced phosphorylation and ubiquitination of β-catenin, and reduced the β-catenin-driven transcription of Pgp. The RhoAK inhibition increased the delivery of Pgp substrates like doxorubicin across the BBB and improved the doxorubicin efficacy against glioblastoma cells co-cultured under a BBB monolayer. Our data demonstrate that in human BBB cells the expression of Pgp is controlled by a cross-talk between canonical and non-canonical Wnt pathways. The disruption of this cross-talk, e.g., by inhibiting RhoAK, downregulates Pgp and increases the delivery of Pgp substrates across the BBB. PMID:24896565

  1. Identification of Canonical Tyrosine-dependent and Non-canonical Tyrosine-independent STAT3 Activation Sites in the Intracellular Domain of the Interleukin 23 Receptor*

    PubMed Central

    Floss, Doreen M.; Mrotzek, Simone; Klöcker, Tobias; Schröder, Jutta; Grötzinger, Joachim; Rose-John, Stefan; Scheller, Jürgen

    2013-01-01

    Signaling of interleukin 23 (IL-23) via the IL-23 receptor (IL-23R) and the shared IL-12 receptor β1 (IL-12Rβ1) controls innate and adaptive immune responses and is involved in the differentiation and expansion of IL-17-producing CD4+ T helper (TH17) cells. Activation of signal transducer and activator of transcription 3 (STAT3) appears to be the major signaling pathway of IL-23, and STAT binding sites were predicted in the IL-23R but not in the IL-12Rβ1 chain. Using site-directed mutagenesis and deletion variants of the murine and human IL-23R, we showed that the predicted STAT binding sites (pYXXQ; including Tyr-504 and Tyr-626 in murine IL-23R and Tyr-484 and Tyr-611 in human IL-23R) mediated STAT3 activation. Furthermore, we identified two uncommon STAT3 binding/activation sites within the murine IL-23R. First, the murine IL-23R carried the Y542PNFQ sequence, which acts as an unusual Src homology 2 (SH2) domain-binding protein activation site of STAT3. Second, we identified a non-canonical, phosphotyrosine-independent STAT3 activation motif within the IL-23R. A third predicted site, Tyr-416 in murine and Tyr-397 in human IL-23R, is involved in the activation of PI3K/Akt and the MAPK pathway leading to STAT3-independent proliferation of Ba/F3 cells upon stimulation with IL-23. In contrast to IL-6-induced short term STAT3 phosphorylation, cellular activation by IL-23 resulted in a slower but long term STAT3 phosphorylation, indicating that the IL-23R might not be a major target of negative feedback inhibition by suppressor of cytokine signaling (SOCS) proteins. In summary, we characterized IL-23-dependent signal transduction with a focus on STAT3 phosphorylation and identified canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the IL-23R. PMID:23673666

  2. Bioinformatics and molecular dynamics simulation study of L1 stalk non-canonical rRNA elements: kink-turns, loops, and tetraloops.

    PubMed

    Krepl, Miroslav; Réblová, Kamila; Koča, Jaroslav; Sponer, Jiří

    2013-05-09

    The L1 stalk is a prominent mobile element of the large ribosomal subunit. We explore the structure and dynamics of its non-canonical rRNA elements, which include two kink-turns, an internal loop, and a tetraloop. We use bioinformatics to identify the L1 stalk RNA conservation patterns and carry out over 11.5 μs of MD simulations for a set of systems ranging from isolated RNA building blocks up to complexes of L1 stalk rRNA with the L1 protein and tRNA fragment. We show that the L1 stalk tetraloop has an unusual GNNA or UNNG conservation pattern deviating from major GNRA and YNMG RNA tetraloop families. We suggest that this deviation is related to a highly conserved tertiary contact within the L1 stalk. The available X-ray structures contain only UCCG tetraloops which in addition differ in orientation (anti vs syn) of the guanine. Our analysis suggests that the anti orientation might be a mis-refinement, although even the anti interaction would be compatible with the sequence pattern and observed tertiary interaction. Alternatively, the anti conformation may be a real substate whose population could be pH-dependent, since the guanine syn orientation requires protonation of cytosine in the tertiary contact. In absence of structural data, we use molecular modeling to explore the GCCA tetraloop that is dominant in bacteria and suggest that the GCCA tetraloop is structurally similar to the YNMG tetraloop. Kink-turn Kt-77 is unusual due to its 11-nucleotide bulge. The simulations indicate that the long bulge is a stalk-specific eight-nucleotide insertion into consensual kink-turn only subtly modifying its structural dynamics. We discuss a possible evolutionary role of helix H78 and a mechanism of L1 stalk interaction with tRNA. We also assess the simulation methodology. The simulations provide a good description of the studied systems with the latest bsc0χOL3 force field showing improved performance. Still, even bsc0χOL3 is unable to fully stabilize an essential

  3. EIN2-dependent regulation of acetylation of histone H3K14 and non-canonical histone H3K23 in ethylene signalling

    PubMed Central

    Zhang, Fan; Qi, Bin; Wang, Likai; Zhao, Bo; Rode, Siddharth; Riggan, Nathaniel D.; Ecker, Joseph R.; Qiao, Hong

    2016-01-01

    Ethylene gas is essential for many developmental processes and stress responses in plants. EIN2 plays a key role in ethylene signalling but its function remains enigmatic. Here, we show that ethylene specifically elevates acetylation of histone H3K14 and the non-canonical acetylation of H3K23 in etiolated seedlings. The up-regulation of these two histone marks positively correlates with ethylene-regulated transcription activation, and the elevation requires EIN2. Both EIN2 and EIN3 interact with a SANT domain protein named EIN2 nuclear associated protein 1 (ENAP1), overexpression of which results in elevation of histone acetylation and enhanced ethylene-inducible gene expression in an EIN2-dependent manner. On the basis of these findings we propose a model where, in the presence of ethylene, the EIN2 C terminus contributes to downstream signalling via the elevation of acetylation at H3K14 and H3K23. ENAP1 may potentially mediate ethylene-induced histone acetylation via its interactions with EIN2 C terminus. PMID:27694846

  4. Regulation of natural competence by the orphan two-component system sensor kinase ChiS involves a non-canonical transmembrane regulator in Vibrio cholerae.

    PubMed

    Yamamoto, Shouji; Mitobe, Jiro; Ishikawa, Takahiko; Wai, Sun Nyunt; Ohnishi, Makoto; Watanabe, Haruo; Izumiya, Hidemasa

    2014-01-01

    In Vibrio cholerae, 41 chitin-inducible genes, including the genes involved in natural competence for DNA uptake, are governed by the orphan two-component system (TCS) sensor kinase ChiS. However, the mechanism by which ChiS controls the expression of these genes is currently unknown. Here, we report the involvement of a novel transcription factor termed 'TfoS' in this process. TfoS is a transmembrane protein that contains a large periplasmic domain and a cytoplasmic AraC-type DNA-binding domain, but lacks TCS signature domains. Inactivation of tfoS abolished natural competence as well as transcription of the tfoR gene encoding a chitin-induced small RNA essential for competence gene expression. A TfoS fragment containing the DNA-binding domain specifically bound to and activated transcription from the tfoR promoter. Intracellular TfoS levels were unaffected by disruption of chiS and coexpression of TfoS and ChiS in Escherichia coli recovered transcription of the chromosomally integrated tfoR::lacZ gene, suggesting that TfoS is post-translationally modulated by ChiS during transcriptional activation; however, this regulation persisted when the canonical phosphorelay residues of ChiS were mutated. The results presented here suggest that ChiS operates a chitin-induced non-canonical signal transduction cascade through TfoS, leading to transcriptional activation of tfoR.

  5. Two-photon absorption of fluorescent protein chromophores incorporating non-canonical amino acids: TD-DFT screening and classical dynamics.

    PubMed

    Alaraby Salem, M; Brown, Alex

    2015-10-14

    Two-photon spectroscopy of fluorescent proteins is a powerful bio-imaging tool characterized by deep tissue penetration and little damage. However, two-photon spectroscopy has lower sensitivity than one-photon microscopy alternatives and hence a protein with a large two-photon absorption cross-section is needed. We use time-dependent density functional theory (TD-DFT) at the B3LYP/6-31+G(d,p) level of theory to screen twenty-two possible chromophores that can be formed upon replacing the amino-acid Tyr66 that forms the green fluorescent protein (GFP) chromophore with a non-canonical amino acid. A proposed chromophore with a nitro substituent was found to have a large two-photon absorption cross-section (29 GM) compared to other fluorescent protein chromophores as determined at the same level of theory. Classical molecular dynamics are then performed on a nitro-modified fluorescent protein to test its stability and study the effect of the conformational flexibility of the chromophore on its two-photon absorption cross-section. The theoretical results show that the large cross-section is primarily due to the difference between the permanent dipole moments of the excited and ground states of the nitro-modified chromophore. This large difference is maintained through the various conformations assumed by the chromophore in the protein cavity. The nitro-derived protein appears to be very promising as a two-photon absorption probe.

  6. Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent

    PubMed Central

    Westernberg, Luise; Conche, Claire; Huang, Yina Hsing; Rigaud, Stephanie; Deng, Yisong; Siegemund, Sabine; Mukherjee, Sayak; Nosaka, Lyn'Al; Das, Jayajit; Sauer, Karsten

    2016-01-01

    β-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptors - key cell fate determinants in eukaryotes. Here, we show that this Notch-dependence is established through antagonistic signaling by the pre-TCR/Notch effector, phosphoinositide 3-kinase (PI3K), and by inositol-trisphosphate 3-kinase B (Itpkb). Canonically, PI3K is counteracted by the lipid-phosphatases Pten and Inpp5d/SHIP-1. In contrast, Itpkb dampens pre-TCR induced PI3K/Akt signaling by producing IP4, a soluble antagonist of the Akt-activating PI3K-product PIP3. Itpkb-/- thymocytes are pre-TCR hyperresponsive, hyperactivate Akt, downstream mTOR and metabolism, undergo an accelerated β-selection and can develop to CD4+CD8+ cells without Notch. This is reversed by inhibition of Akt, mTOR or glucose metabolism. Thus, non-canonical PI3K-antagonism by Itpkb restricts pre-TCR induced metabolic activation to enforce coincidence-detection of pre-TCR expression and Notch-engagement. DOI: http://dx.doi.org/10.7554/eLife.10786.001 PMID:26880557

  7. An amino acid depleted cell-free protein synthesis system for the incorporation of non-canonical amino acid analogs into proteins.

    PubMed

    Singh-Blom, Amrita; Hughes, Randall A; Ellington, Andrew D

    2014-05-20

    Residue-specific incorporation of non-canonical amino acids into proteins is usually performed in vivo using amino acid auxotrophic strains and replacing the natural amino acid with an unnatural amino acid analog. Herein, we present an efficient amino acid depleted cell-free protein synthesis system that can be used to study residue-specific replacement of a natural amino acid by an unnatural amino acid analog. This system combines a simple methodology and high protein expression titers with a high-efficiency analog substitution into a target protein. To demonstrate the productivity and efficacy of a cell-free synthesis system for residue-specific incorporation of unnatural amino acids in vitro, we use this system to show that 5-fluorotryptophan and 6-fluorotryptophan substituted streptavidin retain the ability to bind biotin despite protein-wide replacement of a natural amino acid for the amino acid analog. We envisage this amino acid depleted cell-free synthesis system being an economical and convenient format for the high-throughput screening of a myriad of amino acid analogs with a variety of protein targets for the study and functional characterization of proteins substituted with unnatural amino acids when compared to the currently employed in vivo methodologies.

  8. PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds to Plasmodium falciparum telomeres.

    PubMed

    Sierra-Miranda, Miguel; Vembar, Shruthi S; Delgadillo, Dulce María; Ávila-López, P A; Vargas, Miguel; Hernandez-Rivas, Rosaura

    2017-04-04

    The telomeres of the malaria parasite Plasmodium falciparum are essential not only for chromosome end maintenance during blood stage development in humans but also to generate genetic diversity by facilitating homologous recombination of subtelomeric, multigene virulence families such as var and rifin. However, other than the telomerase PfTERT, proteins that act at P. falciparum telomeres are poorly characterized. To isolate components that bind to telomeres, we performed oligonucleotide pulldowns and electromobility shift assays with a telomeric DNA probe and identified a non-canonical member of the ApiAP2 family of transcription factors, PfAP2Tel (encoded by PF3D7_0622900), as a component of the P. falciparum telomere-binding protein complex. PfAP2Tel is expressed throughout the intra-erythrocytic life cycle and localizes to the nuclear periphery, co-localizing with telomeric clusters. Furthermore, EMSAs using the recombinant protein demonstrated direct binding of PfAP2Tel to telomeric repeats in vitro, while genome-wide chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) corroborated the high specificity of this protein to telomeric ends of all 14 chromosomes in vivo. Taken together, our data describe a novel function for ApiAP2 proteins at chromosome ends and open new avenues to study the molecular machinery that regulates telomere function in P. falciparum.

  9. Mutations in two non-canonical Arabidopsis SWI2/SNF2 chromatin remodeling ATPases cause embryogenesis and stem cell maintenance defects

    PubMed Central

    Sang, Yi; Silva-Ortega, Claudia O.; Wu, Shuang; Yamaguchi, Nobutoshi; Wu, Miin-Feng; Pfluger, Jennifer; Gillmor, C. Stewart; Gallagher, Kimberly L.; Wagner, Doris

    2012-01-01

    Summary SWI2/SNF2 chromatin remodeling ATPases play important roles in plant and metazoan development. While metazoans generally encode one or two SWI2/SNF2 ATPase genes, Arabidopsis encodes four such chromatin regulators: the well-studied BRAHMA and SPLAYED ATPases as well as two closely related non-canonical SWI2/SNF2 ATPases, CHR12 and CHR23. No developmental role has as yet been described for CHR12 and CHR23. Here we show that while strong single chr12 or chr23 mutants are morphologically indistinguishable from the wild type, chr12 chr23 double mutants cause embryonic lethality. The double mutant embryos fail to initiate root and shoot meristems and display few and aberrant cell division. Weak double mutant embryos give rise to viable seedlings with dramatic defects in the maintenance of both the shoot and the root stem cell populations. Paradoxically, the stem cell defects are correlated with increased expression of the stem cell markers WUSCHEL and WOX5. During subsequent development, the meristem defects are partially overcome to allow for the formation of very small, bushy adult plants. Based on the observed morphological defects we named the two chromatin remodelers MINUSCULE 1 and 2. Possible links between minu1 minu2 defects and defects in hormone signaling and replication-coupled chromatin assembly are discussed. PMID:23062007

  10. The bHLH/Per-Arnt-Sim transcription factor SIM2 regulates muscle transcript myomesin2 via a novel, non-canonical E-box sequence

    PubMed Central

    Woods, Susan; Farrall, Alexandra; Procko, Carl; Whitelaw, Murray L.

    2008-01-01

    Despite a growing number of descriptive studies that show Single-minded 2 (Sim2) is not only essential for murine survival, but also upregulated in colon, prostate and pancreatic tumours, there is a lack of direct target genes identified for this basic helix–loop–helix/PAS transcription factor. We have performed a set of microarray experiments aimed at identifying genes that are differentially regulated by SIM2, and successfully verified that the Myomesin2 (Myom2) gene is SIM2-responsive. Although SIM2 has been reported to be a transcription repressor, we find that SIM2 induces transcription of Myom2 and activates the Myom2 promoter sequence when co-expressed with the heterodimeric partner protein, ARNT1, in human embryonic kidney cells. Truncation and mutation of the Myom2 promoter sequence, combined with chromatin immunoprecipitation studies in cells, has lead to the delineation of a non-canonical E-box sequence 5′-AACGTG-3′ that is bound by SIM2/ARNT1 heterodimers. Interestingly, in immortalized human myoblasts knock down of Sim2 results in increased levels of Myom2 RNA, suggesting that SIM2 is acting as a repressor in these cells and so its activity is likely to be highly context dependent. This is the first report of a direct SIM2/ARNT1 target gene with accompanying analysis of a functional response element. PMID:18480125

  11. A Conserved Non-Canonical Docking Mechanism Regulates the Binding of Dual Specificity Phosphatases to Cell Integrity Mitogen-Activated Protein Kinases (MAPKs) in Budding and Fission Yeasts

    PubMed Central

    Sacristán-Reviriego, Almudena; Madrid, Marisa; Cansado, José; Martín, Humberto; Molina, María

    2014-01-01

    Dual-specificity MAPK phosphatases (MKPs) are essential for the negative regulation of MAPK pathways. Similar to other MAPK-interacting proteins, most MKPs bind MAPKs through specific docking domains known as D-motifs. However, we found that the Saccharomyces cerevisiae MKP Msg5 binds the MAPK Slt2 within the cell wall integrity (CWI) pathway through a distinct motif (IYT). Here, we demonstrate that the IYT motif mediates binding of the Msg5 paralogue Sdp1 to Slt2 as well as of the MKP Pmp1 to its CWI MAPK counterpart Pmk1 in the evolutionarily distant yeast Schizosaccharomyces pombe. As a consequence, removal of the IYT site in Msg5, Sdp1 and Pmp1 reduces MAPK trapping caused by the overexpression of catalytically inactive versions of these phosphatases. Accordingly, an intact IYT site is necessary for inactive Sdp1 to prevent nuclear accumulation of Slt2. We also show that both Ile and Tyr but not Thr are essential for the functionality of the IYT motif. These results provide mechanistic insight into MKP-MAPK interplay and stress the relevance of this conserved non-canonical docking site in the regulation of the CWI pathway in fungi. PMID:24465549

  12. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2–JNK signalling in breast cancer

    PubMed Central

    Puvirajesinghe, Tania M.; Bertucci, François; Jain, Ashish; Scerbo, Pierluigi; Belotti, Edwige; Audebert, Stéphane; Sebbagh, Michael; Lopez, Marc; Brech, Andreas; Finetti, Pascal; Charafe-Jauffret, Emmanuelle; Chaffanet, Max; Castellano, Rémy; Restouin, Audrey; Marchetto, Sylvie; Collette, Yves; Gonçalvès, Anthony; Macara, Ian; Birnbaum, Daniel; Kodjabachian, Laurent; Johansen, Terje; Borg, Jean-Paul

    2016-01-01

    The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2–p62/SQSTM1–JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2–p62/SQSTM1 interaction. VANGL2–JNK signalling is thus a potential target for breast cancer therapy. PMID:26754771

  13. Swiss Cheese, a protein involved in progressive neurodegeneration acts as a non-canonical regulatory subunit for PKA-C3

    PubMed Central

    da Cruz, Alexandre Bettencourt; Wentzell, Jill; Kretzschmar, Doris

    2008-01-01

    The Drosophila Swiss Cheese (SWS) protein and its vertebrate orthologue Neuropathy Target Esterase (NTE) are required for neuronal survival and glial integrity. In humans, NTE is the target of organophosphorous compounds which cause a paralyzing axonal degeneration and recently mutations in NTE have been shown to cause a Hereditary Spastic Paraplegia called NTE-related Motor-Neuron Disorder. SWS and NTE are concentrated in the endoplasmic reticulum and both have been shown to have an esterase function against an artificial substrate. However, the functional mechanisms and the pathways in which SWS/NTE are involved in are still widely unknown. Here we show that SWS interacts specifically with the C3 catalytic subunit of cAMP activated protein kinase (PKA-C3) which together with orthologues in mouse (Pkare) and human (PrKX) forms a novel class of catalytic subunits of unknown function. This interaction requires a domain of SWS which shows homology to regulatory subunits of PKA and, like conventional regulatory subunits, the binding of SWS to the PKA-C3 inhibits is function. Consistent with this result, expression of additional PKA-C3 induces degeneration and enhances the neurodegenerative phenotype in sws mutants. We also show that the complex formation with the membrane-bound SWS tethers PKA-C3 to membranes. We therefore propose a model in which SWS acts as a non-canonical subunit for PKA-C3, whereby the complex formation regulates the localization and kinase activity of PKA-C3, and that disruption of this regulation can induce neurodegeneration. PMID:18945896

  14. Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes.

    PubMed

    Zhang, Huan; Chen, Li; Cai, Shao-Hui; Cheng, Hua

    2016-07-01

    Persistent activation of NF-κB is a prerequisite for development of adult T cell leukemia-lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes a viral transforming protein named Tax, which constitutively activates the canonical IκB kinases (IKK), the central regulator of NF-κB signaling. However, the role of the non-canonical IκB kinases, TBK1 and IKKε, in the pathogenesis of HTLV-1-associated leukemia has not been evaluated. We here show that TBK1/IKKε are crucial pro-survival molecules by maintaining persistent activity of Stat3. Consistent with this finding, silencing Stat3 by the specific shRNA or by the chemical inhibitor ruxolitinib results in drastic impediment of leukemia cell growth. We further find that in HTLV-1-transformed T cells expressing Tax, TBK1 co-localizes with the canonical IκB kinases and Tax in the lipid raft microdomains. The wild type Tax, but not the Tax mutant defective in activating the canonical IKK, promotes the lipid raft translocation of TBK1. This phenomenon correlates with Tax activation of both NF-κB and Stat3. Tax does not interact directly with TBK1/IKKε, and it rather engages a molecular crosstalk between the canonical IKKs and TBK1/IKKε. Our data, therefore, demonstrate a key role of TBK1/IKKε in the survival and proliferation of HTLV-1-transformed T cells and implicate a potential therapy targeting TBK1/IKKε and Stat3 in controlling HTLV-1-mediated oncogenesis.

  15. Structure and specificity of a new class of Ca(2+) independent housekeeping sortase from Streptomyces avermitilis provides insights into its non-canonical substrate preference.

    PubMed

    Das, Sreetama; Pawale, Vijaykumar S; Dadireddy, Venkatareddy; Singh, Avinash Kumar; Ramakumar, Suryanarayanarao; Roy, Rajendra P

    2017-03-07

    Surface proteins in Gram-positive bacteria are incorporated into the cell wall through a peptide ligation reaction catalyzed by transpeptidase sortase. Six main classes (A-F) of sortase have been identified of which class A sortase is meant for housekeeping functions. The prototypic housekeeping sortase A (SaSrtA) from Staphylococcus aureus cleaves LPXTG-containing proteins at the scissile T-G peptide bond and ligates Protein-LPXT to the terminal Gly residue of the nascent cross-bridge of peptidoglycan Lipid II precursor. Sortase-mediated ligation ('sortagging') of LPXTG-containing substrates and Gly-terminated nucleophiles occurs in vitro as well as in cellulo in the presence of Ca(2+) and has been applied extensively for protein conjugations. Although majority of applications emanate from SaSrtA, low catalytic efficiency, LPXTG specificity restriction, and Ca(2+) requirement (particularly for in cellulo applications) remains a drawback. Given that Gram-positive bacterial genomes encode a variety of sortases, natural sortase mining can be a viable complementary approach akin to engineering of wild type SaSrtA. Here we describe the structure and specificity of a new class E sortase (SavSrtE) annotated to perform housekeeping roles in Streptomyces avermitilis Biochemical experiments define the attributes of an optimum peptide substrate, demonstrate Ca(2+)-independent activity and provide insights about contrasting functional characteristics of SavSrtE and SaSrtA. Crystal structure, substrate docking and mutagenesis experiments have identified a critical residue that dictates the preference for a non-canonical LAXTG recognition motif over LPXTG. These results have implications for rational tailoring of substrate tolerance in sortases. Besides, Ca(2+) independent orthogonal specificity of SavSrtE is likely to expand the sortagging toolkit.

  16. The Structure of Treponema pallidum Tp0751 (Pallilysin) Reveals a Non-canonical Lipocalin Fold That Mediates Adhesion to Extracellular Matrix Components and Interactions with Host Cells

    PubMed Central

    Pětrošová, Helena; Lithgow, Karen V.; Hof, Rebecca; Wetherell, Charmaine; Kao, Wei-Chien; Lin, Yi-Pin; Ebady, Rhodaba; Cameron, Caroline E.

    2016-01-01

    Syphilis is a chronic disease caused by the bacterium Treponema pallidum subsp. pallidum. Treponema pallidum disseminates widely throughout the host and extravasates from the vasculature, a process that is at least partially dependent upon the ability of T. pallidum to interact with host extracellular matrix (ECM) components. Defining the molecular basis for the interaction between T. pallidum and the host is complicated by the intractability of T. pallidum to in vitro culturing and genetic manipulation. Correspondingly, few T. pallidum proteins have been identified that interact directly with host components. Of these, Tp0751 (also known as pallilysin) displays a propensity to interact with the ECM, although the underlying mechanism of these interactions remains unknown. Towards establishing the molecular mechanism of Tp0751-host ECM attachment, we first determined the crystal structure of Tp0751 to a resolution of 2.15 Å using selenomethionine phasing. Structural analysis revealed an eight-stranded beta-barrel with a profile of short conserved regions consistent with a non-canonical lipocalin fold. Using a library of native and scrambled peptides representing the full Tp0751 sequence, we next identified a subset of peptides that showed statistically significant and dose-dependent interactions with the ECM components fibrinogen, fibronectin, collagen I, and collagen IV. Intriguingly, each ECM-interacting peptide mapped to the lipocalin domain. To assess the potential of these ECM-coordinating peptides to inhibit adhesion of bacteria to host cells, we engineered an adherence-deficient strain of the spirochete Borrelia burgdorferi to heterologously express Tp0751. This engineered strain displayed Tp0751 on its surface and exhibited a Tp0751-dependent gain-of-function in adhering to human umbilical vein endothelial cells that was inhibited in the presence of one of the ECM-interacting peptides (p10). Overall, these data provide the first structural insight into the

  17. MIF inhibits monocytic movement through a non-canonical receptor and disruption of temporal Rho GTPase activities in U-937 cells.

    PubMed

    DiCosmo-Ponticello, Crystal J; Hoover, Daniel; Coffman, Frederick D; Cohen, Stanley; Cohen, Marion C

    2014-09-01

    Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that was initially identified by its ability to inhibit the movement of macrophages. Cell migration is a highly complex process involving changes to the cytoskeleton and cell adhesion molecules, and is regulated by the Rho GTPases. A simple model using human monocytic U-937 cells to elicit the classic MIF response was implemented to examine the mechanism of MIF-induced migration inhibition. Our results demonstrate that MIF inhibits migration of these U-937 cells through a non-canonical receptor, CXCR4, in the absence of the putative primary MIF receptor CD74. Migration inhibition is dependent upon a series of temporal perturbations of the activities of the Rho GTPases: initial activation followed by subsequent inactivation of RhoA, inactivation of Rac1, and cyclic activation of Cdc42. MIF-mediated changes in the activities of the Rho GTPases jointly contributed to migration inhibition in these cells. Collectively, these data suggest that the MIF-mediated migration inhibition is mediated by the outcome of G-protein signaling, and in less adherent cells such as those of the monocyte/macrophage lineage, RhoA directly affects net translocation through its ability to induce cell body contraction. These findings demonstrate that CXCR4 can mediate MIF signaling in the absence of CD74 in addition to serving as a MIF co-receptor along with CD74. These results correlate MIF activity to specific and sequential Rho GTPase activity perturbations, and given that CXCR4 functions in numerous processes, suggests potential roles for the modulation of cell movement in those events including development, cell survival and viral infection.

  18. Identification of a non-canonical E-box motif as a regulatory element in the proximal promoter region of the apolipoprotein E gene.

    PubMed Central

    Salero, Enrique; Giménez, Cecilio; Zafra, Francisco

    2003-01-01

    We have used the yeast one-hybrid system to identify transcription factors with binding capability to specific sequences in proximal regions of the apolipoprotein E gene ( APOE ) promoter. The sequence between -113 and -80 nt, which contains regulatory elements in various cell types, was used as a bait to screen a human brain cDNA library. Four cDNA clones that encoded portions of the human upstream-stimulatory-factor (USF) transcription factor were isolated. Electrophoretic-mobility-shift assays ('EMSAs') using nuclear extracts from various human cell lines as well as from rat brain and liver revealed the formation of two DNA-protein complexes within the sequence CACCTCGTGAC (region -101/-91 of the APOE promoter) that show similarity to the E-box element. The retarded complexes contained USF1, as deduced from competition and supershift assays. Functional experiments using different APOE promoter-luciferase reporter constructs transiently transfected into U87, HepG2 or HeLa cell lines showed that mutations that precluded the formation of complexes decreased the basal activity of the promoter by about 50%. Overexpression of USF1 in U87 glioblastoma cells led to an increased activity of the promoter that was partially mediated by the atypical E-box. The stimulatory effect of USF1 was cell-type specific, as it was not observed in hepatoma HepG2 cells. Similarly, overexpression of a USF1 dominant-negative mutant decreased the basal activity of the promoter in glioblastoma, but not in hepatoma, cells. These data indicated that USF, and probably other related transcription factors, might be involved in the basal transcriptional machinery of APOE by binding to a non-canonical E-box motif within the proximal promoter. PMID:12444925

  19. Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells.

    PubMed

    Mehdawi, Lubna M; Prasad, Chandra Prakash; Ehrnström, Roy; Andersson, Tommy; Sjölander, Anita

    2016-11-01

    The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E2 catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression. Therefore, we have in the current study investigated if the non-canonical ligand WNT5A relates to increased expression of 15-PGDH in colon cancer cells. In the same cohort of patients, we demonstrated a parallel and significant loss of 15-PGDH and WNT5A protein expression in CRC tissues compared with matched normal colon tissues. Furthermore, patients with low 15-PGDH/WNT5A expression in their tumors showed reduced survival compared with patients with high 15-PGDH/WNT5A expression. To investigate if WNT5A signaling directly affects 15-PGDH expression, we performed in vitro analyses of colon cancer cells (HT-29 and Caco-2). Both cell lines, when treated with recombinant WNT5A (rWNT5A) or Foxy-5, a WNT5A-mimicking peptide, responded by increasing their expression of 15-PGDH mRNA and protein. Our investigations showed that rWNT5A and Foxy-5 induced this increased expression of 15-PGDH through reduced β-catenin signaling as well as increased JNK/AP-1 signaling in colon cancer cells. WNT5A signaling also induced increased 15-PGDH expression in a breast cancer cell line both in vitro and in vivo. In agreement, WNT5A signaling also increased the expression of the differentiation markers sucrose-isomaltase and mucin-2 in colon cancer cells. Our results show that WNT5A signaling regulates 15-PGDH expression, thus uncovering a novel mechanism by which WNT5A acts as a tumor suppressor and suggests that increased 15-PGDH expression could be used as an indicator of a positive response to Foxy-5 in patients treated with this WNT5A agonist.

  20. The distribution of Elongation Factor-1 Alpha (EF-1alpha), Elongation Factor-Like (EFL), and a non-canonical genetic code in the ulvophyceae: discrete genetic characters support a consistent phylogenetic framework.

    PubMed

    Gile, Gillian H; Novis, Philip M; Cragg, David S; Zuccarello, Giuseppe C; Keeling, Patrick J

    2009-01-01

    The systematics of the green algal class Ulvophyceae have been difficult to resolve with ultrastructural and molecular phylogenetic analyses. Therefore, we investigated relationships among ulvophycean orders by determining the distribution of two discrete genetic characters previously identified only in the order Dasycladales. First, Acetabularia acetabulum uses the core translation GTPase Elongation Factor 1alpha (EF-1alpha) while most Chlorophyta instead possess the related GTPase Elongation Factor-Like (EFL). Second, the nuclear genomes of dasycladaleans A. acetabulum and Batophora oerstedii use a rare non-canonical genetic code in which the canonical termination codons TAA and TAG instead encode glutamine. Representatives of Ulvales and Ulotrichales were found to encode EFL, while Caulerpales, Dasycladales, Siphonocladales, and Ignatius tetrasporus were found to encode EF-1alpha, in congruence with the two major lineages previously proposed for the Ulvophyceae. The EF-1alpha of I. tetrasporus supports its relationship with Caulerpales/Dasycladales/Siphonocladales, in agreement with ultrastructural evidence, but contrary to certain small subunit rRNA analyses that place it with Ulvales/Ulotrichales. The same non-canonical genetic code previously described in A. acetabulum was observed in EF-1alpha sequences from Parvocaulis pusillus (Dasycladales), Chaetomorpha coliformis, and Cladophora cf. crinalis (Siphonocladales), whereas Caulerpales use the universal code. This supports a sister relationship between Siphonocladales and Dasycladales and further refines our understanding of ulvophycean phylogeny.

  1. Cosmology with dynamical extra dimensions

    NASA Astrophysics Data System (ADS)

    Erickson, Joel K.

    Nearly every attempt to unify the fundamental forces incorporates the idea of compact extra dimensions. The notion was introduced by Kaluza and Klein in the 1920s and is an essential part of contemporary string theory and M-theory. In most treatments the extra dimensions are static. We consider the consequences of extra dimensions with time-varying radii. The radii are modeled by light scalar fields. These may have unusual properties which produce observable effects, such as non-canonical kinetic energies, couplings to matter and radiation, and non-minimal coupling to gravity. Extra dimensions may be responsible for dark energy in the late universe. The simplest model of dark energy is characterized by its equation of state. We show that constraints placed on realistic models by the universality of free fall, variation of fundamental constants and metric tests of gravity are often stricter than bounds on the equation of state. Testing the equivalence principle maybe an effective way of distinguishing some quintessence models from a cosmological constant. In certain dark energy models the speed of sound is much less than the speed of light. We calculate how this affects the cosmic microwave background and show that the speed of sound may be measurable, provided dark energy is sufficiently dense at decoupling. This is another possible signature of quintessence. Dynamical extra dimensions may have consequences for the early universe. In the cyclic model, the universe is described in terms of a series of contractions and expansions of an extra dimension. The big bang is preceded by a big crunch and quantum fluctuations of the scalar field produce structure in universe. We consider how the fluctuations evolve and build over many cycles and show that there are no observable instabilities or adverse effects. In the cyclic model extra dimensions act as both dark energy and as an agent to cause contraction and a big crunch. Previous theorems suggested that contraction

  2. HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5

    PubMed Central

    Newie, Inga; Søkilde, Rolf; Persson, Helena; Jacomasso, Thiago; Gorbatenko, Andrej; Borg, Åke; de Hoon, Michiel; Pedersen, Stine F.; Rovira, Carlos

    2016-01-01

    We previously reported that the human HER2 gene encodes the intronic microRNA mir-4728, which is overexpressed together with its oncogenic host gene and may act independently of the HER2 receptor. More recently, we also reported that the oncogenic miR-21-5p is regulated by 3′ tailing and trimming by the non-canonical poly(A) polymerase PAPD5 and the ribonuclease PARN. Here we demonstrate a dual function for the HER2 locus in upregulation of miR-21-5p; while HER2 signalling activates transcription of mir-21, miR-4728-3p specifically stabilises miR-21-5p through inhibition of PAPD5. Our results establish a new and unexpected oncogenic role for the HER2 locus that is not currently being targeted by any anti-HER2 therapy. PMID:27752128

  3. Canonical and Non-canonical Reelin Signaling

    PubMed Central

    Bock, Hans H.; May, Petra

    2016-01-01

    Reelin is a large secreted glycoprotein that is essential for correct neuronal positioning during neurodevelopment and is important for synaptic plasticity in the mature brain. Moreover, Reelin is expressed in many extraneuronal tissues; yet the roles of peripheral Reelin are largely unknown. In the brain, many of Reelin’s functions are mediated by a molecular signaling cascade that involves two lipoprotein receptors, apolipoprotein E receptor-2 (Apoer2) and very low density-lipoprotein receptor (Vldlr), the neuronal phosphoprotein Disabled-1 (Dab1), and members of the Src family of protein tyrosine kinases as crucial elements. This core signaling pathway in turn modulates the activity of adaptor proteins and downstream protein kinase cascades, many of which target the neuronal cytoskeleton. However, additional Reelin-binding receptors have been postulated or described, either as coreceptors that are essential for the activation of the “canonical” Reelin signaling cascade involving Apoer2/Vldlr and Dab1, or as receptors that activate alternative or additional signaling pathways. Here we will give an overview of canonical and alternative Reelin signaling pathways, molecular mechanisms involved, and their potential physiological roles in the context of different biological settings. PMID:27445693

  4. De Novo Assembly of Human Herpes Virus Type 1 (HHV-1) Genome, Mining of Non-Canonical Structures and Detection of Novel Drug-Resistance Mutations Using Short- and Long-Read Next Generation Sequencing Technologies

    PubMed Central

    Karamitros, Timokratis; Piorkowska, Renata; Katzourakis, Aris; Magiorkinis, Gkikas; Mbisa, Jean Lutamyo

    2016-01-01

    Human herpesvirus type 1 (HHV-1) has a large double-stranded DNA genome of approximately 152 kbp that is structurally complex and GC-rich. This makes the assembly of HHV-1 whole genomes from short-read sequencing data technically challenging. To improve the assembly of HHV-1 genomes we have employed a hybrid genome assembly protocol using data from two sequencing technologies: the short-read Roche 454 and the long-read Oxford Nanopore MinION sequencers. We sequenced 18 HHV-1 cell culture-isolated clinical specimens collected from immunocompromised patients undergoing antiviral therapy. The susceptibility of the samples to several antivirals was determined by plaque reduction assay. Hybrid genome assembly resulted in a decrease in the number of contigs in 6 out of 7 samples and an increase in N(G)50 and N(G)75 of all 7 samples sequenced by both technologies. The approach also enhanced the detection of non-canonical contigs including a rearrangement between the unique (UL) and repeat (T/IRL) sequence regions of one sample that was not detectable by assembly of 454 reads alone. We detected several known and novel resistance-associated mutations in UL23 and UL30 genes. Genome-wide genetic variability ranged from <1% to 53% of amino acids in each gene exhibiting at least one substitution within the pool of samples. The UL23 gene had one of the highest genetic variabilities at 35.2% in keeping with its role in development of drug resistance. The assembly of accurate, full-length HHV-1 genomes will be useful in determining genetic determinants of drug resistance, virulence, pathogenesis and viral evolution. The numerous, complex repeat regions of the HHV-1 genome currently remain a barrier towards this goal. PMID:27309375

  5. In-Frame Amber Stop Codon Replacement Mutagenesis for the Directed Evolution of Proteins Containing Non-Canonical Amino Acids: Identification of Residues Open to Bio-Orthogonal Modification

    PubMed Central

    Arpino, James A. J.; Baldwin, Amy J.; McGarrity, Adam R.; Tippmann, Eric M.; Jones, D. Dafydd

    2015-01-01

    Expanded genetic code approaches are a powerful means to add new and useful chemistry to proteins at defined residues positions. One such use is the introduction of non-biological reactive chemical handles for site-specific biocompatible orthogonal conjugation of proteins. Due to our currently limited information on the impact of non-canonical amino acids (nAAs) on the protein structure-function relationship, rational protein engineering is a “hit and miss” approach to selecting suitable sites. Furthermore, dogma suggests surface exposed native residues should be the primary focus for introducing new conjugation chemistry. Here we describe a directed evolution approach to introduce and select for in-frame codon replacement to facilitate engineering proteins with nAAs. To demonstrate the approach, the commonly reprogrammed amber stop codon (TAG) was randomly introduced in-frame in two different proteins: the bionanotechnologically important cyt b562 and therapeutic protein KGF. The target protein is linked at the gene level to sfGFP via a TEV protease site. In absence of a nAA, an in-frame TAG will terminate translation resulting in a non-fluorescent cell phenotype. In the presence of a nAA, TAG will encode for nAA incorporation so instilling a green fluorescence phenotype on E. coli. The presence of endogenously expressed TEV proteases separates in vivo target protein from its fusion to sfGFP if expressed as a soluble fusion product. Using this approach, we incorporated an azide reactive handle and identified residue positions amenable to conjugation with a fluorescence dye via strain-promoted azide-alkyne cycloaddition (SPAAC). Interestingly, best positions for efficient conjugation via SPAAC were residues whose native side chain were buried through analysis of their determined 3D structures and thus may not have been chosen through rational protein engineering. Molecular modeling suggests these buried native residues could become partially exposed on

  6. Dynamical system of scalar field from 2-dimension to 3-D and its cosmological implications

    NASA Astrophysics Data System (ADS)

    Fang, Wei; Tu, Hong; Huang, Jiasheng; Shu, Chenggang

    2016-09-01

    We give the three-dimensional dynamical autonomous systems for most of the popular scalar field dark energy models including (phantom) quintessence, (phantom) tachyon, K-essence, and general non-canonical scalar field models, change the dynamical variables from variables (x, y, λ ) to observable related variables (w_{φ }, Ω _{φ }, λ ), and show the intimate relationships between those scalar fields that the three-dimensional system of K-essence can reduce to (phantom) tachyon, general non-canonical scalar field can reduce to (phantom) quintessence and K-essence can also reduce to (phantom) quintessence for some special cases. For the applications of the three-dimensional dynamical systems, we investigate several special cases and give the exactly dynamical solutions in detail. In the end of this paper, we argue that it is more convenient and also has more physical meaning to express the differential equations of dynamical systems in (w_{φ }, Ω _{φ }, λ ) instead of variables (x, y, λ ) and to investigate the dynamical system in three dimensions instead of two dimensions. We also raise a question about the possibility of the chaotic behavior in the spatially flat single scalar field FRW cosmological models in the presence of ordinary matter.

  7. Extra Dimensions

    SciTech Connect

    Hewett, J.

    2004-10-05

    The large separation between the weak scale {approx} 10{sup 3} GeV and the traditional scale of gravity--the Planck scale with M{sub PI} {approx} 10{sup 19} GeV--is one of the most puzzling aspects of nature. The origin of this large ratio, as well as its stability under radiative corrections, demands explanation. This is known as the hierarchy problem. One theoretical means of solving this problem is to introduce Supersymmetry. Alternatively one may hope to address the hierarchy by exploiting the geometry of space time. Specifically, recent theories involve the idea that the 3-spatial dimensions in which we live could be a 3-spatial-dimensional ''membrane'' embedded in a much larger extra dimensional space, and that the hierarchy is generated by the geometry of the additional dimensions. Such ideas have led to extra dimensional theories which have verifiable consequences at the TeV scale. Our knowledge of the weak and strong forces extends down to scales of {approx} (100 GeV){sup -1} (or of order 10{sup -15} mm). On the other hand, we have almost no knowledge of gravity at distances less than roughly a millimeter, as direct tests of the gravitational force at the smallest distances are based on torsion-balance experiments, which are mechanically limited. It is thus conceivable that gravity may behave quite differently from the 3-dimensional Newtonian theory at small distances. This leads to the possibility that matter and non-gravitational forces are confined to our 3-dimensional subspace, whereas gravity may propagate throughout a higher dimensional volume. In this case, the gauge forces are trapped within our 3-dimensional space, unaware of the extra dimensions, and maintain their usual behavior. Gravity, on the other hand, would no longer follow the inverse-square force law at distances smaller than the size of the extra dimensions, as the gravitational equivalent of Gauss' Law mandates that the gravitational field spreads out into the full spatial volume

  8. Dimension stone

    USGS Publications Warehouse

    Dolley, T.P.

    2003-01-01

    Dimension stone can be defined as natural rock material quarried to obtain blocks or slabs that meet specifications as to size (width, length and thickness) and shape for architectural or engineering purposes. Color, grain texture and pattern, and surface finish of the stone are also normal requirements. Other important selection criteria are durability (based on mineral composition, hardness and past performance), strength and the ability of the stone to take a polish.

  9. Doing without dimensions

    NASA Astrophysics Data System (ADS)

    Spurgin, C. B.

    1986-03-01

    The author discusses the concept of dimensions of a physical quantity, and the relationship between derived units (expressed in terms of their base units) and the dimensions of the derived quantities. He calls for the replacement of 'dimensions' by base units in the GCE A-level syllabus and provides some recommendations to GCE examining boards.

  10. Dimension of chaotic attractors

    SciTech Connect

    Farmer, J.D.; Ott, E.; Yorke, J.A.

    1982-09-01

    Dimension is perhaps the most basic property of an attractor. In this paper we discuss a variety of different definitions of dimension, compute their values for a typical example, and review previous work on the dimension of chaotic attractors. The relevant definitions of dimension are of two general types, those that depend only on metric properties, and those that depend on probabilistic properties (that is, they depend on the frequency with which a typical trajectory visits different regions of the attractor). Both our example and the previous work that we review support the conclusion that all of the probabilistic dimensions take on the same value, which we call the dimension of the natural measure, and all of the metric dimensions take on a common value, which we call the fractal dimension. Furthermore, the dimension of the natural measure is typically equal to the Lyapunov dimension, which is defined in terms of Lyapunov numbers, and thus is usually far easier to calculate than any other definition. Because it is computable and more physically relevant, we feel that the dimension of the natural measure is more important than the fractal dimension.

  11. Dimensions of Educational Need.

    ERIC Educational Resources Information Center

    Johns, Roe L., Ed.; And Others

    Roe L. Johns and J. Alan Thomas survey the problem of educational need; and Kern Alexander considers the implications of the dimensions of educational need for school financing. Dimensions of need in the following areas are defined: early childhood and basic elementary and secondary education, by William P. McLure; educational programs for…

  12. The Qualitative Dimension.

    ERIC Educational Resources Information Center

    Lodge-Peters, Dianne S.

    The qualitative dimension of educational research methodology is explored, and the literature of qualitative methodology is reviewed so researchers may (1) understand more fully the qualitative dimension as it, in turn, fits within the parameters of educational research as a whole, and (2) have more informed access to the sometimes daunting array…

  13. Navigating between the Dimensions

    ERIC Educational Resources Information Center

    Fleron, Julian F.; Ecke, Volker

    2011-01-01

    Generations have been inspired by Edwin A. Abbott's profound tour of the dimensions in his novella "Flatland: A Romance of Many Dimensions" (1884). This well-known satire is the story of a flat land inhabited by geometric shapes trying to navigate the subtleties of their geometric, social, and political positions. In this article, the authors…

  14. A non-canonical mismatch repair pathway in prokaryotes.

    PubMed

    Castañeda-García, A; Prieto, A I; Rodríguez-Beltrán, J; Alonso, N; Cantillon, D; Costas, C; Pérez-Lago, L; Zegeye, E D; Herranz, M; Plociński, P; Tonjum, T; García de Viedma, D; Paget, M; Waddell, S J; Rojas, A M; Doherty, A J; Blázquez, J

    2017-01-27

    Mismatch repair (MMR) is a near ubiquitous pathway, essential for the maintenance of genome stability. Members of the MutS and MutL protein families perform key steps in mismatch correction. Despite the major importance of this repair pathway, MutS-MutL are absent in almost all Actinobacteria and many Archaea. However, these organisms exhibit rates and spectra of spontaneous mutations similar to MMR-bearing species, suggesting the existence of an alternative to the canonical MutS-MutL-based MMR. Here we report that Mycobacterium smegmatis NucS/EndoMS, a putative endonuclease with no structural homology to known MMR factors, is required for mutation avoidance and anti-recombination, hallmarks of the canonical MMR. Furthermore, phenotypic analysis of naturally occurring polymorphic NucS in a M. smegmatis surrogate model, suggests the existence of M. tuberculosis mutator strains. The phylogenetic analysis of NucS indicates a complex evolutionary process leading to a disperse distribution pattern in prokaryotes. Together, these findings indicate that distinct pathways for MMR have evolved at least twice in nature.

  15. Activation of B cells by non-canonical helper signals.

    PubMed

    Cerutti, Andrea; Cols, Montserrat; Puga, Irene

    2012-09-01

    Cognate interaction between T and B lymphocytes of the adaptive immune system is essential for the production of high-affinity antibodies against microbes, and for the establishment of long-term immunological memory. Growing evidence shows that--in addition to presenting antigens to T and B cells--macrophages, dendritic cells and other cells of the innate immune system provide activating signals to B cells, as well as survival signals to antibody-secreting plasma cells. Here, we discuss how these innate immune cells contribute to the induction of highly diversified and temporally sustained antibody responses, both systemically and at mucosal sites of antigen entry.

  16. A non-canonical mismatch repair pathway in prokaryotes

    PubMed Central

    Castañeda-García, A.; Prieto, A. I.; Rodríguez-Beltrán, J.; Alonso, N.; Cantillon, D.; Costas, C.; Pérez-Lago, L.; Zegeye, E. D.; Herranz, M.; Plociński, P.; Tonjum, T.; García de Viedma, D.; Paget, M.; Waddell, S. J.; Rojas, A. M.; Doherty, A. J.; Blázquez, J.

    2017-01-01

    Mismatch repair (MMR) is a near ubiquitous pathway, essential for the maintenance of genome stability. Members of the MutS and MutL protein families perform key steps in mismatch correction. Despite the major importance of this repair pathway, MutS–MutL are absent in almost all Actinobacteria and many Archaea. However, these organisms exhibit rates and spectra of spontaneous mutations similar to MMR-bearing species, suggesting the existence of an alternative to the canonical MutS–MutL-based MMR. Here we report that Mycobacterium smegmatis NucS/EndoMS, a putative endonuclease with no structural homology to known MMR factors, is required for mutation avoidance and anti-recombination, hallmarks of the canonical MMR. Furthermore, phenotypic analysis of naturally occurring polymorphic NucS in a M. smegmatis surrogate model, suggests the existence of M. tuberculosis mutator strains. The phylogenetic analysis of NucS indicates a complex evolutionary process leading to a disperse distribution pattern in prokaryotes. Together, these findings indicate that distinct pathways for MMR have evolved at least twice in nature. PMID:28128207

  17. The dimensions of indexing.

    PubMed

    Wilbur, W John; Kim, Won

    2003-01-01

    Indexing of documents is an important strategy intended to make the literature more readily available to the user. Here we describe several dimensions of indexing that are important if indexing is to be optimal. These dimensions are coverage, predictability, and transparency. MeSH terms and text words are compared in MEDLINE in regard to these dimensions. Part of our analysis consists in applying AdaBoost with decisions trees as the weak learners to estimate how reliably index terms are being assigned and how complex the criteria are by which they are being assigned. Our conclusions are that MeSH terms are more predictable and more transparent than text words.

  18. Phenylalanine ammonia lyase from Arabidopsis thaliana (AtPAL2): a potent enzyme for the synthesis of non-canonical aromatic alpha-amino acids: Part I: Comparative characterization to the enzymes from Petroselinum crispum (PcPAL1) and Rhodosporidium toruloides (RtPAL).

    PubMed

    Dreßen, Alana; Hilberath, Thomas; Mackfeld, Ursula; Billmeier, Arne; Rudat, Jens; Pohl, Martina

    2017-04-06

    Phenylalanine ammonia lyase (PAL) from Arabidopsis thaliana (AtPAL2) was comparatively characterized to the well-studied enzyme from parsley (PcPAL1) and Rhodosporidium toruloides (RtPAL) with respect to kinetic parameters for the deamination and the amination reaction, pH- and temperature optima and the substrate range of the amination reaction. Whereas both plant enzymes are specific for phenylalanine, the bifunctional enzyme from Rhodosporidium toruloides shows KM-values for L-Phe and L-Tyr in the same order of magnitude and, compared to both plant enzymes, a 10-15-fold higher activity. At 30°C all enzymes were sufficiently stable with half-lives of 3.4days (PcPAL1), 4.6days (AtPAL2) and 9.7days (RtPAL/TAL). Very good results for the amination of various trans-cinnamic acid derivatives were obtained using E. coli cells as whole cell biocatalysts in ammonium carbonate buffer. Investigation of the substrate ranges gave interesting results for the newly tested enzymes from A. thaliana and R. toruloides. Only the latter accepts besides 4-hydroxy-CA also 3-methoxy-4-hydroxy-CA as a substrate, which is an interesting intermediate for the formation of pharmaceutically relevant L-Dopa. AtPAL2 is a very good catalyst for the formation of (S)-3-F-Phe, (S)-4-F-Phe and (S)-2-Cl-Phe. Such non-canonical amino acids are valuable building blocks for the formation of various drug molecules.

  19. Polyhedra and Higher Dimensions.

    ERIC Educational Resources Information Center

    Scott, Paul

    1988-01-01

    Describes the definition and characteristics of a regular polyhedron, tessellation, and pseudopolyhedra with diagrams. Discusses the nature of simplex, hypercube, and cross-polytope in the fourth dimension and beyond. (YP)

  20. Dimensions of Aesthetic Perception.

    ERIC Educational Resources Information Center

    Biaggio, Mary Kay; Supplee, Katherine A.

    1983-01-01

    Examines the validity of three dimensions of aesthetic perception: hedonic value, arousal, and uncertainty. Hedonic interest and arousal factors were found to differ from factors previously reported, while the uncertainty factor paralleled that previously reported. (Author/RH)

  1. Rokhlin Dimension for Flows

    NASA Astrophysics Data System (ADS)

    Hirshberg, Ilan; Szabó, Gábor; Winter, Wilhelm; Wu, Jianchao

    2016-10-01

    We introduce a notion of Rokhlin dimension for one parameter automorphism groups of {C^*} -algebras. This generalizes Kishimoto's Rokhlin property for flows, and is analogous to the notion of Rokhlin dimension for actions of the integers and other discrete groups introduced by the authors and Zacharias in previous papers. We show that finite nuclear dimension and absorption of a strongly self-absorbing {C^*} -algebra are preserved under forming crossed products by flows with finite Rokhlin dimension, and that these crossed products are stable. Furthermore, we show that a flow on a commutative {C^*} -algebra arising from a free topological flow has finite Rokhlin dimension, whenever the spectrum is a locally compact metrizable space with finite covering dimension. For flows that are both free and minimal, this has strong consequences for the associated crossed product {C^{*}} -algebras: Those containing a non-zero projection are classified by the Elliott invariant (for compact manifolds this consists of topological {K} -theory together with the space of invariant probability measures and a natural pairing given by the Ruelle-Sullivan map).

  2. Perceptual dimensions differentiate emotions.

    PubMed

    Cavanaugh, Lisa A; MacInnis, Deborah J; Weiss, Allen M

    2015-08-26

    Individuals often describe objects in their world in terms of perceptual dimensions that span a variety of modalities; the visual (e.g., brightness: dark-bright), the auditory (e.g., loudness: quiet-loud), the gustatory (e.g., taste: sour-sweet), the tactile (e.g., hardness: soft vs. hard) and the kinaesthetic (e.g., speed: slow-fast). We ask whether individuals use perceptual dimensions to differentiate emotions from one another. Participants in two studies (one where respondents reported on abstract emotion concepts and a second where they reported on specific emotion episodes) rated the extent to which features anchoring 29 perceptual dimensions (e.g., temperature, texture and taste) are associated with 8 emotions (anger, fear, sadness, guilt, contentment, gratitude, pride and excitement). Results revealed that in both studies perceptual dimensions differentiate positive from negative emotions and high arousal from low arousal emotions. They also differentiate among emotions that are similar in arousal and valence (e.g., high arousal negative emotions such as anger and fear). Specific features that anchor particular perceptual dimensions (e.g., hot vs. cold) are also differentially associated with emotions.

  3. Selective Attention to Perceptual Dimensions and Switching between Dimensions

    ERIC Educational Resources Information Center

    Meiran, Nachshon; Dimov, Eduard; Ganel, Tzvi

    2013-01-01

    In the present experiments, the question being addressed was whether switching attention between perceptual dimensions and selective attention to dimensions are processes that compete over a common resource? Attention to perceptual dimensions is usually studied by requiring participants to ignore a never-relevant dimension. Selection failure…

  4. Moving between Dimensions

    ERIC Educational Resources Information Center

    Stephenson, Paul

    2012-01-01

    The first word of this item is "imagine". This instruction has the potential to signal a journey through a world of geometry that might leave you spellbound. On the other hand, it could be the start of a roller-coaster ride through three dimensions that will tax both your imagination, and your powers of visualisation. It is likely that you will…

  5. Physics in One Dimension

    ERIC Educational Resources Information Center

    Bertel, Erminald

    2013-01-01

    Due to progress in nanotechnology high-quality quantum wires can nowadays be fabricated. The behavior of particles in one dimension differs significantly from that in three-dimensional (3D) systems, yet the physics of such low-dimensional systems is generally not very well represented in standard undergraduate or graduate curricula. For instance,…

  6. Big Mysteries: Extra Dimensions

    SciTech Connect

    Lincoln, Don

    2014-06-10

    The weakness of gravity compared to the other subatomic forces is a real mystery. While nobody knows the answer, one credible solution is that gravity has access to more spatial dimensions than the other three known forces. In this video, Fermilab's Dr. Don Lincoln describes this idea, with the help of some very urbane characters.

  7. Dimensions of Nonverbal Communication.

    ERIC Educational Resources Information Center

    Overmier, Mary; And Others

    After a brief description of the dimensions of nonverbal communication, this booklet presents 21 activities that deal with nonverbal communication. Activities in the booklet involve body movements (kinesics), facial expressions, eye movements, perception and use of space (proxemics), haptics (touch), paralinguistics (vocal elements that accompany…

  8. Constructing gravitational dimensions

    NASA Astrophysics Data System (ADS)

    Schwartz, Matthew

    2003-07-01

    It would be extremely useful to know whether a particular low energy effective theory might have come from a compactification of a higher dimensional space. Here, this problem is approached from the ground up by considering theories with multiple interacting massive gravitons. It is actually very difficult to construct discrete gravitational dimensions which have a local continuum limit. In fact, any model with only nearest neighbor interactions is doomed. If we could find a non-linear extension for the Fierz-Pauli Lagrangian for a graviton of mass mg, which does not break down until the scale Λ2=(mgMPl), this could be used to construct a large class of models whose continuum limit is local in the extra dimension. But this is shown to be impossible: a theory with a single graviton must break down by Λ3=(m2gMPl)1/3. Next, we look at how the discretization prescribed by the truncation of the Kaluza-Klein tower of an honest extra dimension raises the scale of strong coupling. It dictates an intricate set of interactions among various fields which conspire to soften the strongest scattering amplitudes and allow for a local continuum limit, at least at the tree level. A number of candidate symmetries associated with locality in the discretized dimension are also discussed.

  9. Big Mysteries: Extra Dimensions

    ScienceCinema

    Lincoln, Don

    2016-07-12

    The weakness of gravity compared to the other subatomic forces is a real mystery. While nobody knows the answer, one credible solution is that gravity has access to more spatial dimensions than the other three known forces. In this video, Fermilab's Dr. Don Lincoln describes this idea, with the help of some very urbane characters.

  10. Extra Dimensions of Space

    ERIC Educational Resources Information Center

    Lincoln, Don

    2013-01-01

    They say that there is no such thing as a stupid question. In a pedagogically pure sense, that's probably true. But some questions do seem to flirt dangerously close to being really quite ridiculous. One such question might well be, "How many dimensions of space are there?" I mean, it's pretty obvious that there are three:…

  11. Cultural dimensions of learning

    NASA Astrophysics Data System (ADS)

    Eyford, Glen A.

    1990-06-01

    How, what, when and where we learn is frequently discussed, as are content versus process, or right brain versus left brain learning. What is usually missing is the cultural dimension. This is not an easy concept to define, but various aspects can be identified. The World Decade for Cultural Development emphasizes the need for a counterbalance to a quantitative, economic approach. In the last century poets also warned against brutalizing materialism, and Sorokin and others have described culture more recently in terms of cohesive basic values expressed through aesthetics and institutions. Bloom's taxonomy incorporates the category of affective learning, which internalizes values. If cultural learning goes beyond knowledge acquisition, perhaps the surest way of understanding the cultural dimension of learning is to examine the aesthetic experience. This can use myths, metaphors and symbols, and to teach and learn by using these can help to unlock the human potential for vision and creativity.

  12. Dimensions of Intelligent Systems

    DTIC Science & Technology

    2002-08-01

    strategies - the intelligent parts of a cognitive model. This was necessary to achieve effective time performance - conventional AI techniques were too slow...Dimensions of Intelligent Systems Dr. Gary Berg-Cross Knowledge Strategies Division, SLAG, Inc. Potomac, Maryland 20854, USA 1. Abstract As...NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) SLAG, Inc,Knowledge Strategies Division,Potomac,MD,20854 8

  13. Introduction to Extra Dimensions

    SciTech Connect

    Rizzo, Thomas G.

    2010-07-12

    Extra dimensions provide a very useful tool in addressing a number of the fundamental problems faced by the Standard Model. The following provides a very basic introduction to this very broad subject area as given at the VIII School of the Gravitational and Mathematical Physics Division of the Mexican Physical Society in December 2009. Some prospects for extra dimensional searches at the 7 TeV LHC with {approx}1 fb{sup -1} of integrated luminosity are provided.

  14. Introduction to Extra Dimensions

    SciTech Connect

    Rizzo, Thomas G.; /SLAC

    2010-04-29

    Extra dimensions provide a very useful tool in addressing a number of the fundamental problems faced by the Standard Model. The following provides a very basic introduction to this very broad subject area as given at the VIII School of the Gravitational and Mathematical Physics Division of the Mexican Physical Society in December 2009. Some prospects for extra dimensional searches at the 7 TeV LHC with {approx}1 fb{sup -1} of integrated luminosity are provided.

  15. Infinitely Large New Dimensions

    SciTech Connect

    Arkani-Hamed, Nima; Dimopoulos, Savas; Dvali, Gia; Kaloper, Nemanja

    1999-07-29

    We construct intersecting brane configurations in Anti-de-Sitter space localizing gravity to the intersection region, with any number n of extra dimensions. This allows us to construct two kinds of theories with infinitely large new dimensions, TeV scale quantum gravity and sub-millimeter deviations from Newton's Law. The effective 4D Planck scale M{sub Pl} is determined in terms of the fundamental Planck scale M{sub *} and the AdS radius of curvature L via the familiar relation M{sub Pl}{sup 2} {approx} M{sub *}{sup 2+n} L{sup n}; L acts as an effective radius of compactification for gravity on the intersection. Taking M{sub *} {approx} TeV and L {approx} sub-mm reproduces the phenomenology of theories with large extra dimensions. Alternately, taking M{sub *} {approx} L{sup -1} {approx} M{sub Pl}, and placing our 3-brane a distance {approx} 100M{sub Pl}{sup -1} away from the intersection gives us a theory with an exponential determination of the Weak/Planck hierarchy.

  16. Bond percolation in higher dimensions

    NASA Astrophysics Data System (ADS)

    Corwin, Eric I.; Stinchcombe, Robin; Thorpe, M. F.

    2013-07-01

    We collect results for bond percolation on various lattices from two to fourteen dimensions that, in the limit of large dimension d or number of neighbors z, smoothly approach a randomly diluted Erdős-Rényi graph. We include results on bond-diluted hypersphere packs in up to nine dimensions, which show the mean coordination, excess kurtosis, and skewness evolving smoothly with dimension towards the Erdős-Rényi limit.

  17. Flying in Two Dimensions

    NASA Astrophysics Data System (ADS)

    Prakash, Manu; Bardon, Thibaut

    2012-11-01

    It has long been proposed that insect flight might have evolved on a fluid interface. Surface of a pond provides an ecological niche which is exploited by a large number of species capable of locomotion on a fluid interface. Here we describe the discovery of constrained flight in two dimensions as a novel mode of locomotion used by water lily beetles (genus Galerucella). Because water lily beetles are also capable of three-dimensional free flight, this novel two-dimensional locomotion provides us with a unique model system to explore both the transition between two and three dimensional flight and the associated energetics. Here we present a comparative analysis of this transition in terms of wing stroke angles associated with two and three dimensional flight, as well as modeling surface tension forces on both the horizontal and vertical axes. Special attention is paid to the dynamics and energetics of flight in two-dimensions, focusing on the interaction of the wing strokes with the fluid interface and the capillary-gravity wave drag associated with two-dimensional propulsion. Current Address: Ecole Polytechnique, France.

  18. FRACTAL DIMENSION OF GALAXY ISOPHOTES

    SciTech Connect

    Thanki, Sandip; Rhee, George; Lepp, Stephen E-mail: grhee@physics.unlv.edu

    2009-09-15

    In this paper we investigate the use of the fractal dimension of galaxy isophotes in galaxy classification. We have applied two different methods for determining fractal dimensions to the isophotes of elliptical and spiral galaxies derived from CCD images. We conclude that fractal dimension alone is not a reliable tool but that combined with other parameters in a neural net algorithm the fractal dimension could be of use. In particular, we have used three parameters to segregate the ellipticals and lenticulars from the spiral galaxies in our sample. These three parameters are the correlation fractal dimension D {sub corr}, the difference between the correlation fractal dimension and the capacity fractal dimension D {sub corr} - D {sub cap}, and, thirdly, the B - V color of the galaxy.

  19. Action languages: Dimensions, effects

    NASA Technical Reports Server (NTRS)

    Hayes, Daniel G.; Streeter, Gordon

    1989-01-01

    Dimensions of action languages are discussed for communication between humans and machines, and the message handling capabilities of object oriented programming systems are examined. Design of action languages is seen to be very contextual. Economical and effective design will depend on features of situations, the tasks intended to be accomplished, and the nature of the devices themselves. Current object oriented systems turn out to have fairly simple and straightforward message handling facilities, which in themselves do little to buffer action or even in some cases to handle competing messages. Even so, it is possible to program a certain amount of discretion about how they react to messages. Such thoughtfulness and perhaps relative autonomy of program modules seems prerequisite to future systems to handle complex interactions in changing situations.

  20. The Dimension of Information

    NASA Astrophysics Data System (ADS)

    Preuss, Lucien

    2008-11-01

    To implement Jaynes' vision [1] of applications of Shannon's ideas outside Communication Theory proper, the dimension of information must be clarified, mainly because general applications provide no ready-made set of discrete, mutually exclusive and exhaustive "events" which could play a rôle similar to that of the alphabet which communication theory implicitely supposes known from the outset. For instance, a doctor's "alphabet" may be said to consist of readily distinguishable bundles of symptoms, cures, etc., each of which he considers specific enough to describe an illness of interest. Setting up an appropriate alphabet requires learning, in the same way as a child painfully learns to read letters, and a quantitative assessment of this task depends crucially on the dimension of information. Information is an extensive property, as explicited by the standard equation I = N.H for the amount of information delivered by a succession of N events. All other things remaining equal, doubling the length of a message doubles the amount of information. But by definition, Shannon's uncertainty H on the right-hand side of the equation is a rate, i.e. an intensive property, as illustrated by the fact that the simultaneous throw of two true and identical dice removes less than twice the uncertainty removed by the throw of a single die, as is well-known to poker-players. If the above equation is to be dimensionally consistent, N can not be a pure number, but must have an extensive dimension of its own. The obvious question "which?" was swept under the rug by von Neumann's famous quip [3], which advised to call H an entropy, thereby suggesting improperly that H by itself-without the factor N-is an extensive property like physical entropy. But H only evaluates an amount of information when multiplied by N, which measures an amount of order akin to the chronological order without which any message becomes garbage. In analogy with the decomposition E S.T of energy E into the pair

  1. Scientific Visualization of Extra Dimensions

    NASA Astrophysics Data System (ADS)

    Black, Don V.

    2010-10-01

    In the 21st Century, many theoretical physicists claim that higher dimensions may indeed exist. Arkani-Hamed, Dimopoulos, & Dvali (ADD) and Randall-Sundrum (RS), in addition to Kaluza-Klein (KK) and M-string theorists, have introduced reasonable explanations for the existence of heretofore ``invisible'' higher dimensions. Whether or not these extra dimensions actually exist is irrelevant to their contributions to the visionary conceptualization associated with novel and improved mathematical and physical analysis. Envisioning extra dimensions beyond the three of common experience is a daunting challenge for three dimensional observers. Intuition relies on experience gained in a three dimensional environment. Gaining experience with virtual four dimensional objects and virtual three manifolds in four-space on a personal computer may provide the basis for an intuitive grasp of four dimensions. This presentation is a video ``outtake'' of the author's research into ``Visualizing Extra Spatial Dimensions'' at the University of California at Irvine.

  2. Johannes Kepler and Extra Dimensions

    NASA Astrophysics Data System (ADS)

    Hendry, Archibald W.

    2004-02-01

    How many dimensions are there? The answer used to be four — three spatial and one time dimension. Maybe it still is, though nowadays we hear that the answer may be more, perhaps many more. Many of our students have heard about this on television or read about it. They want to know more. Why do physicists think we need more than three spatial dimensions? What's the point of it all?

  3. Physics in one dimension

    NASA Astrophysics Data System (ADS)

    van Houselt, A.; Schäfer, J.; Zandvliet, H. J. W.; Claessen, R.

    2013-01-01

    With modern microelectronics moving towards smaller and smaller length scales on the (sub-) nm scale, quantum effects (apart from band structure and band gaps) have begun to play an increasingly important role. This especially concerns dimensional confinement to 2D (high electron mobility transistors and integer/fractional quantum Hall effect physics, graphene and topological insulators) and 1D (with electrical connections eventually reaching the quantum limit). Recent developments in the above-mentioned areas have revealed that the properties of electron systems become increasingly exotic as one progresses from the 3D case into lower dimensions. As compared to 2D electron systems, much less experimental progress has been achieved in the field of 1D electron systems. The main reason for the lack of experimental results in this field is related to the difficulty of realizing 1D electron systems. Atom chains created in quantum mechanical break junction set-ups are too short to exhibit the typically 1D signatures. As an alternative, atomic chains can be produced on crystal surfaces, either via assembling them one-by-one using a scanning tunnelling microscope or via self-assembly. The drawback of the latter systems is that the atomic chains are not truly 1D since they are coupled to the underlying crystal and sometimes even to the neighbouring chains. In retrospect, this coupling turns out to be an absolute necessity in the experiment since true 1D systems are disordered at any non-zero temperature [1]. The coupling to the crystal and/or neighbouring chains shifts the phase transition, for example, a Peierls instability, to a non-zero temperature and thus allows experiments to be performed in the ordered state. Here, we want to emphasize that the electronic properties of the 1D electron system are fundamentally different from its 2D and 3D counterparts. The Fermi liquid theory, which is applicable to 2D and 3D electron systems, breaks down spectacularly in the 1D case

  4. Nonminimal universal extra dimensions

    SciTech Connect

    Flacke, Thomas; Menon, A.; Phalen, Daniel J.

    2009-03-01

    In this paper, we investigate the phenomenological implications of boundary localized terms (BLTs) in the model of universal extra dimensions (UED). In particular, we study the electroweak Kaluza-Klein mass spectrum resulting from BLTs and their effect on electroweak symmetry breaking via the five-dimensional Higgs mechanism. We find that the addition of BLTs to massive five-dimensional fields induces a nontrivial extra-dimensional profile for the zero and nonzero Kaluza-Klein (KK) modes. Hence BLTs generically lead to a modification of standard model parameters and are therefore experimentally constrained, even at tree level. We study standard model constraints on three representative nonminimal UED models in detail and find that the constraints on BLTs are weak. On the contrary, nonzero BLTs have a major impact on the spectrum and couplings of nonzero KK modes. For example, there are regions of parameter space where the lightest Kaluza-Klein particle is either the Kaluza-Klein Higgs boson or the first KK mode of the W{sup 3}.

  5. Thermal dimension of quantum spacetime

    NASA Astrophysics Data System (ADS)

    Amelino-Camelia, Giovanni; Brighenti, Francesco; Gubitosi, Giulia; Santos, Grasiele

    2017-04-01

    Recent results suggest that a crucial crossroad for quantum gravity is the characterization of the effective dimension of spacetime at short distances, where quantum properties of spacetime become significant. This is relevant in particular for various scenarios of "dynamical dimensional reduction" which have been discussed in the literature. We are here concerned with the fact that the related research effort has been based mostly on analyses of the "spectral dimension", which involves an unphysical Euclideanization of spacetime and is highly sensitive to the off-shell properties of a theory. As here shown, different formulations of the same physical theory can have wildly different spectral dimension. We propose that dynamical dimensional reduction should be described in terms of the "thermal dimension" which we here introduce, a notion that only depends on the physical content of the theory. We analyze a few models with dynamical reduction both of the spectral dimension and of our thermal dimension, finding in particular some cases where thermal and spectral dimension agree, but also some cases where the spectral dimension has puzzling properties while the thermal dimension gives a different and meaningful picture.

  6. Exterior dimension of fat fractals

    NASA Technical Reports Server (NTRS)

    Grebogi, C.; Mcdonald, S. W.; Ott, E.; Yorke, J. A.

    1985-01-01

    Geometric scaling properties of fat fractal sets (fractals with finite volume) are discussed and characterized via the introduction of a new dimension-like quantity which is called the exterior dimension. In addition, it is shown that the exterior dimension is related to the 'uncertainty exponent' previously used in studies of fractal basin boundaries, and it is shown how this connection can be exploited to determine the exterior dimension. Three illustrative applications are described, two in nonlinear dynamics and one dealing with blood flow in the body. Possible relevance to porous materials and ballistic driven aggregation is also noted.

  7. Dimensions of temperament: an analysis.

    PubMed

    Lorr, M; Stefic, E C

    1976-01-01

    The TDOT recast into a single stimulus format was administered to 150 college Ss. A factor analysis of the items followed by an analysis of item clusters that define each factor indicated the presence of 14 dimensions. Of the 10 bipolar scales of the TDOT, 3 were confirmed as independent dimensions, and 5 were confirmed in part or split into unipolar factors.

  8. Mathematics Teachers' Criteria of Dimension

    ERIC Educational Resources Information Center

    Ural, Alattin

    2014-01-01

    The aim of the study is to determine mathematics teachers' decisions about dimensions of the geometric figures, criteria of dimension and consistency of decision-criteria. The research is a qualitative research and the model applied in the study is descriptive method on the basis of general scanning model. 15 mathematics teachers attended the…

  9. Dimensioning, Tolerancing, and Machine Finishes.

    ERIC Educational Resources Information Center

    Adams, George C.

    Intended for use with the vocational education student interested in technical drawing, this guide provides answers to questions relating to dimensioning and tolerancing machine drawings. It also gives examples of standard dimensioning practices, tolerancing applications, and finish applications. The problems and examples presented are based on…

  10. String universality in ten dimensions.

    PubMed

    Adams, Allan; Taylor, Washington; Dewolfe, Oliver

    2010-08-13

    We show that the N=1 supergravity theories in ten dimensions with gauge groups U(1){496} and E{8}×U(1){248} are not consistent quantum theories. Cancellation of anomalies cannot be made compatible with supersymmetry and Abelian gauge invariance. Thus, in ten dimensions all supersymmetric theories of gravity without known inconsistencies are realized in string theory.

  11. The Dimensions of Maltreatment: Introduction

    ERIC Educational Resources Information Center

    English, Diana J.; Bangdiwala, Shrikant I.; Runyan, Desmond K.

    2005-01-01

    This special issue includes an introduction and seven papers exploring dimensions of maltreatment including type, severity, chronicity, and substantiation status of referrals to CPS, utilizing a subsample of the LONGSCAN studies. Each paper examines one of the dimensions of maltreatment from various perspectives to determine if different…

  12. The Dimensions of Creative Prose

    ERIC Educational Resources Information Center

    Miller, Melvin H.

    1975-01-01

    The thesis in this paper centered around the meaning of "effective" speaking and "effective" writing. The dimensions of effective prose are analyzed as one method of determining what is involved. (Author/RK)

  13. Fourier dimension of random images

    NASA Astrophysics Data System (ADS)

    Ekström, Fredrik

    2016-10-01

    Given a compact set of real numbers, a random C^{m + α}-diffeomorphism is constructed such that the image of any measure concentrated on the set and satisfying a certain condition involving a real number s, almost surely has Fourier dimension greater than or equal to s / (m + α). This is used to show that every Borel subset of the real numbers of Hausdorff dimension s is C^{m + α}-equivalent to a set of Fourier dimension greater than or equal to s / (m + α ). In particular every Borel set is diffeomorphic to a Salem set, and the Fourier dimension is not invariant under Cm-diffeomorphisms for any m.

  14. Radiation reaction in various dimensions

    NASA Astrophysics Data System (ADS)

    Gal'Tsov, Dmitri V.

    2002-07-01

    We discuss the radiation reaction problem for an electric charge moving in flat space-time of arbitrary dimensions. It is shown that four is the unique dimension where a local differential equation exists accounting for the radiation reaction and admitting a consistent mass renormalization (the Lorentz-Dirac equation). In odd dimensions Huygens's principle does not hold, and, as a result, the radiation reaction force depends on the whole past history of a charge (radiative tail). We show that the divergence in the tail integral can be removed by the mass renormalization only in the 2+1 theory. In even dimensions higher than four, divergences cannot be removed by the mass renormalization.

  15. Phenomenology of universal extra dimensions

    SciTech Connect

    Kong, Kyoungchul; Matchev, Konstantin T.; /Florida U.

    2006-10-01

    In this proceeding, the phenomenology of Universal Extra Dimensions (UED), in which all the Standard Model fields propagate, is explored. We focus on models with one universal extra dimension, compactified on an S{sub 1}/Z{sub 2} orbifold. We revisit calculations of Kaluza-Klein (KK) dark matter without an assumption of the KK mass degeneracy including all possible coannihilations. We then contrast the experimental signatures of low energy supersymmetry and UED.

  16. Timbre Dimensions for Musical Control

    NASA Astrophysics Data System (ADS)

    Giese, Gregory Roy

    This dissertation addresses the folowing question: Given the technologies to develop and implement any kind of sound generating and controlling device, what will the instrument designer, the composer, and the performer need to know in order to more fully utilize the dimensions of timbre in music and musical performance? This question is approached from the standpoint of music theory. Definitions of timbre and a few examples of related physical and perceptual research are reviewed. Included is a discussion of the essential elements of musical control and of intelligent organization of sound in music. This discussion raises more questions than can be answered simply. It is an attempt to unravel the nature of sound clues and sound qualities as they convey sound identities and musical gesture. A theoretical simplification of sound dimensions for musical use is proposed. Sounds which can be sustained indefinitely consist of steady-state acoustical dimensions. These dimensions rely upon the perceptual phenomenon of simultaneous fusion (synance). Sounds which can not be sustained indefinitely consist of transitions. Transitions may cause successive fusion (sonance). The discussion of steady-state and transition dimensions includes a review of a few informal experiments. This work reveals problems that will influence the musical use of timbre dimensions. It also leads to a theory for the organization and control of timbre dimensions in music. Among the timbre dimensions discussed are: spectral envelope, harmonic content, brightness, phase, inharmonicity, aperiodicity, and temporal transitions. Questions are raised regarding the perception of harmonic content. The effect of register on perception of tones consisting of from two to nine partials is explored and discussed. The size of interval between partials determines a unique quality. This is most apparent with tones consisting of only two or three partials (dions or trions).

  17. The Sirens of Eleven Dimensions

    NASA Astrophysics Data System (ADS)

    Ramond, Pierre

    While most theorists are tied to the mast of four dimensions, some have found it irresistible to speculate about eleven dimensions, the domain of M-theory. We outline a program which starts from the light-cone description of supergravity, and tracks its divergences to suggest the existence of an infinite component theory which in the lightcone relies on the coset F4/SO(9), long known to be linked to the Exceptional Jordan Algebra

  18. Fractal dimension of alumina aggregates grown in two dimensions

    NASA Technical Reports Server (NTRS)

    Larosa, Judith L.; Cawley, James D.

    1992-01-01

    The concepts of fractal geometry are applied to the analysis of 0.4-micron alumina constrained to agglomerate in two dimensions. Particles were trapped at the bottom surface of a drop of a dilute suspension, and the agglomeration process was directly observed, using an inverted optical microscope. Photographs were digitized and analyzed, using three distinct approaches. The results indicate that the agglomerates are fractal, having a dimension of approximately 1.5, which agrees well with the predictions of the diffusion-limited cluster-cluster aggregation model.

  19. Dimension of fractal basin boundaries

    SciTech Connect

    Park, B.S.

    1988-01-01

    In many dynamical systems, multiple attractors coexist for certain parameter ranges. The set of initial conditions that asymptotically approach each attractor is its basin of attraction. These basins can be intertwined on arbitrary small scales. Basin boundary can be either smooth or fractal. Dynamical systems that have fractal basin boundary show final state sensitivity of the initial conditions. A measure of this sensitivity (uncertainty exponent {alpha}) is related to the dimension of the basin boundary d = D - {alpha}, where D is the dimension of the phase space and d is the dimension of the basin boundary. At metamorphosis values of the parameter, there might happen a conversion from smooth to fractal basin boundary (smooth-fractal metamorphosis) or a conversion from fractal to another fractal basin boundary characteristically different from the previous fractal one (fractal-fractal metamorphosis). The dimension changes continuously with the parameter except at the metamorphosis values where the dimension of the basin boundary jumps discontinuously. We chose the Henon map and the forced damped pendulum to investigate this. Scaling of the basin volumes near the metamorphosis values of the parameter is also being studied for the Henon map. Observations are explained analytically by using low dimensional model map.

  20. Collider searches for extra dimensions

    SciTech Connect

    Landsberg, Greg; /Brown U.

    2004-12-01

    Searches for extra spatial dimensions remain among the most popular new directions in our quest for physics beyond the Standard Model. High-energy collider experiments of the current decade should be able to find an ultimate answer to the question of their existence in a variety of models. Until the start of the LHC in a few years, the Tevatron will remain the key player in this quest. In this paper, we review the most recent results from the Tevatron on searches for large, TeV{sup -1}-size, and Randall-Sundrum extra spatial dimensions, which have reached a new level of sensitivity and currently probe the parameter space beyond the existing constraints. While no evidence for the existence of extra dimensions has been found so far, an exciting discovery might be just steps away.

  1. Correlated Electrons in Reduced Dimensions

    SciTech Connect

    Bonesteel, Nicholas E

    2015-01-31

    This report summarizes the work accomplished under the support of US DOE grant # DE-FG02-97ER45639, "Correlated Electrons in Reduced Dimensions." The underlying hypothesis of the research supported by this grant has been that studying the unique behavior of correlated electrons in reduced dimensions can lead to new ways of understanding how matter can order and how it can potentially be used. The systems under study have included i) fractional quantum Hall matter, which is realized when electrons are confined to two-dimensions and placed in a strong magnetic field at low temperature, ii) one-dimensional chains of spins and exotic quasiparticle excitations of topologically ordered matter, and iii) electrons confined in effectively ``zero-dimensional" semiconductor quantum dots.

  2. Image Segmentation via Fractal Dimension

    DTIC Science & Technology

    1987-12-01

    statistical expectation K = a proportionality constant H = the Hurst exponent , in interval [0,1] (14:249) Eq (4) is a mathematical generalization of...ease, negatively correlated (24:16). The Hurst exponent is directly related to the fractal diment.ion of the process being modelled by the relation (24...24) DzE.I -H (5) where D = the fractal dimension E m the Euclidean dimension H = the Hurst exponent The effect of N1 on a typical trace can be seen

  3. The Visuospatial Dimension of Writing

    ERIC Educational Resources Information Center

    Olive, Thierry; Passerault, Jean-Michel

    2012-01-01

    The authors suggest that writing should be conceived of not only as a verbal activity but also as a visuospatial activity, in which writers process and construct visuospatial mental representations. After briefly describing research on visuospatial cognition, they look at how cognitive researchers have investigated the visuospatial dimension of…

  4. The Feeling Dimension in Reading.

    ERIC Educational Resources Information Center

    Ediger, Marlow

    The feeling dimension of students cannot be ignored in teaching and learning situations. Feelings are there and must not be ignored. Reading stresses word recognition, comprehension of subject matter at diverse levels of complexity, and application of what has been learned. A major ingredient so frequently left out is student appreciation of the…

  5. Heat conduction in three dimensions

    NASA Technical Reports Server (NTRS)

    Danza, T. M.; Fesler, L. W.; Mongan, R. D.

    1980-01-01

    Multidimensional heat conduction program computes transient temperature history and steady state temperatures of complex body geometries in three dimensions. Emphasis is placed on type of problems associated with Space Shuttle thermal protection system, but program could be used in thermal analysis of most three dimensional systems.

  6. The European Dimension in Education.

    ERIC Educational Resources Information Center

    Council of Europe, Strasbourg (France). Directorate of Education, Culture and Sport, Documentation Section.

    This paper addresses concerns about a European dimension in education that has been created by the enlargement of the European Union (EU) (the inclusion of Austria, Finland, and Sweden) and the gradual transformations of institutions into a future federal state. Sections of the paper include: (1) "Introduction"; (2) "Defining the…

  7. Warping the universal extra dimensions

    SciTech Connect

    McDonald, Kristian L.

    2009-07-15

    We develop the necessary ingredients for the construction of realistic models with warped universal extra dimensions. Our investigations are based on the seven-dimensional (7D) spacetime AdS{sub 5}xT{sup 2}/Z{sub 2} and we derive the Kaluza-Klein (KK) spectra for gravitons, bulk vectors, and the TeV brane localized Higgs boson. We show that, starting with a massive 7D fermion, one may obtain a single chiral massless mode whose profile is readily localized towards the Planck or TeV brane. This allows one to place the standard model fermions in the bulk and construct models of flavor as in Randall-Sundrum models. Our solution also admits the familiar KK parity of models with universal extra dimensions so that the lightest odd KK state is stable and may be a dark matter candidate. As an additional feature the AdS{sub 5} warping ensures that the excited modes on the torus, including the dark matter candidate, appear at TeV energies (as is usually assumed in models with universal extra dimensions) even though the Planck scale sets the dimensions for the torus.

  8. Interpretation and the Aesthetic Dimension

    ERIC Educational Resources Information Center

    Mortensen, Charles O.

    1976-01-01

    The author, utilizing a synthesis of philosophic comments on aesthetics, provides a discourse on the aesthetic dimension and offers examples of how interpreters can nurture the innate sense of beauty in man. Poetic forms, such as haiku, are used to relate the aesthetic relationship between man and the environment. (BT)

  9. Compactified Vacuum in Ten Dimensions.

    NASA Astrophysics Data System (ADS)

    Wurmser, Daniel

    1987-09-01

    Since the 1920's, theories which unify gravity with the other fundamental forces have called for more than the four observed dimensions of space-time. According to such a theory, the vacuum consists of flat four-dimensional space-time described by the Minkowski metric M ^4 and a "compactified" space B. The dimensions of B are small, and the space can only be observed at distance scales smaller than the present experimental limit. These theories have had serious difficulties. The equations of gravity severely restrict the possible choices for the space B. The allowed spaces are complicated and difficult to study. The vacuum is furthermore unstable in the sense that a small perturbation causes the compactified dimensions to expand indefinitely. There is an addition a semi-classical argument which implies that the compactified vacuum be annihilated by virtual black holes. It follows that a universe with compactified extra dimensions could not have survived to the present. These results were derived by applying the equations of general relativity to spaces of more than four dimensions. The form of these equations was assumed to be unchanged by an increase in the number of dimensions. Recently, it has been proposed that gravity in more than four dimensions may involve terms of higher order in the curvature as well as the linear terms present in ordinary general relativity. I illustrate the effect of such terms by considering the example B = S^6 where S ^6 is the six-dimensional sphere. Only when the extra terms are included is this choice of the compactified space allowed. I explore the effect of a small perturbation on such a vacuum. The ten-dimensional spherically symmetric potential is examined, and I determine conditions under which the formation of virtual black holes is forbidden. The example M^4 times S^6 is still plagued by the semi -classical instability, but this result does not hold in general. The requirement that virtual black holes be forbidden provides a

  10. Supersymmetric unification requires extra dimensions

    SciTech Connect

    Chen, Mu-Chun; Fallbacher, Maximilian; Ratz, Michael

    2013-05-23

    We discuss settings that predict precision gauge unification in the minimal supersymmetric standard model. We show that, if one requires anomaly freedom and fermion masses while demanding that unification is not an accident, only R symmetries can forbid the supersymmetric Higgs mass term {mu}. We then review the proof that R symmetries are not available in conventional grand unified theories (GUTs) and argue that this prevents natural solutions to the doublet-triplet splitting problem in four dimensions. On the other hand, higher-dimensional GUTs do not suffer from this problem. We briefly comment on an explicit string-derived model in which the {mu} and dimension five proton decay problems are solved by an order four discrete R symmetry, and comment on the higher-dimensional origin of this symmetry.

  11. Black Holes in Higher Dimensions

    NASA Astrophysics Data System (ADS)

    Horowitz, Gary T.

    2012-04-01

    List of contributors; Preface; Part I. Introduction: 1. Black holes in four dimensions Gary Horowitz; Part II. Five Dimensional Kaluza-Klein Theory: 2. The Gregory-Laflamme instability Ruth Gregory; 3. Final state of Gregory-Laflamme instability Luis Lehner and Frans Pretorius; 4. General black holes in Kaluza-Klein theory Gary Horowitz and Toby Wiseman; Part III. Higher Dimensional Solutions: 5. Myers-Perry black holes Rob Myers; 6. Black rings Roberto Emparan and Harvey Reall; Part IV. General Properties: 7. Constraints on the topology of higher dimensional black holes Greg Galloway; 8. Blackfolds Roberto Emparan; 9. Algebraically special solutions in higher dimensions Harvey Reall; 10. Numerical construction of static and stationary black holes Toby Wiseman; Part V. Advanced Topics: 11. Black holes and branes in supergravity Don Marolf; 12. The gauge/gravity duality Juan Maldacena; 13. The fluid/gravity correspondence Veronika Hubeny, Mukund Rangamani and Shiraz Minwalla; 14. Horizons, holography and condensed matter Sean Hartnoll; Index.

  12. Critical gravity in four dimensions.

    PubMed

    Lü, H; Pope, C N

    2011-05-06

    We study four-dimensional gravity theories that are rendered renormalizable by the inclusion of curvature-squared terms to the usual Einstein action with a cosmological constant. By choosing the parameters appropriately, the massive scalar mode can be eliminated and the massive spin-2 mode can become massless. This "critical" theory may be viewed as a four-dimensional analogue of chiral topologically massive gravity, or of critical "new massive gravity" with a cosmological constant, in three dimensions. We find that the on-shell energy for the remaining massless gravitons vanishes. There are also logarithmic spin-2 modes, which have positive energy. The mass and entropy of standard Schwarzschild-type black holes vanish. The critical theory might provide a consistent toy model for quantum gravity in four dimensions.

  13. Critical Gravity in Four Dimensions

    SciTech Connect

    Lue, H.; Pope, C. N.

    2011-05-06

    We study four-dimensional gravity theories that are rendered renormalizable by the inclusion of curvature-squared terms to the usual Einstein action with a cosmological constant. By choosing the parameters appropriately, the massive scalar mode can be eliminated and the massive spin-2 mode can become massless. This ''critical'' theory may be viewed as a four-dimensional analogue of chiral topologically massive gravity, or of critical 'new massive gravity' with a cosmological constant, in three dimensions. We find that the on-shell energy for the remaining massless gravitons vanishes. There are also logarithmic spin-2 modes, which have positive energy. The mass and entropy of standard Schwarzschild-type black holes vanish. The critical theory might provide a consistent toy model for quantum gravity in four dimensions.

  14. Dimension Reduction for Object Ranking

    NASA Astrophysics Data System (ADS)

    Kamishima, Toshihiro; Akaho, Shotaro

    Ordered lists of objects are widely used as representational forms. Such ordered objects include Web search results and bestseller lists. Techniques for processing such ordinal data are being developed, particularly methods for an object ranking task: i.e., learning functions used to sort objects from sample orders. In this article, we propose two dimension reduction methods specifically designed to improve prediction performance in an object ranking task.

  15. Wormholes leading to extra dimensions

    NASA Astrophysics Data System (ADS)

    Bronnikov, K. A.; Skvortsova, M. V.

    2016-10-01

    In 6D general relativity with a scalar field as a source of gravity, a new type of static wormhole solutions is presented: such wormholes connect our universe with a small 2D extra subspace with a universe where this extra subspace is large, and the whole space-time is effectively 6-dimensional. We consider manifolds with the structure M0 x M1 x M2 , where M0 is 2D Lorentzian space-time while each of M1 an M2 can be a 2-sphere or a 2-torus. After selecting possible asymptotic behaviors of the metric functions compatible with the field equations, we give two explicit examples of wormhole solutions with spherical symmetry in our space-time and toroidal extra dimensions. In one example, with a massless scalar field (it is a special case of a well-known more general solution), the extra dimensions have a large constant size at the "far end"; the other example contains a nonzero potential $V(\\phi)$ which provides a 6D anti-de Sitter asymptotic, where all spatial dimensions are infinite.

  16. Gardner transition in finite dimensions

    NASA Astrophysics Data System (ADS)

    Urbani, Pierfrancesco; Biroli, Giulio

    2015-03-01

    Recent works on hard spheres in the limit of infinite dimensions revealed that glass states, envisioned as metabasins in configuration space, can break up in a multitude of separate basins at low enough temperature or high enough pressure, leading to the emergence of new kinds of soft-modes and unusual properties. In this paper we study by perturbative renormalization group techniques the critical properties of this transition, which has been discovered in disordered mean-field models in the 1980s. We find that the upper-critical dimension du, above which mean-field results hold, is strictly larger than six and apparently nonuniversal, i.e., system dependent. Below du, we do not find any perturbative attractive fixed point (except for a tiny region of the one-step replica symmetry breaking parameter), thus showing that the transition in three dimensions either is governed by a nonperturbative fixed point unrelated to the Gaussian mean-field one or becomes first order or does not exist. We also discuss possible relationships with the behavior of spin glasses in a field.

  17. A Short Existence Proof for Correlation Dimension

    NASA Astrophysics Data System (ADS)

    Manning, Anthony; Simon, Károly

    1998-02-01

    The Grassberger-Hentschel-Procaccia correlation dimension has been put on a rigorous basis by Pesin and Tempelman. We simplify their proof that this dimension is given in terms of the measure of neighborhoods of the diagonal.

  18. Model Pores of Molecular Dimension

    PubMed Central

    Quinn, J. A.; Anderson, J. L.; Ho, W. S.; Petzny, W. J.

    1972-01-01

    Extremely uniform pores of near molecular dimension can be formed by the irradiation-etching technique first demonstrated by Price and Walker. The technique has now been developed to the stage where it can be used to fabricate model membranes for examining the various steric, hydrodynamic, and electrodynamic phenomena encountered in transport through molecular-size pores. Methods for preparing and characterizing membranes with pores as small as 25 A (radius) are described in this paper. Results on pore size determination via Knudsen gas flow and electrolyte conduction are compared. Pore wall modification by monolayer deposition is also discussed. PMID:4339801

  19. Noncentrosymmetric superconductors in one dimension

    NASA Astrophysics Data System (ADS)

    Samokhin, K. V.

    2017-02-01

    We study the fermionic boundary modes (Andreev bound states) in a time-reversal invariant one-dimensional superconductor. In the presence of a substrate, spatial inversion symmetry is broken and the electronic properties are strongly affected by an antisymmetric spin-orbit coupling. We assume an arbitrary even number of nondegenerate bands crossing the Fermi level. We show that there is only one possible pairing symmetry in one dimension, an analog of s -wave pairing. The zero-energy Andreev bound states are present if the sign of the gap function in an odd number of the bands is different from all other bands.

  20. BMS Modules in Three Dimensions

    NASA Astrophysics Data System (ADS)

    Campoleoni, A.; González, H. A.; Oblak, B.; Riegler, M.

    We build unitary representations of the BMS algebra and its higher-spin extensions in three dimensions, using induced representations as a guide. Our prescription naturally emerges from an ultrarelativistic limit of highest-weight representations of Virasoro and 𝒲 algebras, which is to be contrasted with nonrelativistic limits that typically give non-unitary representations. To support this dichotomy, we also point out that the ultrarelativistic and non-relativistic limits of generic 𝒲 algebras differ in the structure of their non-linear terms.

  1. Correlation dimension of complex networks.

    PubMed

    Lacasa, Lucas; Gómez-Gardeñes, Jesús

    2013-04-19

    We propose a new measure to characterize the dimension of complex networks based on the ergodic theory of dynamical systems. This measure is derived from the correlation sum of a trajectory generated by a random walker navigating the network, and extends the classical Grassberger-Procaccia algorithm to the context of complex networks. The method is validated with reliable results for both synthetic networks and real-world networks such as the world air-transportation network or urban networks, and provides a computationally fast way for estimating the dimensionality of networks which only relies on the local information provided by the walkers.

  2. Fractal dimension of bioconvection patterns

    NASA Technical Reports Server (NTRS)

    Noever, David A.

    1990-01-01

    Shallow cultures of the motile algal strain, Euglena gracilis, were concentrated to 2 x 10 to the 6th organisms per ml and placed in constant temperature water baths at 24 and 38 C. Bioconvective patterns formed an open two-dimensional structure with random branches, similar to clusters encountered in the diffusion-limited aggregation (DLA) model. When averaged over several example cultures, the pattern was found to have no natural length scale, self-similar branching, and a fractal dimension (d about 1.7). These agree well with the two-dimensional DLA.

  3. Fractal Dimension of Bioconvection Patterns

    NASA Astrophysics Data System (ADS)

    Noever, David A.

    1990-10-01

    Shallow cultures of the motile algal strain, Euglena gracilis, were concentrated to 2× 106 organisms per ml and placed in constant temperature water baths at 24 and 38 C. Bioconvective patterns formed an open two-dimensional structure with random branches, similar to clusters encountered in the diffusion-limited aggregation (DLA) model. When averaged over several example cultures, the pattern was found to have no natural length scale, self-similar branching and a fractal dimension (d˜1.7). These agree well with the two-dimensional DLA.

  4. Extended scaling in high dimensions

    NASA Astrophysics Data System (ADS)

    Berche, B.; Chatelain, C.; Dhall, C.; Kenna, R.; Low, R.; Walter, J.-C.

    2008-11-01

    We apply and test the recently proposed 'extended scaling' scheme in an analysis of the magnetic susceptibility of Ising systems above the upper critical dimension. The data are obtained by Monte Carlo simulations using both the conventional Wolff cluster algorithm and the Prokof'ev-Svistunov worm algorithm. As already observed for other models, extended scaling is shown to extend the high-temperature critical scaling regime over a range of temperatures much wider than that achieved conventionally. It allows for an accurate determination of leading and sub-leading scaling indices, critical temperatures and amplitudes of the confluent corrections.

  5. 16 CFR 1508.3 - Dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Dimensions. 1508.3 Section 1508.3 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION FEDERAL HAZARDOUS SUBSTANCES ACT REGULATIONS REQUIREMENTS FOR FULL-SIZE BABY CRIBS § 1508.3 Dimensions. Full-size baby cribs shall have dimensions as follows:...

  6. NEW DIMENSIONS IN JUNIOR COLLEGE PLANNING.

    ERIC Educational Resources Information Center

    BOYCE, R. DUDLEY; AND OTHERS

    THIS REPORT CONSISTS OF A SERIES OF DISCUSSIONS BY MANY AUTHORS IN FOUR BROAD DIMENSIONS RELATIVE TO JUNIOR COLLEGES. THE FIRST DIMENSION IS PURPOSES AND DEALS WITH THE UNIQUE ROLE OF THE COMMUNITY JUNIOR COLLEGE, PROVISIONS FOR FACILITIES, PROBLEMS, AND POTENTIALITIES. THE SECOND DIMENSION FOCUSES ON PLANNING AND REPORTS ON STUDIES IN PLANNING…

  7. Double shrinking sparse dimension reduction.

    PubMed

    Zhou, Tianyi; Tao, Dacheng

    2013-01-01

    Learning tasks such as classification and clustering usually perform better and cost less (time and space) on compressed representations than on the original data. Previous works mainly compress data via dimension reduction. In this paper, we propose "double shrinking" to compress image data on both dimensionality and cardinality via building either sparse low-dimensional representations or a sparse projection matrix for dimension reduction. We formulate a double shrinking model (DSM) as an l(1) regularized variance maximization with constraint ||x||(2)=1, and develop a double shrinking algorithm (DSA) to optimize DSM. DSA is a path-following algorithm that can build the whole solution path of locally optimal solutions of different sparse levels. Each solution on the path is a "warm start" for searching the next sparser one. In each iteration of DSA, the direction, the step size, and the Lagrangian multiplier are deduced from the Karush-Kuhn-Tucker conditions. The magnitudes of trivial variables are shrunk and the importances of critical variables are simultaneously augmented along the selected direction with the determined step length. Double shrinking can be applied to manifold learning and feature selections for better interpretation of features, and can be combined with classification and clustering to boost their performance. The experimental results suggest that double shrinking produces efficient and effective data compression.

  8. Reflections from the fourth dimension

    NASA Astrophysics Data System (ADS)

    Lefranc, Marc

    2013-01-01

    The knot-theoretic characterization of three-dimensional strange attractors has proved an invaluable tool for comparing models to experiments, understanding the structure of bifurcation diagrams, constructing symbolic encodings or obtaining signatures of chaos. In four dimensions and above, however, all closed curves can be deformed into each other without crossing themselves. Therefore, the fundamental idea of topological analysis, namely that the topological structure of a strange attractor provides signatures of the stretching and folding mechanisms which organize it, must be translated into a different formalism. Here, we discuss two modest attempts to make progress in this direction. First, we illustrate the relevance of catastrophe theory in the analysis of higher-dimensional systems by describing experimental signatures of cusps in weakly coupled chaotic systems. Second, we note that determinism not only precludes intersection of two trajectories but also orientation reversal of phase space volume elements. Enforcing this principle on dynamical triangulations of periodic points advected by the flow leads to higher-dimensional analogues of braids, which in three dimensions appear to provide the same information as usual approaches.

  9. Generalized dimensions applied to speaker identification

    NASA Astrophysics Data System (ADS)

    Hou, Limin; Wang, Shuozhong

    2004-08-01

    This paper describes an application of fractal dimensions to speech processing and speaker identification. There are several dimensions that can be used to characterize speech signals such as box dimension, correlation dimension, etc. We are mainly concerned with the generalized dimensions of speech signals as they provide more information than individual dimensions. Generalized dimensions of arbitrary orders are used in speaker identification in this work. Based on the experimental data, the artificial phase space is generated and smooth behavior of correlation integral is obtained in a straightforward and accurate analysis. Using the dimension D(2) derived from the correlation integral, the generalized dimension D(q) of an arbitrary order q is calculated. Moreover, experiments applying the generalized dimension in speaker identification have been carried out. A speaker recognition dedicated Chinese language speech corpus with PKU-SRSC, recorded by Peking University, was used in the experiments. The results are compared to a baseline speaker identification that uses MFCC features. Experimental results have indicated the usefulness of fractal dimensions in characterizing speaker's identity.

  10. Psychophysical dimensions of tactile perception of textures.

    PubMed

    Okamoto, Shogo; Nagano, Hikaru; Yamada, Yoji

    2013-01-01

    This paper reviews studies on the tactile dimensionality of physical properties of materials in order to determine a common structure for these dimensions. Based on the commonality found in a number of studies and known mechanisms for the perception of physical properties of textures, we conclude that tactile textures are composed of three prominent psychophysical dimensions that are perceived as roughness/smoothness, hardness/softness, and coldness/warmness. The roughness dimension may be divided into two dimensions: macro and fine roughness. Furthermore, it is reasonable to consider that a friction dimension that is related to the perception of moistness/dryness and stickiness/slipperiness exists. Thus, the five potential dimensions of tactile perception are macro and fine roughness, warmness/coldness, hardness/softness, and friction (moistness/dryness, stickiness/slipperiness). We also summarize methods such as psychological experiments and mathematical approaches for structuring tactile dimensions and their limitations.

  11. Dirac Semimetals in Two Dimensions.

    PubMed

    Young, Steve M; Kane, Charles L

    2015-09-18

    Graphene is famous for being a host of 2D Dirac fermions. However, spin-orbit coupling introduces a small gap, so that graphene is formally a quantum spin Hall insulator. Here we present symmetry-protected 2D Dirac semimetals, which feature Dirac cones at high-symmetry points that are not gapped by spin-orbit interactions and exhibit behavior distinct from both graphene and 3D Dirac semimetals. Using a two-site tight-binding model, we construct representatives of three possible distinct Dirac semimetal phases and show that single symmetry-protected Dirac points are impossible in two dimensions. An essential role is played by the presence of nonsymmorphic space group symmetries. We argue that these symmetries tune the system to the boundary between a 2D topological and trivial insulator. By breaking the symmetries we are able to access trivial and topological insulators as well as Weyl semimetal phases.

  12. [Temporal dimensions of suicide: hypothesis].

    PubMed

    Carbonell-Camós, Eliseu

    2008-01-01

    In this article, the author examines the temporal dimensions of suicide by taking into account the multiple existing approaches-circadian physiology, psychiatric or sociological epidemiology of suicide-however promoting a socio-anthropological perspective. From this perspective, suicide is examined as a social phenomenon inscribed in time. By beginning with a concern that is characteristic of anthropology of time, knowingly the relation between time of nature and time of society, the author addresses a key issue of the study of suicide already elaborated by Durkheim, in the relation between change that is a basic expression of the passage of time and suicide. After presenting different scientific contributions on the subject, the author proposes an hypothesis allowing integration of the influence of time related to natural phenomenon (cosmobiological rhythms) and the relation of time to social phenomenon (politico-economic rhythms) in relation with suicide and this, according to Gabennesch's theory of "failed promises."

  13. Ambitwistor Strings in Four Dimensions

    NASA Astrophysics Data System (ADS)

    Geyer, Yvonne; Lipstein, Arthur E.; Mason, Lionel

    2014-08-01

    We develop ambitwistor string theories for four dimensions to obtain new formulas for tree-level gauge and gravity amplitudes with arbitrary amounts of supersymmetry. Ambitwistor space is the space of complex null geodesics in complexified Minkowski space, and in contrast to earlier ambitwistor strings, we use twistors rather than vectors to represent this space. Although superficially similar to the original twistor string theories of Witten, Berkovits, and Skinner, these theories differ in the assignment of world sheet spins of the fields, rely on both twistor and dual twistor representatives for the vertex operators, and use the ambitwistor procedure for calculating correlation functions. Our models are much more flexible, no longer requiring maximal supersymmetry, and the resulting formulas for amplitudes are simpler, having substantially reduced moduli. These are supported on the solutions to the scattering equations refined according to helicity and can be checked by comparison with corresponding formulas of Witten and of Cachazo and Skinner.

  14. Plasma torches dimensioning and optimization

    NASA Astrophysics Data System (ADS)

    Muller, S.

    A set of codes which enable dimensioning and optimization of non transferred plasma torches made up of two coaxial cylindrical electrodes cooled up in the 100 kW power range is described. These torches are used in ballistic, space and industrial fields. The sharp model of exchanges between the electric arc and the plasma producing gas requires a thorough knowledge of the physical properties of this plasma producing gas so a specific study was carried out on the air. Equations taken into account include mass conservation, Navier-Stokes and energy conservation equations. An experimental data bank gathers the plasma torches performances described. The modular structure of the package and its continuous feedback between theoretical and experimental data bank improves constantly with new experimentation.

  15. Accessible solitons of fractional dimension

    SciTech Connect

    Zhong, Wei-Ping; Belić, Milivoj; Zhang, Yiqi

    2016-05-15

    We demonstrate that accessible solitons described by an extended Schrödinger equation with the Laplacian of fractional dimension can exist in strongly nonlocal nonlinear media. The soliton solutions of the model are constructed by two special functions, the associated Legendre polynomials and the Laguerre polynomials in the fraction-dimensional space. Our results show that these fractional accessible solitons form a soliton family which includes crescent solitons, and asymmetric single-layer and multi-layer necklace solitons. -- Highlights: •Analytic solutions of a fractional Schrödinger equation are obtained. •The solutions are produced by means of self-similar method applied to the fractional Schrödinger equation with parabolic potential. •The fractional accessible solitons form crescent, asymmetric single-layer and multilayer necklace profiles. •The model applies to the propagation of optical pulses in strongly nonlocal nonlinear media.

  16. Kolmogorov Flow in Three Dimensions

    NASA Technical Reports Server (NTRS)

    Shebalin, John V.; Woodruff, Stephen L.

    1996-01-01

    A numerical study of the long-time evolution of incompressible Navier-Stokes turbulence forced at a single long-wavelength Fourier mode, i.e., a Kolmogorov flow, has been completed. The boundary conditions are periodic in three dimensions and the forcing is effected by imposing a steady, two-dimensional, sinusoidal shear velocity which is directed along the x-direction and varies along the z-direction. A comparison with experimental data shows agreement with measured cross-correlations of the turbulent velocity components which lie in the mean-flow plane. A statistical analysis reveals that the shear-driven turbulence studied here has significant spectral anisotropy which increases with wave number.

  17. Grand unification in higher dimensions

    NASA Astrophysics Data System (ADS)

    Hall, Lawrence J.; Nomura, Yasunori

    2003-07-01

    We have recently proposed an alternative picture for the physics at the scale of gauge coupling unification, where the unified symmetry is realized in higher dimensions but is broken locally by a symmetry breaking defect. Gauge coupling unification, the quantum numbers of quarks and leptons and the longevity of the proton arise as phenomena of the symmetrical bulk, while the lightness of the Higgs doublets and the masses of the light quarks and leptons probe the symmetry breaking defect. Moreover, the framework is extremely predictive if the effective higher dimensional theory is valid over a large energy interval up to the scale of strong coupling. Precise agreement with experiments is obtained in the simplest theory— SU(5) in five dimensions with two Higgs multiplets propagating in the bulk. The weak mixing angle is predicted to be sin 2θw=0.2313±0.0004, which fits the data with extraordinary accuracy. The compactification scale and the strong coupling scale are determined to be M c≃5×10 14 GeV and M s≃1×10 17 GeV, respectively. Proton decay with a lifetime of order 10 34 years is expected with a variety of final states such as e+π0, and several aspects of flavor, including large neutrino mixing angles, are understood by the geometrical locations of the matter fields. When combined with a particular supersymmetry breaking mechanism, the theory predicts large lepton flavor violating μ→ e and τ→ μ transitions, with all superpartner masses determined by only two free parameters. The predicted value of the bottom quark mass from Yukawa unification agrees well with the data. This paper is mainly a review of the work presented in hep-ph/0103125, hep-ph/0111068, and hep-ph/0205067 [1-3].

  18. On some trees having partition dimension four

    NASA Astrophysics Data System (ADS)

    Ida Bagus Kade Puja Arimbawa, K.; Baskoro, Edy Tri

    2016-02-01

    In 1998, G. Chartrand, E. Salehi and P. Zhang introduced the notion of partition dimension of a graph. Since then, the study of this graph parameter has received much attention. A number of results have been obtained to know the values of partition dimensions of various classes of graphs. However, for some particular classes of graphs, finding of their partition dimensions is still not completely solved, for instances a class of general tree. In this paper, we study the properties of trees having partition dimension 4. In particular, we show that, for olive trees O(n), its partition dimension is equal to 4 if and only if 8 ≤ n ≤ 17. We also characterize all centipede trees having partition dimension 4.

  19. Non-canonical integration events in Pichia pastoris encountered during standard transformation analysed with genome sequencing

    PubMed Central

    Schwarzhans, Jan-Philipp; Wibberg, Daniel; Winkler, Anika; Luttermann, Tobias; Kalinowski, Jörn; Friehs, Karl

    2016-01-01

    The non-conventional yeast Pichia pastoris is a popular host for recombinant protein production in scientific research and industry. Typically, the expression cassette is integrated into the genome via homologous recombination. Due to unknown integration events, a large clonal variability is often encountered consisting of clones with different productivities as well as aberrant morphological or growth characteristics. In this study, we analysed several clones with abnormal colony morphology and discovered unpredicted integration events via whole genome sequencing. These include (i) the relocation of the locus targeted for replacement to another chromosome (ii) co-integration of DNA from the E. coli plasmid host and (iii) the disruption of untargeted genes affecting colony morphology. Most of these events have not been reported so far in literature and present challenges for genetic engineering approaches in this yeast. Especially, the presence and independent activity of E. coli DNA elements in P. pastoris is of concern. In our study, we provide a deeper insight into these events and their potential origins. Steps preventing or reducing the risk for these phenomena are proposed and will help scientists working on genetic engineering of P. pastoris or similar non-conventional yeast to better understand and control clonal variability. PMID:27958335

  20. [The frame of non-canonical theory of heredity: from genes to epigenes].

    PubMed

    Churaev, R N

    2005-01-01

    Particular theory of heredity that exceeds the limits of mendelian genetics is suggested. The model based on five sufficiently obvious assumptions (accepted as axioms) As consequence of these axioms the strict statements concerningfunctional heredity memory were formulated in mathematical terms. Molecular-genetic realization of the memory cells appears as new class of heredity units--epigenes. In the epigenes part f hereditary information is contained, encoded and transmitted beyond the primary structure of DNA molecules of genome. Epigenes capable to conserve sequences of genes functional states in the course of ontogenesis and provide transmission of information contained in this states throw consequent generations. It was shown that epigenes differ from genes at least by encoding method of heredity information. There are three functional-equivalent classes of really existing epigenes mechanisms: dynamic, modificational and transpositional; and there is one hypothetical class--invertional. It was shown that a lot of experimental data concerning epigenetic mechanism of heredity is in accord with theoretical conclusions concerning epigenes existence. Moreover, we constructed an artificial epigenes by genetic engineering methods. The existence of epigenes means that obtaining complete genome sequence, its physical and genetic maps, as well as distinguishing the rules of genes function encoding by its primary structure do not provide complete decoding of hereditary information. The role of epigenes in ontogenesis and phylogenesis was examined. It was shown that even elementary epigenetic systems could determine key ontogenesis events. Epigenetic system could serve as the basis of non-darwinian evolutionary strategies by means of "memorization of rather unsuccessfully steps of evolution" and conservation of alternative variants of ontogenesis. Teleonomic hypothesis on functional heredity memory was formulated. This theory provides explanation of phenomena of acquired features inheritance and molecular mechanisms of stress-induced evolution.

  1. Ciliary intraflagellar transport protein 80 balances canonical versus non-canonical hedgehog signaling for osteoblast differentiation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutation of different IFT proteins cause numerous different clinical bone disorders accompanied with or without the disruption of cilia formation. Currently, there is no any effective treatment for these disorders due to lack of understanding in the function and mechanism of these proteins. IFT80 is...

  2. Non-canonical active site architecture of the radical SAM thiamin pyrimidine synthase

    NASA Astrophysics Data System (ADS)

    Fenwick, Michael K.; Mehta, Angad P.; Zhang, Yang; Abdelwahed, Sameh H.; Begley, Tadhg P.; Ealick, Steven E.

    2015-03-01

    Radical S-adenosylmethionine (SAM) enzymes use a [4Fe-4S] cluster to generate a 5‧-deoxyadenosyl radical. Canonical radical SAM enzymes are characterized by a β-barrel-like fold and SAM anchors to the differentiated iron of the cluster, which is located near the amino terminus and within the β-barrel, through its amino and carboxylate groups. Here we show that ThiC, the thiamin pyrimidine synthase in plants and bacteria, contains a tethered cluster-binding domain at its carboxy terminus that moves in and out of the active site during catalysis. In contrast to canonical radical SAM enzymes, we predict that SAM anchors to an additional active site metal through its amino and carboxylate groups. Superimposition of the catalytic domains of ThiC and glutamate mutase shows that these two enzymes share similar active site architectures, thus providing strong evidence for an evolutionary link between the radical SAM and adenosylcobalamin-dependent enzyme superfamilies.

  3. A non canonical subtilase attenuates the transcriptional activation of defence responses in Arabidopsis thaliana

    PubMed Central

    Serrano, Irene; Buscaill, Pierre; Audran, Corinne; Pouzet, Cécile; Jauneau, Alain; Rivas, Susana

    2016-01-01

    Proteases play crucial physiological functions in all organisms by controlling the lifetime of proteins. Here, we identified an atypical protease of the subtilase family [SBT5.2(b)] that attenuates the transcriptional activation of plant defence independently of its protease activity. The SBT5.2 gene produces two distinct transcripts encoding a canonical secreted subtilase [SBT5.2(a)] and an intracellular protein [SBT5.2(b)]. Concomitant to SBT5.2(a) downregulation, SBT5.2(b) expression is induced after bacterial inoculation. SBT5.2(b) localizes to endosomes where it interacts with and retains the defence-related transcription factor MYB30. Nuclear exclusion of MYB30 results in its reduced transcriptional activation and, thus, suppressed resistance. sbt5.2 mutants, with abolished SBT5.2(a) and SBT5.2(b) expression, display enhanced defence that is suppressed in a myb30 mutant background. Moreover, overexpression of SBT5.2(b), but not SBT5.2(a), in sbt5.2 plants reverts the phenotypes displayed by sbt5.2 mutants. Overall, we uncover a regulatory mode of the transcriptional activation of defence responses previously undescribed in eukaryotes. DOI: http://dx.doi.org/10.7554/eLife.19755.001 PMID:27685353

  4. Reelin Induces Erk1/2 Signaling in Cortical Neurons Through a Non-canonical Pathway*

    PubMed Central

    Lee, Gum Hwa; Chhangawala, Zinal; von Daake, Sventja; Savas, Jeffrey N.; Yates, John R.; Comoletti, Davide; D'Arcangelo, Gabriella

    2014-01-01

    Reelin is an extracellular protein that controls many aspects of pre- and postnatal brain development and function. The molecular mechanisms that mediate postnatal activities of Reelin are not well understood. Here, we first set out to express and purify the full length Reelin protein and a biologically active central fragment. Second, we investigated in detail the signal transduction mechanisms elicited by these purified Reelin proteins in cortical neurons. Unexpectedly, we discovered that the full-length Reelin moiety, but not the central fragment, is capable of activating Erk1/2 signaling, leading to increased p90RSK phosphorylation and the induction of immediate-early gene expression. Remarkably, Erk1/2 activation is not mediated by the canonical signal transduction pathway, involving ApoER2/VLDLR and Dab1, that mediates other functions of Reelin in early brain development. The activation of Erk1/2 signaling likely contributes to the modulation of neuronal maturation and synaptic plasticity by Reelin in the postnatal and adult brain. PMID:24876378

  5. Non-canonical features of the Golgi apparatus in bipolar epithelial neural stem cells

    PubMed Central

    Taverna, Elena; Mora-Bermúdez, Felipe; Strzyz, Paulina J.; Florio, Marta; Icha, Jaroslav; Haffner, Christiane; Norden, Caren; Wilsch-Bräuninger, Michaela; Huttner, Wieland B.

    2016-01-01

    Apical radial glia (aRG), the stem cells in developing neocortex, are unique bipolar epithelial cells, extending an apical process to the ventricle and a basal process to the basal lamina. Here, we report novel features of the Golgi apparatus, a central organelle for cell polarity, in mouse aRGs. The Golgi was confined to the apical process but not associated with apical centrosome(s). In contrast, in aRG-derived, delaminating basal progenitors that lose apical polarity, the Golgi became pericentrosomal. The aRG Golgi underwent evolutionarily conserved, accordion-like compression and extension concomitant with cell cycle-dependent nuclear migration. Importantly, in line with endoplasmic reticulum but not Golgi being present in the aRG basal process, its plasma membrane contained glycans lacking Golgi processing, consistent with direct ER-to-cell surface membrane traffic. Our study reveals hitherto unknown complexity of neural stem cell polarity, differential Golgi contribution to their specific architecture, and fundamental Golgi re-organization upon cell fate change. PMID:26879757

  6. A non canonical subtilase attenuates the transcriptional activation of defence responses in Arabidopsis thaliana.

    PubMed

    Serrano, Irene; Buscaill, Pierre; Audran, Corinne; Pouzet, Cécile; Jauneau, Alain; Rivas, Susana

    2016-09-29

    Proteases play crucial physiological functions in all organisms by controlling the lifetime of proteins. Here, we identified an atypical protease of the subtilase family [SBT5.2(b)] that attenuates the transcriptional activation of plant defence independently of its protease activity. The SBT5.2 gene produces two distinct transcripts encoding a canonical secreted subtilase [SBT5.2(a)] and an intracellular protein [SBT5.2(b)]. Concomitant to SBT5.2(a) downregulation, SBT5.2(b) expression is induced after bacterial inoculation. SBT5.2(b) localizes to endosomes where it interacts with and retains the defence-related transcription factor MYB30. Nuclear exclusion of MYB30 results in its reduced transcriptional activation and, thus, suppressed resistance. sbt5.2 mutants, with abolished SBT5.2(a) and SBT5.2(b) expression, display enhanced defence that is suppressed in a myb30 mutant background. Moreover, overexpression of SBT5.2(b), but not SBT5.2(a), in sbt5.2 plants reverts the phenotypes displayed by sbt5.2 mutants. Overall, we uncover a regulatory mode of the transcriptional activation of defence responses previously undescribed in eukaryotes.

  7. Fancd2 in vivo interaction network reveals a non-canonical role in mitochondrial function

    PubMed Central

    Zhang, Tingting; Du, Wei; Wilson, Andrew F.; Namekawa, Satoshi H.; Andreassen, Paul R.; Meetei, Amom Ruhikanta; Pang, Qishen

    2017-01-01

    Fancd2 is a component of the Fanconi anemia (FA) DNA repair pathway, which is frequently found defective in human cancers. The full repertoire of Fancd2 functions in normal development and tumorigenesis remains to be determined. Here we developed a Flag- and hemagglutinin-tagged Fancd2 knock-in mouse strain that allowed a high throughput mass spectrometry approach to search for Fancd2-binding proteins in different mouse organs. In addition to DNA repair partners, we observed that many Fancd2-interacting proteins are mitochondrion-specific. Fancd2 localizes in the mitochondrion and associates with the nucleoid complex components Atad3 and Tufm. The Atad3-Tufm complex is disrupted in Fancd2−/− mice and those deficient for the FA core component Fanca. Fancd2 mitochondrial localization requires Atad3. Collectively, these findings provide evidence for Fancd2 as a crucial regulator of mitochondrion biosynthesis, and of a molecular link between FA and mitochondrial homeostasis. PMID:28378742

  8. Ethanol Effects Involve Non-canonical Unfolded Protein Response Activation in Yeast Cells

    PubMed Central

    Navarro-Tapia, Elisabet; Pérez-Torrado, Roberto; Querol, Amparo

    2017-01-01

    The unfolded protein response (UPR) is a conserved intracellular signaling pathway that controls transcription of endoplasmic reticulum (ER) homeostasis related genes. Ethanol stress has been recently described as an activator of the UPR response in yeast Saccharomyces cerevisiae, but very little is known about the causes of this activation. Although some authors ensure that the UPR is triggered by the unfolded proteins generated by ethanol in the cell, there are studies which demonstrate that protein denaturation occurs at higher ethanol concentrations than those used to trigger the UPR. Here, we studied UPR after ethanol stress by three different approaches and we concluded that unfolded proteins do not accumulate in the ER under. We also ruled out inositol depletion as an alternative mechanism to activate the UPR under ethanol stress discarding that ethanol effects on the cell decreased inositol levels by different methods. All these data suggest that ethanol, at relatively low concentrations, does not cause unfolded proteins in the yeasts and UPR activation is likely due to other unknown mechanism related with a restructuring of ER membrane due to the effect of ethanol. PMID:28326077

  9. A non-canonical pathway from cochlea to brain signals tissue-damaging noise.

    PubMed

    Flores, Emma N; Duggan, Anne; Madathany, Thomas; Hogan, Ann K; Márquez, Freddie G; Kumar, Gagan; Seal, Rebecca P; Edwards, Robert H; Liberman, M Charles; García-Añoveros, Jaime

    2015-03-02

    Intense noise damages the cochlear organ of Corti, particularly the outer hair cells (OHCs) [1]; however, this epithelium is not innervated by nociceptors of somatosensory ganglia, which detect damage elsewhere in the body. The only sensory neurons innervating the organ of Corti originate from the spiral ganglion, roughly 95% of which innervate exclusively inner hair cells (IHCs) [2-4]. Upon sound stimulation, IHCs release glutamate to activate AMPA-type receptors on these myelinated type-I neurons, which carry the neuronal signals to the cochlear nucleus. The remaining spiral ganglion cells (type IIs) are unmyelinated and contact OHCs [2-4]. Their function is unknown. Using immunoreactivity to cFos, we documented neuronal activation in the brainstem of Vglut3(-/-) mice, in which the canonical auditory pathway (activation of type-I afferents by glutamate released from inner hair cells) is silenced [5, 6]. In these deaf mice, we found responses to noxious noise, which damages hair cells, but not to innocuous noise, in neurons of the cochlear nucleus, but not in the vestibular or trigeminal nuclei. This response originates in the cochlea and not in other areas also stimulated by intense noise (middle ear and vestibule) as it was absent in CD1 mice with selective cochlear degeneration but normal vestibular and somatosensory function. These data imply the existence of an alternative neuronal pathway from cochlea to brainstem that is activated by tissue-damaging noise and does not require glutamate release from IHCs. This detection of noise-induced tissue damage, possibly by type-II cochlear afferents, represents a novel form of sensation that we term auditory nociception.

  10. Non-canonical active site architecture of the radical SAM thiamin pyrimidine synthase

    DOE PAGES

    Fenwick, Michael K.; Mehta, Angad P.; Zhang, Yang; ...

    2015-03-27

    Radical S-adenosylmethionine (SAM) enzymes use a [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical. Canonical radical SAM enzymes are characterized by a β-barrel-like fold and SAM anchors to the differentiated iron of the cluster, which is located near the amino terminus and within the β-barrel, through its amino and carboxylate groups. Here we show that ThiC, the thiamin pyrimidine synthase in plants and bacteria, contains a tethered cluster-binding domain at its carboxy terminus that moves in and out of the active site during catalysis. In contrast to canonical radical SAM enzymes, we predict that SAM anchors to an additional active sitemore » metal through its amino and carboxylate groups. Superimposition of the catalytic domains of ThiC and glutamate mutase shows that these two enzymes share similar active site architectures, thus providing strong evidence for an evolutionary link between the radical SAM and adenosylcobalamin-dependent enzyme superfamilies.« less

  11. Non-canonical active site architecture of the radical SAM thiamin pyrimidine synthase

    SciTech Connect

    Fenwick, Michael K.; Mehta, Angad P.; Zhang, Yang; Abdelwahed, Sameh H.; Begley, Tadhg P.; Ealick, Steven E.

    2015-03-27

    Radical S-adenosylmethionine (SAM) enzymes use a [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical. Canonical radical SAM enzymes are characterized by a β-barrel-like fold and SAM anchors to the differentiated iron of the cluster, which is located near the amino terminus and within the β-barrel, through its amino and carboxylate groups. Here we show that ThiC, the thiamin pyrimidine synthase in plants and bacteria, contains a tethered cluster-binding domain at its carboxy terminus that moves in and out of the active site during catalysis. In contrast to canonical radical SAM enzymes, we predict that SAM anchors to an additional active site metal through its amino and carboxylate groups. Superimposition of the catalytic domains of ThiC and glutamate mutase shows that these two enzymes share similar active site architectures, thus providing strong evidence for an evolutionary link between the radical SAM and adenosylcobalamin-dependent enzyme superfamilies.

  12. Interferon Gamma Induces Protective Non-Canonical Signaling Pathways in Primary Neurons

    PubMed Central

    O'Donnell, Lauren A.; Henkins, Kristen M.; Kulkarni, Apurva; Matullo, Christine M.; Balachandran, Siddharth; Pattisapu, Anil K.; Rall, Glenn F.

    2016-01-01

    The signal transduction molecule, Stat1, is critical for the expression of type I and II interferon (IFN)-responsive genes in most cells; however, we previously showed that primary hippocampal mouse neurons express low basal Stat1, with delayed and attenuated expression of IFN-responsive genes. Moreover, IFNγ-dependent resolution of a neurotropic viral challenge in permissive mice is Stat1-independent. Here, we show that exogenous INFγ has no deleterious impact on neuronal viability, and staurosporine-induced apoptosis in neurons is significantly blunted by the addition of INFγ, suggesting that INFγ confers a pro-survival signal in neurons. To identify the pathways induced by INFγ in neurons, the activation of alternative signal transducers associated with INFγ signaling was assessed. Rapid and pronounced activation of extracellular signal regulated kinase (Erk1/2) was observed in neurons, compared to a modest response in fibroblasts. Moreover, the absence of Stat1 in primary fibroblasts led to enhanced Erk activation following IFNγ addition, implying that the cell-specific availability of signal transducers can diversify the cellular response following IFN engagement. PMID:26190522

  13. Reassignment of a rare sense codon to a non-canonical amino acid in Escherichia coli

    PubMed Central

    Mukai, Takahito; Yamaguchi, Atsushi; Ohtake, Kazumasa; Takahashi, Mihoko; Hayashi, Akiko; Iraha, Fumie; Kira, Satoshi; Yanagisawa, Tatsuo; Yokoyama, Shigeyuki; Hoshi, Hiroko; Kobayashi, Takatsugu; Sakamoto, Kensaku

    2015-01-01

    The immutability of the genetic code has been challenged with the successful reassignment of the UAG stop codon to non-natural amino acids in Escherichia coli. In the present study, we demonstrated the in vivo reassignment of the AGG sense codon from arginine to l-homoarginine. As the first step, we engineered a novel variant of the archaeal pyrrolysyl-tRNA synthetase (PylRS) able to recognize l-homoarginine and l-N6-(1-iminoethyl)lysine (l-NIL). When this PylRS variant or HarRS was expressed in E. coli, together with the AGG-reading tRNAPylCCU molecule, these arginine analogs were efficiently incorporated into proteins in response to AGG. Next, some or all of the AGG codons in the essential genes were eliminated by their synonymous replacements with other arginine codons, whereas the majority of the AGG codons remained in the genome. The bacterial host's ability to translate AGG into arginine was then restricted in a temperature-dependent manner. The temperature sensitivity caused by this restriction was rescued by the translation of AGG to l-homoarginine or l-NIL. The assignment of AGG to l-homoarginine in the cells was confirmed by mass spectrometric analyses. The results showed the feasibility of breaking the degeneracy of sense codons to enhance the amino-acid diversity in the genetic code. PMID:26240376

  14. To ~P or Not to ~P? Non-canonical activation by two-component response regulators

    PubMed Central

    Desai, Stuti K.; Kenney, Linda J.

    2016-01-01

    Summary Bacteria sense and respond to their environment through the use of two-component regulatory systems. The ability to adapt to a wide range of environmental stresses is directly related to the number of two-component systems an organism possesses. Recent advances in this area have identified numerous variations on the archetype systems that employ a sensor kinase and a response regulator. It is now evident that many orphan regulators that lack cognate kinases do not rely on phosphorylation for activation and new roles for unphosphorylated response regulators have been identified. The significance of recent findings and suggestions for further research are discussed. PMID:27656860

  15. A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K+ Channels

    PubMed Central

    Schewe, Marcus; Nematian-Ardestani, Ehsan; Sun, Han; Musinszki, Marianne; Cordeiro, Sönke; Bucci, Giovanna; de Groot, Bert L.; Tucker, Stephen J.; Rapedius, Markus; Baukrowitz, Thomas

    2016-01-01

    Summary Two-pore domain (K2P) K+ channels are major regulators of excitability that endow cells with an outwardly rectifying background “leak” conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way “check valve” within the filter because outward movement of K+ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K+-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage. PMID:26919430

  16. A non-canonical multisubunit RNA polymerase encoded by a giant bacteriophage.

    PubMed

    Yakunina, Maria; Artamonova, Tatyana; Borukhov, Sergei; Makarova, Kira S; Severinov, Konstantin; Minakhin, Leonid

    2015-12-02

    The infection of Pseudomonas aeruginosa by the giant bacteriophage phiKZ is resistant to host RNA polymerase (RNAP) inhibitor rifampicin. phiKZ encodes two sets of polypeptides that are distantly related to fragments of the two largest subunits of cellular multisubunit RNAPs. Polypeptides of one set are encoded by middle phage genes and are found in the phiKZ virions. Polypeptides of the second set are encoded by early phage genes and are absent from virions. Here, we report isolation of a five-subunit RNAP from phiKZ-infected cells. Four subunits of this enzyme are cellular RNAP subunits homologs of the non-virion set; the fifth subunit is a protein of unknown function. In vitro, this complex initiates transcription from late phiKZ promoters in rifampicin-resistant manner. Thus, this enzyme is a non-virion phiKZ RNAP responsible for transcription of late phage genes. The phiKZ RNAP lacks identifiable assembly and promoter specificity subunits/factors characteristic for eukaryal, archaeal and bacterial RNAPs and thus provides a unique model for comparative analysis of the mechanism, regulation and evolution of this important class of enzymes.

  17. Planck limits on non-canonical generalizations of large-field inflation models

    NASA Astrophysics Data System (ADS)

    Stein, Nina K.; Kinney, William H.

    2017-04-01

    In this paper, we consider two case examples of Dirac-Born-Infeld (DBI) generalizations of canonical large-field inflation models, characterized by a reduced sound speed, cS < 1. The reduced speed of sound lowers the tensor-scalar ratio, improving the fit of the models to the data, but increases the equilateral-mode non-Gaussianity, fequil.NL, which the latest results from the Planck satellite constrain by a new upper bound. We examine constraints on these models in light of the most recent Planck and BICEP/Keck results, and find that they have a greatly decreased window of viability. The upper bound on fequil.NL corresponds to a lower bound on the sound speed and a corresponding lower bound on the tensor-scalar ratio of r ~ 0.01, so that near-future Cosmic Microwave Background observations may be capable of ruling out entire classes of DBI inflation models. The result is, however, not universal: infrared-type DBI inflation models, where the speed of sound increases with time, are not subject to the bound.

  18. Non-canonical features of the Golgi apparatus in bipolar epithelial neural stem cells.

    PubMed

    Taverna, Elena; Mora-Bermúdez, Felipe; Strzyz, Paulina J; Florio, Marta; Icha, Jaroslav; Haffner, Christiane; Norden, Caren; Wilsch-Bräuninger, Michaela; Huttner, Wieland B

    2016-02-16

    Apical radial glia (aRG), the stem cells in developing neocortex, are unique bipolar epithelial cells, extending an apical process to the ventricle and a basal process to the basal lamina. Here, we report novel features of the Golgi apparatus, a central organelle for cell polarity, in mouse aRGs. The Golgi was confined to the apical process but not associated with apical centrosome(s). In contrast, in aRG-derived, delaminating basal progenitors that lose apical polarity, the Golgi became pericentrosomal. The aRG Golgi underwent evolutionarily conserved, accordion-like compression and extension concomitant with cell cycle-dependent nuclear migration. Importantly, in line with endoplasmic reticulum but not Golgi being present in the aRG basal process, its plasma membrane contained glycans lacking Golgi processing, consistent with direct ER-to-cell surface membrane traffic. Our study reveals hitherto unknown complexity of neural stem cell polarity, differential Golgi contribution to their specific architecture, and fundamental Golgi re-organization upon cell fate change.

  19. Non-canonical transcription initiation: the expanding universe of transcription initiating substrates.

    PubMed

    Barvík, Ivan; Rejman, Dominik; Panova, Natalya; Šanderová, Hana; Krásný, Libor

    2017-03-01

    RNA polymerase (RNAP) is the central enzyme of transcription of the genetic information from DNA into RNA. RNAP recognizes four main substrates: ATP, CTP, GTP and UTP. Experimental evidence from the past several years suggests that, besides these four NTPs, other molecules can be used to initiate transcription: (i) ribooligonucleotides (nanoRNAs) and (ii) coenzymes such as NAD+, NADH, dephospho-CoA and FAD. The presence of these molecules at the 5΄ ends of RNAs affects the properties of the RNA. Here, we discuss the expanding portfolio of molecules that can initiate transcription, their mechanism of incorporation, effects on RNA and cellular processes, and we present an outlook toward other possible initiation substrates.

  20. A Non-canonical Melanin Biosynthesis Pathway Protects Aspergillus terreus Conidia from Environmental Stress.

    PubMed

    Geib, Elena; Gressler, Markus; Viediernikova, Iuliia; Hillmann, Falk; Jacobsen, Ilse D; Nietzsche, Sandor; Hertweck, Christian; Brock, Matthias

    2016-05-19

    Melanins are ubiquitous pigments found in all kingdoms of life. Most organisms use them for protection from environmental stress, although some fungi employ melanins as virulence determinants. The human pathogenic fungus Aspergillus fumigatus and related Ascomycetes produce dihydroxynaphthalene- (DHN) melanin in their spores, the conidia, and use it to inhibit phagolysosome acidification. However, biosynthetic origin of melanin in a related fungus, Aspergillus terreus, has remained a mystery because A. terreus lacks genes for synthesis of DHN-melanin. Here we identify genes coding for an unusual NRPS-like enzyme (MelA) and a tyrosinase (TyrP) that A. terreus expressed under conidiation conditions. We demonstrate that MelA produces aspulvinone E, which is activated for polymerization by TyrP. Functional studies reveal that this new pigment, Asp-melanin, confers resistance against UV light and hampers phagocytosis by soil amoeba. Unexpectedly, Asp-melanin does not inhibit acidification of phagolysosomes, thus likely contributing specifically to survival of A. terreus conidia in acidic environments.

  1. Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland

    PubMed Central

    Okolowsky, Nadia; Furth, Priscilla A.; Hamel, Paul A.

    2014-01-01

    Mesenchymal dysplasia (mes) mice harbour a truncation in the C-terminal region of the Hh-ligand receptor, Patched-1 (mPtch1). While the mes variant of mPtch1 binds to Hh-ligands with an affinity similar to that of wild type mPtch1 and appears to normally regulate canonical Hh-signalling via smoothened, the mes mutation causes, among other non-lethal defects, a block to mammary ductal elongation at puberty. We demonstrated previously Hh-signalling induces the activation of Erk1/2 and c-src independently of its control of smo activity. Furthermore, mammary epithelial cell-directed expression of an activated allele of c-src rescued the block to ductal elongation in mes mice, albeit with delayed kinetics. Given that this rescue was accompanied by an induction in estrogen receptor-alpha (ERα) expression and that complex regulatory interactions between ERα and c-src are required for normal mammary gland development, it was hypothesized that expression of ERα would also overcome the block to mammary ductal elongation at puberty in the mes mouse. We demonstrate here that conditional expression of ERα in luminal mammary epithelial cells on the mes background facilitates ductal morphogenesis with kinetics similar to that of the MMTV-c-srcAct mice. We demonstrate further that Erk1/2 is activated in primary mammary epithelial cells by Shh-ligand and that this activation is blocked by the inhibitor of c-src, PP2, is partially blocked by the ERα inhibitor, ICI 182780 but is not blocked by the smo-inhibitor, SANT-1. These data reveal an apparent Hh-signalling cascade operating through c-src and ERα that is required for mammary gland morphogenesis at puberty. PMID:24769368

  2. Psychological Dimensions of Cross-Cultural Differences

    DTIC Science & Technology

    2013-05-01

    AFRL-OSR-VA-TR-2013-0214 Psychological Dimensions of Cross- Cultural Differences Saucier, Gerard University of Oregon May...Psychological Dimensions of Cross- Cultural Differences Grant Research Final Performance Report – February 2013 prepared by Gerard Saucier, Principal...Psychological Dimensions of Cross- Cultural Differences Contract/Grant Number: FA9550-09-1-0398 Reporting period: June 1, 2009 to November 30, 2012

  3. The international dimensions of neuroethics.

    PubMed

    Lombera, Sofia; Illes, Judy

    2009-08-01

    Neuroethics, in its modern form, investigates the impact of brain science in four basic dimensions: the self, social policy, practice and discourse. In this study, we analyzed a set of 461 peer-reviewed articles with neuroethics content, published by authors from 32 countries. We analyzed the data for: (1) trends in the development of international neuroethics over time, and (2) how challenges at the intersection of ethics and neuroscience are viewed in countries that are considered developed by International Monetary Fund (IMF) standards, and in those that are developing. Our results demonstrate a steady increase in global participation in neuroethics from 1989 to 2005, characterized by an increase in numbers of articles published specifically on neuroethics, journals publishing these articles, and countries contributing to the literature. The focus from all countries was on the practice of brain science and the amelioration of neurological disease. Indicators of technology creation and diffusion in developing countries were specifically correlated with increases in publications concerning policy implications of brain science. Neuroethics is an international endeavor and, as such, should be sensitive to the impact that context has on acceptance and use of technological innovation.

  4. THE INTERNATIONAL DIMENSIONS OF NEUROETHICS

    PubMed Central

    LOMBERA, SOFIA; ILLES, JUDY

    2008-01-01

    Neuroethics, in its modern form, investigates the impact of brain science in four basic dimensions: the self, social policy, practice and discourse. In this study, we analyzed a set of 461 peer-reviewed articles with neuroethics content, published by authors from 32 countries. We analyzed the data for: (1) trends in the development of international neuroethics over time, and (2) how challenges at the intersection of ethics and neuroscience are viewed in countries that are considered developed by International Monetary Fund (IMF) standards, and in those that are developing. Our results demonstrate a steady increase in global participation in neuroethics from 1989 to 2005, characterized by an increase in numbers of articles published specifically on neuroethics, journals publishing these articles, and countries contributing to the literature. The focus from all countries was on the practice of brain science and the amelioration of neurological disease. Indicators of technology creation and diffusion in developing countries were specifically correlated with increases in publications concerning policy implications of brain science. Neuroethics is an international endeavor and, as such, should be sensitive to the impact that context has on acceptance and use of technological innovation. PMID:18445073

  5. Deconstructing Signaling in Three Dimensions

    PubMed Central

    2015-01-01

    Cells in vivo exist within the context of a multicellular tissue, where their behavior is governed by homo- and heterotypic cell–cell interactions, the material properties of the extracellular matrix, and the distribution of various soluble and physical factors. Most methods currently used to study and manipulate cellular behavior in vitro, however, sacrifice physiological relevance for experimental expediency. The fallacy of such approaches has been highlighted by the recent development and application of three-dimensional culture models to cell biology, which has revealed striking phenotypic differences in cell survival, migration, and differentiation in genetically identical cells simply by varying culture conditions. These perplexing findings beg the question of what constitutes a three-dimensional culture and why cells behave so differently in two- and three-dimensional culture formats. In the following review, we dissect the fundamental differences between two- and three-dimensional culture conditions. We begin by establishing a basic definition of what “three dimensions” means at different biological scales and discuss how dimensionality influences cell signaling across different length scales. We identify which three-dimensional features most potently influence intracellular signaling and distinguish between conserved biological principles that are maintained across culture conditions and cellular behaviors that are sensitive to microenvironmental context. Finally, we highlight state-of-the-art molecular tools amenable to the study of signaling in three dimensions under conditions that facilitate deconstruction of signaling in a more physiologically relevant manner. PMID:24649923

  6. Contagion Shocks in One Dimension

    NASA Astrophysics Data System (ADS)

    Bertozzi, Andrea L.; Rosado, Jesus; Short, Martin B.; Wang, Li

    2015-02-01

    We consider an agent-based model of emotional contagion coupled with motion in one dimension that has recently been studied in the computer science community. The model involves movement with a speed proportional to a "fear" variable that undergoes a temporal consensus averaging based on distance to other agents. We study the effect of Riemann initial data for this problem, leading to shock dynamics that are studied both within the agent-based model as well as in a continuum limit. We examine the behavior of the model under distinguished limits as the characteristic contagion interaction distance and the interaction timescale both approach zero. The limiting behavior is related to a classical model for pressureless gas dynamics with "sticky" particles. In comparison, we observe a threshold for the interaction distance vs. interaction timescale that produce qualitatively different behavior for the system - in one case particle paths do not cross and there is a natural Eulerian limit involving nonlocal interactions and in the other case particle paths can cross and one may consider only a kinetic model in the continuum limit.

  7. Optoacoustic imaging in five dimensions

    NASA Astrophysics Data System (ADS)

    Deán-Ben, X. L.; Gottschalk, Sven; Fehm, Thomas F.; Razansky, Daniel

    2015-03-01

    We report on an optoacoustic imaging system capable of acquiring volumetric multispectral optoacoustic data in real time. The system is based on simultaneous acquisition of optoacoustic signals from 256 different tomographic projections by means of a spherical matrix array. Thereby, volumetric reconstructions can be done at high frame rate, only limited by the pulse repetition rate of the laser. The developed tomographic approach presents important advantages over previously reported systems that use scanning for attaining volumetric optoacoustic data. First, dynamic processes, such as the biodistribution of optical biomarkers, can be monitored in the entire volume of interest. Second, out-of-plane and motion artifacts that could degrade the image quality when imaging living specimens can be avoided. Finally, real-time 3D performance can obviously save time required for experimental and clinical observations. The feasibility of optoacoustic imaging in five dimensions, i.e. real time acquisition of volumetric datasets at multiple wavelengths, is reported. In this way, volumetric images of spectrally resolved chromophores are rendered in real time, thus offering an unparallel imaging performance among the current bio-imaging modalities. This performance is subsequently showcased by video-rate visualization of in vivo hemodynamic changes in mouse brain and handheld visualization of blood oxygenation in deep human vessels. The newly discovered capacities open new prospects for translating the optoacoustic technology into highly performing imaging modality for biomedical research and clinical practice with multiple applications envisioned, from cardiovascular and cancer diagnostics to neuroimaging and ophthalmology.

  8. Spontaneous symmetry breaking in quasi one dimension

    SciTech Connect

    Satpathi, Urbashi Deo, P. Singha

    2015-06-24

    Electronic charge and spin separation leading to charge density wave and spin density wave is well established in one dimension in the presence and absence of Coulomb interaction. We start from quasi one dimension and show the possibility of such a transition in quasi one dimension as well as in two dimensions by going to a regime where it can be shown for electrons that just interact via Fermi statistics. Such density waves arise due to internal symmetry breaking in a many fermion quantum system. We can extend this result to very wide rings with infinitely many electrons including Coulomb interaction.

  9. Ising spin glasses in dimension five

    NASA Astrophysics Data System (ADS)

    Lundow, P. H.; Campbell, I. A.

    2017-01-01

    Ising spin-glass models with bimodal, Gaussian, uniform, and Laplacian interaction distributions in dimension five are studied through detailed numerical simulations. The data are analyzed in both the finite-size scaling regime and the thermodynamic limit regime. It is shown that the values of critical exponents and of dimensionless observables at criticality are model dependent. Models in a single universality class have identical values for each of these critical parameters, so Ising spin-glass models in dimension five with different interaction distributions each lie in different universality classes. This result confirms conclusions drawn from measurements in dimension four and dimension two.

  10. Ising spin glasses in dimension five.

    PubMed

    Lundow, P H; Campbell, I A

    2017-01-01

    Ising spin-glass models with bimodal, Gaussian, uniform, and Laplacian interaction distributions in dimension five are studied through detailed numerical simulations. The data are analyzed in both the finite-size scaling regime and the thermodynamic limit regime. It is shown that the values of critical exponents and of dimensionless observables at criticality are model dependent. Models in a single universality class have identical values for each of these critical parameters, so Ising spin-glass models in dimension five with different interaction distributions each lie in different universality classes. This result confirms conclusions drawn from measurements in dimension four and dimension two.

  11. Origin of Everything and the 21 Dimensions of the Universe

    NASA Astrophysics Data System (ADS)

    Loev, Mark

    2009-03-01

    The Dimensions of the Universe correspond with the Dimensions of the human body. The emotion that is a positive for every dimension is Love. The negative emotion that effects each dimension are listed. All seven negative emotions effect Peace, Love and Happiness. 21st Dimension: Happiness Groin & Heart 20th Dimension: Love Groin & Heart 19th Dimension: Peace Groin & heart 18th Dimension: Imagination Wave Eyes Anger 17th Dimension: Z Wave / Closed Birth 16th Dimension: Electromagnetic Wave Ears Anger 15th Dimension: Universal Wave Skin Worry 14th Dimension: Lover Wave Blood Hate 13th Dimension: Disposal Wave Buttocks Fear 12th Dimension: Builder Wave Hands Hate 11th Dimension: Energy Wave Arms Fear 10th Dimension: Time Wave Brain Pessimism 9th Dimension: Gravity Wave Legs Fear 8th Dimension: Sweet Wave Pancreas Fear 7th Dimension: File Wave Left Lung Fear 6th Dimension: Breathing Wave Right Lung Fear 5th Dimension: Digestive Wave Stomach Fear 4th Dimension: Swab Wave Liver Guilt 3rd Dimension: Space Wave Face Sadness 2nd Dimension: Line Wave Mouth Revenge 1st Dimension: Dot Wave Nose Sadness The seven deadly sins correspond: Anger Hate Sadness Fear Worry Pessimism Revenge Note: Guilt is fear

  12. Four Essential Dimensions of Workplace Learning

    ERIC Educational Resources Information Center

    Hopwood, Nick

    2014-01-01

    Purpose: This conceptual paper aims to argue that times, spaces, bodies and things constitute four essential dimensions of workplace learning. It examines how practices relate or hang together, taking Gherardi's texture of practices or connectedness in action as the foundation for making visible essential but often overlooked dimensions of…

  13. Bilocal field theory in four dimensions

    SciTech Connect

    Hori, T. )

    1993-07-15

    A bilocal field theory having Moebius gauge invariance is proposed. In four dimensions there exists a zero momentum state of the first-quantized model which belongs to a nontrivial BRS cohomology class. A field theory Lagrangian having gauge invariance only in four dimensions is constructed.

  14. Unconscious Evaluation of Faces on Social Dimensions

    ERIC Educational Resources Information Center

    Stewart, Lorna H.; Ajina, Sara; Getov, Spas; Bahrami, Bahador; Todorov, Alexander; Rees, Geraint

    2012-01-01

    It has been proposed that two major axes, dominance and trustworthiness, characterize the social dimensions of face evaluation. Whether evaluation of faces on these social dimensions is restricted to conscious appraisal or happens at a preconscious level is unknown. Here we provide behavioral evidence that such preconscious evaluations exist and…

  15. Quantum Field Theory in (0 + 1) Dimensions

    ERIC Educational Resources Information Center

    Boozer, A. D.

    2007-01-01

    We show that many of the key ideas of quantum field theory can be illustrated simply and straightforwardly by using toy models in (0 + 1) dimensions. Because quantum field theory in (0 + 1) dimensions is equivalent to quantum mechanics, these models allow us to use techniques from quantum mechanics to gain insight into quantum field theory. In…

  16. Interlocked molecules: Moving into another dimension

    NASA Astrophysics Data System (ADS)

    Fournel-Marotte, Karine; Coutrot, Frédéric

    2016-12-01

    Molecular daisy-chain structures are typically made up of two interlocked components and can exhibit muscle-like contraction and extension in one dimension. Zinc-based multicomponent systems that can operate in two and three dimensions have now been designed and synthesized.

  17. Understanding Dimensions of Organizational Evaluation Capacity

    ERIC Educational Resources Information Center

    Bourgeois, Isabelle; Cousins, J. Bradley

    2013-01-01

    Organizational evaluation capacity building has been a topic of increasing interest in recent years. However, the actual dimensions of evaluation capacity have not been clearly articulated through empirical research. This study sought to address this gap by identifying the key dimensions of evaluation capacity in Canadian federal government…

  18. Quality Dimensions of Internet Search Engines.

    ERIC Educational Resources Information Center

    Xie, M.; Wang, H.; Goh, T. N.

    1998-01-01

    Reviews commonly used search engines (AltaVista, Excite, infoseek, Lycos, HotBot, WebCrawler), focusing on existing comparative studies; considers quality dimensions from the customer's point of view based on a SERVQUAL framework; and groups these quality expectations in five dimensions: tangibles, reliability, responsiveness, assurance, and…

  19. Positioner with long travel in two dimensions

    DOEpatents

    Trumper, David L.; Williams, Mark E.

    1997-12-23

    A precision positioning system is provided which provides long travel in two of the linear dimensions, while using non-contact bearings for both a first subassembly which provides long travel in one of the linear dimension and a second subassembly which provides long travel in the second linear dimension. The first or upper subassembly is preferably a magnetic subassembly which, in addition to providing long travel, also compensates or positions in three rotary dimensions and in the third linear dimension. The second subassembly is preferably either an air bearing or magnetic subassembly and is normally used only to provide long travel. Angled surfaces may be provided for magnetic bearings and capacitive or other gap sensing probes may be mounted to the stage and ground flush with the bearing actuators to provide more precise gap measurements.

  20. Correspondence between Soft and Rapidity Anomalous Dimensions

    NASA Astrophysics Data System (ADS)

    Vladimirov, Alexey A.

    2017-02-01

    We establish a correspondence between ultraviolet singularities of soft factors for multiparticle production and rapidity singularities of soft factors for multiparton scattering. This correspondence is a consequence of the conformal mapping between scattering geometries. The correspondence is valid to all orders of perturbation theory and in this way, provides one with a proof of rapidity renormalization procedure for multiparton scattering [including the transverse momentum dependent (TMD) factorization as a special case]. As a by-product, we obtain an exact relation between the rapidity anomalous dimension and the well-known soft anomalous dimension. The three-loop expressions for TMD and a general multiparton scattering rapidity anomalous dimension are derived.

  1. Effective dimension reduction for sparse functional data.

    PubMed

    Yao, F; Lei, E; Wu, Y

    2015-06-01

    We propose a method of effective dimension reduction for functional data, emphasizing the sparse design where one observes only a few noisy and irregular measurements for some or all of the subjects. The proposed method borrows strength across the entire sample and provides a way to characterize the effective dimension reduction space, via functional cumulative slicing. Our theoretical study reveals a bias-variance trade-off associated with the regularizing truncation and decaying structures of the predictor process and the effective dimension reduction space. A simulation study and an application illustrate the superior finite-sample performance of the method.

  2. Three loop cusp anomalous dimension in QCD.

    PubMed

    Grozin, Andrey; Henn, Johannes M; Korchemsky, Gregory P; Marquard, Peter

    2015-02-13

    We present the full analytic result for the three loop angle-dependent cusp anomalous dimension in QCD. With this result, infrared divergences of planar scattering processes with massive particles can be predicted to that order. Moreover, we define a closely related quantity in terms of an effective coupling defined by the lightlike cusp anomalous dimension. We find evidence that this quantity is universal for any gauge theory and use this observation to predict the nonplanar n(f)-dependent terms of the four loop cusp anomalous dimension.

  3. Searching for extra-dimensions at CMS

    NASA Astrophysics Data System (ADS)

    Benucci, Leonardo

    2009-06-01

    A possible solution to the hierarchy problem is the presence of extra space dimensions beyond the three ones which are known from our everyday experience. The phenomenological ADD model of large extra-dimensions predicts a ETmiss +jet signature. Randall-Sundrum-type extra-dimensions predict di-lepton and di-jet resonances. This contribution addresses an overview of experimental issues and discovery potential for these new particles at the LHC, focusing on perspectives with the CMS detector during early data taking.

  4. Shape invariant potentials in higher dimensions

    SciTech Connect

    Sandhya, R.; Sree Ranjani, S.; Kapoor, A.K.

    2015-08-15

    In this paper we investigate the shape invariance property of a potential in one dimension. We show that a simple ansatz allows us to reconstruct all the known shape invariant potentials in one dimension. This ansatz can be easily extended to arrive at a large class of new shape invariant potentials in arbitrary dimensions. A reformulation of the shape invariance property and possible generalizations are proposed. These may lead to an important extension of the shape invariance property to Hamiltonians that are related to standard potential problems via space time transformations, which are found useful in path integral formulation of quantum mechanics.

  5. Effective dimension reduction for sparse functional data

    PubMed Central

    YAO, F.; LEI, E.; WU, Y.

    2015-01-01

    Summary We propose a method of effective dimension reduction for functional data, emphasizing the sparse design where one observes only a few noisy and irregular measurements for some or all of the subjects. The proposed method borrows strength across the entire sample and provides a way to characterize the effective dimension reduction space, via functional cumulative slicing. Our theoretical study reveals a bias-variance trade-off associated with the regularizing truncation and decaying structures of the predictor process and the effective dimension reduction space. A simulation study and an application illustrate the superior finite-sample performance of the method. PMID:26566293

  6. Phenomenology of Supersymmetric Large Extra Dimensions

    SciTech Connect

    Hewett, JoAnne L.

    2002-12-09

    We study the phenomenology of a supersymmetric bulk in the scenario of large extra dimensions. The virtual exchange of gravitino KK states in selectron pair production in polarized e{sup +}e{sup -} collisions is examined. The leading order operator for this exchange is dimension six, in contrast to that of graviton KK exchange which induces a dimension eight operator at lowest order. Some kinematic distributions for selectron production are presented. These processes yield an enormous sensitivity to the fundamental higher dimensional Planck scale.

  7. Correspondence between Soft and Rapidity Anomalous Dimensions.

    PubMed

    Vladimirov, Alexey A

    2017-02-10

    We establish a correspondence between ultraviolet singularities of soft factors for multiparticle production and rapidity singularities of soft factors for multiparton scattering. This correspondence is a consequence of the conformal mapping between scattering geometries. The correspondence is valid to all orders of perturbation theory and in this way, provides one with a proof of rapidity renormalization procedure for multiparton scattering [including the transverse momentum dependent (TMD) factorization as a special case]. As a by-product, we obtain an exact relation between the rapidity anomalous dimension and the well-known soft anomalous dimension. The three-loop expressions for TMD and a general multiparton scattering rapidity anomalous dimension are derived.

  8. Cartesian-coordinate dimensioning for plumbing systems

    NASA Technical Reports Server (NTRS)

    Buirgy, P. A.

    1971-01-01

    Nonprogressive dimensioning method specifies Cartesian coordinates for each critical point in detail drawings of precision plumbing and ducting components to avoid tolerance accumulation. Method permits direct fabrication of tubing shapes without necessitating generation of a preproduction tubing mockup.

  9. Dark energy, inflation, and extra dimensions

    SciTech Connect

    Steinhardt, Paul J.; Wesley, Daniel

    2009-05-15

    We consider how accelerated expansion, whether due to inflation or dark energy, imposes strong constraints on fundamental theories obtained by compactification from higher dimensions. For theories that obey the null energy condition (NEC), we find that inflationary cosmology is impossible for a wide range of compactifications; and a dark energy phase consistent with observations is only possible if both Newton's gravitational constant and the dark energy equation of state vary with time. If the theory violates the NEC, inflation and dark energy are only possible if the NEC-violating elements are inhomogeneously distributed in the compact dimensions and vary with time in precise synchrony with the matter and energy density in the noncompact dimensions. Although our proofs are derived assuming general relativity applies in both four and higher dimensions and certain forms of metrics, we argue that similar constraints must apply for more general compactifications.

  10. Evolution Of The Concept Of Dimension

    NASA Astrophysics Data System (ADS)

    Journeau, Philippe F.

    2007-04-01

    Concepts of time elapsing `in' a space measuring the real emerge over the centuries. But Kant refutes absolute time and defines it, with space, as forms reacting to Newtonian mechanics. Einstein and Minkowski open a 20th century where time is a dimension, a substratum of reality `with' space rather than `in' it. Kaluza-Klein and String theories then develop a trend of additional spatial dimensions while de Broglie and Bohm open the possiblity that form, to begin with wave, be a reality together `with' a space-time particle. Other recent theories, such as spin networks, causal sets and twistor theory, even head to the idea of other "systems of dimensions." On the basis of such progresses and recent experiments the paper then considers a background independent fourfold time-form-action-space system of dimensions.

  11. Quantum simulation of an extra dimension.

    PubMed

    Boada, O; Celi, A; Latorre, J I; Lewenstein, M

    2012-03-30

    We present a general strategy to simulate a D+1-dimensional quantum system using a D-dimensional one. We analyze in detail a feasible implementation of our scheme using optical lattice technology. The simplest nontrivial realization of a fourth dimension corresponds to the creation of a bi-volume geometry. We also propose single- and many-particle experimental signatures to detect the effects of the extra dimension.

  12. Supersymmetric {sigma}-models in 2-dimensions

    SciTech Connect

    Zumino, B. |

    1997-02-01

    The author gives a brief introduction to supersymmetric {sigma}-models in two space-time dimensions. The topics he covers are: the bosonic {sigma}-model; supersymmetry in two dimensions; complex manifolds; the Kaehler and hyper-Kaehler case; and chiral supersymmetries. The lesson to be learned from the lecture is that the number of supersymmetries is intimately related to the geometric structure of the target space manifold: more geometric structure corresponds to more supersymmetries.

  13. Psychological and Organizational Climate: Dimensions and Relationships

    DTIC Science & Technology

    1977-03-07

    five of six psychological climate dimensions found for 4,315 U. S. Navy enlisted men were generalizable to comparison samples of firemen (n - 398) and...Comparison of psychological climate dimensions across samples , Psychological climate components from the Navy sample were compared to components derived from...psycho- logical climate componerts. A subset of the Navy sample was used and aggregated scores were constructed ’or 223 divisions, 97 departments, and

  14. Global Environmental change: Understanding the Human Dimensions

    SciTech Connect

    Morrisette, P.M.

    1993-01-01

    This book is from the National Research Council's Committee on the Human dimensions of Global Change. The object is to examine what is known about human dimensions of global environmental change, identify the major immediate needs for knowledge, and recommend a strategy over the next 5-10 years. Case studies are used in human causes of global change. issues related to theory, methods, and data are covered, as well as institutional needs for interdicipinary approaches.

  15. The a-function in six dimensions

    NASA Astrophysics Data System (ADS)

    Gracey, J. A.; Jack, I.; Poole, C.

    2016-01-01

    The a-function is a proposed quantity defined in even dimensions which has a monotonic behaviour along RG flows, related to the β-functions via a gradient flow equation. We study the a-function for a general scalar theory in six dimensions, using the β-functions up to three-loop order for both the overline{MS} and MOM schemes (the latter presented here for the first time at three loops).

  16. The Correlation Fractal Dimension of Complex Networks

    NASA Astrophysics Data System (ADS)

    Wang, Xingyuan; Liu, Zhenzhen; Wang, Mogei

    2013-05-01

    The fractality of complex networks is studied by estimating the correlation dimensions of the networks. Comparing with the previous algorithms of estimating the box dimension, our algorithm achieves a significant reduction in time complexity. For four benchmark cases tested, that is, the Escherichia coli (E. Coli) metabolic network, the Homo sapiens protein interaction network (H. Sapiens PIN), the Saccharomyces cerevisiae protein interaction network (S. Cerevisiae PIN) and the World Wide Web (WWW), experiments are provided to demonstrate the validity of our algorithm.

  17. Editorial: Focus on Extra Space Dimensions

    NASA Astrophysics Data System (ADS)

    Agashe, Kaustubh; Pomarol, Alex

    2010-07-01

    Experiments at the Large Hadron Collider (LHC) have just started. In addition to verifying the Standard Model (SM) of particle physics, these experiments will probe a new energy frontier and test extensions of the SM. The existence of extra dimensions is one of the most attractive possibilities for physics beyond the SM. This focus issue contains a collection of articles addressing both theoretical and phenomenological aspects of extra-dimensional models. Focus on Extra Space Dimensions Contents Minimal universal extra dimensions in CalcHEP/CompHEP AseshKrishna Datta, Kyoungchul Kong and Konstantin T Matchev Disordered extra dimensions Karim Benakli Codimension-2 brane-bulk matching: examples from six and ten dimensions Allan Bayntun, C P Burgess and Leo van Nierop Gauge threshold corrections in warped geometry Kiwoon Choi, Ian-Woo Kim and Chang Sub Shin Holographic methods and gauge-Higgs unification in flat extra dimensions Marco Serone Soft-wall stabilization Joan A Cabrer, Gero von Gersdorff and Mariano Quirós Warped five-dimensional models: phenomenological status and experimental prospects Hooman Davoudiasl, Shrihari Gopalakrishna, Eduardo Pontón and José Santiago

  18. Determination of key dimensions for a glove sizing system by analyzing the relationships between hand dimensions.

    PubMed

    Kwon, Ochae; Jung, Kihyo; You, Heecheon; Kim, Hee-Eun

    2009-07-01

    The present study identified key dimensions for the development of a glove sizing system by analyzing the relationships between hand dimensions and demonstrated the construction process of glove sizing systems based on the selected key dimensions. Three hand dimensions (HL: hand length; HC: hand circumference; HB: hand breadth) were selected as the candidates of glove key dimensions by surveying the literature and industry practices of glove sizing systems. Of the key dimension candidates, HL and HC were selected by examining the results of correlation and multiple regression analyses on the 1988 US Army hand anthropometric data. A cross-tabulation of HL and HC with an interval length of 1.3 cm was constructed for each gender and the corresponding lengths and circumferences of cells covering more than 2% of the population were used to provide glove sizing parameters. It was identified that the glove sizing system for males is different from that for females and has more size categories.

  19. Fractal dimension and architecture of trabecular bone.

    PubMed

    Fazzalari, N L; Parkinson, I H

    1996-01-01

    The fractal dimension of trabecular bone was determined for biopsies from the proximal femur of 25 subjects undergoing hip arthroplasty. The average age was 67.7 years. A binary profile of the trabecular bone in the biopsy was obtained from a digitized image. A program written for the Quantimet 520 performed the fractal analysis. The fractal dimension was calculated for each specimen, using boxes whose sides ranged from 65 to 1000 microns in length. The mean fractal dimension for the 25 subjects was 1.195 +/- 0.064 and shows that in Euclidean terms the surface extent of trabecular bone is indeterminate. The Quantimet 520 was also used to perform bone histomorphometric measurements. These were bone volume/total volume (BV/TV) (per cent) = 11.05 +/- 4.38, bone surface/total volume (BS/TV) (mm2/mm3) = 1.90 +/- 0.51, trabecular thickness (Tb.Th) (mm) = 0.12 +/- 0.03, trabecular spacing (Tb.Sp) (mm) = 1.03 +/- 0.36, and trabecular number (Tb.N) (number/mm) = 0.95 +/- 0.25. Pearsons' correlation coefficients showed a statistically significant relationship between the fractal dimension and all the histomorphometric parameters, with BV/TV (r = 0.85, P < 0.0001), BS/TV (r = 0.74, P < 0.0001), Tb.Th (r = 0.50, P < 0.02), Tb.Sp (r = -0.81, P < 0.0001), and Tb.N (r = 0.76, P < 0.0001). This method for calculating fractal dimension shows that trabecular bone exhibits fractal properties over a defined box size, which is within the dimensions of a structural unit for trabecular bone. Therefore, the fractal dimension of trabecular bone provides a measure which does not rely on Euclidean descriptors in order to describe a complex geometry.

  20. Fractal Dimension in Epileptic EEG Signal Analysis

    NASA Astrophysics Data System (ADS)

    Uthayakumar, R.

    Fractal Analysis is the well developed theory in the data analysis of non-linear time series. Especially Fractal Dimension is a powerful mathematical tool for modeling many physical and biological time signals with high complexity and irregularity. Fractal dimension is a suitable tool for analyzing the nonlinear behaviour and state of the many chaotic systems. Particularly in analysis of chaotic time series such as electroencephalograms (EEG), this feature has been used to identify and distinguish specific states of physiological function.Epilepsy is the main fatal neurological disorder in our brain, which is analyzed by the biomedical signal called Electroencephalogram (EEG). The detection of Epileptic seizures in the EEG Signals is an important tool in the diagnosis of epilepsy. So we made an attempt to analyze the EEG in depth for knowing the mystery of human consciousness. EEG has more fluctuations recorded from the human brain due to the spontaneous electrical activity. Hence EEG Signals are represented as Fractal Time Series.The algorithms of fractal dimension methods have weak ability to the estimation of complexity in the irregular graphs. Divider method is widely used to obtain the fractal dimension of curves embedded into a 2-dimensional space. The major problem is choosing initial and final step length of dividers. We propose a new algorithm based on the size measure relationship (SMR) method, quantifying the dimensional behaviour of irregular rectifiable graphs with minimum time complexity. The evidence for the suitability (equality with the nature of dimension) of the algorithm is illustrated graphically.We would like to demonstrate the criterion for the selection of dividers (minimum and maximum value) in the calculation of fractal dimension of the irregular curves with minimum time complexity. For that we design a new method of computing fractal dimension (FD) of biomedical waveforms. Compared to Higuchi's algorithm, advantages of this method include

  1. The Many Dimensions of Program Management

    NASA Technical Reports Server (NTRS)

    Dean, Edwin B.

    1992-01-01

    For the purposes of this paper, program refers to a collection of activities or projects which must be performed according to a plan or schedule. The Space Exploration Initiative within the National Aeronautics and Space Administration (NASA) is an example. Dimensionality refers to both the various perspectives of a program and to the components within that perspective. It is, thus, appropriate to think of dimensions of dimensionality. For example, one dimension or perspective of a program is the projects which perform the program. Within the project dimension, the individual projects are the components of that dimensionality. The number of projects defines the spatial dimensionality of the project dimension. Thus, each perspective or dimension has a dimensionality of its own. The structure and associated values of all the various perspectives of a program define the program. A project refers to the collection of activities required to conceive, sell, design, develop, evaluate, produce, operate, support, evolve, and retire a given system. A project thus effects the life cycle of given system. A project is, thus, the system to conceive, sell, design, develop, evaluate, produce, operate, support, evolve, and retire a system. A program, thus, effects the life cycle of the collection of projects required to effect the collection of systems required to implement the program.

  2. Accelerated Dimension-Independent Adaptive Metropolis

    DOE PAGES

    Chen, Yuxin; Keyes, David E.; Law, Kody J.; ...

    2016-10-27

    This work describes improvements from algorithmic and architectural means to black-box Bayesian inference over high-dimensional parameter spaces. The well-known adaptive Metropolis (AM) algorithm [33] is extended herein to scale asymptotically uniformly with respect to the underlying parameter dimension for Gaussian targets, by respecting the variance of the target. The resulting algorithm, referred to as the dimension-independent adaptive Metropolis (DIAM) algorithm, also shows improved performance with respect to adaptive Metropolis on non-Gaussian targets. This algorithm is further improved, and the possibility of probing high-dimensional (with dimension d 1000) targets is enabled, via GPU-accelerated numerical libraries and periodically synchronized concurrent chains (justimore » ed a posteriori). Asymptotically in dimension, this GPU implementation exhibits a factor of four improvement versus a competitive CPU-based Intel MKL parallel version alone. Strong scaling to concurrent chains is exhibited, through a combination of longer time per sample batch (weak scaling) and yet fewer necessary samples to convergence. The algorithm performance is illustrated on several Gaussian and non-Gaussian target examples, in which the dimension may be in excess of one thousand.« less

  3. Accelerated Dimension-Independent Adaptive Metropolis

    SciTech Connect

    Chen, Yuxin; Keyes, David E.; Law, Kody J.; Ltaief, Hatem

    2016-10-27

    This work describes improvements from algorithmic and architectural means to black-box Bayesian inference over high-dimensional parameter spaces. The well-known adaptive Metropolis (AM) algorithm [33] is extended herein to scale asymptotically uniformly with respect to the underlying parameter dimension for Gaussian targets, by respecting the variance of the target. The resulting algorithm, referred to as the dimension-independent adaptive Metropolis (DIAM) algorithm, also shows improved performance with respect to adaptive Metropolis on non-Gaussian targets. This algorithm is further improved, and the possibility of probing high-dimensional (with dimension d 1000) targets is enabled, via GPU-accelerated numerical libraries and periodically synchronized concurrent chains (justi ed a posteriori). Asymptotically in dimension, this GPU implementation exhibits a factor of four improvement versus a competitive CPU-based Intel MKL parallel version alone. Strong scaling to concurrent chains is exhibited, through a combination of longer time per sample batch (weak scaling) and yet fewer necessary samples to convergence. The algorithm performance is illustrated on several Gaussian and non-Gaussian target examples, in which the dimension may be in excess of one thousand.

  4. Extension of star coordinates into three dimensions

    NASA Astrophysics Data System (ADS)

    Cooprider, Nathan D.; Burton, Robert P.

    2007-01-01

    Traditional Star Coordinates displays a multi-variate data set by mapping it to two Cartesian dimensions. This technique facilitates cluster discovery and multi-variate analysis, but binding to two dimensions hides features of the data. Three-dimensional Star Coordinates spreads out data elements to reveal features. This allows the user more intuitive freedom to explore and process the data sets. Three-dimensional Star Coordinates is implemented by extending the data structures and transformation facilities of traditional Star Coordinates. We have given high priority to maintaining the simple, traditional interface. We simultaneously extend existing features, such as scaling of axes, and add new features, such as system rotation in three dimensions. These extensions and additions enhance data visualization and cluster discovery. We use three examples to demonstrate the advantage of three-dimensional Star Coordinates over the traditional system. First, in an analysis of customer churn data, system rotation in three dimensions gives the user new insight into the data. Second, in cluster discovery of car data, the additional dimension allows the true shape of the data to be seen more easily. Third, in a multi-variate analysis of cities, the perception of depth increases the degree to which multi-variate analysis can occur.

  5. Spectral Dimension of a Percolation Network

    NASA Astrophysics Data System (ADS)

    Rudra, Jayanta

    2005-03-01

    While the fractal dimension df describes the self-similar static nature of the lattice, the spectral dimension ds dictates the dynamic properties on it. Alexander and Orbach^1 conjectured that the spectral dimension might be exactly 4/3 for percolation networks with embedding euclidian dimension de >= 2. Recent numerical simulations^2, however, could not decisively prove or disprove this conjecture, although there are other indirect evidences that it is true. We believe that the failure of the simulations to decisively check the validity of the conjecture is due to the non-stochastic nature of the methods. Most of these simulations are Monte Carlo Methods based on a random-walk model and, in spite of very large number of walks on huge lattices, the results do not reach the satisfactory level. In this work we apply a stochastic approach^3 to determine the spectral dimension of percolation network for de >= 2 and check the validity of the Alexander-Orbach-conjecture. Due to its stochastic nature this method is numerically superior and more accurate than the conventional Monte Carlo simulations. References: 1. S. Alexander and R. Orbach, J. Phys. Lett. (Paris) 43 (1982) L625. 2. N. Pitsianis, G. Bleris and P. Argyrakis, Phys. Rev. B 39 (1989) 7097. 3. J. Rudra and J. Kozak, Phys. Lett A 151 (1990) 429.

  6. The "fourth dimension" of gene transcription.

    PubMed

    O'Malley, Bert W

    2009-05-01

    The three dimensions of space provide our relationship to position on the earth, but the fourth dimension of time has an equally profound influence on our lives. Everything from light and sound to weather and biology operate on the principle of measurable temporal periodicity. Consequently, a wide variety of time clocks affect all aspects of our existence. The annual (and biannual) cycles of activity, metabolism, and mating, the monthly physiological clocks of women and men, and the 24-h diurnal rhythms of humans are prime examples. Should it be surprising to us that the fourth dimension also impinges upon gene expression and that the genome itself is regulated by the fastest running of all biological clocks? Recent evidence substantiates the existence of such a ubiquitin-dependent transcriptional clock that is based upon the activation and destruction of transcriptional coactivators.

  7. Some trees with partition dimension three

    NASA Astrophysics Data System (ADS)

    Fredlina, Ketut Queena; Baskoro, Edy Tri

    2016-02-01

    The concept of partition dimension of a graph was introduced by Chartrand, E. Salehi and P. Zhang (1998) [2]. Let G(V, E) be a connected graph. For S ⊆ V (G) and v ∈ V (G), define the distance d(v, S) from v to S is min{d(v, x)|x ∈ S}. Let Π be an ordered partition of V (G) and Π = {S1, S2, ..., Sk }. The representation r(v|Π) of vertex v with respect to Π is (d(v, S1), d(v, S2), ..., d(v, Sk)). If the representations of all vertices are distinct, then the partition Π is called a resolving partition of G. The partition dimension of G is the minimum k such that G has a resolving partition with k partition classes. In this paper, we characterize some classes of trees with partition dimension three, namely olive trees, weeds, and centipedes.

  8. Trabecular Pattern Analysis Using Fractal Dimension

    NASA Astrophysics Data System (ADS)

    Ishida, Takayuki; Yamashita, Kazuya; Takigawa, Atsushi; Kariya, Komyo; Itoh, Hiroshi

    1993-04-01

    Feature extraction from a digitized image is advantageous for the detection of signs of disease. In this work, we attempted to evaluate bone trabecular pattern changes in osteoporosis using the fractal dimension and the root mean square (RMS) values. The relationship between the fractal dimension and the 1st moment of the power spectrum is explored, and we investigated the relationship between the results of this analysis and the bone mineral density (BMD) value which was measured using dual-energy X-ray absorptiometry (DEXA). As a result, we were able to extract useful information, using the fractal dimension and the RMS value of the radiographs (lateral view of the lumbar vertebrae), for the diagnosis of osteoporosis. Abnormal clinical cases were separated from normal cases based on the evaluation values. Negligible correlation between the BMD value and these indexes was observed.

  9. Interdependent Lattice Networks in High Dimensions

    NASA Astrophysics Data System (ADS)

    Lowinger, Steven; Cwilich, Gabriel; Buldyrev, Sergey

    We study the mutual percolation of two interdependent lattice networks following the procedure outlined by Buldyrev et al 1 . We studied lattices of dimensions 2, 3, 4, 5 and 6. We imposed that the length of interdependent links connecting the nodes from one lattice to the other be less than a certain value, r. We find that for each dimension, D <6, there is a value of r =rI >1 such that for r >=rI, the cascading failures occur as a discontinuous first order transition, while for r dimension of the lattice increases. For D = 6, rI = 1, which is the same as in random regular (RR) graphs with the same degree (coordination number) of nodes. D = 6 is the upper critical dimension for classical percolation, the point at which the critical exponents of the lattice model become identical to those of RR graphs. We found that in all dimensions the maximal vulnerability of the networks, as a function of r , is achieved at a distance of r =rmax >rI, but forr >rmax the vulnerability starts to decrease as r --> ∞ . However, the decrease becomes less significant as the dimension increases and becomes negligible for D = 6. Results on how the parameters of the transition scale with the size of the system will be presented. [1] Catastrophic cascade of failures in interdependent networks, Buldyrev, Parshani, Paul, Stanley& Havlin, Nature, 464, 1025-1028 (15 April 2010)

  10. Anomalous mass dimension in multiflavor QCD

    NASA Astrophysics Data System (ADS)

    Doff, A.; Natale, A. A.

    2016-10-01

    Models of strongly interacting theories with a large mass anomalous dimension (γm) provide an interesting possibility for the dynamical origin of the electroweak symmetry breaking. A laboratory for these models is QCD with many flavors, which may present a nontrivial fixed point associated to a conformal region. Studies based on conformal field theories and on Schwinger-Dyson equations have suggested the existence of bounds on the mass anomalous dimension at the fixed points of these models. In this note we discuss γm values of multiflavor QCD exhibiting a nontrivial fixed point and affected by relevant four-fermion interactions.

  11. Electroweak symmetry breaking by extra dimensions

    SciTech Connect

    Hsin-Chia Cheng; Bogdan A. Dobrescu and Christopher T. Hill

    2000-05-25

    Electroweak symmetry breaking may be naturally induced by the observed quark and gauge fields in extra dimensions without a fundamental Higgs field. The authors show that a composite Higgs doublet can arise as a bound state of (t,b){sub L} and a linear combination of the Kaluza-Klein states of t{sub R}, due to QCD in extra dimensions. The top quark mass depends on the number of active t{sub R} Kaluza-Klein modes, and is consistent with the experimental value.

  12. Mineral resource of the month: dimension stone

    USGS Publications Warehouse

    Dolley, Thomas P.

    2012-01-01

    The article offers information on dimension stone (DS) that are quarried as natural rock for a specific size and dimension chosen for its color, strength, durability. Varieties of metamorphic, igneous or sedimentary rocks are used but DS rocks are mainly marble, granite and slate that can be found from Maine to Alabama in the U.S., in the Carrara District of Italy as well as in Greece, China and Brazil. It also notes the advent of steel and concrete in construction that ceased the use of DS.

  13. Microscopic Primordial Black Holes and Extra Dimensions

    SciTech Connect

    Conley, John A.; Wizansky, Tommer

    2006-11-15

    We examine the production and evolution of microscopic black holes in the early universe in the large extra dimensions scenario. We demonstrate that, unlike in the standard four-dimensional cosmology, in large extra dimensions absorption of matter from the primordial plasma by the black holes is significant and can lead to rapid growth of the black hole mass density. This effect can be used to constrain the conditions present in the very early universe. We demonstrate that this constraint is applicable in regions of parameter space not excluded by existing bounds.

  14. Constraints on extra dimensions from atomic spectroscopy

    NASA Astrophysics Data System (ADS)

    Dahia, F.; Lemos, A. S.

    2016-10-01

    We consider a hydrogen atom confined in a thick brane embedded in a higher-dimensional space. Due to effects of the extra dimensions, the gravitational potential is amplified in distances smaller than the size of the supplementary space, in comparison with the Newtonian potential. Studying the influence of the gravitational interaction modified by the extra dimensions on the energy levels of the hydrogen atom, we find independent constraints for the higher-dimensional Planck mass in terms of the thickness of the brane by using accurate measurements of atomic transition frequencies. The constraints are very stringent for narrow branes.

  15. National narcissism: Internal dimensions and international correlates.

    PubMed

    Cai, Huajian; Gries, Peter

    2013-08-01

    In studies conducted in the United States and China, we explored the impact of national narcissism, grandiosity, and entitlement, demonstrating that: (a) national narcissism was distinct from both individual narcissism and collective self-esteem (patriotism); (b) national entitlement and national grandiosity constituted two distinct dimensions of national narcissism; and (c) national narcissism, national grandiosity, and national entitlement, but not individual narcissism, were uniquely predictive of political attitudes, foreign policy preferences, and purchase intentions. Together, these findings provided convergent evidence for the utility of national narcissism and its two internal dimensions, national entitlement and national grandiosity.

  16. Electrodynamics in One Dimension: Radiation and Reflection

    ERIC Educational Resources Information Center

    Asti, G.; Coisson, R.

    2011-01-01

    Problems involving polarized plane waves and currents on sheets perpendicular to the wavevector involve only one component of the fields, so it is possible to discuss electrodynamics in one dimension. Taking for simplicity linearly polarized sinusoidal waves, we can derive the field emitted by currents (analogous to dipole radiation in three…

  17. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules..., vegetables, and other dry commodities other than cranberries, and of a barrel for cranberries, with which the..., and other dry commodities other than cranberries (inches) Barrel for cranberries (inches) Diameter...

  18. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules..., vegetables, and other dry commodities other than cranberries, and of a barrel for cranberries, with which the..., and other dry commodities other than cranberries (inches) Barrel for cranberries (inches) Diameter...

  19. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules..., vegetables, and other dry commodities other than cranberries, and of a barrel for cranberries, with which the..., and other dry commodities other than cranberries (inches) Barrel for cranberries (inches) Diameter...

  20. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules..., vegetables, and other dry commodities other than cranberries, and of a barrel for cranberries, with which the..., and other dry commodities other than cranberries (inches) Barrel for cranberries (inches) Diameter...

  1. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules..., vegetables, and other dry commodities other than cranberries, and of a barrel for cranberries, with which the..., and other dry commodities other than cranberries (inches) Barrel for cranberries (inches) Diameter...

  2. On dimension reduction in Gaussian filters

    NASA Astrophysics Data System (ADS)

    Solonen, Antti; Cui, Tiangang; Hakkarainen, Janne; Marzouk, Youssef

    2016-04-01

    A priori dimension reduction is a widely adopted technique for reducing the computational complexity of stationary inverse problems. In this setting, the solution of an inverse problem is parameterized by a low-dimensional basis that is often obtained from the truncated Karhunen-Loève expansion of the prior distribution. For high-dimensional inverse problems equipped with smoothing priors, this technique can lead to drastic reductions in parameter dimension and significant computational savings. In this paper, we extend the concept of a priori dimension reduction to non-stationary inverse problems, in which the goal is to sequentially infer the state of a dynamical system. Our approach proceeds in an offline-online fashion. We first identify a low-dimensional subspace in the state space before solving the inverse problem (the offline phase), using either the method of ‘snapshots’ or regularized covariance estimation. Then this subspace is used to reduce the computational complexity of various filtering algorithms—including the Kalman filter, extended Kalman filter, and ensemble Kalman filter—within a novel subspace-constrained Bayesian prediction-and-update procedure (the online phase). We demonstrate the performance of our new dimension reduction approach on various numerical examples. In some test cases, our approach reduces the dimensionality of the original problem by orders of magnitude and yields up to two orders of magnitude in computational savings.

  3. Visual Learning. Dimensions in Early Learning Series.

    ERIC Educational Resources Information Center

    Buktenica, Norman A.

    A volume in the "Dimensions in Early Learning Series" this monograph proposes suggestions for parents and teachers to supplement normal classroom procedures in the area of visual learning. Chapter I concludes that a child's development of visual skills is directly influenced by inborn tendencies, physical characteristics, and environmental…

  4. The Personal Dimension in Doing Oral History.

    ERIC Educational Resources Information Center

    Long, Roger D.

    1991-01-01

    Discusses a history professor's attempt to awaken students' interest by assigning an oral history project rather than a traditional research paper. Reports that adding to the personal dimension to the project increased students enthusiasm and introduced them to problems of historical research and historiography. Includes problems of reliability…

  5. Attitudes toward computers: a new attitudinal dimension.

    PubMed

    Wang, Lei; Chen, Yang; Shi, Junqi

    2007-10-01

    The present study examined the reliability and the construct validity of a questionnaire designed to measure the attitudes toward computers in everyday life. A total of 2,050 participants responded to the questionnaire. Confirmatory factor analysis suggests that attitudes toward computers are composed of three dimensions: sense of benefit, sense of dependence, and sense of harm.

  6. Bilingual Idiosyncratic Dimensions of Language Attitudes

    ERIC Educational Resources Information Center

    Santello, Marco

    2015-01-01

    The goal of this study is to identify new dimensions of language attitudes to allow for both their multidimensionality and possible language-specificity stemming from local sociolinguistic environments. Adopting a two-step methodology comprising (1) elicitation of adjectives in group interviews and (2) employment of the semantic differential…

  7. Problems with Generalising: Pythagoras in N Dimensions

    ERIC Educational Resources Information Center

    Foster, Colin

    2013-01-01

    Pythagoras' theorem in two and three dimensions appears in General Mathematics, Units 1-2, section 6 (Geometry and trigonometry: Shape and measurement) in the Victorian Certificate of Education Mathematics Study Design (Victorian Curriculum Assessment Authority, 2010). It also comes in Further Mathematics, Units 3-4 (Applications: Geometry and…

  8. Super-Ehlers in any dimension

    NASA Astrophysics Data System (ADS)

    Ferrara, Sergio; Marrani, Alessio; Trigiante, Mario

    2012-11-01

    We classify the enhanced helicity symmetry of the Ehlers group to extended supergravity theories in any dimension. The vanishing character of the pseudo-Riemannian cosets occurring in this analysis is explained in terms of Poincaré duality .The latter resides in the nature of regularly embedded quotient subgroups which are noncompact rank preserving.

  9. Introduction to Geometric Dimensioning and Tolerancing.

    ERIC Educational Resources Information Center

    Proebstle, Donald C.

    Intended for drafting students in engineering drawing classes, the text provides basic definitions and explanations, as well as sample illustrations to be used as guides in dimensioning class projects by this technique. The content is divided into three units plus an appendix. Unit 1 discusses basic concepts, including the importance of the…

  10. Equivalence of superintegrable systems in two dimensions

    SciTech Connect

    Kress, J. M.

    2007-03-15

    In two dimensions, all nondegenerate superintegrable systems having constants quadratic in the momenta possess a quadratic algebra. In this paper, it is shown how the quadratic algebra can be used to classify all such systems into seven classes that are preserved by coupling constant metamorphosis.

  11. General Relativity in (1 + 1) Dimensions

    ERIC Educational Resources Information Center

    Boozer, A. D.

    2008-01-01

    We describe a theory of gravity in (1 + 1) dimensions that can be thought of as a toy model of general relativity. The theory should be a useful pedagogical tool, because it is mathematically much simpler than general relativity but shares much of the same conceptual structure; in particular, it gives a simple illustration of how gravity arises…

  12. Information and Knowledge Management: Dimensions and Approaches

    ERIC Educational Resources Information Center

    Schlögl, Christian

    2005-01-01

    Introduction: Though literature on information and knowledge management is vast, there is much confusion concerning the meaning of these terms. Hence, this article should give some orientation and work out the main aspects of information and knowledge management. Method: An author co-citation analysis, which identified the main dimensions of…

  13. The Historical Dimension of Environmental Design Education

    ERIC Educational Resources Information Center

    Purser, Robert S.

    1978-01-01

    If we hope to make history more relevant in art education, it behooves us to re-examine current historiographic techniques and interpretations. In dealing with the historical dimension of environmental design, three areas of concern are considered: 1) the lack of published works integrating design areas, 2) selective interpreting of environmental…

  14. Cooperative light scattering in any dimension

    NASA Astrophysics Data System (ADS)

    Hill, Tyler; Sanders, Barry C.; Deng, Hui

    2017-03-01

    We present a theory of cooperative light scattering valid in any dimension: connecting theories for an open line, open plane, and open space in the nonrelativistic regime. This theory includes near-field and dipole-orientation effects, highlighting how field-mode confinement controls the phenomena. We present an experimental implementation for planar collective effects.

  15. Demonstration of Replicable Dimensions of Health Behaviors

    DTIC Science & Technology

    1988-10-06

    the antecedents of these behavioral dimensions should help define potential targets for behavior modification programs and permit evaluations of those...defining observations that can be used for measurement. The behavior modification implications are linked to the assumption that behaviors which co-occur

  16. Pointwise dimensions of the lorenz attractor.

    PubMed

    Gratrix, Sam; Elgin, John N

    2004-01-09

    We discuss a connection between two complementary views of the Lorenz attractor: the first is the accepted view where the attractor has a smooth measure on a fractal support. This complex system is alternatively manifest as a self-similar curve for the pointwise dimension alpha. We describe why the latter approach is accessible for the analysis of an experimental signal.

  17. Endangered Species: Real Life in Two Dimensions

    ERIC Educational Resources Information Center

    Henderson, Lynette K.

    2012-01-01

    The focus of "Endangered Species: Real Life in Two Dimensions" is to create awareness about a critical environmental issue. There is a special urgency to this project because large numbers of animal species are currently endangered or on the brink of extinction. In addition to being enlightened about this important topic through research, students…

  18. Gendered Dimensions of Smoking among College Students

    ERIC Educational Resources Information Center

    Nichter, Mimi; Nichter, Mark; Lloyd-Richardson, Elizabeth E.; Flaherty, Brian; Carkoglu, Asli; Taylor, Nicole

    2006-01-01

    Ethnographic research, including interviews, focus groups, and observations were conducted to explore gendered dimensions of smoking among low level smokers, including the acceptability of smoking in different contexts; reasons for smoking; the monitoring of self and friends' smoking; and shared smoking as a means of communicating concern and…

  19. The FMI: Dimensions of Follower Maturity

    ERIC Educational Resources Information Center

    Moore, Loren I.

    1976-01-01

    The Follower Maturity Index (FMI) is an instrument derived from leadership theory and based on observations of verbal and nonverbal behavior of followers in task groups. Dimensions of follower maturity--achievement, responsibility, experience, activity, dependence, variety, interests, perspective, position, and awareness--are discussed. For…

  20. The Intercultural Dimension in Language Teaching.

    ERIC Educational Resources Information Center

    Quinn, Brendan

    Increased emphasis on the cultural dimension in second language instruction has appeared in recent years, as evidenced in the content of standardized school-leaving tests used in Great Britain. One purpose of the cultural element of instruction is to make real the language being learned, but another is to stress its potential usefulness. Some…

  1. The Three Pedagogical Dimensions of Nietzsche's Philosophy.

    ERIC Educational Resources Information Center

    Aloni, Nimrod

    1989-01-01

    Nietzche is presented as a counternihilistic philosopher-educator who explored cultural conditions and ways of life that could lift man to higher modes of existence. Three pedagogical dimensions of Nietzsche's work are explored: recovery of health and worth as education's aim, endorsement of holistic education, harmonious combination of themes and…

  2. Promoting European Dimensions in Lifelong Learning.

    ERIC Educational Resources Information Center

    Field, John, Ed.

    This collection of 19 essays shares the lessons of a wealth of experience and challenges professionals to open up adult learning to a variety of international perspectives. The first essay, "Building a European Dimension: A Realistic Response to Globalization?" (John Field), is an introduction to the essays. The six essays in Section I,…

  3. Exploring the Sociopolitical Dimensions of Global Warming

    ERIC Educational Resources Information Center

    Sadler, Troy D.; Klosterman, Michelle L.

    2009-01-01

    The authors present an activity to help high school students conceptualize the sociopolitical complexity of global warming through an exploration of varied perspectives on the issue. They argue that socioscientific issues such as global warming present important contexts for learning science and that the social and political dimensions of these…

  4. Science in Primary Schools: The Multicultural Dimension.

    ERIC Educational Resources Information Center

    Peacock, Alan, Ed.

    This book brings together a number of perspectives on building a multicultural dimension into science teaching in the United Kingdom. Part 1 gives a variety of practical ideas for use in multi-ethnic and all-white classrooms, heeding the constraints of the National Curriculum. Part 2 examines the underlying rationale for a multicultural approach…

  5. The Characteristic Dimensions of the Nanoworld

    ERIC Educational Resources Information Center

    Wautelet, M.; Duvivier, D.

    2007-01-01

    Nanoscience is defined as the study of phenomena and manipulation of materials at atomic, molecular and macromolecular scales, where properties differ significantly from those at larger scale. It is the aim of this paper to examine the characteristic dimensions for which the properties of nanosystems differ significantly from those at a larger…

  6. Scattering in three dimensions from rational maps

    NASA Astrophysics Data System (ADS)

    Cachazo, Freddy; He, Song; Yuan, Ellis Ye

    2013-10-01

    The complete tree-level S-matrix of four dimensional super Yang-Mills and supergravity has compact forms as integrals over the moduli space of certain rational maps. In this note we derive formulas for amplitudes in three dimensions by using the fact that when amplitudes are dressed with proper wave functions dimensional reduction becomes straightforward. This procedure leads to formulas in terms of rational maps for three dimensional maximally supersymmetric Yang-Mills and gravity theories. The integrand of the new formulas contains three basic structures: Parke-Taylor-like factors, Vandermonde determinants and resultants. Integrating out some of the Grassmann directions produces formulas for theories with less than maximal supersymmetry, which exposes yet a fourth kind of structure. Combining all four basic structures we start a search for consistent S-matrices in three dimensions. Very nicely, the most natural ones are those corresponding to ABJM and BLG theories. We also make a connection between the power of a resultant in the integrand, representations of the Poincaré group, infrared behavior and conformality of a theory. Extensions to other theories in three dimensions and to arbitrary dimensions are also discussed.

  7. Epistemic Sensibility: Third Dimension of Virtue Epistemology

    ERIC Educational Resources Information Center

    Belbase, Shashidhar

    2012-01-01

    The author tries to argue how epistemic sensibility as virtue sensibility can complement virtue epistemology. Many philosophers interrelated virtue reliabilism (e.g., Brogaard, 2006) and virtue responsibilism (e.g., Code, 1987) to virtue epistemology as two dimensions with many diverging and a few converging characters. The possible new dimension…

  8. Broken Scale Invariance and Anomalous Dimensions

    DOE R&D Accomplishments Database

    Wilson, K. G.

    1970-05-01

    Mack and Kastrup have proposed that broken scale invariance is a symmetry of strong interactions. There is evidence from the Thirring model and perturbation theory that the dimensions of fields defined by scale transformations will be changed by the interaction from their canonical values. We review these ideas and their consequences for strong interactions.

  9. Influences of aquifer properties on flow dimensions in dolomites.

    PubMed

    Verbovsek, Timotej

    2009-01-01

    The paper focuses on analyses and correlations of flow dimensions in different dolomite aquifers in Slovenia. Flow dimensions are obtained through the reinterpretation of 72 pumping tests with the generalized radial flow model, based on the fractional flow dimension. The average value of flow dimensions is 2.16 for all dolomites. A study of flow dimensions in individual aquifers categorized according to their lithological properties shows that higher dimensions occur in massive late-diagenetic Cordevolian and Anisian dolomites compared with bedded Main, Baca, and especially Lower Triassic dolomites, which contain a greater proportion of noncarbonate minerals. Partially penetrating wells have higher flow dimensions than fully penetrating wells. Flow dimensions are poorly correlated with hydraulic conductivities of fractures. When comparing the quantities of major dissolved minerals, obtained by hydrogeochemical inverse modeling, with the values of flow dimensions, the Cordevolian and Anisian dolomites are found to exhibit the highest values of both dissolved dolomite and flow dimensions, indicating that greater dissolution occurs at higher flow dimensions. For other aquifers, data points are more scattered and the correlation is mostly poor. When compared with three-dimensional fractal dimensions of fracture networks, there is no correlation with flow dimensions. However, almost all the values of flow dimensions are lower than the corresponding fractal dimensions in dolomites (average D= 2.77), possibly indicating the channeling of flow within the available space of the fracture networks, consequently reducing the flow dimensions.

  10. Source Dimensions Are Retrieved Independently in Multidimensional Monitoring Tasks

    ERIC Educational Resources Information Center

    Starns, Jeffrey J.; Hicks, Jason L.

    2005-01-01

    In 3 experiments, the authors determined whether remembering a source dimension created a more complete internal reinstatement of the encoded event and thus cued access to other source dimensions. Results consistently showed that memory for the 2 source dimensions was correlated: correct responses on 1 dimension were typically associated with…

  11. Application of Fractal Dimension on Palsar Data

    NASA Astrophysics Data System (ADS)

    Singh, Dharmendra; Pant, Triloki

    Study of land cover is the primal task of remote sensing where microwave imaging plays an important role. As an alternate of optical imaging, microwave, in particular, Synthetic Aperture Radar (SAR) imaging is very popular. With the advancement of technology, multi-polarized images are now available, e.g., ALOS-PALSAR (Phased Array type L-band SAR), which are beneficial because each of the polarization channel shows different sensitivity to various land features. Further, using the textural features, various land classes can be classified on the basis of the textural measures. One of the textural measure is fractal dimension. It is noteworthy that fractal dimension is a measure of roughness and thus various land classes can be distinguished on the basis of their roughness. The value of fractal dimension for the surfaces lies between 2.0 and 3.0 where 2.0 represents a smooth surface while 3.0 represents drastically rough surface. The study area covers subset images lying between 2956'53"N, 7750'32"E and 2950'40"N, 7757'19"E. The PALSAR images of the year 2007 and 2009 are considered for the study. In present paper a fractal based classification of PALSAR images has been performed for identification of Water, Urban and Agricultural Area. Since fractals represent the image texture, hence the present study attempts to find the fractal properties of land covers to distinguish them from one another. For the purpose a context has been defined on the basis of a moving window, which is used to estimate the local fractal dimension and then moved over the whole image. The size of the window is an important issue for estimation of textural measures which is considered to be 55 in present study. This procedure, in response, produces a textural map called fractal map. The fractal map is constituted with the help of local fractal dimension values and can be used for contextual classification. In order to study the fractal properties of PALSAR images, the three polarization images

  12. Systems and methods for displaying data in split dimension levels

    SciTech Connect

    Stolte, Chris; Hanrahan, Patrick

    2015-07-28

    Systems and methods for displaying data in split dimension levels are disclosed. In some implementations, a method includes: at a computer, obtaining a dimensional hierarchy associated with a dataset, wherein the dimensional hierarchy includes at least one dimension and a sub-dimension of the at least one dimension; and populating information representing data included in the dataset into a visual table having a first axis and a second axis, wherein the first axis corresponds to the at least one dimension and the second axis corresponds to the sub-dimension of the at least one dimension.

  13. Emergent spacetime in stochastically evolving dimensions

    NASA Astrophysics Data System (ADS)

    Afshordi, Niayesh; Stojkovic, Dejan

    2014-12-01

    Changing the dimensionality of the space-time at the smallest and largest distances has manifold theoretical advantages. If the space is lower dimensional in the high energy regime, then there are no ultraviolet divergencies in field theories, it is possible to quantize gravity, and the theory of matter plus gravity is free of divergencies or renormalizable. If the space is higher dimensional at cosmological scales, then some cosmological problems (including the cosmological constant problem) can be attacked from a completely new perspective. In this paper, we construct an explicit model of "evolving dimensions" in which the dimensions open up as the temperature of the universe drops. We adopt the string theory framework in which the dimensions are fields that live on the string worldsheet, and add temperature dependent mass terms for them. At the Big Bang, all the dimensions are very heavy and are not excited. As the universe cools down, dimensions open up one by one. Thus, the dimensionality of the space we live in depends on the energy or temperature that we are probing. In particular, we provide a kinematic Brandenberger-Vafa argument for how a discrete causal set, and eventually a continuum (3 + 1)-dim spacetime along with Einstein gravity emerges in the Infrared from the worldsheet action. The (3 + 1)-dim Planck mass and the string scale become directly related, without any compactification. Amongst other predictions, we argue that LHC might be blind to new physics even if it comes at the TeV scale. In contrast, cosmic ray experiments, especially those that can register the very beginning of the shower, and collisions with high multiplicity and density of particles, might be sensitive to the dimensional cross-over.

  14. On the additive properties of the fat-shattering dimension.

    PubMed

    Asor, Ohad; Duan, Hubert Haoyang; Kontorovich, Aryeh

    2014-12-01

    The properties of the VC-dimension under various compositions are well-understood, but this is much less the case for classes of continuous functions. In this brief, we show that a commonly used scale-sensitive dimension, Vγ, is much less well-behaved under Minkowski summation than its VC cousin, while the fat-shattering dimension retains some compositional similarity to the VC-dimension. As an application, we analyze the fat-shattering dimension of trigonometric functions and series.

  15. Selection of Dimensions for an Anthropometric Data Base. Volume 2. Dimension Evaluation Sheets

    DTIC Science & Technology

    1986-05-30

    VARIABLE NAME: HIP CIRCUMFERENCE 7 INCHES BELOW WAIST A. THE DIMENSION AND MAJOR ELEMENTS OF ITS MEASUREMENT: I. DESCRIPTION: The horizontal circumference of...SURVEYS OF U.S. MILITARY PERSONNEL VARIABLE NAME: HIP CIRCUMFERENCE 7 INCHES BELOW WAIST OVER FOUNDATION GARMENT A. THE DIMENSION AND MAJOR ELEMENTS OF...ITS MEASUREMENT: I. DESCRIPTION: The horizontal circumference of the hips measured 7 inches below the level of the waist of a subject wearing a

  16. The tacit dimension of clinical judgment.

    PubMed Central

    Goldman, G. M.

    1990-01-01

    Two distinct views of the nature of clinical judgment are identified and contrasted. The dominant view that clinical judgment is a fully explicit process is compared to the relatively neglected view that tacit knowledge plays a substantial role in the clinician's mental operations. The tacit dimension of medical thinking is explored at length. The discussion suggests severe limits when applying decision analysis, expert systems, and computer-aided cost-benefit review to medicine. The goals and practices of postgraduate medical education are also examined from this perspective, as are various other implications for the clinician. The paper concludes that it is valuable to explore the nature of medical thinking in order to improve clinical practice and education. Such explorations should, however, take cognizance of the often overlooked tacit dimension of clinical judgment. Possible constraints on the medical applicability of both formal expert systems and heavily didactic instructional programs are considered. PMID:2356625

  17. Applications of Variance Fractal Dimension: a Survey

    NASA Astrophysics Data System (ADS)

    Phinyomark, Angkoon; Phukpattaranont, Pornchai; Limsakul, Chusak

    2012-04-01

    Chaotic dynamical systems are pervasive in nature and can be shown to be deterministic through fractal analysis. There are numerous methods that can be used to estimate the fractal dimension. Among the usual fractal estimation methods, variance fractal dimension (VFD) is one of the most significant fractal analysis methods that can be implemented for real-time systems. The basic concept and theory of VFD are presented. Recent research and the development of several applications based on VFD are reviewed and explained in detail, such as biomedical signal processing and pattern recognition, speech communication, geophysical signal analysis, power systems and communication systems. The important parameters that need to be considered in computing the VFD are discussed, including the window size and the window increment of the feature, and the step size of the VFD. Directions for future research of VFD are also briefly outlined.

  18. The Ising Spin Glass in dimension four

    NASA Astrophysics Data System (ADS)

    Lundow, P. H.; Campbell, I. A.

    2015-09-01

    The critical behaviors of the bimodal and Gaussian Ising spin glass (ISG) models in dimension four are studied through extensive numerical simulations, and from an analysis of high temperature series expansion (HTSE) data of Klein et al. (1991). The simulations include standard finite size scaling measurements, thermodynamic limit regime measurements, and analyses which provide estimates of critical exponents without any consideration of the critical temperature. The higher order HTSE series for the bimodal model provide accurate estimates of the critical temperature and critical exponents. These estimates are independent of and fully consistent with the simulation values. Comparisons between ISG models in dimension four show that the critical exponents and the critical constants for dimensionless observables depend on the form of the interaction distribution of the model.

  19. Lepton flavor violation in extra dimension models

    SciTech Connect

    Chang, W.-F.; Ng, John N.

    2005-03-01

    Models involving large extra spatial dimension(s) have interesting predictions on lepton flavor violating processes. We consider some five-dimensional (5D) models which are related to neutrino mass generation or address the fermion masses hierarchy problem. We study the signatures in low energy experiments that can discriminate the different models. The focus is on muon-electron conversion in nuclei {mu}{yields}e{gamma} and {mu}{yields}3e processes and their {tau} counterparts. Their links with the active neutrino mass matrix are investigated. We show that in the models we discussed the branching ratio of {mu}{yields}e{gamma} like rare process is much smaller than the ones of {mu}{yields}3e like processes. This is in sharp contrast to most of the traditional wisdom based on four-dimensional (4D) gauge models. Moreover, some rare tau decays are more promising than the rare muon decays.

  20. Causal Dynamical Triangulations in Four Dimensions

    NASA Astrophysics Data System (ADS)

    Görlich, Andrzej

    2011-11-01

    Recent results obtained within a non-perturbative approach to quantum gravity based on the method of four-dimensional Causal Dynamical Triangulations are described. The phase diagram of the model consists of three phases. In the physically most interesting phase, the time-translational symmetry is spontaneously broken. Calculations of expectation values required introducing procedures taking into account the inhomogeneity of configurations. It was shown that the dynamically emerged four-dimensional background geometry corresponds to a Euclidean de Sitter space and reveals no fractality at large distances. Measurements of the covariance matrix of scale factor fluctuations allowed to reconstruct the effective action, which remained in agreement with the discrete minisuperspace action. Values of the Hausdorff dimension and spectral dimension of three-dimensional spatial slices suggest their fractal nature, which was confirmed by a direct analysis of triangulation structure. The Monte Carlo algorithm used to obtain presented results is described.

  1. Counting lattice animals in high dimensions

    NASA Astrophysics Data System (ADS)

    Luther, Sebastian; Mertens, Stephan

    2011-09-01

    We present an implementation of Redelemeier's algorithm for the enumeration of lattice animals in high-dimensional lattices. The implementation is lean and fast enough to allow us to extend the existing tables of animal counts, perimeter polynomials and series expansion coefficients in d-dimensional hypercubic lattices for 3 <= d <= 10. From the data we compute formulae for perimeter polynomials for lattice animals of size n <= 11 in arbitrary dimension d. When amended by combinatorial arguments, the new data suffice to yield explicit formulae for the number of lattice animals of size n <= 14 and arbitrary d. We also use the enumeration data to compute numerical estimates for growth rates and exponents in high dimensions that agree very well with Monte Carlo simulations and recent predictions from field theory.

  2. What is the dimension of citation space?

    NASA Astrophysics Data System (ADS)

    Clough, James R.; Evans, Tim S.

    2016-04-01

    Citation networks represent the flow of information between agents. They are constrained in time and so form directed acyclic graphs which have a causal structure. Here we provide novel quantitative methods to characterise that structure by adapting methods used in the causal set approach to quantum gravity by considering the networks to be embedded in a Minkowski spacetime and measuring its dimension using Myrheim-Meyer and Midpoint-scaling estimates. We illustrate these methods on citation networks from the arXiv, supreme court judgements from the USA, and patents and find that otherwise similar citation networks have measurably different dimensions. We suggest that these differences can be interpreted in terms of the level of diversity or narrowness in citation behaviour.

  3. On the magical supergravities in six dimensions

    NASA Astrophysics Data System (ADS)

    Günaydin, M.; Samtleben, H.; Sezgin, E.

    2011-07-01

    Magical supergravities are a very special class of supergravity theories whose symmetries and matter content in various dimensions correspond to symmetries and underlying algebraic structures of the remarkable geometries of the Magic Square of Freudenthal, Rozenfeld and Tits. These symmetry groups include the exceptional groups and some of their special subgroups. In this paper, we study the general gaugings of these theories in six dimensions which lead to new couplings between vector and tensor fields. We show that in the absence of hypermultiplet couplings the gauge group is uniquely determined by a maximal set of commuting translations within the isometry group SO(n,1) of the tensor multiplet sector. Moreover, we find that in general the gauge algebra allows for central charges that may have nontrivial action on the hypermultiplet scalars. We determine the new minimal couplings, Yukawa couplings and the scalar potential.

  4. Multi-photon entanglement in high dimensions

    NASA Astrophysics Data System (ADS)

    Malik, Mehul; Erhard, Manuel; Huber, Marcus; Krenn, Mario; Fickler, Robert; Zeilinger, Anton

    2016-04-01

    Forming the backbone of quantum technologies today, entanglement has been demonstrated in physical systems as diverse as photons, ions and superconducting circuits. Although steadily pushing the boundary of the number of particles entangled, these experiments have remained in a two-dimensional space for each particle. Here we show the experimental generation of the first multi-photon entangled state where both the number of particles and dimensions are greater than two. Two photons in our state reside in a three-dimensional space, whereas the third lives in two dimensions. This asymmetric entanglement structure only appears in multiparticle entangled states with d > 2. Our method relies on combining two pairs of photons, high-dimensionally entangled in their orbital angular momentum. In addition, we show how this state enables a new type of ‘layered’ quantum communication protocol. Entangled states such as these serve as a manifestation of the complex dance of correlations that can exist within quantum mechanics.

  5. Resonances from two universal extra dimensions

    SciTech Connect

    Burdman, Gustavo; Dobrescu, Bogdan A.; Ponton, Eduardo

    2006-10-01

    Standard model gauge bosons propagating in two universal extra dimensions give rise to heavy spin-1 and spin-0 particles. The lightest of these, carrying Kaluza-Klein numbers (1,0), may be produced only in pairs at colliders, whereas the (1,1) modes, which are heavier by a factor of {radical}(2), may be singly produced. We show that the cascade decays of (1,1) particles generate a series of closely-spaced narrow resonances in the tt invariant mass distribution. At the Tevatron, s-channel production of (1,1) gluons and electroweak bosons will be sensitive to tt resonances up to masses in the 0.5-0.7 TeV range. Searches at the LHC for resonances originating from several higher-level modes will further test the existence of two universal extra dimensions.

  6. Denaturated proteins: Draining effect and molecular dimensions

    NASA Astrophysics Data System (ADS)

    Dondos, A.

    2010-09-01

    Using equations derived from the synthetic macromolecules, we calculate the dimensions in solution of the denaturated proteins. For these calculations, we use a value for the Flory’s parameter Φ obtained from an equation established for the polymers presenting a draining effect, and which is lower than the value of 2.6×10 23 (cgs) generally used. The obtained values for the dimensions of the denaturated proteins (end to end distance, statistical segment length and relation from the end to end distance and the number of residue) using the method proposed here are in good agreement with the values obtained from Flory and co-workers. On the contrary, the values obtained in this work are different from the values proposed by other authors who do not take into account the draining effect and use a value for Φ equal to 2.6×10 23.

  7. Validation of a three-dimensional hand scanning and dimension extraction method with dimension data.

    PubMed

    Li, Zhizhong; Chang, Chien-Chi; Dempsey, Patrick G; Ouyang, Lusha; Duan, Jiyang

    2008-11-01

    A three-level experiment was developed to validate a 3-D hand scanning and dimension extraction method with dimension data. At the first level, a resin hand model of a participant was fabricated to test the repeatability of the dimension data obtained by the 3-D method. At the second level, the actual hand of that participant was measured repeatedly using both the 3-D method and the traditional manual measurement method. The repeatability for both methods was investigated and compared. The influence of posture keeping, surface deformation and other human issues were also examined on the second level. At the third level, a group of participants were recruited and their hands were measured using both methods to examine any differences between the two methods on statistical descriptives. Significant differences, which varied among dimension types (length, depth/breadth, and circumference), were found between the 3-D method and the traditional method. 3-D anthropometric measurement and dimension extraction has become a prospective technology. The proposed three-level experiment provides a systematic method for validation of the repeatability of a 3-D method and compatibility between dimension data from a 3-D method and a traditional method.

  8. Linear dimension reduction and Bayes classification

    NASA Technical Reports Server (NTRS)

    Decell, H. P., Jr.; Odell, P. L.; Coberly, W. A.

    1978-01-01

    An explicit expression for a compression matrix T of smallest possible left dimension K consistent with preserving the n variate normal Bayes assignment of X to a given one of a finite number of populations and the K variate Bayes assignment of TX to that population was developed. The Bayes population assignment of X and TX were shown to be equivalent for a compression matrix T explicitly calculated as a function of the means and covariances of the given populations.

  9. The Cartan algorithm in five dimensions

    NASA Astrophysics Data System (ADS)

    McNutt, D. D.; Coley, A. A.; Forget, A.

    2017-03-01

    In this paper, we introduce an algorithm to determine the equivalence of five dimensional spacetimes, which generalizes the Karlhede algorithm for four dimensional general relativity. As an alternative to the Petrov type classification, we employ the alignment classification to algebraically classify the Weyl tensor. To illustrate the algorithm, we discuss three examples: the singly rotating Myers-Perry solution, the Kerr (Anti-) de Sitter solution, and the rotating black ring solution. We briefly discuss some applications of the Cartan algorithm in five dimensions.

  10. Kinks, extra dimensions, and gravitational waves

    SciTech Connect

    O'Callaghan, Eimear; Gregory, Ruth

    2011-03-01

    We investigate in detail the gravitational wave signal from kinks on cosmic (super)strings, including the kinematical effects from the internal extra dimensions. We find that the signal is suppressed, however, the effect is less significant that that for cusps. Combined with the greater incidence of kinks on (super)strings, it is likely that the kink signal offers the better chance for detection of cosmic (super)strings.

  11. 16 CFR 1508.3 - Dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... both of the sides or ends, the measurement shall be determined from the largest diameter of the first...) Interior. The interior dimensions shall be 71±1.6 centimeters (28±5/8 inches) wide as measured between the innermost surfaces of the crib sides and 133±1.6 centimeters (523/8±5/8 inches) long as measured between...

  12. Spherical gravitational collapse in N dimensions

    SciTech Connect

    Goswami, Rituparno; Joshi, Pankaj S.

    2007-10-15

    We investigate here spherically symmetric gravitational collapse in a space-time with an arbitrary number of dimensions and with a general type I matter field, which is a broad class that includes most of the physically reasonable matter forms. We show that given the initial data for matter in terms of the initial density and pressure profiles at an initial surface t=t{sub i} from which the collapse evolves, there exist the rest of the initial data functions and classes of solutions of Einstein equations which we construct here, such that the space-time evolution goes to a final state which is either a black hole or a naked singularity, depending on the nature of initial data and evolutions chosen, and subject to validity of the weak energy condition. The results are discussed and analyzed in the light of the cosmic censorship hypothesis in black hole physics. The formalism here combines the earlier results on gravitational collapse in four dimensions in a unified treatment. Also the earlier work is generalized to higher-dimensional space-times to allow a study of the effect of the number of dimensions on the possible final outcome of the collapse in terms of either a black hole or naked singularity. No restriction is adopted on the number of dimensions, and other limiting assumptions such as self-similarity of space-time are avoided, in order to keep the treatment general. Our methodology allows us to consider to an extent the genericity and stability aspects related to the occurrence of naked singularities in gravitational collapse.

  13. Core dimensions of recovery: a psychometric analysis.

    PubMed

    Gordon, Sarah E; Ellis, Pete M; Siegert, Richard J; Walkey, Frank H

    2014-07-01

    Core recovery dimensions lie between the large general factor of recovery and its underlying components. Identifying these could enhance recovery frameworks, practice and research. In contrast to existing conceptually based taxonomies, we sought to empirically identify the core dimensions of recovery through further psychometric analysis of a robust eleven factor (sub-scale) consumer recovery outcome measure, My Voice, My Life. We subjected the sub-scale scores of 504 consumers to further principal components analyses, beginning with a single unrotated factor and progressing through two to nine factors with varimax rotation. We found the five-factor solution to provide an orderly intermediate configuration with the eleven recovery factors having either aligned and/or disengaged through the process to result in the following core dimensions: (1) Belonging and relating (encompassing the individual factors of spirituality, culture, and relationships); (2) Being and doing (encompassing the individual factors of physical health, day-to-day life, and quality of life); (3) Thinking and feeling (encompassing the individual factors of recovery, mental health, and hope and empowerment); (4) Resources (which maintained its independence); and (5) Satisfaction with Services (which also maintained its independence). We compare this empirical configuration with conceptually based taxonomies.

  14. A Survey of Dimension Reduction Techniques

    SciTech Connect

    Fodor, I K

    2002-05-09

    Advances in data collection and storage capabilities during the past decades have led to an information overload in most sciences. Researchers working in domains as diverse as engineering, astronomy, biology, remote sensing, economics, and consumer transactions, face larger and larger observations and simulations on a daily basis. Such datasets, in contrast with smaller, more traditional datasets that have been studied extensively in the past, present new challenges in data analysis. Traditional statistical methods break down partly because of the increase in the number of observations, but mostly because of the increase in the number of variables associated with each observation. The dimension of the data, is the number of variables that are measured on each observation. High-dimensional datasets present many mathematical challenges as well as some opportunities, and are bound to give rise to new theoretical developments. One of the problems with high-dimensional datasets is that, in many cases, not all the measured variables are ''important'' for understanding the underlying phenomena of interest. While certain computationally expensive novel methods can construct predictive models with high accuracy from high-dimensional data, it is still of interest in many applications to reduce the dimension of the original data prior to any modeling of the data. In this paper, we described several dimension reduction methods.

  15. Piecewise linear dimension reduction for nonnegative data

    NASA Astrophysics Data System (ADS)

    Shen, Bin; Wang, Qifan; Allebach, Jan P.

    2015-03-01

    In past decade, the increasing popularity of imaging devices, especially smart phones, has led to a great increase in the amount of visual data. The rapidly increasing large scale data pose challenges to the storage and computational resources, and make many computer vision and pattern recognition tasks prohibitively expensive. Dimension reduction techniques explore hidden structures of the original high dimensional data and learn new low dimensional representation to alleviate the challenges. Popular dimension reduction techniques, such as PCA and NMF, do an efficient linear mapping to low dimensional space, while nonlinear techniques overcomes the limitation of linearity at the cost of expensive computational cost (e.g. computing the pairwise distance to find the geodesic distance). In this paper, a piecewise linear dimension reduction technique with global consistency and smoothness constraint is proposed to overcome the restriction of linearity at relatively low cost. Extensive experimental results show that the proposed methods outperform the linear method in the scenario of clustering both consistently and significantly.

  16. Vlasov simulation in multiple spatial dimensions

    SciTech Connect

    Rose, Harvey A.; Daughton, William

    2011-12-15

    A long-standing challenge encountered in modeling plasma dynamics is achieving practical Vlasov equation simulation in multiple spatial dimensions over large length and time scales. While direct multi-dimension Vlasov simulation methods using adaptive mesh methods [M. Gutnic et al., Comput. Phys. Commun. 164, 214 (2004)] have recently shown promising results in two dimensions (2D) [J. W. Banks et al., Phys. Plasmas 18, 052102 (2011); B. I. Cohen et al., November 10, 2010, http://meetings.aps.org/link/BAPS.2010.DPP.NP9.142], in this paper, we present an alternative, the Vlasov multi dimensional (VMD) model, that is specifically designed to take advantage of solution properties in regimes when plasma waves are confined to a narrow cone, as may be the case for stimulated Raman scatter in large optic f laser beams. Perpendicular grid spacing large compared to a Debye length is then possible without instability or loss of accuracy, enabling an order 10 decrease in required computational resources compared to standard particle in cell (PIC) methods in 2D, with another reduction of that order in 3D. Further advantage compared to PIC methods accrues in regimes where particle noise is an issue. VMD and PIC results in a 2D model of localized Langmuir waves are in qualitative agreement.

  17. New Dimensions for Randall-Sundrum Phenomenology

    SciTech Connect

    Davoudiasl, Hooman; Rizzo, Thomas G.

    2008-09-30

    We consider a 6D extension of the Randall-Sundrum (RS) model, RS6, where the Standard Model (SM) gauge fields are allowed to propagate in an additional dimension, compactified on S{sup 1} or S{sup 1}/Z{sub 2}. In a minimal scenario, fermions propagate in the 5D RS subspace and their localization provides a model of flavor. New Kaluza-Klein (KK) states, corresponding to excitations of the gauge fields along the 6th dimension, appear near the TeV scale. The new gauge KK modes behave differently from those in the 5D warped models. These RS6 states have couplings with strong dependence on 5D field localization and, within the SM, only interact with heavy fermions and the Higgs sector, to a very good approximation. Thus, the collider phenomenology of the new gauge KK states sensitively depends on the 5D fermion geography. We briefly discuss inclusion of SM fermions in all 6 dimensions, as well as the possibility of going beyond 6D.

  18. Random holographic "large worlds" with emergent dimensions

    NASA Astrophysics Data System (ADS)

    Trugenberger, Carlo A.

    2016-11-01

    I propose a random network model governed by a Gaussian weight corresponding to Ising link antiferromagnetism as a model for emergent quantum space-time. In this model, discrete space is fundamental, not a regularization; its spectral dimension ds is not a model input but is, rather, completely determined by the antiferromagnetic coupling constant. Perturbative terms suppressing triangles and favoring squares lead to locally Euclidean ground states that are Ricci flat "large worlds" with power-law extension. I then consider the quenched graphs of lowest energy for ds=2 and ds=3 , and I show how quenching leads to the spontaneous emergence of embedding spaces of Hausdorff dimension dH=4 and dH=5 , respectively. One of the additional, spontaneous dimensions can be interpreted as time, causality being an emergent property that arises in the large N limit (with N the number of vertices). For ds=2 , the quenched graphs constitute a discrete version of a 5D-space-filling surface with a number of fundamental degrees of freedom scaling like N2 /5, a graph version of the holographic principle. These holographic degrees of freedom can be identified with the squares of the quenched graphs, which, being triangle-free, are the fundamental area (or loop) quanta.

  19. Ghosts and Tachyons in the Fifth Dimension

    NASA Astrophysics Data System (ADS)

    Pospelov, Maxim

    We present several solutions for the five-dimensional gravity models in the presence of bulk ghosts and tachyons to argue that these "troublesome" fields can be a useful model-building tool. The ghost-like signature of the kinetic term for a bulk scalar creates a minimum in the scale factor, removing the necessity for a negative tension brane in models with the compactified fifth dimension. It is shown that the model with the positive tension branes and a ghost field in the bulk leads to the radion stabilization. The bulk scalar with the variable sign kinetic term can be used to model both positive and negative tension branes of a finite width in the compact dimension. Finally, we present several ghost and tachyon field configurations in the bulk that lead to the localization of gravity in four dimensions, including one solution with the Gaussian profile for the metric, gμν(y) = ημν exp{-αy2}, which leads to a stronger localization of gravity than the Randall-Sundrum model.

  20. Knowledge dimensions in hypothesis test problems

    NASA Astrophysics Data System (ADS)

    Krishnan, Saras; Idris, Noraini

    2012-05-01

    The reformation in statistics education over the past two decades has predominantly shifted the focus of statistical teaching and learning from procedural understanding to conceptual understanding. The emphasis of procedural understanding is on the formulas and calculation procedures. Meanwhile, conceptual understanding emphasizes students knowing why they are using a particular formula or executing a specific procedure. In addition, the Revised Bloom's Taxonomy offers a twodimensional framework to describe learning objectives comprising of the six revised cognition levels of original Bloom's taxonomy and four knowledge dimensions. Depending on the level of complexities, the four knowledge dimensions essentially distinguish basic understanding from the more connected understanding. This study identifiesthe factual, procedural and conceptual knowledgedimensions in hypothesis test problems. Hypothesis test being an important tool in making inferences about a population from sample informationis taught in many introductory statistics courses. However, researchers find that students in these courses still have difficulty in understanding the underlying concepts of hypothesis test. Past studies also show that even though students can perform the hypothesis testing procedure, they may not understand the rationale of executing these steps or know how to apply them in novel contexts. Besides knowing the procedural steps in conducting a hypothesis test, students must have fundamental statistical knowledge and deep understanding of the underlying inferential concepts such as sampling distribution and central limit theorem. By identifying the knowledge dimensions of hypothesis test problems in this study, suitable instructional and assessment strategies can be developed in future to enhance students' learning of hypothesis test as a valuable inferential tool.

  1. Correlation dimension of woodwind multiphonic tones.

    PubMed

    Keefe, D H; Laden, B

    1991-10-01

    A multiphonic is a regime of oscillation of woodwind musical instruments that is perceived as two or more simultaneously sounding pitches. The frequencies fl,m of the line spectral components of a measured woodwind multiphonic tone fit a biperiodic spectrum at low- to mid-playing levels. For the saxophone and clarinet multiphonics investigated, the two basis frequencies of the biperiodic spectrum are phase locked, that is, their ratio is equal to a ratio of small integers. A broadband spectrum is present in multiphonic spectra that exceeds instrumentation noise and window leakage associated with signal processing. The correlation dimension D of P. Grassberger and I. Procaccia [Physica D 9, 189-208 (1983)] is measured by embedding a single measured time series in higher-dimensional space, so as to reconstruct the phase space of the dynamical system. The time delay used in the dimensional reconstruction is chosen using information theory. For the particular multiphonics analyzed, the correlation dimension ranges from 2.5 to 2.9 for the saxophone and from 1.3 to 2.2 for the clarinet. One clarinet multiphonic shows possible additional dynamical complexity at small length scales in the embedding space, with a correlation dimension of 3.3. These results give quantitative evidence that some, but not all, multiphonic tones possess a strange attractor.

  2. Dimension Reduction With Extreme Learning Machine.

    PubMed

    Kasun, Liyanaarachchi Lekamalage Chamara; Yang, Yan; Huang, Guang-Bin; Zhang, Zhengyou

    2016-08-01

    Data may often contain noise or irrelevant information, which negatively affect the generalization capability of machine learning algorithms. The objective of dimension reduction algorithms, such as principal component analysis (PCA), non-negative matrix factorization (NMF), random projection (RP), and auto-encoder (AE), is to reduce the noise or irrelevant information of the data. The features of PCA (eigenvectors) and linear AE are not able to represent data as parts (e.g. nose in a face image). On the other hand, NMF and non-linear AE are maimed by slow learning speed and RP only represents a subspace of original data. This paper introduces a dimension reduction framework which to some extend represents data as parts, has fast learning speed, and learns the between-class scatter subspace. To this end, this paper investigates a linear and non-linear dimension reduction framework referred to as extreme learning machine AE (ELM-AE) and sparse ELM-AE (SELM-AE). In contrast to tied weight AE, the hidden neurons in ELM-AE and SELM-AE need not be tuned, and their parameters (e.g, input weights in additive neurons) are initialized using orthogonal and sparse random weights, respectively. Experimental results on USPS handwritten digit recognition data set, CIFAR-10 object recognition, and NORB object recognition data set show the efficacy of linear and non-linear ELM-AE and SELM-AE in terms of discriminative capability, sparsity, training time, and normalized mean square error.

  3. Dimension Reduction with Extreme Learning Machine.

    PubMed

    Liyanaarachchi Lekamalage, Chamara; Yang, Yan; Huang, Guang-Bin; Zhang, Zhengyou

    2016-05-18

    Data may often contain noise or irrelevant information which negatively affect the generalization capability of machine learning algorithms. The objective of dimension reduction algorithms such as Principal Component Analysis (PCA), Non-negative Matrix Factorization (NMF), random projection (RP) and auto-encoder (AE) is to reduce the noise or irrelevant information of the data. The features of PCA (eigenvectors) and linear AE is not able to represent data as parts (e.g. nose in a face image); On the other hand, NMF and non-linear AE is maimed by slow learning speed and RP only represents a subspace of original data. This paper introduces a dimension reduction framework which to some extend represents data as parts, has fast learning speed and learns the between-class scatter subspace. To this end, this paper investigates a linear and nonlinear dimension reduction framework referred to as Extreme Learning Machine Auto-Encoder (ELM-AE) and Sparse Extreme Learning Machine Auto-Encoder (SELM-AE). In contrast to tied weight auto-encoder (TAE), the hidden neurons in ELMAE and SELM-AE need not be tuned, their parameters (e.g, input weights in additive neurons) are initialized using orthogonal and sparse random weights respectively. Experimental results on USPS handwritten digit recognition dataset, CIFAR-10 object recognition and NORB object recognition data set show the efficacy of linear and non-linear ELM-AE and SELM-AE in terms of discriminative capability, sparsity, training time and Normalized Mean Square Error (NMSE).

  4. Economical quantum cloning in any dimension

    SciTech Connect

    Durt, Thomas; Fiurasek, Jaromir; Cerf, Nicolas J.

    2005-11-15

    The possibility of cloning a d-dimensional quantum system without an ancilla is explored, extending on the economical phase-covariant cloning machine for qubits found in Phys. Rev. A 60, 2764 (1999). We prove the impossibility of constructing an economical version of the optimal universal 1{yields}2 cloning machine in any dimension. We also show, using an ansatz on the generic form of cloning machines, that the d-dimensional 1{yields}2 phase-covariant cloner, which optimally clones all balanced superpositions with arbitrary phases, can be realized economically only in dimension d=2. The used ansatz is supported by numerical evidence up to d=7. An economical phase-covariant cloner can nevertheless be constructed for d>2, albeit with a slightly lower fidelity than that of the optimal cloner requiring an ancilla. Finally, using again an ansatz on cloning machines, we show that an economical version of the 1{yields}2 Fourier-covariant cloner, which optimally clones the computational basis and its Fourier transform, is also possible only in dimension d=2.

  5. Dimension Analysis of Continuous Functions with Unbounded Variation

    NASA Astrophysics Data System (ADS)

    Wang, Jun; Yao, Kui

    In this paper, we mainly discuss fractal dimensions of continuous functions with unbounded variation. First, we prove that Hausdorff dimension, Packing dimension and Modified Box-counting dimension of continuous functions containing one UV point are 1. The above conclusion still holds for continuous functions containing finite UV points. More generally, we show the result that Hausdorff dimension of continuous functions containing countable UV points is 1 also. Finally, Box dimension of continuous functions containing countable UV points has been proved to be 1 when f(x) is self-similar.

  6. Diffusion in κ-deformed space and spectral dimension

    NASA Astrophysics Data System (ADS)

    Anjana, V.

    2016-03-01

    In this paper, we derive the expression for spectral dimension using a modified diffusion equation in the κ-deformed spacetime. We start with the Beltrami-Laplace operator in the κ-Minkowski spacetime and obtain the deformed diffusion equation. From the solution of this deformed diffusion equation, we calculate the spectral dimension which depends on the deformation parameter “a = 1 κ” and also on an integer “l”, apart from the topological dimension. Using this, we show that, for large diffusion times the spectral dimension approaches the usual topological dimension whereas spectral dimension diverges to + ∞ for l ≥ 0 and -∞ for l < 0 at high energies.

  7. The Global Statistics of Return Times: Return Time Dimensions Versus Generalized Measure Dimensions

    NASA Astrophysics Data System (ADS)

    Mantica, Giorgio

    2010-03-01

    We investigate return times in dynamical systems, i.e. the time required by a trajectory to complete a return journey to a neighborhood of the initial position. In particular, we study the relations holding between the scaling exponents of phase-space moments of return times in balls of diminishing radius, on the one side, and the generalized dimensions of invariant measures, on the other. Because of a heuristic use of Kac theorem, the former have been used in place of the latter in numerical and experimental investigations: to mark the distinction, we call them return time dimensions. We derive a full set of inequalities linking generalized dimensions of invariant measures and return time dimensions. We comment on their optimality with the aid of two maps due to von Neumann-Kakutani and to Gaspard-Wang. We conjecture a formula for the return time dimensions in a typical system. We only assume that the dynamical system under investigation is ergodic and that motion takes place in a compact, finite dimensional space.

  8. Holland's Theory of Vocational Choice and Postulated Value Dimensions.

    ERIC Educational Resources Information Center

    Laudeman, Kent A.; Griffeth, Paul

    1978-01-01

    The validity of Holland's vocational personality types and their relationship to value dimensions were examined in light of Holland's theory of vocational choice. The results generally supported Holland's postulated personality typologies and value dimensions. (Author/JKS)

  9. Diff-invariant kinetic terms in arbitrary dimensions

    NASA Astrophysics Data System (ADS)

    Barbero G., J. Fernando; Villaseñor, Eduardo J.

    2002-06-01

    We study the physical content of quadratic diff-invariant Lagrangians in arbitrary dimensions by using covariant symplectic techniques. This paper extends previous results in dimension four. We discuss the difference between the even and odd dimensional cases.

  10. Dynamics of particles near black hole with higher dimensions

    NASA Astrophysics Data System (ADS)

    Sharif, M.; Iftikhar, Sehrish

    2016-07-01

    This paper explores the dynamics of particles in higher dimensions. For this purpose, we discuss some interesting features related to the motion of particles near a Myers-Perry black hole with arbitrary extra dimensions as well as a single non-zero spin parameter. Assuming it as a supermassive black hole at the center of the galaxy, we calculate red-blue shifts in the equatorial plane for the far away observer as well as the corresponding black hole parameters of the photons. Next, we study the Penrose process and find that the energy gain of the particle depends on the variation of the black hole dimensions. Finally, we discuss the center of mass energy for 11 dimensions, which indicates a similar behavior to that of four dimensions but it is higher in four dimensions than five or more dimensions. We conclude that higher dimensions have a great impact on the particle dynamics.

  11. Interdependent lattice networks in high dimensions

    NASA Astrophysics Data System (ADS)

    Lowinger, Steven; Cwilich, Gabriel A.; Buldyrev, Sergey V.

    2016-11-01

    We study the mutual percolation of two interdependent lattice networks ranging from two to seven dimensions, denoted as D . We impose that the length (measured as chemical distance) of interdependency links connecting nodes in the two lattices be less than or equal to a certain value, r . For each value of D and r , we find the mutual percolation threshold, pc[D ,r ] , below which the system completely collapses through a cascade of failures following an initial destruction of a fraction (1 -p ) of the nodes in one of the lattices. We find that for each dimension, D <6 , there is a value of r =rI>1 such that for r ≥rI the cascading failures occur as a discontinuous first-order transition, while for r dimensions, the interdependent lattices reach maximal vulnerability (maximal pc[D ,r ] ) at a distance r =rmax>rI , and for r >rmax the vulnerability starts to decrease as r →∞ . However, the decrease becomes less significant as D increases, and pc[D ,rmax] -pc[D ,∞ ] decreases exponentially with D . We also investigate the dependence of pc[D ,r ] on the system size as well as how the nature of the transition changes as the number of lattice sites, N →∞ .

  12. Limiting Maximum Magnitude by Fault Dimensions (Invited)

    NASA Astrophysics Data System (ADS)

    Stirling, M. W.

    2010-12-01

    A standard practise of seismic hazard modeling is to combine fault and background seismicity sources to produce a multidisciplinary source model for a region. Background sources are typically modeled with a Gutenberg-Richter magnitude-frequency distribution developed from historical seismicity catalogs, and fault sources are typically modeled with earthquakes that are limited in size by the mapped fault rupture dimensions. The combined source model typically exhibits a Gutenberg-Richter-like distribution due to there being many short faults relative to the number of longer faults. The assumption that earthquakes are limited by the mapped fault dimensions therefore appears to be consistent with the Gutenberg-Richter relationship, one of the fundamental laws of seismology. Recent studies of magnitude-frequency distributions for California and New Zealand have highlighted an excess of fault-derived earthquakes relative to the log-linear extrapolation of the Gutenberg-Richter relationship from the smaller magnitudes (known as the “bulge”). Relaxing the requirement of maximum magnitude being limited by fault dimensions is a possible solution for removing the “bulge” to produce a perfectly log-linear Gutenberg-Richter distribution. An alternative perspective is that the “bulge” does not represent a significant departure from a Gutenberg-Richter distribution, and may simply be an artefact of a small earthquake dataset relative to the more plentiful data at the smaller magnitudes. In other words the uncertainty bounds of the magnitude-frequency distribution at the moderate-to-large magnitudes may be far greater than the size of the “bulge”.

  13. VASP- VARIABLE DIMENSION AUTOMATIC SYNTHESIS PROGRAM

    NASA Technical Reports Server (NTRS)

    White, J. S.

    1994-01-01

    VASP is a variable dimension Fortran version of the Automatic Synthesis Program, ASP. The program is used to implement Kalman filtering and control theory. Basically, it consists of 31 subprograms for solving most modern control problems in linear, time-variant (or time-invariant) control systems. These subprograms include operations of matrix algebra, computation of the exponential of a matrix and its convolution integral, and the solution of the matrix Riccati equation. The user calls these subprograms by means of a FORTRAN main program, and so can easily obtain solutions to most general problems of extremization of a quadratic functional of the state of the linear dynamical system. Particularly, these problems include the synthesis of the Kalman filter gains and the optimal feedback gains for minimization of a quadratic performance index. VASP, as an outgrowth of the Automatic Synthesis Program, has the following improvements: more versatile programming language; more convenient input/output format; some new subprograms which consolidate certain groups of statements that are often repeated; and variable dimensioning. The pertinent difference between the two programs is that VASP has variable dimensioning and more efficient storage. The documentation for the VASP program contains a VASP dictionary and example problems. The dictionary contains a description of each subroutine and instructions on its use. The example problems include dynamic response, optimal control gain, solution of the sampled data matrix Riccati equation, matrix decomposition, and a pseudo-inverse of a matrix. This program is written in FORTRAN IV and has been implemented on the IBM 360. The VASP program was developed in 1971.

  14. Large Extra Dimension and Dark Matter Detection

    NASA Astrophysics Data System (ADS)

    Qin, Bo; Starkman, Glenn D.; Silk, Joseph

    2008-01-01

    If our space has the large extra dimensions as proposed by Arkani-Hamed, Dimopoulos and Dvali (ADD), then gravity would start to deviate from Newtonian gravity and be greatly enhanced in sub-millimeter scales. Here we show that in the ADD scenario, gravity could play an important role (compared to the weak interaction) in the interactions between dark matter particles and the electron. We find that for typical WIMP dark matter, such dark matter-electron ``gravitational'' scattering cross section may be much larger than the dark matter-nucleon cross section constrained by current dark matter experiments.

  15. Wavelet frames and admissibility in higher dimensions

    NASA Astrophysics Data System (ADS)

    Führ, Hartmut

    1996-12-01

    This paper is concerned with the relations between discrete and continuous wavelet transforms on k-dimensional Euclidean space. We start with the construction of continuous wavelet transforms with the help of square-integrable representations of certain semidirect products, thereby generalizing results of Bernier and Taylor. We then turn to frames of L2(Rk) and to the question, when the functions occurring in a given frame are admissible for a given continuous wavelet transform. For certain frames we give a characterization which generalizes a result of Daubechies to higher dimensions.

  16. Instantons and Massless Fermions in Two Dimensions

    DOE R&D Accomplishments Database

    Callan, C. G. Jr.; Dashen, R.; Gross, D. J.

    1977-05-01

    The role of instantons in the breakdown of chiral U(N) symmetry is studied in a two dimensional model. Chiral U(1) is always destroyed by the axial vector anomaly. For N = 2 chiral SU(N) is also spontaneously broken yielding massive fermions and three (decoupled) Goldstone bosons. For N greater than or equal to 3 the fermions remain massless. Realistic four dimensional theories are believed to behave in a similar way but the critical N above which the fermions cease to be massive is not known in four dimensions.

  17. Mars Radar Opens a Planet's Third Dimension

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Radar sounder instruments orbiting Mars have looked beneath the Martian surface and opened up the third dimension for planetary exploration. The technique's success is prompting scientists to think of all the other places in the Solar System where they would like to use radar sounders.

    The first radar sounder at Mars was the Mars Advanced Radar for Subsurface and Ionospheric Sounding (MARSIS) on the European Space Agency's Mars Express Orbiter. It has been joined by the complementary Shallow Subsurface Radar (SHARAD), operating at a different wavelength aboard NASA's Mars Reconnaissance Orbiter. The data in this animation are from SHARAD.

  18. Estimation of fractal dimensions from transect data

    SciTech Connect

    Loehle, C.

    1994-04-01

    Fractals are a useful tool for analyzing the topology of objects such as coral reefs, forest canopies, and landscapes. Transects are often studied in these contexts, and fractal dimensions computed from them. An open question is how representative a single transect is. Transects may also be used to estimate the dimensionality of a surface. Again the question of representativeness of the transect arises. These two issues are related. This note qualifies the conditions under which transect data may be considered to be representative or may be extrapolated, based on both theoretical and empirical results.

  19. Rotating boson stars in five dimensions

    SciTech Connect

    Hartmann, Betti; Kleihaus, Burkhard; Kunz, Jutta; List, Meike

    2010-10-15

    We study rotating boson stars in five spacetime dimensions. The boson fields consist of a complex doublet scalar field. Considering boson stars rotating in two orthogonal planes with both angular momenta of equal magnitude, a special ansatz for the boson field and the metric allows for solutions with nontrivial dependence on the radial coordinate only. The charge of the scalar field equals the sum of the angular momenta. The rotating boson stars are globally regular and asymptotically flat. For our choice of a sextic potential, the rotating boson star solutions possess a flat spacetime limit. We study the solutions in flat and curved spacetime.

  20. Split universal extra dimension and dark matter

    SciTech Connect

    Park, Seong Chan; Shu Jing

    2009-05-01

    Motivated by the recent observation of the high energy electron and positron excesses in cosmic ray by PAMELA and ATIC/PPB-BETS, we suggest an anomaly-free scenario for the universal extra dimension that localizes the standard model quarks and splits the spectrum of Kaluza-Klein (KK) quarks from KK leptons. When the SM quarks are 'well localized' at the boundaries, the most stringent bound of the model (1/R>510 GeV) comes from the resonance search for the Tevatron dijet channels. Even at the early stage of LHC, one can discover the second KK gluon for masses up to 4 TeV.

  1. Hertzian contact in two and three dimensions

    NASA Technical Reports Server (NTRS)

    Tripp, J. H.

    1985-01-01

    The basic solution to the problem of mechanical contact between elastically deforming solids was proposed by Hertz over a century ago and has been used by tribologists and others ever since in a steadily increasing number of applications. While the theoretical development is not conceptually difficult and treatments exist to suit all tastes, it is nonetheless interesting to trace the relationships among the solutions in different dimensions. Such an approach is used herein to shed light on the curious and sometimes perplexing behavior of line contacts. A number of the more frequently used contact expressions together as a convenient reference and for comparative purposes.

  2. Chern-Simons gravity in four dimensions

    NASA Astrophysics Data System (ADS)

    Morales, Ivan; Neves, Bruno; Oporto, Zui; Piguet, Olivier

    2017-02-01

    Five-dimensional Chern-Simons theory with (anti-)de Sitter SO(1,5) or SO(2,4) gauge invariance presents an alternative to general relativity with cosmological constant. We consider the zero modes of its Kaluza-Klein compactification to four dimensions. Solutions with vanishing torsion are obtained in the cases of a spherically symmetric 3-space and of a homogeneous and isotropic 3-space, which reproduce the Schwarzshild-de Sitter and Λ CDM cosmological solutions of general relativity. We also check that vanishing torsion is a stable feature of the solutions.

  3. Auditory location as an encoding dimension.

    PubMed

    Weeks, R A

    1975-05-01

    In two experiments, subjects were given five successive short-term memory tests. In Experiment 1, recall was not significantly facilitated when memory material in the final test was delivered to the ear opposite to the one that received the memory material in the four preceding tests. In Experiment 2, events were presented from two differentially located speakers rather than through headphones. A shift across speakers on the final test did produce proactive interference release. These findings suggest spatial location as a potential encoding dimension of verbal material.

  4. Timelike Killing spinors in seven dimensions

    SciTech Connect

    Cariglia, Marco; Conamhna, Oisin A.P. Mac

    2004-12-15

    We employ the G-structure formalism to study supersymmetric solutions of minimal and SU(2) gauged supergravities in seven dimensions admitting Killing spinors with an associated timelike Killing vector. The most general such Killing spinor defines a SU(3) structure. We deduce necessary and sufficient conditions for the existence of a timelike Killing spinor on the bosonic fields of the theories, and find that such configurations generically preserve one out of 16 supersymmetries. Using our general supersymmetric ansatz we obtain numerous new solutions, including squashed or deformed anti-de Sitter solutions of the gauged theory, and a large class of Goedel-like solutions with closed timelike curves.

  5. Some promising dimensions for behavioral community technology

    PubMed Central

    Fawcett, Stephen B.; Mathews, R. Mark; Fletcher, R. Kay

    1980-01-01

    In recent years, the search for effective and replicable approaches to planned change in communities has escalated. Applied behavior analysts have participated in these efforts to remedy existing community problems and to increase the capacities of community residents to meet their goals. Examples of behavioral technologies for community settings are described and their advantages are noted. Criteria for more contextually appropriate community technologies are suggested and strategies for developing behavioral methods according to these criteria are described. This paper outlines some promising dimensions for behavioral community technology and discusses several possible limitations to a behavioral approach to addressing societal problems. PMID:16795630

  6. Combining contingency tables with missing dimensions.

    PubMed

    Dominici, F

    2000-06-01

    We propose a methodology for estimating the cell probabilities in a multiway contingency table by combining partial information from a number of studies when not all of the variables are recorded in all studies. We jointly model the full set of categorical variables recorded in at least one of the studies, and we treat the variables that are not reported as missing dimensions of the study-specific contingency table. For example, we might be interested in combining several cohort studies in which the incidence in the exposed and nonexposed groups is not reported for all risk factors in all studies while the overall numbers of cases and cohort size is always available. To account for study-to-study variability, we adopt a Bayesian hierarchical model. At the first stage of the model, the observation stage, data are modeled by a multinomial distribution with fixed total number of observations. At the second stage, we use the logistic normal (LN) distribution to model variability in the study-specific cells' probabilities. Using this model and data augmentation techniques, we reconstruct the contingency table for each study regardless of which dimensions are missing, and we estimate population parameters of interest. Our hierarchical procedure borrows strength from all the studies and accounts for correlations among the cells' probabilities. The main difficulty in combining studies recording different variables is in maintaining a consistent interpretation of parameters across studies. The approach proposed here overcomes this difficulty and at the same time addresses the uncertainty arising from the missing dimensions. We apply our modeling strategy to analyze data on air pollution and mortality from 1987 to 1994 for six U.S. cities by combining six cross-classifications of low, medium, and high levels of mortality counts, particulate matter, ozone, and carbon monoxide with the complication that four of the six cities do not report all the air pollution variables. Our

  7. Strategies for Reuse of Learning Objects: Context Dimensions

    ERIC Educational Resources Information Center

    Strijker, Allard; Collis, Betty

    2006-01-01

    Based on research in ten projects in a university, corporate learning, and military context, a set of dimensions is found that can help decision makers to develop strategies for reuse (Strijker, 2004). This article describes how these dimensions and their relation with human and technical aspects can be used in a reuse strategy. The dimensions can…

  8. Pre-Service Teachers' Concept Images on Fractal Dimension

    ERIC Educational Resources Information Center

    Karakus, Fatih

    2016-01-01

    The analysis of pre-service teachers' concept images can provide information about their mental schema of fractal dimension. There is limited research on students' understanding of fractal and fractal dimension. Therefore, this study aimed to investigate the pre-service teachers' understandings of fractal dimension based on concept image. The…

  9. Key Dimensions of a Multicultural Art Education Curriculum

    ERIC Educational Resources Information Center

    Chin, Christina

    2013-01-01

    In an effort to encourage further integration of multicultural curricula, this article aims to detail several key dimensions of multicultural education, particularly as they apply to art education. Drawing on Banks's (1994b, 1995b, 1996e, 2004) dimensions for multicultural education, these dimensions include content integration, equity…

  10. The Cultural Dimensions of Language Teaching and Learning

    ERIC Educational Resources Information Center

    Risager, Karen

    2011-01-01

    Language teaching and learning has many different cultural dimensions, and over the years more and more of these have been the subject of research. The first dimension to be explored was that of content: the images of target language countries and the world that were offered in textbooks and presented in class. The next dimension was that of the…

  11. Dimensions of Acculturation in Native American College Students

    ERIC Educational Resources Information Center

    Reynolds, Amy L.; Sodano, Sandro M.; Ecklund, Timothy R.; Guyker, Wendy

    2012-01-01

    Exploratory and confirmatory factor analyses were applied to the responses of two respective independent samples of Native American college students on the Native American Acculturation Scale (NAAS). Three correlated dimensions were found to underlie NAAS items and these dimensions may also comprise a broader higher order dimension of Native…

  12. Institutional Quality Assessment of Higher Education: Dimensions, Criteria and Indicators

    ERIC Educational Resources Information Center

    Savickiene, Izabela; Pukelis, Kestutis

    2004-01-01

    The article discusses dimensions and criteria, which are used to assess the quality of higher education in different countries. The paper presents dimensions and criteria that could be appropriate for assessment of the quality of higher education at Lithuanian universities. Quality dimensions, assessment criteria and indicators are defined and…

  13. 16 CFR 501.6 - Cellulose sponges, irregular dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Cellulose sponges, irregular dimensions. 501... REQUIREMENTS AND PROHIBITIONS UNDER PART 500 § 501.6 Cellulose sponges, irregular dimensions. Variety packages of cellulose sponges of irregular dimensions, are exempted from the requirements of § 500.25 of...

  14. 16 CFR 501.6 - Cellulose sponges, irregular dimensions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Cellulose sponges, irregular dimensions. 501... REQUIREMENTS AND PROHIBITIONS UNDER PART 500 § 501.6 Cellulose sponges, irregular dimensions. Variety packages of cellulose sponges of irregular dimensions, are exempted from the requirements of § 500.25 of...

  15. 16 CFR 501.6 - Cellulose sponges, irregular dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Cellulose sponges, irregular dimensions. 501... REQUIREMENTS AND PROHIBITIONS UNDER PART 500 § 501.6 Cellulose sponges, irregular dimensions. Variety packages of cellulose sponges of irregular dimensions, are exempted from the requirements of § 500.25 of...

  16. 16 CFR 501.6 - Cellulose sponges, irregular dimensions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Cellulose sponges, irregular dimensions. 501... REQUIREMENTS AND PROHIBITIONS UNDER PART 500 § 501.6 Cellulose sponges, irregular dimensions. Variety packages of cellulose sponges of irregular dimensions, are exempted from the requirements of § 500.25 of...

  17. 16 CFR 501.6 - Cellulose sponges, irregular dimensions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Cellulose sponges, irregular dimensions. 501... REQUIREMENTS AND PROHIBITIONS UNDER PART 500 § 501.6 Cellulose sponges, irregular dimensions. Variety packages of cellulose sponges of irregular dimensions, are exempted from the requirements of § 500.25 of...

  18. Perceptual dimensions for a dynamic tactile display

    NASA Astrophysics Data System (ADS)

    Pappas, Thrasyvoulos N.; Tartter, Vivien C.; Seward, Andrew G.; Genzer, Boris; Gourgey, Karen; Kretzschmar, Ilona

    2009-02-01

    We propose a new approach for converting graphical and pictorial information into tactile patterns that can be displayed in a static or dynamic tactile device. The key components of the proposed approach are (1) an algorithm that segments a scene into perceptually uniform segments; (2) a procedure for generating perceptually distinct tactile patterns; and (3) a mapping of the visual textures of the segments into tactile textures that convey similar concepts. We used existing digital halftoning and other techniques to generate a wide variety of tactile textures. We then conducted formal and informal subjective tests with sighted (but visually blocked) and visually-impaired subjects to determine the ability of human tactile perception to perceive differences among them. In addition to generating perceptually distinguishable tactile patterns, our goal is to identify significant dimensions of tactile texture perception, which will make it possible to map different visual attributes into independent tactile attributes. Our experimental results indicate that it is poosible to generate a number of perceptually distinguishable tactile patterns, and that different dimensions of tactile texture perception can indeed be identified.

  19. Understanding rigid body motion in arbitrary dimensions

    NASA Astrophysics Data System (ADS)

    Leyvraz, Francois

    2015-05-01

    Why would anyone wish to generalize the already unappetizing subject of rigid body motion to an arbitrary number of dimensions? At first sight, the subject seems to be both repellent and superfluous. The author will try to argue that an approach involving no specific three-dimensional constructs is actually easier to grasp than the traditional approach and might thus be generally useful to understand rigid body motion both in three dimensions and in the general case. Specific differences between the viewpoint suggested here and the usual one include the following: here angular velocities are systematically treated as antisymmetric matrices, a symmetric tensor I quite different from the moment of inertia tensor plays a central role, whereas the latter is shown to be a far more complex object, namely a tensor of rank four. A straightforward way to define it is given. The Euler equation is derived and the use of Noether’s theorem to obtain conserved quantities is illustrated. Finally the equations of motion for a heavy top as well as for two bodies linked by a spherical joint are derived to display the simplicity and the power of the method.

  20. Simple SO(10) GUT in five dimensions

    NASA Astrophysics Data System (ADS)

    Fukuyama, Takeshi; Okada, Nobuchika

    2008-07-01

    A simple supersymmetric SO(10) grand unified theory (GUT) in five dimensions is considered. The fifth dimension is compactified on the S1/(Z2×Z2') orbifold possessing two inequivalent fixed points. In our setup, all matter and Higgs multiplets reside on one brane (PS brane) where the original SO(10) gauge group is broken down to the Pati-Salam (PS) gauge group, SU(4)c×SU(2)L×SU(2)R, by the orbifold boundary condition, while only the SO(10) gauge multiplet resides in the bulk. The further breaking of the PS symmetry to the standard model gauge group is realized by Higgs multiplets on the PS brane as usual in four-dimensional models. Proton decay is fully suppressed. In our simple setup, the gauge coupling unification is realized after incorporating threshold corrections of Kaluza-Klein modes. When supersymmetry is assumed to be broken on the other brane, supersymmetry breaking is transmitted to the PS brane through the gaugino mediation with the bulk gauge multiplet.

  1. Dimensions of Credibility in Models and Simulations

    NASA Technical Reports Server (NTRS)

    Steele, Martin J.

    2008-01-01

    Based on the National Aeronautics and Space Administration's (NASA's) work in developing a standard for models and simulations (M&S), the subject of credibility in M&S became a distinct focus. This is an indirect result from the Space Shuttle Columbia Accident Investigation Board (CAIB), which eventually resulted in an action, among others, to improve the rigor in NASA's M&S practices. The focus of this action came to mean a standardized method for assessing and reporting results from any type of M&S. As is typical in the standards development process, this necessarily developed into defming a common terminology base, common documentation requirements (especially for M&S used in critical decision making), and a method for assessing the credibility of M&S results. What surfaced in the development of the NASA Standard was the various dimensions credibility to consider when accepting the results from any model or simulation analysis. The eight generally relevant factors of credibility chosen in the NASA Standard proved only one aspect in the dimensionality of M&S credibility. At the next level of detail, the full comprehension of some of the factors requires an understanding along a couple of dimensions as well. Included in this discussion are the prerequisites for the appropriate use of a given M&S, the choice of factors in credibility assessment with their inherent dimensionality, and minimum requirements for fully reporting M&S results.

  2. KK parity in warped extra dimension

    NASA Astrophysics Data System (ADS)

    Agashe, Kaustubh; Falkowski, Adam; Low, Ian; Servant, Géraldine

    2008-04-01

    We construct models with a Kaluza-Klein (KK) parity in a five-dimensional warped geometry, in an attempt to address the little hierarchy problem present in setups with bulk Standard Model fields. The lightest KK particle (LKP) is stable and can play the role of dark matter. We consider the possibilities of gluing two identical slices of AdS5 in either the UV (IR-UV-IR model) or the IR region (UV-IR-UV model) and discuss the model-building issues as well as phenomenological properties in both cases. In particular, we find that the UV-IR-UV model is not gravitationally stable and that additional mechanisms might be required in the IR-UV-IR model to address flavor issues. Collider signals of the warped KK parity are different from either the conventional warped extra dimension without KK parity, in which the new particles are not necessarily pair-produced, or the KK parity in flat universal extra dimensions, where each KK level is nearly degenerate in mass. Dark matter and collider properties of a TeV mass KK Z gauge boson as the LKP are discussed.

  3. SOCIAL, HISTORICAL AND CULTURAL DIMENSIONS OF TUBERCULOSIS.

    PubMed

    Mason, Paul H; Roy, Anupom; Spillane, Jayden; Singh, Puneet

    2016-03-01

    Tuberculosis (TB) researchers and clinicians, by virtue of the social disease they study, are drawn into an engagement with ways of understanding illness that extend beyond the strictly biomedical model. Primers on social science concepts directly relevant to TB, however, are lacking. The particularities of TB disease mean that certain social science concepts are more relevant than others. Concepts such as structural violence can seem complicated and off-putting. Other concepts, such as gender, can seem so familiar that they are left relatively unexplored. An intimate familiarity with the social dimensions of disease is valuable, particularly for infectious diseases, because the social model is an important complement to the biomedical model. This review article offers an important introduction to a selection of concepts directly relevant to TB from health sociology, medical anthropology and social cognitive theory. The article has pedagogical utility and also serves as a useful refresher for those researchers already engaged in this genre of work. The conceptual tools of health sociology, medical anthropology and social cognitive theory offer insightful ways to examine the social, historical and cultural dimensions of public health. By recognizing cultural experience as a central force shaping human interactions with the world, TB researchers and clinicians develop a more nuanced consideration of how health, illness and medical treatment are understood, interpreted and confronted.

  4. Dimension-based statistical learning of vowels.

    PubMed

    Liu, Ran; Holt, Lori L

    2015-12-01

    Speech perception depends on long-term representations that reflect regularities of the native language. However, listeners rapidly adapt when speech acoustics deviate from these regularities due to talker idiosyncrasies such as foreign accents and dialects. To better understand these dual aspects of speech perception, we probe native English listeners' baseline perceptual weighting of 2 acoustic dimensions (spectral quality and vowel duration) toward vowel categorization and examine how they subsequently adapt to an "artificial accent" that deviates from English norms in the correlation between the 2 dimensions. At baseline, listeners rely relatively more on spectral quality than vowel duration to signal vowel category, but duration nonetheless contributes. Upon encountering an "artificial accent" in which the spectral-duration correlation is perturbed relative to English language norms, listeners rapidly down-weight reliance on duration. Listeners exhibit this type of short-term statistical learning even in the context of nonwords, confirming that lexical information is not necessary to this form of adaptive plasticity in speech perception. Moreover, learning generalizes to both novel lexical contexts and acoustically distinct altered voices. These findings are discussed in the context of a mechanistic proposal for how supervised learning may contribute to this type of adaptive plasticity in speech perception.

  5. DIMENSION-BASED STATISTICAL LEARNING OF VOWELS

    PubMed Central

    Liu, Ran; Holt, Lori L.

    2015-01-01

    Speech perception depends on long-term representations that reflect regularities of the native language. However, listeners rapidly adapt when speech acoustics deviate from these regularities due to talker idiosyncrasies such as foreign accents and dialects. To better understand these dual aspects of speech perception, we probe native English listeners’ baseline perceptual weighting of two acoustic dimensions (spectral quality and vowel duration) towards vowel categorization and examine how they subsequently adapt to an “artificial accent” that deviates from English norms in the correlation between the two dimensions. At baseline, listeners rely relatively more on spectral quality than vowel duration to signal vowel category, but duration nonetheless contributes. Upon encountering an “artificial accent” in which the spectral-duration correlation is perturbed relative to English language norms, listeners rapidly down-weight reliance on duration. Listeners exhibit this type of short-term statistical learning even in the context of nonwords, confirming that lexical information is not necessary to this form of adaptive plasticity in speech perception. Moreover, learning generalizes to both novel lexical contexts and acoustically-distinct altered voices. These findings are discussed in the context of a mechanistic proposal for how supervised learning may contribute to this type of adaptive plasticity in speech perception. PMID:26280268

  6. Dynamical Electroweak Symmetry Breaking from Extra Dimensions

    NASA Astrophysics Data System (ADS)

    Hashimoto, Michio; Tanabashi, Masaharu; Yamawaki, Koichi

    2003-08-01

    We study the dynamical electroweak symmetry breaking (DEWSB) in the D(= 6, 8, ⋯)-dimensional bulk with compactified extra dimensions. We identify the critical binding strength for triggering the DEWSB, based on the ladder Schwinger-Dyson equation. In the top mode standard model with extra dimensions, where the standard model gauge bosons and the third generation of quarks and leptons are put in the bulk, we analyze the most attractive channel (MAC) by using renormalization group equations (RGEs) of (dimensionless) bulk gauge couplings and determine the effective cutoff where the MAC coupling exceeds the critical value. We then find that the top-condensation can take place for D = 8. Combining RGEs of top-Yukawa and Higgs-quartic couplings with compositeness conditions, we predict the top mass, mt = 173 - 180 GeV, and the Higgs mass, mH = 181 - 211 GeV, for D = 8, where we took the universal compactification scale 1/R = 1 - 100 TeV.

  7. Units for quantities of dimension one

    NASA Astrophysics Data System (ADS)

    Dybkaer, René

    2004-02-01

    All quantities of dimension one are said to have the SI coherent derived unit "one" with the symbol '1'. (Single quotation marks are used here sometimes to indicate a quote, name, term or symbol; double quotation marks flag a concept when necessary.) Conventionally, the term and symbol may not be combined with the SI prefixes (except for the special terms and symbols for one and 1: radian, rad, and steradian, sr). This restriction is understandable, but leads to correct yet impractical alternatives and ISO deprecated symbols such as ppm or in some cases redundant combinations of units, such as mg/kg. "Number of entities" is dimensionally independent of the current base quantities and should take its rightful place among them. The corresponding base unit is "one". A working definition is given. Other quantities of dimension one are derived as fraction, ratio, efficiency, relative quantity, relative increment or characteristic number and may also use the unit "one", whether considered to be base or derived. The special term 'uno' and symbol 'u' in either case are proposed, allowing combination with SI prefixes.

  8. BOOK REVIEW: Quantum Physics in One Dimension

    NASA Astrophysics Data System (ADS)

    Logan, David

    2004-05-01

    To a casual ostrich the world of quantum physics in one dimension may sound a little one-dimensional, suitable perhaps for those with an unhealthy obsession for the esoteric. Nothing of course could be further from the truth. The field is remarkably rich and broad, and for more than fifty years has thrown up innumerable challenges. Theorists, realising that the role of interactions in 1D is special and that well known paradigms of higher dimensions (Fermi liquid theory for example) no longer apply, took up the challenge of developing new concepts and techniques to understand the undoubted pecularities of one-dimensional systems. And experimentalists have succeeded in turning pipe dreams into reality, producing an impressive and ever increasing array of experimental realizations of 1D systems, from the molecular to the mesoscopic---spin and ladder compounds, organic superconductors, carbon nanotubes, quantum wires, Josephson junction arrays and so on. Many books on the theory of one-dimensional systems are however written by experts for experts, and tend as such to leave the non-specialist a touch bewildered. This is understandable on both fronts, for the underlying theoretical techniques are unquestionably sophisticated and not usually part of standard courses in many-body theory. A brave author it is then who aims to produce a well rounded, if necessarily partial, overview of quantum physics in one dimension, accessible to a beginner yet taking them to the edge of current research, and providing en route a thorough grounding in the fundamental ideas, basic methods and essential phenomenology of the field. It is of course the brave who succeed in this world, and Thierry Giamarchi does just that with this excellent book, written by an expert for the uninitiated. Aimed in particular at graduate students in theoretical condensed matter physics, and assumimg little theoretical background on the part of the reader (well just a little), Giamarchi writes in a refreshingly

  9. Genetic associations between the ADHD symptom dimensions and Cloninger's temperament dimensions in adult twins.

    PubMed

    Merwood, Andrew; Asherson, Philip; Larsson, Henrik

    2013-06-01

    Previous studies have identified phenotypic associations between Cloninger's temperament dimensions and the symptoms of attention deficit hyperactivity disorder (ADHD) in adults. However the underlying aetiology of these associations remains unclear. We investigate the extent to which genetic and environmental influences contribute to the relationship between temperament and ADHD, examining the ADHD symptoms of inattention (IA) and hyperactivity/impulsivity (HI) separately. Participants were 886 adult twin pairs aged 19-20 years. ADHD symptoms of IA and HI were measured using a DSM-IV based rating scale. Temperament was measured using Cloninger's Temperament and Character Inventory (TCI), across four dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS). The twin method was used to decompose phenotypic variance/covariance among these variables into genetic and environmental components. We found that NS was genetically associated with both ADHD symptom dimensions (IA and HI), but that HA was genetically associated with IA only. There was also some evidence of genetic association between PS, IA and HI. These findings suggest that unique profiles of temperament are genetically related to the two ADHD symptom dimensions in adults. Further work is now needed to elucidate the mechanisms that underlie both the combined and separate symptom factor domains of ADHD.

  10. Experimental realization of dimension witnesses based on quantum state discrimination

    NASA Astrophysics Data System (ADS)

    Sun, Yong-Nan; Liu, Zhao-Di; Sun, Jun; Chen, Geng; Xu, Xiao-Ye; Wu, Yu-Chun; Tang, Jian-Shun; Han, Yong-Jian; Li, Chuan-Feng; Guo, Guang-Can

    2016-11-01

    The dimension witness is an important concept in fundamental physics and quantum information processing which allows one to test the dimension of an unknown physical system in a device independent manner. Here, we report an experimental test of classical and quantum dimensions in a prepare and measure scenario through dimension witnesses based on quantum state discrimination. In our work, we have not only distinguished between quantum and classical systems of the same dimension (two, three, and four dimensions) but also distinguished between real and complex two-level quantum systems. We have also shown the strong link between dimension witnesses and quantum state discrimination which was introduced in N. Brunner, M. Navascués, and T. Vértesi [Phys. Rev. Lett. 110, 150501 (2013), 10.1103/PhysRevLett.110.150501].

  11. On partially massless theory in 3 dimensions

    SciTech Connect

    Alexandrov, Sergei; Deffayet, Cédric

    2015-03-24

    We analyze the first-order formulation of the ghost-free bigravity model in three-dimensions known as zwei-dreibein gravity. For a special choice of parameters, it was argued to have an additional gauge symmetry and give rise to a partially massless theory. We provide a thorough canonical analysis and identify that whether the theory becomes partially massless depends on the form of the stability condition of the secondary constraint responsible for the absence of the ghost. Generically, it is found to be an equation for a Lagrange multiplier implying that partially massless zwei-dreibein gravity does not exist. However, for special backgrounds this condition is identically satisfied leading to the presence of additional symmetries, which however disappear at quadratic order in perturbations.

  12. How to track protists in three dimensions

    NASA Astrophysics Data System (ADS)

    Drescher, Knut; Leptos, Kyriacos C.; Goldstein, Raymond E.

    2009-01-01

    We present an apparatus optimized for tracking swimming micro-organisms in the size range of 10-1000 μm, in three dimensions (3Ds), far from surfaces, and with negligible background convective fluid motion. Charge coupled device cameras attached to two long working distance microscopes synchronously image the sample from two perpendicular directions, with narrow band dark-field or bright-field illumination chosen to avoid triggering a phototactic response. The images from the two cameras can be combined to yield 3D tracks of the organism. Using additional, highly directional broad-spectrum illumination with millisecond timing control the phototactic trajectories in 3D of organisms ranging from Chlamydomonas to Volvox can be studied in detail. Surface-mediated hydrodynamic interactions can also be investigated without convective interference. Minimal modifications to the apparatus allow for studies of chemotaxis and other taxes.

  13. Laboratory alluvial fans in one dimension.

    PubMed

    Guerit, L; Métivier, F; Devauchelle, O; Lajeunesse, E; Barrier, L

    2014-08-01

    When they reach a flat plain, rivers often deposit their sediment load into a cone-shaped structure called alluvial fan. We present a simplified experimental setup that reproduces, in one dimension, basic features of alluvial fans. A mixture of water and glycerol transports and deposits glass beads between two transparent panels separated by a narrow gap. As the beads, which mimic natural sediments, get deposited in this gap, they form an almost one-dimensional fan. At a moderate sediment discharge, the fan grows quasistatically and maintains its slope just above the threshold for sediment transport. The water discharge determines this critical slope. At leading order, the sediment discharge only controls the velocity at which the fan grows. A more detailed analysis reveals a slight curvature of the fan profile, which relates directly to the rate at which sediments are transported.

  14. The resurgence of the cusp anomalous dimension

    NASA Astrophysics Data System (ADS)

    Aniceto, Inês

    2016-02-01

    This work addresses the resurgent properties of the cusp anomalous dimension’s strong coupling expansion, obtained from the integral Beisert-Eden-Staudacher (BES) equation. This expansion is factorially divergent, and its first non-perturbative corrections are related to the mass gap of the O(6)σ -model. The factorial divergence can also be analyzed from a resurgence perspective. Building on the work of Basso and Korchemsky, a transseries ansatz for the cusp anomalous dimension is proposed and the corresponding expected large-order behaviour studied. One finds non-perturbative phenomena in both the positive and negative real coupling directions, which need to be included to address the analyticity conditions coming from the BES equation. After checking the resurgence structure of the proposed transseries, it is shown that it naturally leads to an unambiguous resummation procedure, furthermore allowing for a strong/weak coupling interpolation.

  15. [The metaphysical dimension of animal ethics].

    PubMed

    Walz, Norbert

    2008-01-01

    Utilitarian ethics recognises animals as moral objects, but it does not attribute an absolute value to human or non-human individuals. Animal ethics according to Regan defines the non-human individual as an inherent value, but concedes that humans should be given precedence over animals if a situation involves a decision between life and death. Such life and death decisions relate to the fundamental structures of biological nature. To individuals these fundamental structures (the paradox of life and death) will necessarily appear absurd. The metaphysical dimension of animal ethics tries to shed light on the connections between life and death, body and mind that underly ethical discussions and searches for alternatives to the natural organisation of life.

  16. Topological mirror insulators in one dimension

    NASA Astrophysics Data System (ADS)

    Lau, Alexander; van den Brink, Jeroen; Ortix, Carmine

    2016-10-01

    We demonstrate the existence of topological insulators in one dimension (1D) protected by mirror and time-reversal symmetries. They are characterized by a nontrivial Z2 topological invariant defined in terms of the "partial" polarizations, which we show to be quantized in the presence of a 1D mirror point. The topological invariant determines the generic presence or absence of integer boundary charges at the mirror-symmetric boundaries of the system. We check our findings against spin-orbit coupled Aubry-André-Harper models that can be realized, e.g., in cold-atomic Fermi gases loaded in one-dimensional optical lattices or in density- and Rashba spin-orbit-modulated semiconductor nanowires. In this setup, in-gap end-mode Kramers doublets appearing in the topologically nontrivial state effectively constitute a double-quantum dot with spin-orbit coupling.

  17. Probes of Universal Extra Dimensions at Colliders

    SciTech Connect

    Rizzo, Thomas G.

    2001-06-28

    In the Universal Extra Dimensions model of Appelquist, Cheng and Dobrescu, all of the Standard Model fields are placed in the bulk and thus have Kaluza-Klein (KK) excitations. These KK states can only be pair produced at colliders due to the tree-level conservation of KK number, with the lightest of them being stable and possibly having a mass as low as {approx_equal} 350 400 GeV. After calculating the contribution to g-2 in this model we investigate the production cross sections and signatures for these particles at both hadron and lepton colliders. We demonstrate that these signatures critically depend upon whether the lightest KK states remain stable or are allowed to decay by any of a number of new physics mechanisms. These mechanisms which induce KK decays are studied in detail.

  18. Universal Dynamic Fragmentation in D Dimensions

    NASA Astrophysics Data System (ADS)

    Âström, J. A.; Ouchterlony, F.; Linna, R. P.; Timonen, J.

    2004-06-01

    A generic model is introduced for brittle fragmentation in D dimensions, and this model is shown to lead to a fragment-size distribution with two distinct components. In the small fragment-size limit a scale-invariant size distribution results from a crack branching-merging process. At larger sizes the distribution becomes exponential as a result of a Poisson process, which introduces a large-scale cutoff. Numerical simulations are used to demonstrate the validity of the distribution for D=2. Data from laboratory-scale experiments and large-scale quarry blastings of granitic gneiss confirm its validity for D=3. In the experiments the nonzero grain size of rock causes deviation from the ideal model distribution in the small-size limit. The size of the cutoff seems to diverge at the minimum energy sufficient for fragmentation to occur, but the scaling exponent is not universal.

  19. Black hole production and large extra dimensions.

    PubMed

    Cheung, Kingman

    2002-06-03

    Black hole (BH) production at colliders is possible when the colliding energy is above the Planck scale, which can effectively be at TeV scale in models of large extra dimensions. In this work, we study the production of black holes at colliders and discuss the possible signatures. We point out the " ij-->BH+others" subprocesses, in which the BH and other standard-model particles are produced with a large transverse momentum. When the BH decays, it gives a signature that consists of particles of high multiplicity in a boosted spherical shape on one side of the event and a few numbers of high p(T) partons on the other side, which provide very useful tags for the event.

  20. Unitarity constraints on dimension-six operators

    NASA Astrophysics Data System (ADS)

    Corbett, Tyler; Éboli, O. J. P.; Gonzalez-Garcia, M. C.

    2015-02-01

    We obtain the partial-wave unitarity constraints on dimension-six operators stemming from the analyses of vector boson and Higgs scattering processes as well as the inelastic scattering of standard model fermions into electroweak gauge bosons. We take into account all coupled channels, all possible helicity amplitudes, and explore a six-dimensional parameter space of anomalous couplings. Our analysis shows that for those operators affecting the Higgs couplings, present 90% confidence level constraints from global data analysis of Higgs and electroweak data are such that unitarity is not violated if √{s }≤3.2 TeV . For the purely gauge-boson operator OW W W, the present bounds from triple-gauge-boson analysis indicate that within its presently allowed 90% confidence level range unitarity can be violated in f f¯'→V V' at center-of-mass energy √{s }≥2.4 TeV .

  1. Rotating black lens solution in five dimensions

    SciTech Connect

    Chen Yu; Teo, Edward

    2008-09-15

    It has recently been shown that a stationary, asymptotically flat vacuum black hole in five space-time dimensions with two commuting axial symmetries must have an event horizon with either a spherical, ring or lens-space topology. In this paper, we study the third possibility, a so-called black lens with L(n,1) horizon topology. Using the inverse scattering method, we construct a black-lens solution with the simplest possible rod structure, and possessing a single asymptotic angular momentum. Its properties are then analyzed; in particular, it is shown that there must either be a conical singularity or a naked curvature singularity present in the space-time.

  2. Dimensions of emotion dysregulation in bulimia nervosa.

    PubMed

    Lavender, Jason M; Wonderlich, Stephen A; Peterson, Carol B; Crosby, Ross D; Engel, Scott G; Mitchell, James E; Crow, Scott J; Smith, Tracey L; Klein, Marjorie H; Goldschmidt, Andrea B; Berg, Kelly C

    2014-05-01

    The goal of this study was to examine associations between dimensions of emotion dysregulation and eating disorder (ED) symptoms in bulimia nervosa (BN). This investigation used baseline data from a BN treatment study that included 80 adults (90% women) with full or subthreshold BN. Participants completed the Difficulties in Emotion Regulation Scale (DERS) and the Eating Disorders Examination interview. The Eating Disorders Examination global score was significantly correlated with the DERS total score, as well as several DERS subscales: nonacceptance, impulse and strategies. Further, the DERS goals subscale was found to be uniquely associated with frequency of purging and driven exercise, although none of the subscales were associated with frequency of objective binge eating. Findings indicate that emotion dysregulation is associated with ED symptoms in BN, suggesting the utility of interventions that address emotion regulation skills deficits in the treatment of the disorder.

  3. Massive = 2 supergravity in three dimensions

    NASA Astrophysics Data System (ADS)

    Alkaç, Gökhan; Basanisi, Luca; Bergshoeff, Eric A.; Ozkan, Mehmet; Sezgin, Ergin

    2015-02-01

    There exists two distinct off-shell = 2 supergravities in three dimensions. They are also referred to as = (1, 1) and = (2, 0) supergravities, and they arise from the coupling of the Weyl multiplet to a compensating scalar or vector multiplet, respectively, followed by fixing of conformal symmetries. The = ( p, q) terminology refers to the underlying anti-de Sitter superalgebras OSp(2, p) ⊕ OSp(2, q) with R-symmetry group SO( p) × SO( q). We construct off-shell invariants of these theories up to fourth order in derivatives. As an application of these results, we determine the special combinations of the = (1, 1) invariants that admit anti-de Sitter vacuum solution about which there is a ghost-free massive spin-2 multiplet of propagating modes. We also show that the =(2,0) invariants do not allow such possibility.

  4. On partially massless theory in 3 dimensions

    NASA Astrophysics Data System (ADS)

    Alexandrov, Sergei; Deffayet, Cédric

    2015-03-01

    We analyze the first-order formulation of the ghost-free bigravity model in three-dimensions known as zwei-dreibein gravity. For a special choice of parameters, it was argued to have an additional gauge symmetry and give rise to a partially massless theory. We provide a thorough canonical analysis and identify that whether the theory becomes partially massless depends on the form of the stability condition of the secondary constraint responsible for the absence of the ghost. Generically, it is found to be an equation for a Lagrange multiplier implying that partially massless zwei-dreibein gravity does not exist. However, for special backgrounds this condition is identically satisfied leading to the presence of additional symmetries, which however disappear at quadratic order in perturbations.

  5. Cephalometric estimation of vertical dimension of occlusion.

    PubMed

    Orthlieb, J D; Laurent, M; Laplanche, O

    2000-09-01

    The literature does not establish a single proven method for determining lower facial height, which is called the Vertical Dimension of Occlusion (VDO), and the concept of a vertical comfort range is generally accepted. This study aimed to test the statistical significance of correlations of mandibular shape versus lower facial height in occlusion, using cephalometric measurements. Correlations for 505 consecutive healthy adults were calculated between angles that estimate the lower facial height and angles that estimate the mandibular shape. The mandibular angle (gonial) showed a higher coefficient of correlation (r = 0.691) than the inferior gonial angle. The dispersion remained large, i.e. r2 = 0.478. Cephalometric measurements, despite theirs imperfections, could help the practitioner to understand what the best course of treatment would be in order to obtain a lower facial height in occlusion showing a skeletal harmony with the mandibular shape.

  6. Prediction of stature using hand dimensions.

    PubMed

    Agnihotri, Arun Kumar; Agnihotri, Smriti; Jeebun, Nilima; Googoolye, Krishna

    2008-11-01

    In this study, an attempt was made to find out possible correlations between hand dimensions and stature using linear and curvilinear regression models for both genders. The study was conducted amongst 250 medical students (125 male and 125 female) aged 18-30 years. Each student has been studied for measurements of stature, hand length and hand breadth. To explain stature, all the explanatory variables like age, sex, hand length (right and left) and hand breadth (right and left) were included for model generation using SPSS. A general linear regression model was found to be best explanatory in both males and females, however, amongst the curvilinear models; the exponential model emerged as the 'best' in explaining stature of the individual. Left hand length alone explained very significantly (P<0.001).

  7. Tornado intensity estimated from damage path dimensions.

    PubMed

    Elsner, James B; Jagger, Thomas H; Elsner, Ian J

    2014-01-01

    The Newcastle/Moore and El Reno tornadoes of May 2013 are recent reminders of the destructive power of tornadoes. A direct estimate of a tornado's power is difficult and dangerous to get. An indirect estimate on a categorical scale is available from a post-storm survery of the damage. Wind speed bounds are attached to the scale, but the scale is not adequate for analyzing trends in tornado intensity separate from trends in tornado frequency. Here tornado intensity on a continuum is estimated from damage path length and width, which are measured on continuous scales and correlated to the EF rating. The wind speeds on the EF scale are treated as interval censored data and regressed onto the path dimensions and fatalities. The regression model indicates a 25% increase in expected intensity over a threshold intensity of 29 m s(-1) for a 100 km increase in path length and a 17% increase in expected intensity for a one km increase in path width. The model shows a 43% increase in the expected intensity when fatalities are observed controlling for path dimensions. The estimated wind speeds correlate at a level of .77 (.34, .93) [95% confidence interval] with a small sample of wind speeds estimated independently from a doppler radar calibration. The estimated wind speeds allow analyses to be done on the tornado database that are not possible with the categorical scale. The modeled intensities can be used in climatology and in environmental and engineering applications. Research is needed to understand the upward trends in path length and width.

  8. Proteome-wide measurement of non-canonical bacterial mistranslation by quantitative mass spectrometry of protein modifications

    PubMed Central

    Cvetesic, Nevena; Semanjski, Maja; Soufi, Boumediene; Krug, Karsten; Gruic-Sovulj, Ita; Macek, Boris

    2016-01-01

    The genetic code is virtually universal in biology and was likely established before the advent of cellular life. The extent to which mistranslation occurs is poorly understood and presents a fundamental question in basic research and production of recombinant proteins. Here we used shotgun proteomics combined with unbiased protein modification analysis to quantitatively analyze in vivo mistranslation in an E. coli strain with a defect in the editing mechanism of leucyl-tRNA synthetase. We detected the misincorporation of a non-proteinogenic amino acid norvaline on 10% of all measured leucine residues under microaerobic conditions and revealed preferential deployment of a tRNALeu(CAG) isoacceptor during norvaline misincorporation. The strain with the norvalylated proteome demonstrated a substantial reduction in cell fitness under both prolonged aerobic and microaerobic cultivation. Unlike norvaline, isoleucine did not substitute for leucine even under harsh error-prone conditions. Our study introduces shotgun proteomics as a powerful tool in quantitative analysis of mistranslation. PMID:27377007

  9. Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor.

    PubMed

    Marotta, Christopher B; Dilworth, Crystal N; Lester, Henry A; Dougherty, Dennis A

    2014-02-01

    Nicotinic acetylcholine receptors (nAChRs) containing the α5 subunit are of interest because genome-wide association studies and candidate gene studies have identified polymorphisms in the α5 gene that are linked to an increased risk for nicotine dependence, lung cancer, and/or alcohol addiction. To probe the functional impact of an α5 subunit on nAChRs, a method to prepare a homogeneous population of α5-containing receptors must be developed. Here we use a gain of function (9') mutation to isolate populations of α5-containing nAChRs for characterization by electrophysiology. We find that the α5 subunit modulates nAChR rectification when co-assembled with α4 and β2 subunits. We also probe the α5-α4 interface for possible ligand-binding interactions. We find that mutations expected to ablate an agonist-binding site involving the α5 subunit have no impact on receptor function. The most straightforward interpretation of this observation is that agonists do not bind at the α5-α4 interface, in contrast to what has recently been demonstrated for the α4-α4 interface in related receptors. In addition, our mutational results suggest that the α5 subunit does not replace the α4 or β2 subunits and is relegated to occupying only the auxiliary position of the pentameric receptor.

  10. PreTIS: A Tool to Predict Non-canonical 5’ UTR Translational Initiation Sites in Human and Mouse

    PubMed Central

    Reuter, Kerstin; Helms, Volkhard

    2016-01-01

    Translation of mRNA sequences into proteins typically starts at an AUG triplet. In rare cases, translation may also start at alternative non–AUG codons located in the annotated 5’ UTR which leads to an increased regulatory complexity. Since ribosome profiling detects translational start sites at the nucleotide level, the properties of these start sites can then be used for the statistical evaluation of functional open reading frames. We developed a linear regression approach to predict in–frame and out–of–frame translational start sites within the 5’ UTR from mRNA sequence information together with their translation initiation confidence. Predicted start codons comprise AUG as well as near–cognate codons. The underlying datasets are based on published translational start sites for human HEK293 and mouse embryonic stem cells that were derived by the original authors from ribosome profiling data. The average prediction accuracy of true vs. false start sites for HEK293 cells was 80%. When applied to mouse mRNA sequences, the same model predicted translation initiation sites observed in mouse ES cells with an accuracy of 76%. Moreover, we illustrate the effect of in silico mutations in the flanking sequence context of a start site on the predicted initiation confidence. Our new webservice PreTIS visualizes alternative start sites and their respective ORFs and predicts their ability to initiate translation. Solely, the mRNA sequence is required as input. PreTIS is accessible at http://service.bioinformatik.uni-saarland.de/pretis. PMID:27768687

  11. Non-canonical protein-DNA interactions identified by ChIP are not artifacts”: response

    PubMed Central

    2013-01-01

    Background Studies of protein association with DNA on a genome wide scale are possible through methods like ChIP-Chip or ChIP-Seq. Massive problems with false positive signals in our own experiments motivated us to revise the standard ChIP-Chip protocol. Analysis of chromosome wide binding of the alternative sigma factor σ32 in Escherichia coli with this new protocol resulted in detection of only a subset of binding sites found in a previous study by Wade and colleagues. We suggested that the remainder of binding sites detected in the previous study are likely to be false positives. In a recent article the Wade group claimed that our conclusion is wrong and that the disputed sites are genuine σ32 binding sites. They further claimed that the non-detection of these sites in our study was due to low data quality. Results/discussion We respond to the criticism of Wade and colleagues and discuss some general questions of ChIP-based studies. We outline why the quality of our data is sufficient to derive meaningful results. Specific points are: (i) the modifications we introduced into the standard ChIP-Chip protocol do not necessarily result in a low dynamic range, (ii) correlation between ChIP-Chip replicates should not be calculated based on the whole data set as done in transcript analysis, (iii) control experiments are essential for identifying false positives. Suggestions are made how ChIP-based methods could be further optimized and which alternative approaches can be used to strengthen conclusions. Conclusion We appreciate the ongoing discussion about the ChIP-Chip method and hope that it helps other scientist to analyze and interpret their results. The modifications we introduced into the ChIP-Chip protocol are a first step towards reducing false positive signals but there is certainly potential for further optimization. The discussion about the σ32 binding sites in question highlights the need for alternative approaches and further investigation of appropriate methods for verification. PMID:24053571

  12. Extracellular Matrix Proteome and Phosphoproteome of Potato Reveals Functionally Distinct and Diverse Canonical and Non-Canonical Proteoforms

    PubMed Central

    Elagamey, Eman; Narula, Kanika; Sinha, Arunima; Aggarwal, Pooja Rani; Ghosh, Sudip; Chakraborty, Niranjan; Chakraborty, Subhra

    2016-01-01

    The extracellular matrix (ECM) has a molecular machinery composed of diverse proteins and proteoforms that combine properties of tensile strength with extensibility exhibiting growth-regulatory functions and self- and non-self-recognition. The identification of ECM proteoforms is the prerequisite towards a comprehensive understanding of biological functions accomplished by the outermost layer of the cell. Regulatory mechanisms of protein functions rely on post-translational modifications, phosphorylation in particular, affecting enzymatic activity, interaction, localization and stability. To investigate the ECM proteoforms, we have isolated the cell wall proteome and phosphoproteome of a tuberous crop, potato (Solanum tuberosum). LC-MS/MS analysis led to the identification of 38 proteins and 35 phosphoproteins of known and unknown functions. The findings may provide a better understanding of biochemical machinery and the integrated protein and phosphoprotein network of ECM for future functional studies of different developmental pathways and guidance cues in mechanosensing and integrity signaling. PMID:28248230

  13. Time-Course Gene Expression Profiling Reveals a Novel Role of Non-Canonical WNT Signaling During Neural Induction

    PubMed Central

    Huang, Cindy Tzu-Ling; Tao, Yunlong; Lu, Jianfeng; Jones, Jeffrey R.; Fowler, Lucas; Weick, Jason P.; Zhang, Su-Chun

    2016-01-01

    The process of neuroepithelial differentiation from human pluripotent stem cells (PSCs) resembles in vivo neuroectoderm induction in the temporal course, morphogenesis, and biochemical changes. This in vitro model is therefore well-suited to reveal previously unknown molecular mechanisms underlying neural induction in humans. By transcriptome analysis of cells along PSC differentiation to early neuroepithelia at day 6 and definitive neuroepithelia at day 10, we found downregulation of genes that are associated with TGF-β and canonical WNT/β-CATENIN signaling, confirming the roles of classical signaling in human neural induction. Interestingly, WNT/Ca2+ signaling was upregulated. Pharmacological inhibition of the downstream effector of WNT/Ca2+ pathway, Ca2+/calmodulin-dependent protein kinase II (CaMKII), led to an inhibition of the neural marker PAX6 and upregulation of epidermal marker K18, suggesting that Ca2+/CaMKII signaling promotes neural induction by preventing the alternative epidermal fate. In addition, our analyses revealed known and novel expression patterns of genes that are involved in DNA methylation, histone modification, as well as epithelial-mesenchymal transition, highlighting potential roles of those genes and signaling pathways during neural differentiation. PMID:27600186

  14. [3D structure of DKK1 indicates its involvement in both canonical and non-canonical Wnt pathways].

    PubMed

    Khalili, S; Rasaee, M J; Bamdad, T

    2017-01-01

    Dikkoppf-1 (DKK1) is an antagonist of the canonical Wnt signaling pathway. The importance of DKK1 as a diagnostic and therapeutic agent in a wide range of diseases along with its significance in a variety of biological processes accentuate the necessity to decipher its 3D structure that would pave the way towards the development of relevant selective inhibitors. A DKK1 structure model predicted by the Robetta server with structural refinements including a 10 ns molecular dynamics run was subjected to functional and docking analyses. We hypothesize that the N-terminal region of the DKK1 molecule could be functionally important for both canonical and noncanonical Wnt pathways. Moreover, it seems that DKK1 could be involved in interactions with the Frizzled receptors, leading to the activation of the Planar Cell Polarity (PCP) pathway (activation of Jun N-terminal kinase (JNK) Pathway) and Wnt/Ca^(2+) pathway (activation of CamKII).

  15. Importin α1 Mediates Yorkie Nuclear Import via an N-terminal Non-canonical Nuclear Localization Signal.

    PubMed

    Wang, Shimin; Lu, Yi; Yin, Meng-Xin; Wang, Chao; Wu, Wei; Li, Jinhui; Wu, Wenqing; Ge, Ling; Hu, Lianxin; Zhao, Yun; Zhang, Lei

    2016-04-08

    The Hippo signaling pathway controls organ size by orchestrating cell proliferation and apoptosis. When the Hippo pathway was inactivated, the transcriptional co-activator Yorkie translocates into the nucleus and forms a complex with transcription factor Scalloped to promote the expression of Hippo pathway target genes. Therefore, the nuclear translocation of Yorkie is a critical step in Hippo signaling. Here, we provide evidence that the N-terminal 1-55 amino acids of Yorkie, especially Arg-15, were essential for its nuclear localization. By mass spectrometry and biochemical analyses, we found that Importin α1 can directly interact with the Yorkie N terminus and drive Yorkie into the nucleus. Further experiments show that the upstream component Hippo can inhibit Importin α1-mediated Yorkie nuclear import. Taken together, we identified a potential nuclear localization signal at the N-terminal end of Yorkie as well as a critical role for Importin α1 in Yorkie nuclear import.

  16. Characterization of a Non-Canonical Signal Peptidase Cleavage Site in a Replication Protein from Tomato Ringspot Virus

    PubMed Central

    Wei, Ting; Chisholm, Joan

    2016-01-01

    The NTB-VPg polyprotein from tomato ringspot virus is an integral membrane replication protein associated with endoplasmic reticulum membranes. A signal peptidase (SPase) cleavage was previously detected in the C-terminal region of NTB-VPg downstream of a 14 amino acid (aa)-long hydrophobic region (termed TM2). However, the exact location of the cleavage site was not determined. Using in vitro translation assays, we show that the SPase cleavage site is conserved in the NTB-VPg protein from various ToRSV isolates, although the rate of cleavage varies from one isolate to another. Systematic site-directed mutagenesis of the NTB-VPg SPase cleavage sites of two ToRSV isolates allowed the identification of sequences that affect cleavage efficiency. We also present evidence that SPase cleavage in the ToRSV-Rasp2 isolate occurs within a GAAGG sequence likely after the AAG (GAAG/G). Mutation of a downstream MAAV sequence to AAAV resulted in SPase cleavage at both the natural GAAG/G and the mutated AAA/V sequences. Given that there is a distance of seven aa between the two cleavage sites, this indicates that there is flexibility in the positioning of the cleavage sites relative to the inner surface of the membrane and the SPase active site. SPase cleavage sites are typically located 3–7 aa downstream of the hydrophobic region. However, the NTB-VPg GAAG/G cleavage site is located 17 aa downstream of the TM2 hydrophobic region, highlighting unusual features of the NTB-VPg SPase cleavage site. A putative 11 aa-long amphipathic helix was identified immediately downstream of the TM2 region and five aa upstream of the GAAG/G cleavage site. Based on these results, we present an updated topology model in which the hydrophobic and amphipathic domains form a long tilted helix or a bent helix in the membrane lipid bilayer, with the downstream cleavage site(s) oriented parallel to the membrane inner surface. PMID:27589230

  17. Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα

    PubMed Central

    Wunderle, Lina; Knopf, Julia D.; Kühnle, Nathalie; Morlé, Aymeric; Hehn, Beate; Adrain, Colin; Strisovsky, Kvido; Freeman, Matthew; Lemberg, Marius K.

    2016-01-01

    Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes. PMID:27264103

  18. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways

    PubMed Central

    Zappia, Carlos Daniel; Granja-Galeano, Gina; Fernández, Natalia; Shayo, Carina; Davio, Carlos; Fitzsimons, Carlos P.; Monczor, Federico

    2015-01-01

    Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat inflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with the high morbidity levels of such inflammatory conditions, these receptors are the targets of a vast number of approved drugs, and in many situations their ligands are co-administered. However, this drug association has no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling could affect GR-mediated activity, impacting on its transcriptional outcome. Indeed, our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-protein βγ subunits and a parallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamine and clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation and transrepression in a gene-specific manner. Our work provides a delineation of molecular mechanisms underlying the widespread clinical association of antihistamines and GR agonists, which may contribute to future dosage optimization and reduction of well-described side effects associated with glucocorticoid administration. PMID:26635083

  19. A Transposable Element within the Non-canonical Telomerase RNA of Arabidopsis thaliana Modulates Telomerase in Response to DNA Damage

    PubMed Central

    Xu, Hengyi; Nelson, Andrew D. L.; Shippen, Dorothy E.

    2015-01-01

    Long noncoding RNAs (lncRNAs) have emerged as critical factors in many biological processes, but little is known about how their regulatory functions evolved. One of the best-studied lncRNAs is TER, the essential RNA template for telomerase reverse transcriptase. We previously showed that Arabidopsis thaliana harbors three TER isoforms: TER1, TER2 and TER2S. TER1 serves as a canonical telomere template, while TER2 is a novel negative regulator of telomerase activity, induced in response to double-strand breaks (DSBs). TER2 contains a 529 nt intervening sequence that is removed along with 36 nt at the RNA 3’ terminus to generate TER2S, an RNA of unknown function. Here we investigate how A. thaliana TER2 acquired its regulatory function. Using data from the 1,001 Arabidopsis genomes project, we report that the intervening sequence within TER2 is derived from a transposable element termed DSB responsive element (DRE). DRE is found in the TER2 loci of most but not all A. thaliana accessions. By analyzing accessions with (TER2) and without DRE (TER2Δ) we demonstrate that this element is responsible for many of the unique properties of TER2, including its enhanced binding to TERT and telomerase inhibitory function. We show that DRE destabilizes TER2, and further that TER2 induction by DNA damage reflects increased RNA stability and not increased transcription. DRE-mediated changes in TER2 stability thus provide a rapid and sensitive switch to fine-tune telomerase enzyme activity. Altogether, our data shows that invasion of the TER2 locus by a small transposon converted this lncRNA into a DNA damage sensor that modulates telomerase enzyme activity in response to genome assault. PMID:26075395

  20. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling

    PubMed Central

    Quin, Jaclyn; Chan, Keefe T.; Devlin, Jennifer R.; Cameron, Donald P.; Diesch, Jeannine; Cullinane, Carleen; Ahern, Jessica; Khot, Amit; Hein, Nadine; George, Amee J.; Hannan, Katherine M; Poortinga, Gretchen; Sheppard, Karen E.; Khanna, Kum Kum; Johnstone, Ricky W.; Drygin, Denis; McArthur, Grant A.; Pearson, Richard B.

    2016-01-01

    RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy. PMID:27391441