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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

    Sibley, Christopher R; Blazquez, Lorea; Ule, Jernej

    2016-07-01

    Recent improvements in experimental and computational techniques that are 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 minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies. PMID:27240813

  3. Canonical and non-canonical Notch ligands

    PubMed Central

    D’SOUZA, BRENDAN; MELOTY-KAPELLA, LAURENCE; WEINMASTER, GERRY

    2015-01-01

    Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated non-canonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and non-canonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatio-temporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch are presented. We also discuss how ligand post-translational modification, endocytosis, proteolysis and spatio-temporal expression regulate their signaling activity. PMID:20816393

  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. PMID:27503683

  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 translation in RNA viruses

    PubMed Central

    Brierley, Ian

    2012-01-01

    Viral protein synthesis is completely dependent upon the translational machinery of the host cell. However, many RNA virus transcripts have marked structural differences from cellular mRNAs that preclude canonical translation initiation, such as the absence of a 5′ cap structure or the presence of highly structured 5′UTRs containing replication and/or packaging signals. Furthermore, whilst the great majority of cellular mRNAs are apparently monocistronic, RNA viruses must often express multiple proteins from their mRNAs. In addition, RNA viruses have very compact genomes and are under intense selective pressure to optimize usage of the available sequence space. Together, these features have driven the evolution of a plethora of non-canonical translational mechanisms in RNA viruses that help them to meet these challenges. Here, we review the mechanisms utilized by RNA viruses of eukaryotes, focusing on internal ribosome entry, leaky scanning, non-AUG initiation, ribosome shunting, reinitiation, ribosomal frameshifting and stop-codon readthrough. The review will highlight recently discovered examples of unusual translational strategies, besides revisiting some classical cases. PMID:22535777

  7. Non-canonical inflation in supergravity

    NASA Astrophysics Data System (ADS)

    Gwyn, Rhiannon; Lehners, Jean-Luc

    2014-05-01

    We investigate the effect of non-canonical kinetic terms on inflation in supergravity. We find that the biggest impact of such higher-derivative kinetic terms is due to the corrections to the potential that they induce via their effect on the auxiliary fields, which now have a cubic equation of motion. This is in contrast to the usual (non-supersymmetric) effective field theory expansion which assumes that mass-suppressed higher-derivative terms do not affect the lower-derivative terms already present. We demonstrate with several examples that such changes in the potential can significantly modify the inflationary dynamics. Our results have immediate implications for effective descriptions of inflation derived from string theory, where higher-derivative kinetic terms are generally present. In addition we elucidate the structure of the theory in the parameter range where there are three real solutions to the auxiliary field's equation of motion, studying the resulting three branches of the theory, and finding that one of them suffers from a singularity in the speed of propagation of fluctuations.

  8. Non-canonical inflation coupled to matter

    NASA Astrophysics Data System (ADS)

    Céspedes, Sebastián; Davis, Anne-Christine

    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.

  9. Non-Canonical Notch Signaling in Cancer and Immunity

    PubMed Central

    Ayaz, Furkan; Osborne, Barbara A.

    2014-01-01

    Canonical Notch signaling is initiated by γ-secretase-mediated cleavage of the Notch receptor, leading to the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-Jκ, resulting in the activation of downstream target genes. While canonical Notch signaling is well known to play an active role in several steps during development as well in multiple cell fate decisions, recent evidence from both invertebrate and vertebrate systems indicates that non-canonical, RBP-Jκ-independent signaling is important in several cellular processes including oncogenesis and activation of T lymphocytes. These observations raise the possibility that, through an understanding of non-canonical Notch signaling, novel strategies for inhibiting Notch signaling may prove useful in the design of therapies targeted to block aberrant Notch activity. In this mini-review, we will examine the current data demonstrating a non-canonical role for Notch signaling in both cancer and the immune system and suggest a better understanding of non-canonical signaling may reveal novel strategies to block Notch signaling in disease. PMID:25538890

  10. Non-canonical generalizations of slow-roll inflation models

    SciTech Connect

    Tzirakis, Konstantinos; Kinney, William H. E-mail: whkinney@buffalo.edu

    2009-01-15

    We consider non-canonical generalizations of two classes of single-field inflation models. First, we study the non-canonical version of ''ultra-slow roll'' inflation, which is a class of inflation models for which quantum modes do not freeze at horizon crossing, but instead evolve rapidly on superhorizon scales. Second, we consider the non-canonical generalization of the simplest ''chaotic'' inflation scenario, with a potential dominated by a quadratic (mass) term for the inflaton. We find a class of related non-canonical solutions with polynomial potentials, but with varying speed of sound. These solutions are characterized by a constant field velocity, and we dub such models isokinetic inflation. As in the canonical limit, isokinetic inflation has a slightly red-tilted power spectrum, consistent with current data. Unlike the canonical case, however, these models can have an arbitrarily small tensor/scalar ratio. Of particular interest is that isokinetic inflation is marked by a correlation between the tensor/scalar ratio and the amplitude of non-Gaussianity such that parameter regimes with small tensor/scalar ratio have large associated non-Gaussianity, which is a distinct observational signature.

  11. 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. PMID:25114307

  12. The degeneracy problem in non-canonical inflation

    SciTech Connect

    Easson, Damien A.; Powell, Brian A. E-mail: brian.powell007@gmail.com

    2013-03-01

    While attempting to connect inflationary theories to observational physics, a potential difficulty is the degeneracy problem: a single set of observables maps to a range of different inflaton potentials. Two important classes of models affected by the degeneracy problem are canonical and non-canonical models, the latter marked by the presence of a non-standard kinetic term that generates observables beyond the scalar and tensor two-point functions on CMB scales. The degeneracy problem is manifest when these distinguishing observables go undetected. We quantify the size of the resulting degeneracy in this case by studying the most well-motivated non-canonical theory having Dirac-Born-Infeld Lagrangian. Beyond the scalar and tensor two-point functions on CMB scales, we then consider the possible detection of equilateral non-Gaussianity at Planck-precision and a measurement of primordial gravitational waves from prospective space-based laser interferometers. The former detection breaks the degeneracy with canonical inflation but results in poor reconstruction prospects, while the latter measurement enables a determination of n{sub T} which, while not breaking the degeneracy, can be shown to greatly improve the non-canonical reconstruction.

  13. Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma

    PubMed Central

    Razumilava, Nataliya; Gradilone, Sergio A.; Smoot, Rory L.; Mertens, Joachim C.; Bronk, Steven F.; Sirica, Alphonse E.; Gores, Gregory J.

    2014-01-01

    Background & Aims: The Hedgehog signaling pathway contributes to cholangiocarcinoma biology. However, canonical Hedgehog signaling requires cilia, and cholangiocarcinoma cells often do not express cilia. To resolve this paradox, we examined non-canonical (G-protein coupled, pertussis toxin sensitive) Hedgehog signaling in cholangiocarcinoma cells. Methods: Human [non-malignant (H69), malignant (HuCC-T1 and Mz-ChA-1)] and rat [non-malignant (BDE1 and NRC), and malignant (BDEneu)] cell lines were employed for this study. A BDEΔLoop2 cell line with the dominant-negative receptor Patched-1 was generated with the Sleeping Beauty transposon transfection system. Results: Cilia expression was readily identified in non-malignant, but not in malignant cholangiocarcinoma cell lines. Although the canonical Hh signaling pathway was markedly attenuated in cholangiocarcinoma cells, they were chemotactic to purmorphamine, a small-molecule direct Smoothened agonist. Purmorphamine also induced remodeling of the actin cytoskeleton with formation of filopodia and lamellipodia-like protrusions. All these biological features of cell migration were pertussis toxin sensitive, a feature of G-protein coupled (Gis) receptors. To further test the role of Hedgehog signaling in vivo, we employed a syngeneic orthotopic rat model of cholangiocarcinoma. In vivo, genetic inhibition of the Hedgehog signaling pathway employing BDEΔLoop2 cells or pharmacological inhibition with a small-molecule antagonist of Smoothened, vismodegib, was tumor and metastasis suppressive. Conclusions: Cholangiocarcinoma cells exhibit non-canonical Hedgehog signaling with chemotaxis despite impaired cilia expression. This non-canonical Hedgehog signaling pathway appears to contribute to cholangiocarcinoma progression, thereby, supporting a role for Hedgehog pathway inhibition in human cholangiocarcinoma. PMID:24239776

  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.

  16. The genetic incorporation of thirteen novel non-canonical amino acids

    PubMed Central

    Tuley, Alfred; Wang, Yane-Shih; Fang, Xinqiang; Kurra, Yadagiri; Rezenom, Yohannes H.

    2014-01-01

    Thirteen novel non-canonical amino acids were synthesized and tested for suppression of an amber codon using a mutant pyrrolysyl-tRNA synthetase–tRNACUAPyl pair. Suppression was observed with varied efficiencies. One non-canonical amino acid in particular contains an azide that can be applied for site-selective protein labeling. PMID:24473369

  17. 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.

  18. Complex phylogenetic distribution of a non-canonical genetic code in green algae

    PubMed Central

    2010-01-01

    Background A non-canonical nuclear genetic code, in which TAG and TAA have been reassigned from stop codons to glutamine, has evolved independently in several eukaryotic lineages, including the ulvophycean green algal orders Dasycladales and Cladophorales. To study the phylogenetic distribution of the standard and non-canonical genetic codes, we generated sequence data of a representative set of ulvophycean green algae and used a robust green algal phylogeny to evaluate different evolutionary scenarios that may account for the origin of the non-canonical code. Results This study demonstrates that the Dasycladales and Cladophorales share this alternative genetic code with the related order Trentepohliales and the genus Blastophysa, but not with the Bryopsidales, which is sister to the Dasycladales. This complex phylogenetic distribution whereby all but one representative of a single natural lineage possesses an identical deviant genetic code is unique. Conclusions We compare different evolutionary scenarios for the complex phylogenetic distribution of this non-canonical genetic code. A single transition to the non-canonical code followed by a reversal to the canonical code in the Bryopsidales is highly improbable due to the profound genetic changes that coincide with codon reassignment. Multiple independent gains of the non-canonical code, as hypothesized for ciliates, are also unlikely because the same deviant code has evolved in all lineages. Instead we favor a stepwise acquisition model, congruent with the ambiguous intermediate model, whereby the non-canonical code observed in these green algal orders has a single origin. We suggest that the final steps from an ambiguous intermediate situation to a non-canonical code have been completed in the Trentepohliales, Dasycladales, Cladophorales and Blastophysa but not in the Bryopsidales. We hypothesize that in the latter lineage an initial stage characterized by translational ambiguity was not followed by final

  19. 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. PMID:27477600

  20. 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

  1. Place and Summation Coding for Canonical and Non-Canonical Finger Numeral Representations

    ERIC Educational Resources Information Center

    Di Luca, Samuel; Lefevre, Nathalie; Pesenti, Mauro

    2010-01-01

    Fingers can be used to express numerical magnitudes, and cultural habits about the fixed order in which fingers are raised determine which configurations become canonical and which non-canonical. Although both types of configuration carry magnitude information, it has been shown that the canonical ones are recognized faster and directly linked to…

  2. Role of a non-canonical surface of Rad6 in ubiquitin conjugating activity

    PubMed Central

    Kumar, Pankaj; Magala, Pearl; Geiger-Schuller, Kathryn R.; Majumdar, Ananya; Tolman, Joel R.; Wolberger, Cynthia

    2015-01-01

    Rad6 is a yeast E2 ubiquitin conjugating enzyme that monoubiquitinates histone H2B in conjunction with the E3, Bre1, but can non-specifically modify histones on its own. We determined the crystal structure of a Rad6∼Ub thioester mimic, which revealed a network of interactions in the crystal in which the ubiquitin in one conjugate contacts Rad6 in another. The region of Rad6 contacted is located on the distal face of Rad6 opposite the active site, but differs from the canonical E2 backside that mediates free ubiquitin binding and polyubiquitination activity in other E2 enzymes. We find that free ubiquitin interacts weakly with both non-canonical and canonical backside residues of Rad6 and that mutations of non-canonical residues have deleterious effects on Rad6 activity comparable to those observed to mutations in the canonical E2 backside. The effect of non-canonical backside mutations is similar in the presence and absence of Bre1, indicating that contacts with non-canonical backside residues govern the intrinsic activity of Rad6. Our findings shed light on the determinants of intrinsic Rad6 activity and reveal new ways in which contacts with an E2 backside can regulate ubiquitin conjugating activity. PMID:26286193

  3. Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling.

    PubMed

    Gao, Hua; Chakraborty, Goutam; Zhang, Zhanguo; Akalay, Intissar; Gadiya, Mayur; Gao, Yaquan; Sinha, Surajit; Hu, Jian; Jiang, Cizhong; Akram, Muzaffar; Brogi, Edi; Leitinger, Birgit; Giancotti, Filippo G

    2016-06-30

    Genetic screening identifies the atypical tetraspanin TM4SF1 as a strong mediator of metastatic reactivation of breast cancer. Intriguingly, TM4SF1 couples the collagen receptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2 and, hence, to PKCα. The latter kinase phosphorylates and activates JAK2, leading to the activation of STAT3. This non-canonical mechanism of signaling induces the expression of SOX2 and NANOG; sustains the manifestation of cancer stem cell traits; and drives metastatic reactivation in the lung, bone, and brain. Bioinformatic analyses and pathological studies corroborate the clinical relevance of these findings. We conclude that non-canonical DDR1 signaling enables breast cancer cells to exploit the ubiquitous interstitial matrix component collagen I to undergo metastatic reactivation in multiple target organs. PMID:27368100

  4. The role of non-canonical SNAREs in synaptic vesicle recycling

    PubMed Central

    Ramirez, Denise M.O.; Kavalali, Ege T.

    2012-01-01

    An increasing number of studies suggest that distinct pools of synaptic vesicles drive specific forms of neurotransmission. Interspersed with these functional studies are analyses of the synaptic vesicle proteome which have consistently detected the presence of so-called “non-canonical” SNAREs that typically function in fusion and trafficking of other subcellular structures within the neuron. The recent identification of certain non-canonical vesicular SNAREs driving spontaneous (e.g., VAMP7 and vti1a) or evoked asynchronous (e.g., VAMP4) release integrates and corroborates existing data from functional and proteomic studies and implies that at least some complement of non-canonical SNAREs resident on synaptic vesicles function in neurotransmission. Here, we discuss the specific roles in neurotransmission of proteins homologous to each member of the classical neuronal SNARE complex consisting of synaptobrevin2, syntaxin-1 and SNAP-25. PMID:22645707

  5. Horizon-preserving dualities and perturbations in non-canonical scalar field cosmologies

    SciTech Connect

    Geshnizjani, Ghazal; Kinney, William H.; Dizgah, Azadeh Moradinezhad E-mail: whkinney@buffalo.edu

    2012-02-01

    We generalize the cosmological duality between inflation and cyclic contraction under the interchange a↔H to the case of non-canonical scalar field theories with varying speed of sound. The single duality in the canonical case generalizes to a family of three dualities constructed to leave the cosmological acoustic horizon invariant. We find three classes of models: (I) DBI inflation, (II) the non-canonical generalization of cyclic contraction, and (III) a new cosmological solution with rapidly decreasing speed of sound and relatively slowly growing scale factor, which we dub stalled cosmology. We construct dual analogs to the inflationary slow roll approximation, and solve for the curvature perturbation in all three cases. Both cyclic contraction and stalled cosmology predict a strongly blue spectrum for the curvature perturbations inconsistent with observations.

  6. Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis.

    PubMed

    Eid, André; Torres-Padilla, Maria-Elena

    2016-06-01

    An intense period of chromatin remodeling takes place after fertilization in mammals, which is thought necessary for epigenetic reprogramming to start a new developmental program. While much attention has been given to the role of Polycomb Repressive Complex 2 (PRC2) and to canonical PRC1 complexes during this process, little is known as to whether there is any contribution of non-canonical PRC1 in shaping the chromatin landscape after fertilization. Here, we first describe in detail the temporal dynamics and abundance of H2A ubiquitylation (H2AK119ub), a histone modification catalyzed by PRC1, during pre-implantation mouse development. In addition, we have analyzed the presence of the 2 characteristic subunits of non-canonical PRC1 complexes, RYBP and its homolog YAF-2. Our results indicate that H2AK119ub is inherited from the sperm, rapidly removed from the paternal chromatin after fertilization, but detected again prior to the first mitosis, suggesting that PRC1 activity occurs as early as the zygotic stage. RYBP and YAF-2, together with the non-canonical subunit L3MBTL2, are all present during pre-implantation development but show different temporal dynamics. While RYBP is absent in the zygote, it is strongly induced from the 4-cell stage onwards. YAF-2 is inherited maternally and localizes to the pericentromeric regions in the zygote, is strongly induced between the 2- and 4-cell stages but then remains weak to undetectable subsequently. All together, our data suggest that non-canonical PRC1 is active during pre-implantation development and should be regarded as an additional component during epigenetic reprogramming and in the establishment of cellular plasticity of the early embryo. PMID:27081692

  7. Impacts of non-canonical El Niño patterns on Atlantic hurricane activity

    NASA Astrophysics Data System (ADS)

    Larson, Sarah; Lee, Sang-Ki; Wang, Chunzai; Chung, Eui-Seok; Enfield, David

    2012-07-01

    The impact of non-canonical El Niño patterns, typically characterized by warmer than normal sea surface temperatures (SSTs) in the central tropical Pacific, on Atlantic tropical cyclone (TC) is explored by using composites of key Atlantic TC indices and tropospheric vertical wind shear over the Atlantic main development region (MDR). The highlight of our major findings is that, while the canonical El Niño pattern has a strong suppressing influence on Atlantic TC activity, non-canonical El Niño patterns considered in this study, namely central Pacific warming, El Niño Modoki, positive phase Trans-Niño, and positive phase Pacific meridional mode, all have insubstantial impact on Atlantic TC activity. This result becomes more conclusive when the impact of MDR SST is removed from the Atlantic TC indices and MDR wind shear by using the method of linear regression. Further analysis suggests that the tropical Pacific SST anomalies associated with the non-canonical El Niño patterns are not strong enough to cause a substantial warming of the tropical troposphere in the Atlantic region, which is the key factor that increases the wind shear and atmospheric static stability over the MDR. During the recent decades, the non-canonical El Niños have been more frequent while the canonical El Niño has been less frequent. If such a trend continues in the future, it is expected that the suppressing effect of El Niño on Atlantic TC activity will diminish and thus the MDR SST will play a more important role in controlling Atlantic TC activity in the coming decades.

  8. Impacts of non-canonical El Niño patterns on Atlantic hurricane activity

    NASA Astrophysics Data System (ADS)

    Larson, S.; Lee, S.; Wang, C.; Chung, E.; Enfield, D. B.

    2012-12-01

    The impact of non-canonical El Niño patterns, typically characterized by warmer than normal sea surface tempera- tures (SSTs) in the central tropical Pacific, on Atlantic tropical cyclone (TC) is explored by using composites of key Atlantic TC indices and tropospheric vertical wind shear over the Atlantic main development region (MDR). The highlight of our major findings is that, while the canonical El Niño pattern has a strong suppressing influence on Atlantic TC activity, non-canonical El Niño patterns con- sidered in this study, namely central Pacific warming, El Niño Modoki, positive phase Trans-Niño, and positive phase Pacific meridional mode, all have insubstantial impact on Atlantic TC activity. This result becomes more conclu- sive when the impact of MDR SST is removed from the Atlantic TC indices and MDR wind shear by using the method of linear regression. Further analysis suggests that the tropical Pacific SST anomalies associated with the non- canonical El Niño patterns are not strong enough to cause a substantial warming of the tropical troposphere in the Atlantic region, which is the key factor that increases the wind shear and atmospheric static stability over the MDR. During the recent decades, the non-canonical El Niños have been more frequent while the canonical El Niño has been less frequent. If such a trend continues in the future, it is expected that the suppressing effect of El Niño on Atlantic TC activity will diminish and thus the MDR SST will play a more important role in controlling Atlantic TC activity in the coming decades.

  9. Sulf1 has ligand-dependent effects on canonical and non-canonical Wnt signalling

    PubMed Central

    Fellgett, Simon W.; Maguire, Richard J.; Pownall, Mary Elizabeth

    2015-01-01

    ABSTRACT Wnt signalling plays essential roles during embryonic development and is known to be mis-regulated in human disease. There are many molecular mechanisms that ensure tight regulation of Wnt activity. One such regulator is the heparan-sulfate-specific 6-O-endosulfatase Sulf1. Sulf1 acts extracellularly to modify the structure of heparan sulfate chains to affect the bio-availability of Wnt ligands. Sulf1 could, therefore, influence the formation of Wnt signalling complexes to modulate the activation of both canonical and non-canonical pathways. In this study, we use well-established assays in Xenopus to investigate the ability of Sulf1 to modify canonical and non-canonical Wnt signalling. In addition, we model the ability of Sulf1 to influence morphogen gradients using fluorescently tagged Wnt ligands in ectodermal explants. We show that Sulf1 overexpression has ligand-specific effects on Wnt signalling: it affects membrane accumulation and extracellular levels of tagged Wnt8a and Wnt11b ligands differently, and inhibits the activity of canonical Wnt8a but enhances the activity of non-canonical Wnt11b. PMID:25681501

  10. MicroRNA Target Recognition: Insights from Transcriptome-Wide Non-Canonical Interactions

    PubMed Central

    Seok, Heeyoung; Ham, Juyoung; Jang, Eun-Sook; Chi, Sung Wook

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs (∼22 nucleotides) regulating gene expression at the post-transcriptional level. By directing the RNA-induced silencing complex (RISC) to bind specific target mRNAs, miRNA can repress target genes and affect various biological phenotypes. Functional miRNA target recognition is known to majorly attribute specificity to consecutive pairing with seed region (position 2–8) of miRNA. Recent advances in a transcriptome-wide method of mapping miRNA binding sites (Ago HITS-CLIP) elucidated that a large portion of miRNA-target interactions in vivo are mediated not only through the canonical “seed sites” but also via non-canonical sites (∼15–80%), setting the stage to expand and determine their properties. Here we focus on recent findings from transcriptome-wide non-canonical miRNA-target interactions, specifically regarding “nucleation bulges” and “seed-like motifs”. We also discuss insights from Ago HITS-CLIP data alongside structural and biochemical studies, which highlight putative mechanisms of miRNA target recognition, and the biological significance of these non-canonical sites mediating marginal repression. PMID:27117456

  11. 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

  12. MicroRNA Target Recognition: Insights from Transcriptome-Wide Non-Canonical Interactions.

    PubMed

    Seok, Heeyoung; Ham, Juyoung; Jang, Eun-Sook; Chi, Sung Wook

    2016-05-31

    MicroRNAs (miRNAs) are small non-coding RNAs (∼22 nucleotides) regulating gene expression at the post-transcriptional level. By directing the RNA-induced silencing complex (RISC) to bind specific target mRNAs, miRNA can repress target genes and affect various biological phenotypes. Functional miRNA target recognition is known to majorly attribute specificity to consecutive pairing with seed region (position 2-8) of miRNA. Recent advances in a transcriptome-wide method of mapping miRNA binding sites (Ago HITS-CLIP) elucidated that a large portion of miRNA-target interactions in vivo are mediated not only through the canonical "seed sites" but also via non-canonical sites (∼15-80%), setting the stage to expand and determine their properties. Here we focus on recent findings from transcriptome-wide non-canonical miRNA-target interactions, specifically regarding "nucleation bulges" and "seed-like motifs". We also discuss insights from Ago HITS-CLIP data alongside structural and biochemical studies, which highlight putative mechanisms of miRNA target recognition, and the biological significance of these non-canonical sites mediating marginal repression. PMID:27117456

  13. 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

    2016-01-01

    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

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

    NASA Astrophysics Data System (ADS)

    Banijamali, A.; Ghasemi, E.

    2016-04-01

    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.

  15. AI-06NON-CANONICAL NF-kB SIGNALING DRIVES THE AGGRESSIVE INVASIVENESS OF GLIOBLASTOMA

    PubMed Central

    Cherry, Evan; Lee, Dong; Jung, Jiung; Sitcheran, Raquel

    2014-01-01

    The aggressive migration and invasion of glioblastoma multiforme (GBM) cells into healthy brain tissue are major factors contributing to the therapy resistance and poor prognosis of this malignancy. Aberrant activation of NF-kB has been shown to play key roles in the invasiveness and pathogenesis of many cancers, including GBM. Most of these studies have focused on canonical NF-kB signaling, which is mediated by RelA and p50. Activation of the canonical NF-kB pathway is induced by IkB kinase-b (IKKb), whose inhibition has been pursued as a therapeutic approach to attenuate NF-kB activation in cancer with limited success to-date. We have recently shown that the alternative, or non-canonical, NF-kB signaling pathway mediated by RelB, predominates in a very aggressive GBM subtype. Here, we investigate this previously unrecognized role for non-canonical NF-kB signaling in CNS tumor initiation and progression. Using both established and primary GBM tumor lines, we show that in high RelB-expressing GBM cells, loss of RelB inhibits invasion to a greater extent than loss of RelA. Furthermore, RelB expression is sufficient to promote invasion in RelA-deficient GBM cells. Stimulation with Tumor Nectosis Factor Weak Inducer of Apoptosis (TWEAK) preferentially activates non-canonical NF-kB signaling and regulation of Matrix Metalloproteinase 9 (MMP9) expression, resulting in strongly increased invasion. Finally, we show that a key upstream regulator of RelB, NF-kB-inducing kinase (NIK), induces dramatic cell shape changes, increases tumor cell invasion and promotes aggressive orthotopic tumor growth in mouse xenografts. These results not only expand on previously described roles for TWEAK in promoting tumor cell survival, but also demonstrate a potent pro-invasion function for NIK in aggressive GBM and, potentially, other RelB-driven tumors. Notably, oncogenic functions of the non-canonical NF-kB pathway remain poorly elucidated in the CNS. Our data highlight the therapeutic

  16. 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. PMID:25936631

  17. 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.

  18. 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

  19. Remarks on the "Non-canonicity Puzzle": Lagrangian Symmetries of the Einstein-Hilbert Action

    NASA Astrophysics Data System (ADS)

    Kiriushcheva, N.; Komorowski, P. G.; Kuzmin, S. V.

    2012-07-01

    Given the non-canonical relationship between variables used in the Hamiltonian formulations of the Einstein-Hilbert action (due to Pirani, Schild, Skinner (PSS) and Dirac) and the Arnowitt-Deser-Misner (ADM) action, and the consequent difference in the gauge transformations generated by the first-class constraints of these two formulations, the assumption that the Lagrangians from which they were derived are equivalent leads to an apparent contradiction that has been called "the non-canonicity puzzle". In this work we shall investigate the group properties of two symmetries derived for the Einstein-Hilbert action: diffeomorphism, which follows from the PSS and Dirac formulations, and the one that arises from the ADM formulation. We demonstrate that unlike the diffeomorphism transformations, the ADM transformations (as well as others, which can be constructed for the Einstein-Hilbert Lagrangian using Noether's identities) do not form a group. This makes diffeomorphism transformations unique (the term "canonical" symmetry might be suggested). If the two Lagrangians are to be called equivalent, canonical symmetry must be preserved. The interplay between general covariance and the canonicity of the variables used is discussed.

  20. 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

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

    PubMed

    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

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

    PubMed

    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

  3. Non-canonical signaling mode of the epidermal growth factor receptor family

    PubMed Central

    Lee, Heng-Huan; Wang, Ying-Nai; Hung, Mien-Chie

    2015-01-01

    Epidermal growth factor receptor (EGFR) and its family members are key players in both physiological and pathological settings for which they are well recognized as models for investigating the functions and regulations of other membrane receptor tyrosine kinases (RTKs) and serve as therapeutic targets critical to clinical need and fundamental research. The canonical view of the pivotal functions in the EGFR family has been well documented as being an initiator of signaling amplification cascades from the plasma membrane to different subcellular compartments via receptor endocytic trafficking, intermolecular interaction, and kinase-substrate reaction in a temporalspatial manner. However, several lines of evidence have identified non-canonical roles of the EGFR family, acting as a transcriptional factor and a chromatin regulator in the nucleus to regulate gene expression, DNA replication, and DNA damage repair. Moreover, the EGFR family can even exert its impact outside the host cell through exosomal vesicle secretion. The emerging concept of the non-canonical roles of the EGFR family reveals an astonishing and elaborate scheme on the molecular functions of membrane RTKs, offering new insights into the receptor biology as well as the development of comprehensive therapeutic strategies in the future. PMID:26693051

  4. 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

  5. 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

  6. Non-Canonical Wnt Predominates in Activated Rat Hepatic Stellate Cells, Influencing HSC Survival and Paracrine Stimulation of Kupffer Cells

    PubMed Central

    Corbett, Laura; Mann, Jelena; Mann, Derek A.

    2015-01-01

    The Wnt system is highly complex and is comprised of canonical and non-canonical pathways leading to the activation of gene expression. Our aim was to examine changes in the expression of Wnt ligands and regulators during hepatic stellate cell (HSC) transdifferentiation and assess the relative contributions of the canonical and non-canonical Wnt pathways in fibrogenic activated HSC. The expression profile of Wnt ligands and regulators in HSC was not supportive for a major role for β-catenin-dependent canonical Wnt signalling, this verified by inability to induce Topflash reporter activity in HSC even when expressing a constitutive active β-catenin. We detected expression of Wnt5a in activated HSC which can signal via non-canonical mechanisms and showed evidence for non-canonical signalling in these cells involving phosphorylation of Dvl2 and pJNK. Stimulation of HSC or Kupffer cells with Wnt5a regulated HSC apoptosis and expression of TGF-β1 and MCP1 respectively. We were unable to confirm a role for β-catenin-dependent canonical Wnt in HSC and instead propose autocrine and paracrine functions for Wnts expressed by activated HSC via non-canonical pathways. The data warrant detailed investigation of Wnt5a in liver fibrosis. PMID:26566235

  7. Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences

    PubMed Central

    Arensdorf, Angela M.; Diedrichs, Danilo; Rutkowski, D. Thomas

    2013-01-01

    The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes. PMID:24348511

  8. Non-canonical scalar fields and their applications in cosmology and astrophysics

    NASA Astrophysics Data System (ADS)

    Gauthier, Christopher S.

    In this thesis we will discuss several issues concerning cosmological applications of non-canonical scalar fields, which are generically referred to as k-essence. First, we consider two examples of k-essence. These are the rolling tachyon and static spherically symmetric solutions of non-canonical scalar fields in flat space. We find constraints on the form of the allowed interactions in the first case and on the choice of boundary conditions in the latter. For the rolling tachyon we find that at late times the tachyon matter behaves like a non-relativistic dust, thus making it a dark matter candidate. For the static spherically symmetric solutions we show that solutions which are finite at the origin must have negative energy density there. Next, we consider static spherically symmetric solutions of non-canonical scalar fields coupled to gravity as a way to explain dark matter halos as a coherent state of the scalar field. Consistent solutions are found with a smooth scalar profile which can describe observed rotation curves. The non-trivial solutions have negative energy density near the origin, though the total energy is positive. We also reconsider the no scalar hair theorems for black holes with emphasis on asymptotic boundary conditions and superluminal propagation. After this we show that, for general scalar fields, stationary configurations are possible for shift symmetric theories only. This symmetry with respect to constant translations in field space should either be manifest in the original field variables or reveal itself after an appropriate field redefinition. In particular this result implies that neither k-essence nor quintessence can have exact steady state/Bondi accretion onto black holes. Finally, we find that stationary field configurations are necessarily linear in Killing time, provided that shift symmetry is realized in terms of these field variables. The next discussion outlines a general program for reconstructing the action of non-canonical

  9. 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

  10. 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.

  11. KLF4 transcriptionally activates non-canonical WNT5A to control epithelial stratification

    PubMed Central

    Tetreault, Marie-Pier; Weinblatt, Daniel; Shaverdashvili, Khvaramze; Yang, Yizeng; Katz, Jonathan P.

    2016-01-01

    Epithelial differentiation and stratification are essential for normal homeostasis, and disruption of these processes leads to both injury and cancer. The zinc-finger transciption factor KLF4 is a key driver of epithelial differentiation, yet the mechanisms and targets by which KLF4 controls differentiation are not well understood. Here, we define WNT5A, a non-canonical Wnt ligand implicated in epithelial differentiation, repair, and cancer, as a direct transcriptional target that is activated by KLF4 in squamous epithelial cells. Further, we demonstrate functionally that WNT5A mediates KLF4 control of epithelial differentiation and stratification, as treatment of keratinocytes with WNT5A rescues defective epithelial stratification resulting from KLF4 loss. Finally, we show that the small GTPase CDC42 is regulated by KLF4 in a WNT5A dependent manner. As such, we delineate a novel pathway for epithelial differentiation and stratification and define potential therapeutic targets for epithelial diseases. PMID:27184424

  12. 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

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

    PubMed

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

    2014-01-01

    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. PMID:24496182

  14. 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.

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

    PubMed

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

    2016-02-17

    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

  16. 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

  17. LRP6 exerts non-canonical effects on Wnt signaling during neural tube closure.

    PubMed

    Gray, Jason D; Kholmanskikh, Stanislav; Castaldo, Bozena S; Hansler, Alex; Chung, Heekyung; Klotz, Brian; Singh, Shawn; Brown, Anthony M C; Ross, M Elizabeth

    2013-11-01

    Low-density lipoprotein receptor related protein 6 (Lrp6) mutational effects on neurulation were examined using gain (Crooked tail, Lrp6(Cd)) and loss (Lrp6(-)) of function mouse lines. Two features often associated with canonical Wnt signaling, dorsal-ventral patterning and proliferation, were no different from wild-type (WT) in the Lrp6(Cd/Cd) neural tube. Lrp6(-/-) embryos showed reduced proliferation and subtle patterning changes in the neural folds. Cell polarity defects in both Lrp6(Cd/Cd) and Lrp6(-/-) cranial folds were indicated by cell shape, centrosome displacement and failure of F-actin and GTP-RhoA accumulation at the apical surface. Mouse embryonic fibroblasts (MEFs) derived from Lrp6(Cd/Cd) or Lrp6(-/-) embryos exhibited elevated and decreased RhoA basal activity levels, respectively. While ligand-independent activation of canonical Wnt signaling, bypassing Lrp-Frizzled receptors, did not activate RhoA, non-canonical Wnt5a stimulation of RhoA activity was impaired in Lrp6(-/-) MEFs. RhoA inhibition exacerbated NTDs in cultured Lrp6 knockout embryos compared with WT littermates. In contrast, a ROCK inhibitor rescued Lrp6(Cd/Cd) embryos from NTDs. Lrp6 co-immunoprecipitated with Disheveled-associated activator of morphogenesis 1 (DAAM1), a formin promoting GEF activity in Wnt signaling. Biochemical and cell biological data revealed intracellular accumulation of Lrp6(Cd) protein where interaction with DAAM1 could account for observed elevated RhoA activity. Conversely, null mutation that eliminates Lrp6 interaction with DAAM1 led to lower basal RhoA activity in Lrp6(-/-) embryos. These results indicate that Lrp6 mediates not only canonical Wnt signaling, but can also modulate non-canonical pathways involving RhoA-dependent mechanisms to impact neurulation, possibly through intracellular complexes with DAAM1. PMID:23773994

  18. Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration

    SciTech Connect

    Cheng Chingwen Yeh Juching; Fan Taiping; Smith, Stephen K.; Charnock-Jones, D. Stephen

    2008-01-11

    Cell to cell interaction is one of the key processes effecting angiogenesis and endothelial cell function. Wnt signalling is mediated through cell-cell interaction and is involved in many developmental processes and cellular functions. In this study, we investigated the possible function of Wnt5a and the non-canonical Wnt pathway in human endothelial cells. We found that Wnt5a-mediated non-canonical Wnt signalling regulated endothelial cell proliferation. Blocking this pathway using antibody, siRNA or a down-stream inhibitor led to suppression of endothelial cell proliferation, migration, and monolayer wound closure. We also found that the mRNA level of Wnt5a is up-regulated when endothelial cells are treated with a cocktail of inflammatory cytokines. Our findings suggest non-canonical Wnt signalling plays a role in regulating endothelial cell growth and possibly in angiogenesis.

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

    PubMed

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

    2016-05-01

    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

  20. 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.

  1. 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

  2. Canonical and non-canonical Wnt proteins program dendritic cell responses for tolerance

    PubMed Central

    Oderup, Cecilia; LaJevic, Melissa; Butcher, Eugene C.

    2013-01-01

    Antigen presenting dendritic cells (DC) interpret environmental signals to orchestrate local and systemic immune responses. They govern the balance between tolerance and inflammation at epithelial surfaces, where the immune system must provide robust pathogen responses while maintaining tolerance to commensal flora and food antigens. The Wnt family of secreted proteins, which control epithelial as well as hematopoietic development and homeostasis, is emerging as an important regulator of inflammation. Here we show that canonical and non-canonical Wnts directly stimulate murine DC production of anti-inflammatory cytokines. Wnt3A triggers canonical β-catenin signaling and preferentially induces DC TGF-β and VEGF production, whereas Wnt5A induces IL-10 through alternative pathways. The Wnts also alter DC responses to microbe- or pathogen-associated molecular patterns (PAMPs), inhibiting pro-inflammatory cytokine induction in response to toll like receptor ligands and promoting DC generation of Foxp3+ regulatory T cells. Moreover, although both Wnts suppress pro-inflammatory responses to bacterial endotoxin and to TLR1/2, TLR7 and TLR9 ligands, Wnt5A but not Wnt3A inhibits IL-6 production in response to the viral mimic, polyinosinic:polycytidylic acid. Wnt family members thus directly and differentially regulate DC functions, an ability that may contribute to the balance between tolerance and inflammation at epithelial sites of exposure to microbes and environmental antigens. PMID:23677472

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

    PubMed

    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

  4. Monitoring mRNA Translation in Neuronal Processes Using Fluorescent Non-Canonical Amino Acid Tagging.

    PubMed

    Kos, Aron; Wanke, Kai A; Gioio, Anthony; Martens, Gerard J; Kaplan, Barry B; Aschrafi, Armaz

    2016-05-01

    A steady accumulation of experimental data argues that protein synthesis in neurons is not merely restricted to the somatic compartment, but also occurs in several discrete cellular micro-domains. Local protein synthesis is critical for the establishment of synaptic plasticity in mature dendrites and in directing the growth cones of immature axons, and has been associated with cognitive impairment in mice and humans. Although in recent years a number of important mechanisms governing this process have been described, it remains technically challenging to precisely monitor local protein synthesis in individual neuronal cell parts independent from the soma. This report presents the utility of employing microfluidic chambers for the isolation and treatment of single neuronal cellular compartments. Furthermore, it is demonstrated that a protein synthesis assay, based on fluorescent non-canonical amino acid tagging (FUNCAT), can be combined with this cell culture system to label nascent proteins within a discrete structural and functional domain of the neuron. Together, these techniques could be employed for the detection of protein synthesis within developing and mature neurites, offering an effective approach to elucidate novel mechanisms controlling synaptic maintenance and plasticity. PMID:27026294

  5. 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

  6. 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

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

    PubMed Central

    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

    2016-01-01

    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. PMID:26940118

  8. 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

    2015-01-01

    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. PMID:25895666

  9. 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. PMID:24720618

  10. Dynamic ruffling distortion of the heme substrate in non-canonical heme oxygenase enzymes.

    PubMed

    Graves, Amanda B; Horak, Erik H; Liptak, Matthew D

    2016-06-14

    Recent work by several groups has established that MhuD, IsdG, and IsdI are non-canonical heme oxygenases that induce significant out-of-plane ruffling distortions of their heme substrates enroute to mycobilin or staphylobilin formation. However, clear explanations for the observations of "nested" S = ½ VTVH MCD saturation magnetization curves at cryogenic temperatures, and exchange broadened (1)H NMR resonances at physiologically-relevant temperatures have remained elusive. Here, MCD and NMR data have been acquired for F23A and F23W MhuD-heme-CN, in addition to MCD data for IsdI-heme-CN, in order to complete assembly of a library of spectroscopic data for cyanide-inhibited ferric heme with a wide range of ruffling deformations. The spectroscopic data were used to evaluate a number of computational models for cyanide-inhibited ferric heme, which ultimately led to the development of an accurate NEVPT2/CASSCF model. The resulting model has a shallow, double-well potential along the porphyrin ruffling coordinate, which provides clear explanations for the unusual MCD and NMR data. The shallow, double-well potential also implies that MhuD-, IsdG-, and IsdI-bound heme is dynamic, and the functional implications of these dynamics are discussed. PMID:27273757

  11. Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation

    PubMed Central

    Sanclimens, Glòria; Moure, Alejandra; Masip, Isabel; González-Ruiz, Domingo; Rubio, Nuria; Crosas, Bernat; Meca-Cortés, Óscar; Loukili, Noureddine; Plans, Vanessa; Morreale, Antonio; Blanco, Jerónimo; Ortiz, Angel R.; Messeguer, Àngel; Thomson, Timothy M.

    2010-01-01

    Background Several pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-κB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev. Methodology/Principal Findings By applying a selection based on in vivo protein-protein interaction assays of compounds from a combinatorial chemical library followed by virtual screening, we have developed small molecules that efficiently antagonize the Ubc13-Uev1 protein-protein interaction, inhibiting the enzymatic activity of the heterodimer. In mammalian cells, they inhibit lysine 63-type polyubiquitylation of PCNA, inhibit activation of NF-κB by TNF-α and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells. Conclusions/Significance This is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications. PMID:20613989

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

    PubMed

    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

    2016-01-01

    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. PMID:26940118

  13. Non-Canonical (RANKL-Independent) Pathways of Osteoclast Differentiation and Their Role in Musculoskeletal Diseases.

    PubMed

    Sabokbar, A; Mahoney, D J; Hemingway, F; Athanasou, N A

    2016-08-01

    Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone-resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFα lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-β), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone. PMID:26578261

  14. 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. PMID:27346354

  15. 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. PMID:27079465

  16. Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis

    PubMed Central

    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

    2016-01-01

    SUMMARY 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 sixty 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 Notch receptors 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. PMID:27346354

  17. 20-hydroxyecdysone mediates non-canonical regulation of mosquito vitellogenins through alternative splicing

    PubMed Central

    Provost-Javier, K. N.; Rasgon, J. L.

    2015-01-01

    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. PMID:24720618

  18. 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.

  19. 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.

  20. DWARF14 is a non-canonical hormone receptor for strigolactone.

    PubMed

    Yao, Ruifeng; Ming, Zhenhua; Yan, Liming; Li, Suhua; Wang, Fei; Ma, Sui; Yu, Caiting; Yang, Mai; Chen, Li; Chen, Linhai; Li, Yuwen; Yan, Chun; Miao, Di; Sun, Zhongyuan; Yan, Jianbin; Sun, Yuna; Wang, Lei; Chu, Jinfang; Fan, Shilong; He, Wei; Deng, Haiteng; Nan, Fajun; Li, Jiayang; Rao, Zihe; Lou, Zhiyong; Xie, Daoxin

    2016-08-25

    Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The α/β hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone. PMID:27479325

  1. 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. PMID:26891693

  2. Peters plus syndrome mutations disrupt a non-canonical ER quality control mechanism

    PubMed Central

    Vasudevan, Deepika; Takeuchi, Hideyuki; Johar, Sumreet Singh; Majerus, Elaine; Haltiwanger, Robert S.

    2014-01-01

    Background O-Fucose is added to cysteine-rich domains called Thrombospondin type 1 repeats (TSRs) by Protein O-fucosyltransferase 2 (POFUT2) and is elongated with glucose by β3-glucosyltransferase (B3GLCT). Mutations in B3GLCT result in Peters Plus Syndrome (PPS), an autosomal recessive disorder characterized by eye and other developmental defects. Although 49 putative targets are known, the function of the disaccharide and its role in PPS remain unexplored. Results Here we show that while POFUT2 is required for secretion of all targets tested, B3GLCT only affects the secretion of a subset, consistent with the observation that B3GLCT mutant phenotypes in PPS patients are less severe than embryonic lethal phenotypes of Pofut2-null mice. O-Glycosylation occurs co-translationally, as TSRs fold. Mass spectral analysis reveals that TSRs from mature, secreted protein are stoichiometrically modified with the disaccharide, while TSRs from protein still folding in the ER are partially modified, suggesting that O-glycosylation marks folded TSRs and promotes ER exit. In vitro unfolding assays demonstrate that fucose and glucose stabilize folded TSRs in an additive manner. In vitro refolding assays under redox conditions showed that POFUT2 recognizes, glycosylates, and stabilizes the folded form of TSRs, resulting in a net acceleration of folding. Conclusions While known ER quality control machinery rely on identifying and tagging unfolded proteins, we find that POFUT2 and B3GLCT mediate a non-canonical ER quality control mechanism that recognizes folded TSRs and stabilizes them by glycosylation. Our findings provide a molecular basis for the defects observed in PPS and potential targets that contribute to the pathology. PMID:25544610

  3. On the non-canonical noncommutative Wheeler-Dewitt equation for Schwarzschild and Kantowski-Sachs black holes

    NASA Astrophysics Data System (ADS)

    Zarrinkamar, S.; Hassanabadi, H.; Rajabi, A. A.

    2013-03-01

    The interior of both Schwarzschild and Kantowski-Sachs black holes is studied via a non-canonical noncommutative extension of the Wheeler-DeWitt equation in the interesting work (Bastos et al. in Phys. Rev. D 84:024005, 2011) by neglecting the cubic and quartic terms arising the Hamiltonian. Here, we consider the problem when these terms are present and provide a more realistic analytical solution to the problem.

  4. 5-HT2B antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation

    PubMed Central

    Hutcheson, Joshua D.; Ryzhova, Larisa M.; Setola, Vincent; Merryman, W. David

    2012-01-01

    Transforming growth factor-β1 (TGF-β1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-β1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT2B) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-β1-dependent manner. Therefore, we hypothesized that antagonism of 5-HT2B opposes TGF-β1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5-HT2B antagonism with canonical and non-canonical TGF-β1 pathways to inhibit TGF-β1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT2B antagonism. Interestingly, 5-HT2B antagonism does not inhibit canonical TGF-β1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT2B antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT2B antagonism prevents non-canonical TGF-β1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-β1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT2B antagonism as a novel therapeutic approach for CAVD that merits further investigation. PMID:22940605

  5. BMP regulates regional gene expression in the dorsal otocyst through canonical and non-canonical intracellular pathways.

    PubMed

    Ohta, Sho; Wang, Baolin; Mansour, Suzanne L; Schoenwolf, Gary C

    2016-06-15

    The inner ear consists of two otocyst-derived, structurally and functionally distinct components: the dorsal vestibular and ventral auditory compartments. BMP signaling is required to form the vestibular compartment, but how it complements other required signaling molecules and acts intracellularly is unknown. Using spatially and temporally controlled delivery of signaling pathway regulators to developing chick otocysts, we show that BMP signaling regulates the expression of Dlx5 and Hmx3, both of which encode transcription factors essential for vestibular formation. However, although BMP regulates Dlx5 through the canonical SMAD pathway, surprisingly, it regulates Hmx3 through a non-canonical pathway involving both an increase in cAMP-dependent protein kinase A activity and the GLI3R to GLI3A ratio. Thus, both canonical and non-canonical BMP signaling establish the precise spatiotemporal expression of Dlx5 and Hmx3 during dorsal vestibular development. The identification of the non-canonical pathway suggests an intersection point between BMP and SHH signaling, which is required for ventral auditory development. PMID:27151948

  6. 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.

  7. 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.

  8. Reconstitution of a functional IS608 single-strand transpososome: role of non-canonical base pairing.

    PubMed

    He, Susu; Hickman, Alison B; Dyda, Fred; Johnson, Neil P; Chandler, Michael; Ton-Hoang, Bao

    2011-10-01

    Single-stranded (ss) transposition, a recently identified mechanism adopted by members of the widespread IS200/IS605 family of insertion sequences (IS), is catalysed by the transposase, TnpA. The transposase of IS608, recognizes subterminal imperfect palindromes (IP) at both IS ends and cleaves at sites located at some distance. The cleavage sites, C, are not recognized directly by the protein but by short sequences 5' to the foot of each IP, guide (G) sequences, using a network of canonical ('Watson-Crick') base interactions. In addition a set of non-canonical base interactions similar to those found in RNA structures are also involved. We have reconstituted a biologically relevant complex, the transpososome, including both left and right ends and TnpA, which catalyses excision of a ss DNA circle intermediate. We provide a detailed picture of the way in which the IS608 transpososome is assembled and demonstrate that both C and G sequences are essential for forming a robust transpososome detectable by EMSA. We also address several questions central to the organization and function of the ss transpososome and demonstrate the essential role of non-canonical base interactions in the IS608 ends for its stability by using point mutations which destroy individual non-canonical base interactions. PMID:21745812

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

    PubMed

    Beerman, R W; Jongens, T A

    2011-05-01

    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-S(N)) begins at a canonical start codon (ATG), whereas translation of the minor, larger form (dFMR1-L(N)) 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-S(N) or dFMR1-L(N). Expression analyses throughout development revealed that dFMR1-S(N) is required for normal dFMR1-L(N) expression levels in adult brains. In situ expression analyses showed that either dFMR1-S(N) or dFMR1-L(N) is individually sufficient for proper dFMR1 localization in the nervous system. Functional studies demonstrated that both dFMR1-S(N) and dFMR1-L(N) 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

  10. Non-canonical dynamic mechanisms of interaction between the p66Shc protein and Met receptor

    PubMed Central

    Landry, Mélissa; Pomerleau, Véronique; Saucier, Caroline

    2016-01-01

    Met receptor tyrosine kinase (RTK) is known to bind to the three distinct protein isoforms encoded by the ShcA (Shc) gene. Structure–function studies have unveiled critical roles for p52Shc-dependent signalling pathways in Met-regulated biological functions. The molecular basis of the interaction between the Met and p52Shc proteins is well-defined, but not for the longest protein isoform, p66Shc. In the present study, co-immunoprecipitation assays were performed in human embryonic kidney 293 (HEK293) cells, transiently co-transfected with Met and p66Shc mutants, in order to define the molecular determinants involved in mediating Met–p66Shc interaction. Our results show that p66Shc interacts constitutively with the receptor Met, and the Grb2 (growth factor receptor-bound protein-2) and Gab1 (Grb2-associated binder-1) adaptor proteins. Although its phosphotyrosine-binding domain (PTB) and Src homology 2 (SH2) domains co-ordinate p66Shc binding to non-activated Met receptor, these phosphotyrosine-binding modules, and its collagen homology domain 2 (CH2) region, exert negative constraints. In contrast, p66Shc interaction with the activated Met depends mainly on the integrity of its PTB domain, and to a lesser extent of its SH2 domain. Even though not required for the recruitment of p66Shc, tyrosine phosphorylation of p66Shc by activated Met enhances these interactions by mechanisms not reliant on the integrity of the Met multisubstrate-binding site. In turn, this increases phosphotyrosine-dependent p66Shc–Grb2–Gab1 complex formation away from the receptor, while blocking Grb2 and Gab1 recruitment to activated Met. In conclusion, we identify, for the first time, a novel non-canonical dynamic mode of interaction between Met and the p66 protein isoform of Shc and its effects on rewiring binding effector complexes according to the activation state of the receptor. PMID:27048591

  11. Non-canonical dynamic mechanisms of interaction between the p66Shc protein and Met receptor.

    PubMed

    Landry, Mélissa; Pomerleau, Véronique; Saucier, Caroline

    2016-06-01

    Met receptor tyrosine kinase (RTK) is known to bind to the three distinct protein isoforms encoded by the ShcA (Shc) gene. Structure-function studies have unveiled critical roles for p52Shc-dependent signalling pathways in Met-regulated biological functions. The molecular basis of the interaction between the Met and p52Shc proteins is well-defined, but not for the longest protein isoform, p66Shc. In the present study, co-immunoprecipitation assays were performed in human embryonic kidney 293 (HEK293) cells, transiently co-transfected with Met and p66Shc mutants, in order to define the molecular determinants involved in mediating Met-p66Shc interaction. Our results show that p66Shc interacts constitutively with the receptor Met, and the Grb2 (growth factor receptor-bound protein-2) and Gab1 (Grb2-associated binder-1) adaptor proteins. Although its phosphotyrosine-binding domain (PTB) and Src homology 2 (SH2) domains co-ordinate p66Shc binding to non-activated Met receptor, these phosphotyrosine-binding modules, and its collagen homology domain 2 (CH2) region, exert negative constraints. In contrast, p66Shc interaction with the activated Met depends mainly on the integrity of its PTB domain, and to a lesser extent of its SH2 domain. Even though not required for the recruitment of p66Shc, tyrosine phosphorylation of p66Shc by activated Met enhances these interactions by mechanisms not reliant on the integrity of the Met multisubstrate-binding site. In turn, this increases phosphotyrosine-dependent p66Shc-Grb2-Gab1 complex formation away from the receptor, while blocking Grb2 and Gab1 recruitment to activated Met. In conclusion, we identify, for the first time, a novel non-canonical dynamic mode of interaction between Met and the p66 protein isoform of Shc and its effects on rewiring binding effector complexes according to the activation state of the receptor. PMID:27048591

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

    PubMed Central

    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. PMID:27347343

  13. BMP and non-canonical Wnt signaling are required for inhibition of secondary tail formation in zebrafish.

    PubMed

    Yang, Yi; Thorpe, Chris

    2011-06-01

    The role of bone morphogenetic protein (BMP) signaling in specifying cell fate in the zebrafish tailbud has been well established. In addition to a loss of ventral tissues, such as ventral tailfin and cloaca, some embryos with compromised BMP signaling produce an additional phenotype: a ventrally located secondary tail containing both somitic muscle and notochord. This phenotype has been proposed to reflect a fate-patterning defect due to a change in a hypothesized BMP activity gradient. Here, we show that a defect in morphogenetic movements, not fate patterning, underlies the formation of secondary tails in BMP-inhibited embryos. Our data indicate that BMP signaling is activated in the ventroposterior tailbud to promote cell migration during tailbud protrusion, and that defective migration of these cells in BMP mutants ultimately leads to bifurcation of the caudal notochord. Additionally, we show that non-canonical Wnt signaling is also required for proper tail morphogenesis, possibly by maintaining cohesion of notochord progenitors by regulation of cadherin localization. We propose a model in which BMP and the non-canonical Wnt pathway regulate tail morphogenesis by controlling cell migration and cell adhesion within the tailbud. PMID:21610036

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

    PubMed Central

    Yousif, Ashraf S.; Stanlie, Andre; Begum, Nasim A.

    2014-01-01

    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. PMID:24994819

  15. 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. PMID:24994819

  16. Can Wnt5a and Wnt non-canonical pathways really mediate adipocyte de-differentiation in a tumour microenvironment?

    PubMed

    Chirumbolo, Salvatore; Bjørklund, Geir

    2016-09-01

    Wnt5a has been recently reported as a possible triggering factor of adipocyte de-differentiation into an adipocyte-derived fibroblast in the tumour microenvironment of pancreas cancer. The Wnt/β-catenin pathway was described in processes involving de-differentiation and epithelial-mesenchymal transition but some Wnt family-belonging molecules exert an adipogenic role on adipocyte, while other ones, such as Wnt10b or Wnt3a, an anti-adipogenic role. Although this ability depends on the different tumoural microenvironments, it is intriguing to ascertain if some Wnt molecules, participating in the non-canonical pathway, may be targeted as fundamental factors able to trigger the desmoplastic reaction of peritumoural white adipose tissue. PMID:27391920

  17. 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

  18. Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth.

    PubMed

    D'Amico, Davide; Antonucci, Laura; Di Magno, Laura; Coni, Sonia; Sdruscia, Giulia; Macone, Alberto; Miele, Evelina; Infante, Paola; Di Marcotullio, Lucia; De Smaele, Enrico; Ferretti, Elisabetta; Ciapponi, Laura; Giangaspero, Felice; Yates, John R; Agostinelli, Enzo; Cardinali, Beatrice; Screpanti, Isabella; Gulino, Alberto; Canettieri, Gianluca

    2015-10-12

    Developmental Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs), and its aberrant activation is a leading cause of medulloblastoma. We show here that Hedgehog promotes polyamine biosynthesis in GCPs by engaging a non-canonical axis leading to the translation of ornithine decarboxylase (ODC). This process is governed by AMPK, which phosphorylates threonine 173 of the zinc finger protein CNBP in response to Hedgehog activation. Phosphorylated CNBP increases its association with Sufu, followed by CNBP stabilization, ODC translation, and polyamine biosynthesis. Notably, CNBP, ODC, and polyamines are elevated in Hedgehog-dependent medulloblastoma, and genetic or pharmacological inhibition of this axis efficiently blocks Hedgehog-dependent proliferation of medulloblastoma cells in vitro and in vivo. Together, these data illustrate an auxiliary mechanism of metabolic control by a morphogenic pathway with relevant implications in development and cancer. PMID:26460945

  19. Non-canonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens

    PubMed Central

    Knodler, Leigh A.; Crowley, Shauna M.; Sham, Ho Pan; Yang, Hyungjun; Wrande, Marie; Ma, Caixia; Ernst, Robert K.; Steele-Mortimer, Olivia; Celli, Jean; Vallance, Bruce A.

    2014-01-01

    Summary Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11 deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human orthologue of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore an epithelial cell intrinsic non-canonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface. PMID:25121752

  20. Non-canonical roles of tRNAs and tRNA mimics in bacterial cell biology.

    PubMed

    Katz, Assaf; Elgamal, Sara; Rajkovic, Andrei; Ibba, Michael

    2016-08-01

    Transfer RNAs (tRNAs) are the macromolecules that transfer activated amino acids from aminoacyl-tRNA synthetases to the ribosome, where they are used for the mRNA guided synthesis of proteins. Transfer RNAs are ancient molecules, perhaps even predating the existence of the translation machinery. Albeit old, these molecules are tremendously conserved, a characteristic that is well illustrated by the fact that some bacterial tRNAs are efficient and specific substrates of eukaryotic aminoacyl-tRNA synthetases and ribosomes. Considering their ancient origin and high structural conservation, it is not surprising that tRNAs have been hijacked during evolution for functions outside of translation. These roles beyond translation include synthetic, regulatory and information functions within the cell. Here we provide an overview of the non-canonical roles of tRNAs and their mimics in bacteria, and discuss some of the common themes that arise when comparing these different functions. PMID:27169680

  1. HhAntag, a Hedgehog Signaling Antagonist, Suppresses Chondrogenesis and Modulates Canonical and Non-Canonical BMP Signaling.

    PubMed

    Mundy, Christina; Bello, Adebayo; Sgariglia, Federica; Koyama, Eiki; Pacifici, Maurizio

    2016-05-01

    Chondrogenesis subtends the development of most skeletal elements and involves mesenchymal cell condensations differentiating into growth plate chondrocytes that proliferate, undergo hypertrophy, and are replaced by bone. In the pediatric disorder Hereditary Multiple Exostoses, however, chondrogenesis occurs also at ectopic sites and causes formation of benign cartilaginous tumors--exostoses--near the growth plates. No treatment is currently available to prevent or reverse exostosis formation. Here, we asked whether chondrogenesis could be stopped by targeting the hedgehog pathway, one of its major regulators. Micromass cultures of limb mesenchymal cells were treated with increasing amounts of the hedgehog inhibitor HhAntag or vehicle. The drug effectively blocked chondrogenesis and did so in a dose-dependent manner as monitored by: alcian blue-positive cartilage nodule formation; gene expression of cartilage marker genes; and reporter activity in Gli1-LacZ cell cultures. HhAntag blocked chondrogenesis even when the cultures were co-treated with bone morphogenetic protein 2 (rhBMP-2), a strong pro-chondrogenic factor. Immunoblots showed that HhAntag action included modulation of canonical (pSmad1/5/8) and non-canonical (pp38) BMP signaling. In cultures co-treated with HhAntag plus rhBMP-2, there was a surprising strong up-regulation of pp38 levels. Implantation of rhBMP-2-coated beads near metacarpal elements in cultured forelimb explants induced formation of ectopic cartilage that however, was counteracted by HhAntag co-treatment. Collectively, our data indicate that HhAntag inhibits not only hedgehog signaling, but also modulates canonical and non-canonical BMP signaling and blocks basal and rhBMP2-stimulated chondrogenesis, thus representing a potentially powerful drug-based strategy to counter ectopic cartilage growth or induce its involution. PMID:26363135

  2. Upstream stimulatory factor activates the vasopressin promoter via multiple motifs, including a non-canonical E-box.

    PubMed Central

    Coulson, Judy M; Edgson, Jodie L; Marshall-Jones, Zoe V; Mulgrew, Robert; Quinn, John P; Woll, Penella J

    2003-01-01

    We have described previously a complex E-box enhancer (-147) of the vasopressin promoter in small-cell lung cancer (SCLC) extracts [Coulson, Fiskerstrand, Woll and Quinn, (1999) Biochem. J. 344, 961-970]. Upstream stimulatory factor (USF) heterodimers were one of the complexes binding to this site in vitro. We now report that USF overexpression in non-SCLC (NSCLC) cells can functionally activate vasopressin promoter-driven reporters that are otherwise inactive in this type of lung cancer cell. Site-directed mutagenesis and electrophoretic mobility-shift analysis demonstrate that although the -147 E-box contributes, none of the previously predicted E-boxes (-147, -135, -34) wholly account for this USF-mediated activation in NSCLC. 5' Deletion showed the key promoter region as -52 to +42; however, USF-2 binding was not reliant on the -34 E-box, but on a novel adjacent CACGGG non-canonical E-box at -42 (motif E). This mediated USF binding in both SCLC and USF-2-transfected NSCLC cells. Mutation of motif E or the non-canonical TATA box abolished activity, implying both are required for transcriptional initiation on overexpression of USF-2. Co-transfected dominant negative USF confirmed that binding was required through motif E for function, but that the classical activation domain of USF was not essential. USF-2 bound motif E with 10-fold lower affinity than the -147 E-box. In NSCLC, endogenous USF-2 expression is low, and this basal level appears to be insufficient to activate transcription of arginine vasopressin (AVP). In summary, we have demonstrated a novel mechanism for USF activation, which contributes to differential vasopressin expression in lung cancer. PMID:12403649

  3. Cysteine-free non-canonical C-intein for versatile protein C-terminal labeling through trans-splicing.

    PubMed

    Dai, Xudong; Xun, Qijing; Liu, Xiang-Qin; Meng, Qing

    2015-10-01

    Site-specific protein labeling are powerful means of protein research and engineering; however, new and improved labeling methods are greatly needed. Split inteins catalyze a protein trans-splicing reaction that can be used for enzymatic and nearly seamless protein labeling. Non-canonical S11 split intein has been used in an earlier method of protein C-terminal labeling; however, its relatively large (~150 aa) N-intein fused to the target protein often hindered protein expression, folding, and solubility. To solve this problem, here, we have designed and demonstrated a new method of protein C-terminal labeling, by first engineering a functional non-canonical S1 split intein that has an extremely small (12 aa) N-intein and a cysteine-free C-intein. An engineered Rma DnaB S1 split intein was modified to have a cysteine-free C-intein, while still retaining its robust trans-splicing function, which permitted the C-extein in a C-precursor to have a single cysteine for easy and specific linkage with desired labeling groups. The resulting new and generally useful method has two unique advantages: (1) The extremely small (12 aa) N-intein, which must be fused to the C terminus of the target protein, is less likely to hinder the protein expression, folding, and solubility; and (2) the single cysteine in the C-extein may be readily linked to a variety of labeling or modification groups using commercially available reagents. PMID:26227407

  4. 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. PMID:24594642

  5. 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.

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

    PubMed

    Kaiser, Annette; Langer, Barbara; 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

  7. 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

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

    PubMed Central

    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; Mae Diehl, Anna; Trebicka, Jonel

    2015-01-01

    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. PMID:26412302

  9. 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…

  10. 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.

  11. 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.

  12. A non-canonical DNA structure is a binding motif for the transcription factor SP1 in vitro

    PubMed Central

    Raiber, Eun-Ang; Kranaster, Ramon; Lam, Enid; Nikan, Mehran; Balasubramanian, Shankar

    2012-01-01

    SP1 is a ubiquitous transcription factor that is involved in the regulation of various house-keeping genes. It is known that it acts by binding to a double-stranded consensus motif. Here, we have discovered that SP1 binds also to a non-canonical DNA structure, a G-quadruplex, with high affinity. In particular, we have studied the SP1 binding site within the promoter region of the c-KIT oncogene and found that this site can fold into an anti-parallel two-tetrad G-quadruplex. SP1 pull-down experiments from cellular extracts, together with biophysical binding assays revealed that SP1 has a comparable binding affinity for this G-quadruplex structure and the canonical SP1 duplex sequence. Using SP1 ChIP-on-chip data sets, we have also found that 87% of SP1 binding sites overlap with G-quadruplex forming sequences. Furthermore, while many of these immuoprecipitated sequences (36%) even lack the minimal SP1 consensus motif, 5′-GGGCGG-3′, we have shown that 77% of them are putative G-quadruplexes. Collectively, these data suggest that SP1 is able to bind both, canonical SP1 duplex DNA as well as G-quadruplex structures in vitro and we hypothesize that both types of interactions may occur in cells. PMID:22021377

  13. Secreted multifunctional Glyceraldehyde-3-phosphate dehydrogenase sequesters lactoferrin and iron into cells via a non-canonical pathway

    PubMed Central

    Chauhan, Anoop S.; Rawat, Pooja; Malhotra, Himanshu; Sheokand, Navdeep; Kumar, Manoj; Patidar, Anil; Chaudhary, Surbhi; Jakhar, Priyanka; Raje, Chaaya I.; Raje, Manoj

    2015-01-01

    Lactoferrin is a crucial nutritionally important pleiotropic molecule and iron an essential trace metal for all life. The current paradigm is that living organisms have evolved specific membrane anchored receptors along with iron carrier molecules for regulated absorption, transport, storage and mobilization of these vital nutrients. We present evidence for the existence of non-canonical pathway whereby cells actively forage these vital resources from beyond their physical boundaries, by secreting the multifunctional housekeeping enzyme Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) into the extracellular milieu. This effect’s an autocrine/paracrine acquisition of target ligand into the cell. Internalization by this route is extensively favoured even by cells that express surface receptors for lactoferrin and involves urokinase plasminogen activator receptor (uPAR). We also demonstrate the operation of this phenomenon during inflammation, as an arm of the innate immune response where lactoferrin denies iron to invading microorganisms by chelating it and then itself being sequestered into surrounding host cells by GAPDH. PMID:26672975

  14. Hirsutella sinensis mycelium suppresses interleukin-1β and interleukin-18 secretion by inhibiting both canonical and non-canonical inflammasomes.

    PubMed

    Huang, Tsung-Teng; Chong, Kowit-Yu; Ojcius, David M; Wu, Yi-Hui; Ko, Yun-Fei; Wu, Cheng-Yeu; Martel, Jan; Lu, Chia-Chen; Lai, Hsin-Chih; Young, John D

    2013-01-01

    Cordyceps sinensis is a medicinal mushroom used for centuries in Asian countries as a health supplement and tonic. Hirsutella sinensis-the anamorphic, mycelial form of C. sinensis-possesses similar properties, and is increasingly used as a health supplement. Recently, C. sinensis extracts were shown to inhibit the production of the pro-inflammatory cytokine IL-1β in lipopolysaccharide-treated macrophages. However, the molecular mechanism underlying this process has remained unclear. In addition, whether H. sinensis mycelium (HSM) extracts also inhibit the production of IL-1β has not been investigated. In the present study, the HSM extract suppresses IL-1β and IL-18 secretion, and ATP-induced activation of caspase-1. Notably, we observed that HSM not only reduced expression of the inflammasome component NLRP1 and the P2X7R but also reduced the activation of caspase-4, and ATP-induced ROS production. These findings reveal that the HSM extract has anti-inflammatory properties attributed to its ability to inhibit both canonical and non-canonical inflammasomes. PMID:23459183

  15. Non-canonical roles for caveolin in regulation of membrane repair and mitochondria: implications for stress adaptation with age.

    PubMed

    Schilling, Jan M; Patel, Hemal H

    2016-08-15

    Many different theories of ageing have been proposed but none has served the unifying purpose of defining a molecular target that can limit the structural and functional decline associated with age that ultimately leads to the demise of the organism. We propose that the search for a molecule with these unique properties must account for regulation of the signalling efficiency of multiple cellular functions that degrade with age due to a loss of a particular protein. We suggest caveolin as one such molecule that serves as a regulator of key processes in signal transduction. We define a particular distinction between cellular senescence and ageing and propose that caveolin plays a distinct role in each of these processes. Caveolin is traditionally thought of as a membrane-localized protein regulating signal transduction via membrane enrichment of specific signalling molecules. Ultimately we focus on two non-canonical roles for caveolin - membrane repair and regulation of mitochondrial function - which may be novel features of stress adaptation, especially in the setting of ageing. The end result of preserving membrane structure and mitochondrial function is maintenance of homeostatic signalling, preserving barrier function, and regulating energy production for cell survival and resilient ageing. PMID:26333003

  16. The Non-canonical Tetratricopeptide Repeat (TPR) Domain of Fluorescent (FLU) Mediates Complex Formation with Glutamyl-tRNA Reductase*

    PubMed Central

    Zhang, Min; Zhang, Feilong; Fang, Ying; Chen, Xuemin; Chen, Yuhong; Zhang, Wenxia; Dai, Huai-En; Lin, Rongcheng; Liu, Lin

    2015-01-01

    The tetratricopeptide repeat (TPR)-containing protein FLU is a negative regulator of chlorophyll biosynthesis in plants. It directly interacts through its TPR domain with glutamyl-tRNA reductase (GluTR), the rate-limiting enzyme in the formation of δ-aminolevulinic acid (ALA). Delineation of how FLU binds to GluTR is important for understanding the molecular basis for FLU-mediated repression of synthesis of ALA, the universal tetrapyrrole precursor. Here, we characterize the FLU-GluTR interaction by solving the crystal structures of the uncomplexed TPR domain of FLU (FLUTPR) at 1.45-Å resolution and the complex of the dimeric domain of GluTR bound to FLUTPR at 2.4-Å resolution. Three non-canonical TPR motifs of each FLUTPR form a concave surface and clamp the helix bundle in the C-terminal dimeric domain of GluTR. We demonstrate that a 2:2 FLUTPR-GluTR complex is the functional unit for FLU-mediated GluTR regulation and suggest that the formation of the FLU-GluTR complex prevents glutamyl-tRNA, the GluTR substrate, from binding with this enzyme. These results also provide insights into the spatial regulation of ALA synthesis by the membrane-located FLU protein. PMID:26037924

  17. 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.

  18. Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases

    PubMed Central

    Cannavo, Alessandro; Liccardo, Daniela; Eguchi, Akito; Elliott, Katherine J.; Traynham, Christopher J.; Ibetti, Jessica; Eguchi, Satoru; Leosco, Dario; Ferrara, Nicola; Rengo, Giuseppe; Koch, Walter J.

    2016-01-01

    Hyper-aldosteronism is associated with myocardial dysfunction including induction of cardiac fibrosis and maladaptive hypertrophy. Mechanisms of these cardiotoxicities are not fully understood. Here we show that mineralocorticoid receptor (MR) activation by aldosterone leads to pathological myocardial signalling mediated by mitochondrial G protein-coupled receptor kinase 2 (GRK2) pro-death activity and GRK5 pro-hypertrophic action. Moreover, these MR-dependent GRK2 and GRK5 non-canonical activities appear to involve cross-talk with the angiotensin II type-1 receptor (AT1R). Most importantly, we show that ventricular dysfunction caused by chronic hyper-aldosteronism in vivo is completely prevented in cardiac Grk2 knockout mice (KO) and to a lesser extent in Grk5 KO mice. However, aldosterone-induced cardiac hypertrophy is totally prevented in Grk5 KO mice. We also show human data consistent with MR activation status in heart failure influencing GRK2 levels. Therefore, our study uncovers GRKs as targets for ameliorating pathological cardiac effects associated with high-aldosterone levels. PMID:26932512

  19. Body-fixed orbit-attitude hovering control over an asteroid using non-canonical Hamiltonian structure

    NASA Astrophysics Data System (ADS)

    Wang, Yue; Xu, Shijie

    2015-12-01

    The orbit-attitude hovering means that both the position and attitude of the spacecraft are kept to be stationary in the asteroid body-fixed frame. The orbit-attitude hovering is discussed in the framework of the gravitationally coupled orbit-attitude dynamics, also called the full dynamics, in which the spacecraft is modeled as a rigid body to take into account the gravitational orbit-attitude coupling naturally. A feedback hovering control law is proposed by using the non-canonical Hamiltonian structure of the problem, which is consisted of two potential shapings and one energy dissipation. The first potential shaping is to create an artificial equilibrium at the desired hovering position-attitude. Then, the second potential shaping modifies the potential further so that the artificial equilibrium is a minimum of the modified Hamiltonian on the invariant manifold. Finally, the energy dissipation leads the motion to converge asymptotically to the minimum of the modified Hamiltonian, i.e., the artificial equilibrium for hovering. The feasibility of the hovering control law is verified through numerical simulations. The proposed hovering control law has a simple form and can be implemented by the spacecraft autonomously with little computation. This feature can be attributed to the utilization of the Hamiltonian structure and natural dynamical behaviors of the system in the control law design.

  20. Identification of novel non-canonical RNA-binding sites in Gemin5 involved in internal initiation of translation

    PubMed Central

    Fernandez-Chamorro, Javier; Piñeiro, David; Gordon, James M. B.; Ramajo, Jorge; Francisco-Velilla, Rosario; Macias, Maria J.; Martinez-Salas, Encarnación

    2014-01-01

    Ribonucleic acid (RNA)-binding proteins are key players of gene expression control. We have shown that Gemin5 interacts with internal ribosome entry site (IRES) elements and modulates initiation of translation. However, little is known about the RNA-binding sites of this protein. Here we show that the C-terminal region of Gemin5 bears two non-canonical bipartite RNA-binding sites, encompassing amino acids 1297–1412 (RBS1) and 1383–1508 (RBS2). While RBS1 exhibits greater affinity for RNA than RBS2, it does not affect IRES-dependent translation in G5-depleted cells. In solution, the RBS1 three-dimensional structure behaves as an ensemble of flexible conformations rather than having a defined tertiary structure. However, expression of the polypeptide G51383–1508, bearing the low RNA-binding affinity RBS2, repressed IRES-dependent translation. A comparison of the RNA-binding capacity and translation control properties of constructs expressed in mammalian cells to that of the Gemin5 proteolysis products observed in infected cells reveals that non-repressive products accumulated during infection while the repressor polypeptide is not stable. Taken together, our results define the low affinity RNA-binding site as the minimal element of the protein being able to repress internal initiation of translation. PMID:24598255

  1. Global proteogenomic analysis of human MHC class I-associated peptides derived from non-canonical reading frames.

    PubMed

    Laumont, Céline M; Daouda, Tariq; Laverdure, Jean-Philippe; Bonneil, Éric; Caron-Lizotte, Olivier; Hardy, Marie-Pierre; Granados, Diana P; Durette, Chantal; Lemieux, Sébastien; Thibault, Pierre; Perreault, Claude

    2016-01-01

    In view of recent reports documenting pervasive translation outside of canonical protein-coding sequences, we wished to determine the proportion of major histocompatibility complex (MHC) class I-associated peptides (MAPs) derived from non-canonical reading frames. Here we perform proteogenomic analyses of MAPs eluted from human B cells using high-throughput mass spectrometry to probe the six-frame translation of the B-cell transcriptome. We report that ∼ 10% of MAPs originate from allegedly noncoding genomic sequences or exonic out-of-frame translation. The biogenesis and properties of these 'cryptic MAPs' differ from those of conventional MAPs. Cryptic MAPs come from very short proteins with atypical C termini, and are coded by transcripts bearing long 3'UTRs enriched in destabilizing elements. Relative to conventional MAPs, cryptic MAPs display different MHC class I-binding preferences and harbour more genomic polymorphisms, some of which are immunogenic. Cryptic MAPs increase the complexity of the MAP repertoire and enhance the scope of CD8 T-cell immunosurveillance. PMID:26728094

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

    PubMed

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

    2016-05-01

    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

  3. 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. PMID:27086143

  4. Generation of protein kinase Ck1α mutants which discriminate between canonical and non-canonical substrates

    PubMed Central

    Bustos, Victor H.; Marin, Oriano; Meggio, Flavio; Cesaro, Luca; Allende, Catherine C.; Allende, Jorge E.; Pinna, Lorenzo A.

    2005-01-01

    Protein kinase CK1 denotes a family of pleiotropic serine/threonine protein kinases implicated in a variety of cellular functions. Typically, CK1 acts as a ‘phosphate-directed’ kinase whose targeting is primed by a single phosphorylated side chain at position n−3 or n−4 relative to serine/threonine, but increasing evidence is accumulating that CK1 can also engage some of its substrates at sites that do not conform to this canonical consensus. In the present paper, we show that CK1α phosphorylates with the same efficiency phosphopeptides primed by a phosphoserine residue at either n−3 [pS(−3)] or n−4 [pS(−4)] positions. The phosphorylation efficiency of the pS(−4) peptide, and to a lesser extent that of the pS(−3) peptide, is impaired by the triple mutation of the lysine residues in the K229KQK232 stretch to alanine residues, promoting 40-fold and 6-fold increases of Km respectively. In both cases, the individual mutation of Lys232 is as detrimental as the triple mutation. A kinetic alanine-scan analysis with a series of substituted peptide substrates in which the priming phosphoserine residue was effectively replaced by a cluster of four aspartate residues was also consistent with a crucial role of Lys232 in the recognition of the acidic determinant at position n−4. In sharp contrast, the phosphorylation of β-catenin and of a peptide including the non-canonical β-catenin site (Ser45) lacking acidic/phosphorylated determinants upstream is not significantly affected by mutations in the KKQK stretch. These data provide a molecular insight into the structural features that underlie the site specificity of CK1α and disclose the possibility of developing strategies for the preferential targeting of subsets of CK1 substrates. PMID:15975091

  5. 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. PMID:27434301

  6. Non-canonical Activation of Akt in Serum-Stimulated Fibroblasts, Revealed by Comparative Modeling of Pathway Dynamics

    PubMed Central

    Nim, Tri Hieu; Luo, Le; White, Jacob K.; Clément, Marie-Véronique; Tucker-Kellogg, Lisa

    2015-01-01

    The dynamic behaviors of signaling pathways can provide clues to pathway mechanisms. In cancer cells, excessive phosphorylation and activation of the Akt pathway is responsible for cell survival advantages. In normal cells, serum stimulation causes brief peaks of extremely high Akt phosphorylation before reaching a moderate steady-state. Previous modeling assumed this peak and decline behavior (i.e., “overshoot”) was due to receptor internalization. In this work, we modeled the dynamics of the overshoot as a tool for gaining insight into Akt pathway function. We built an ordinary differential equation (ODE) model describing pathway activation immediately upstream of Akt phosphorylation at Thr308 (Aktp308). The model was fit to experimental measurements of Aktp308, total Akt, and phosphatidylinositol (3,4,5)-trisphosphate (PIP3), from mouse embryonic fibroblasts with serum stimulation. The canonical Akt activation model (the null hypothesis) was unable to recapitulate the observed delay between the peak of PIP3 (at 2 minutes), and the peak of Aktp308 (at 30–60 minutes). From this we conclude that the peak and decline behavior of Aktp308 is not caused by PIP3 dynamics. Models for alternative hypotheses were constructed by allowing an arbitrary dynamic curve to perturb each of 5 steps of the pathway. All 5 of the alternative models could reproduce the observed delay. To distinguish among the alternatives, simulations suggested which species and timepoints would show strong differences. Time-series experiments with membrane fractionation and PI3K inhibition were performed, and incompatible hypotheses were excluded. We conclude that the peak and decline behavior of Aktp308 is caused by a non-canonical effect that retains Akt at the membrane, and not by receptor internalization. Furthermore, we provide a novel spline-based method for simulating the network implications of an unknown effect, and we demonstrate a process of hypothesis management for guiding efficient

  7. 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

  8. 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. PMID:23077590

  9. 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.

  10. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells.

    PubMed

    Perkins, Timothy N; Dentener, Mieke A; Stassen, Frank R; Rohde, Gernot G; Mossman, Brooke T; Wouters, Emiel F M; Reynaert, Niki L

    2016-06-15

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. PMID:27095093

  11. Mutant cycles at CFTR's non-canonical ATP-binding site support little interface separation during gating.

    PubMed

    Szollosi, Andras; Muallem, Daniella R; Csanády, László; Vergani, Paola

    2011-06-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel belonging to the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily. ABC proteins share a common molecular mechanism that couples ATP binding and hydrolysis at two nucleotide-binding domains (NBDs) to diverse functions. This involves formation of NBD dimers, with ATP bound at two composite interfacial sites. In CFTR, intramolecular NBD dimerization is coupled to channel opening. Channel closing is triggered by hydrolysis of the ATP molecule bound at composite site 2. Site 1, which is non-canonical, binds nucleotide tightly but is not hydrolytic. Recently, based on kinetic arguments, it was suggested that this site remains closed for several gating cycles. To investigate movements at site 1 by an independent technique, we studied changes in thermodynamic coupling between pairs of residues on opposite sides of this site. The chosen targets are likely to interact based on both phylogenetic analysis and closeness on structural models. First, we mutated T460 in NBD1 and L1353 in NBD2 (the corresponding site-2 residues become energetically coupled as channels open). Mutation T460S accelerated closure in hydrolytic conditions and in the nonhydrolytic K1250R background; mutation L1353M did not affect these rates. Analysis of the double mutant showed additive effects of mutations, suggesting that energetic coupling between the two residues remains unchanged during the gating cycle. We next investigated pairs 460-1348 and 460-1375. Although both mutations H1348A and H1375A produced dramatic changes in hydrolytic and nonhydrolytic channel closing rates, in the corresponding double mutants these changes proved mostly additive with those caused by mutation T460S, suggesting little change in energetic coupling between either positions 460-1348 or positions 460-1375 during gating. These results provide independent support for a gating model in which ATP-bound composite site 1 remains

  12. Non-canonical Activation of Akt in Serum-Stimulated Fibroblasts, Revealed by Comparative Modeling of Pathway Dynamics.

    PubMed

    Nim, Tri Hieu; Luo, Le; White, Jacob K; Clément, Marie-Véronique; Tucker-Kellogg, Lisa

    2015-11-01

    The dynamic behaviors of signaling pathways can provide clues to pathway mechanisms. In cancer cells, excessive phosphorylation and activation of the Akt pathway is responsible for cell survival advantages. In normal cells, serum stimulation causes brief peaks of extremely high Akt phosphorylation before reaching a moderate steady-state. Previous modeling assumed this peak and decline behavior (i.e., "overshoot") was due to receptor internalization. In this work, we modeled the dynamics of the overshoot as a tool for gaining insight into Akt pathway function. We built an ordinary differential equation (ODE) model describing pathway activation immediately upstream of Akt phosphorylation at Thr308 (Aktp308). The model was fit to experimental measurements of Aktp308, total Akt, and phosphatidylinositol (3,4,5)-trisphosphate (PIP3), from mouse embryonic fibroblasts with serum stimulation. The canonical Akt activation model (the null hypothesis) was unable to recapitulate the observed delay between the peak of PIP3 (at 2 minutes), and the peak of Aktp308 (at 30-60 minutes). From this we conclude that the peak and decline behavior of Aktp308 is not caused by PIP3 dynamics. Models for alternative hypotheses were constructed by allowing an arbitrary dynamic curve to perturb each of 5 steps of the pathway. All 5 of the alternative models could reproduce the observed delay. To distinguish among the alternatives, simulations suggested which species and timepoints would show strong differences. Time-series experiments with membrane fractionation and PI3K inhibition were performed, and incompatible hypotheses were excluded. We conclude that the peak and decline behavior of Aktp308 is caused by a non-canonical effect that retains Akt at the membrane, and not by receptor internalization. Furthermore, we provide a novel spline-based method for simulating the network implications of an unknown effect, and we demonstrate a process of hypothesis management for guiding efficient

  13. Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension.

    PubMed

    Yun, Kangsun; Ajima, Rieko; Sharma, Nirmala; Costantini, Frank; Mackem, Susan; Lewandoski, Mark; Yamaguchi, Terry P; Perantoni, Alan O

    2014-12-20

    Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UBs) in mutants emerge as doublets from the intermediate mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the glial cell line-derived neurotrophic factor (Gdnf) expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in the mesoderm with an inducible Cre at E7.5 results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before the formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role of Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations. PMID:25082826

  14. 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

  15. A/T gap tolerance in the core sequence and flanking sequence requirements of non-canonical p53 response elements.

    PubMed

    Cai, Bi-He; Chao, Chung-Faye; Lin, Hwang-Chi; Huang, Hua-Ying; Kannagi, Reiji; Chen, Jang-Yi

    2016-06-01

    The canonical core sequence of the p53 response element, CATG, has a two-base A/T gap. Previously, we found that p53 can also activate a non-canonical four-base A/T gap CATATG core sequence. In this study, we investigated the possible number of A/T bases used by p53 and showed that a six-base A/T gap CATATATG core sequence was the maximum A/T gap in the p53 response element that could be upregulated by p53 and p63. Canonical and non-canonical p53 response elements also have three-base flanking sequences. A/T bases could be substituted by G/C bases, including CACACG and CGTGTG, but not CGCGCG. We found that the SV40 promoter with functional six- and two-base A/T gap core sequences could be activated by TAp63γ and that TAp63γ could upregulate SV40 small and large T antigens expression in COS7 cells. We also found that the distal region of PUMA promoter with functional two six-base A/T gap core sequences could be activated by TAp63γ in 293T cells. These new findings could provide novel rules for the non-canonical p53 family response element and could extend the entire p53 family regulation network. PMID:26823482

  16. Non-canonical Wnt signaling through Wnt5a/b and a novel Wnt11 gene, Wnt11b, regulates cell migration during avian gastrulation

    PubMed Central

    Hardy, Katharine M.; Garriock, Robert J.; Yatskievych, Tatiana A.; D’Agostino, Susan L.; Antin, Parker B.; Krieg, Paul A.

    2008-01-01

    Knowledge of the molecular mechanisms regulating cell ingression, epithelial-mesenchymal transition and migration movements during amniote gastrulation is steadily improving. In the frog and fish embryo, Wnt5 and Wnt11 ligands are expressed around the blastopore and play an important role in regulating cell movements associated with gastrulation. In the chicken embryo, although Wnt5a and Wnt5b are expressed in the primitive streak, the known Wnt11 gene is expressed in paraxial and intermediate mesoderm and in differentiated myocardial cells. Here, we identify a previously uncharacterized chicken Wnt11 gene, Wnt11b, that is orthologous to the frog Wnt11 and zebrafish Wnt11 (silberblick) genes. Chicken Wnt11b is expressed in the primitive streak in a pattern similar to chicken Wnt5a and Wnt5b. When non-canonical Wnt signaling is blocked using a Dishevelled dominant negative protein, gastrulation movements are inhibited and cells accumulate in the primitive streak. Furthermore, disruption of non-canonical Wnt signaling by overexpression of full length or dominant negative Wnt11b or Wnt5a constructions abrogates normal cell migration through the primitive streak. We conclude that non-canonical Wnt signaling, mediated in part by Wnt11b, is important for regulation of gastrulation cell movements in the avian embryo. PMID:18602094

  17. Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation.

    PubMed

    Brinkmann, Eva-Maria; Mattes, Benjamin; Kumar, Rahul; Hagemann, Anja I H; Gradl, Dietmar; Scholpp, Steffen; Steinbeisser, Herbert; Kaufmann, Lilian T; Özbek, Suat

    2016-06-24

    Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a-Ror2 complexes at the membrane, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains also promotes Ror2-mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation. PMID:27129770

  18. Down-Regulation of Canonical and Up-Regulation of Non-Canonical Wnt Signalling in the Carcinogenic Process of Squamous Cell Lung Carcinoma

    PubMed Central

    Weich, Alexander; Kiss, Edit; Barko, Szilvia; Kovacs, Tamas; Avdicevic, Monika; D’Souza, Vijay K.; Rapp, Judit; Kvell, Krisztian; Jakab, Laszlo; Nyitrai, Miklos; Molnar, Tamas F.; Thickett, David R.; Laszlo, Terezia; Pongracz, Judit E.

    2013-01-01

    The majority of lung cancers (LC) belong to the non-small cell lung carcinoma (NSCLC) type. The two main NSCLC sub-types, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC), respond differently to therapy. Whereas the link between cigarette smoke and lung cancer risk is well established, the relevance of non-canonical Wnt pathway up-regulation detected in SCC remains poorly understood. The present study was undertaken to investigate further the molecular events in canonical and non-canonical Wnt signalling during SCC development. A total of 20 SCC and AC samples with matched non-cancerous controls were obtained after surgery. TaqMan array analysis confirmed up-regulation of non-canonical Wnt5a and Wnt11 and identified down-regulation of canonical Wnt signalling in SCC samples. The molecular changes were tested in primary small airway epithelial cells (SAEC) and various lung cancer cell lines (e.g. A549, H157, etc). Our studies identified Wnt11 and Wnt5a as regulators of cadherin expression and potentiated relocation of β-catenin to the nucleus as an important step in decreased cellular adhesion. The presented data identifies additional details in the regulation of SCC that can aid identification of therapeutic drug targets in the future. PMID:23505429

  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. PMID:26389665

  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. PMID:27534378

  1. Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-κB signalling

    PubMed Central

    Saldanha-Araujo, Felipe; Haddad, Rodrigo; de Farias, Kelen C R Malmegrim; Souza, Alessandra de Paula Alves; Palma, Patrícia V; Araujo, Amélia G; Orellana, Maristela D; Voltarelli, Julio C; Covas, Dimas T; Zago, Marco A; Panepucci, Rodrigo A

    2012-01-01

    Abstract Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T cells into regulatory T cells in vitro. The marker CD69 is a target of canonical nuclear factor kappa-B (NF-κB) signalling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 (BAY) and a siRNA against v-rel reticuloendotheliosis viral oncogene homolog B (RELB) were used to explore the differential roles of canonical and non-canonical NF-κB signalling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signalling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signalling on the third day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signalling. PMID:21777379

  2. 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

  3. Hepatic Progenitor Cells Contribute to the Progression of 2-Acetylaminofluorene/Carbon Tetrachloride-Induced Cirrhosis via the Non-Canonical Wnt Pathway.

    PubMed

    Chen, Jiamei; Zhang, Xiao; Xu, Ying; Li, Xuewei; Ren, Shuang; Zhou, Yaning; Duan, Yuyou; Zern, Mark; Zhang, Hua; Chen, Gaofeng; Liu, Chenghai; Mu, Yongping; Liu, Ping

    2015-01-01

    Hepatic progenitor cells (HPCs) appear to play an important role in chronic liver injury. In this study, cirrhosis was induced in F-344 rats (n = 32) via subcutaneous injection of 50% carbon tetrachloride (CCl4) twice a week for 8 weeks. Then, 30% CCl4 was administered in conjunction with intragastric 2-acetylaminofluorine (2-AAF) for 4 weeks to induce activation of HPCs. WB-F344 cells were used to provide direct evidence for differentiation of HPCs to myofibroblasts. The results showed that after administration of 2-AAF, the hydroxyproline content and the expressions of α-SMA, Col I, Col IV, TGF-β1, CD68, TNF-α, CK19 and OV6 were significantly increased. OV6 and α-SMA were largely co-expressed in fibrous septum and the expressions of Wnt5b, frizzled2, frizzled3 and frizzled6 were markedly increased, while β-catenin expression was not statistically different among the different groups. Consistent with the above results, WB-F344 cells, treated with TGF-β1 in vitro, differentiated into myofibroblasts and α-SMA, Col I, Col IV, Wnt5b and frizzled2 expressions were significantly increased, while β-catenin expression was decreased. After blocking the non-canonical Wnt pathway via WIF-1, the Wnt5b level was down regulated, and α-SMA and F-actin expressions were significantly decreased in the WIF-1-treated cells. In conclusion, these results indicate that HPCs appear to differentiate into myofibroblasts and exhibit a profibrotic effect in progressive cirrhosis via activation of the non-canonical Wnt pathway. Blocking the non-canonical Wnt pathway can inhibit the differentiation of HPCs into myofibroblasts, suggesting that blocking this pathway and changing the fate of differentiated HPCs may be a potential treatment for cirrhosis. PMID:26087010

  4. 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. PMID:26881431

  5. 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

  6. Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism

    PubMed Central

    Bradley, K; Cavaco, B; Bowl, M; Harding, B; Young, A; Thakker, R

    2005-01-01

    More than 99% of all splice sites conform to consensus sequences that usually include the invariant dinucleotides gt and ag at the 5' and 3' ends of the introns, respectively. We report on the utilisation of a non-consensus (non-canonical) donor splice site within exon 1 of the HRPT2 gene in familial isolated primary hyperparathyroidism (FIHP). HRPT2 mutations are more frequently associated with the hyperparathyroidism-jaw tumour syndrome (HPT-JT). Patients with FIHP were identified to have a donor splice site mutation, IVS1+1 g→a, and the consequences of this for RNA processing were investigated. The mutant mRNA lacked 30 bp and DNA sequence analysis revealed this to result from utilisation of an alternative cryptic non-canonical donor splice site (gaatgt) in exon 1 together with the normally occurring acceptor splice site in intron 1. Translation of this mutant mRNA predicted the in-frame loss of 10 amino acids in the encoded protein, termed PARAFIBROMIN. Thus, these FIHP patients are utilising a ga-ag splice site pair, which until recently was considered to be incompatible with splicing but is now known to occur as a rare (<0.02%) normal splicing variant. PMID:16061557

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

    PubMed Central

    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. PMID:26881431

  8. Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor growth in the bone and its expression induces non-canonical autophagy

    PubMed Central

    Gaur, Sanchaika; Wen, Yunfei; Song, Jian H.; Parikh, Nila U.; Mangala, Lingegowda S.; Blessing, Alicia M.; Ivan, Cristina; Wu, Sherry Y.; Varkaris, Andreas; Shi, Yan; Lopez-Berestein, Gabriel; Frigo, Daniel E.; Sood, Anil K.; Gallick, Gary E.

    2015-01-01

    While several new therapies are FDA-approved for bone-metastatic prostate cancer (PCa), patient survival has only improved marginally. Here, we report that chitosan nanoparticle-mediated delivery of miR-34a, a tumor suppressive microRNA that downregulates multiple gene products involved in PCa progression and metastasis, inhibited prostate tumor growth and preserved bone integrity in a xenograft model representative of established PCa bone metastasis. Expression of miR-34a induced apoptosis in PCa cells, and, in accord with downregulation of targets associated with PCa growth, including MET and Axl and c-Myc, also induced a form of non-canonical autophagy that is independent of Beclin-1, ATG4, ATG5 and ATG7. MiR-34a-induced autophagy is anti-proliferative in prostate cancer cells, as blocking apoptosis still resulted in growth inhibition of tumor cells. Thus, combined effects of autophagy and apoptosis are responsible for miR-34a-mediated prostate tumor growth inhibition, and have translational impact, as this non-canonical form of autophagy is tumor inhibitory. Together, these results provide a new understanding of the biological effects of miR-34a and highlight the clinical potential for miR-34a delivery as a treatment for bone metastatic prostate cancer. PMID:26313360

  9. Muscle fiber type specific activation of the slow myosin heavy chain 2 promoter by a non-canonical E-box.

    PubMed

    Weimer, Kristina; DiMario, Joseph X

    2016-01-22

    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 86 bp 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

  10. 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

  11. 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

  12. 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

    2016-01-01

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

    PubMed

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

    2015-10-01

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

  14. 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. PMID:24349481

  15. 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. PMID:23416528

  16. 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

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

    PubMed

    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

  18. PAPERCLIP Identifies MicroRNA Targets and a Role of CstF64/64tau in Promoting Non-canonical poly(A) Site Usage.

    PubMed

    Hwang, Hun-Way; Park, Christopher Y; Goodarzi, Hani; Fak, John J; Mele, Aldo; Moore, Michael J; Saito, Yuhki; Darnell, Robert B

    2016-04-12

    Accurate and precise annotation of 3' UTRs is critical for understanding how mRNAs are regulated by microRNAs (miRNAs) and RNA-binding proteins (RBPs). Here, we describe a method, poly(A) binding protein-mediated mRNA 3' end retrieval by crosslinking immunoprecipitation (PAPERCLIP), that shows high specificity for mRNA 3' ends and compares favorably with existing 3' end mapping methods. PAPERCLIP uncovers a previously unrecognized role of CstF64/64tau in promoting the usage of a selected group of non-canonical poly(A) sites, the majority of which contain a downstream GUKKU motif. Furthermore, in the mouse brain, PAPERCLIP discovers extended 3' UTR sequences harboring functional miRNA binding sites and reveals developmentally regulated APA shifts, including one in Atp2b2 that is evolutionarily conserved in humans and results in the gain of a functional binding site of miR-137. PAPERCLIP provides a powerful tool to decipher post-transcriptional regulation of mRNAs through APA in vivo. PMID:27050522

  19. A non-canonical di-acidic signal at the C-terminus of Kv1.3 determines anterograde trafficking and surface expression.

    PubMed

    Martínez-Mármol, Ramón; Pérez-Verdaguer, Mireia; Roig, Sara R; Vallejo-Gracia, Albert; Gotsi, Pelagia; Serrano-Albarrás, Antonio; Bahamonde, María Isabel; Ferrer-Montiel, Antonio; Fernández-Ballester, Gregorio; Comes, Núria; Felipe, Antonio

    2013-12-15

    Impairment of Kv1.3 expression at the cell membrane in leukocytes and sensory neuron contributes to the pathophysiology of autoimmune diseases and sensory syndromes. Molecular mechanisms underlying Kv1.3 channel trafficking to the plasma membrane remain elusive. We report a novel non-canonical di-acidic signal (E483/484) at the C-terminus of Kv1.3 essential for anterograde transport and surface expression. Notably, homologous motifs are conserved in neuronal Kv1 and Shaker channels. Biochemical analysis revealed interactions with the Sec24 subunit of the coat protein complex II. Disruption of this complex retains the channel at the endoplasmic reticulum. A molecular model of the Kv1.3-Sec24a complex suggests salt-bridges between the di-acidic E483/484 motif in Kv1.3 and the di-basic R750/752 sequence in Sec24. These findings identify a previously unrecognized motif of Kv channels essential for their expression on the cell surface. Our results contribute to our understanding of how Kv1 channels target to the cell membrane, and provide new therapeutic strategies for the treatment of pathological conditions. PMID:24144698

  20. Silver Ions in Non-canonical DNA Base Pairs: Metal-Mediated Mismatch Stabilization of 2'-Deoxyadenosine and 7-Deazapurine Derivatives with 2'-Deoxycytidine and 2'-Deoxyguanosine.

    PubMed

    Yang, Haozhe; Seela, Frank

    2016-09-01

    Novel silver-mediated dA-dC, dA*-dC, and dA*-dG base pairs were formed in a natural DNA double helix environment (dA* denotes 7-deaza-dA, 7-deaza-7-iodo-dA, and 7-cyclopropyl-7-deaza-dA). 7-Deazapurine nucleosides enforce silver ion binding and direct metal-mediated base pair formation to their Watson-Crick face. New phosphoramidites were prepared from 7-deaza-dA, 7-deaza-7-iodo-dA, and 7-cyclopropyl-7-deaza-dA, which contain labile isobutyryl protecting groups. Solid-phase synthesis furnished oligonucleotides that contain mismatches in near central positions. Increased thermal stabilities (higher Tm values) were observed for oligonucleotide duplexes with non-canonical dA*-dC and dA-dC pairs in the presence of silver ions. The stability of the silver-mediated base pairs was pH dependent. Silver ion binding was not observed for the dA-dG mismatch but took place when mismatches were formed between 7-deazaadenine and guanine. The specific binding of silver ions was confirmed by stoichiometric UV titration experiments, which proved that one silver ion is captured by one mismatch. The stability increase of canonical DNA mismatches might have an impact on cellular DNA repair. PMID:27492501

  1. Variant mapping of the Apo(B) AT rich minisatellite. Dependence on nucleotide sequence of the copy number variations. Instability of the non-canonical alleles.

    PubMed Central

    Desmarais, E; Vigneron, S; Buresi, C; Cambien, F; Cambou, J P; Roizes, G

    1993-01-01

    Because of its variations in length, the AT rich Hyper-Variable Region (HVR) of the 3' end of the Apolipoprotein B gene is used as a polymorphic maker in genetic studies. It contains a SspI site in its repeated motif and we used this feature to precisely analyse the internal structure of the different alleles found at this locus in a Caucasian population. We performed total digestion on 194 alleles as well as Minisatellite Variant Repeat mapping (MVR mapping: partial digestion) on 54. The results show that the level of length variability (in copy number) of the 5' end of this locus is at least two times higher than that of the 3' end. This could be correlated with the difference in nucleotide sequence between the two parts of the HVR and suggests the dependence on the primary structure of the mechanism that produces length variability. A molecular model is proposed to explain this result. Moreover, the sharp analysis of the minisatellite structure by the distribution of SspI sites reveals differences between long and short alleles, indicating that in most cases, no recombination occurs between alleles of different sizes. Finally the rare alleles exhibit a non-canonical structure. These important points could explain the bimodal distribution of the frequencies of the alleles in the population. Images PMID:8502559

  2. 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. PMID:24236404

  3. 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

  4. Binding of USF to a non-canonical E-box following stress results in a cell-specific derepression of the lama3 gene.

    PubMed

    Virolle, Thierry; Coraux, Christelle; Ferrigno, Olivier; Cailleteau, Laurence; Ortonne, Jean-Paul; Pognonec, Philippe; Aberdam, Daniel

    2002-04-15

    Expression of the lama3 gene, encoding the laminin alpha3A chain, is restricted to specialized epithelia. We previously showed that lama3 gene expression is controlled by an epithelial enhancer through the cooperative effect of AP-1 binding sites. In fibroblasts, there is no lama3 expression because of the recruitment of a repressor complex absent or inactive in epithelial cells. In this paper, we show evidence that this repression of the lama3 gene is relieved by exogenous and UV-induced USF-1 through its interaction with a non-canonical E-box site. Using a chromatin immunoprecipitation assay, we find that UV stress induces USF to bind to the lama3 promoter in vivo. We further demonstrate that this loss of cell specificity is directly related to the accessibility of the E-box, resulting in a strong induction in fibroblasts, while expression remains constitutively high in keratinocytes. This accessibility appears to be dependent upon the recruitment of a fibroblastic repressor complex. Therefore, we speculate that anchorage of this repressor complex in fibroblasts modifies the enhancer geometry, allowing USF to interact under stress-inducing conditions with its heptameric binding site. PMID:11937633

  5. Simultaneous analysis of the non-canonical amino acids norleucine and norvaline in biopharmaceutical-related fermentation processes by a new ultra-high performance liquid chromatography approach.

    PubMed

    Biermann, Michael; Bardl, Bettina; Vollstädt, Sebastian; Linnemann, Julia; Knüpfer, Uwe; Seidel, Guido; Horn, Uwe

    2013-04-01

    In this study, a precise and reliable ultra-high performance liquid chromatography (UHPLC) method for the simultaneous determination of non-canonical (norvaline and norleucine) and standard amino acids (aspartic acid, glutamic acid, serine, histidine, glycine, threonine, arginine, tyrosine, methionine, valine, phenylalanine, isoleucine, leucine) in biopharmaceutical-related fermentation processes was established. After pre-column derivatization with ortho-phthaldialdehyde and 2-mercaptoethanol, the derivatives were separated on a sub-2 μm particle C18 reverse-phase column. Identification and quantification of amino acids were carried out by fluorescence detection. To test method feasibility on standard HPLC instruments, the assay was properly transferred to a core-shell particle C18 reverse-phase column. The limits of detection showed excellent sensitivity by values from 0.06 to 0.17 pmol per injection and limits of quantification between 0.19 and 0.89 pmol. In the present study, the newly established UHPLC method was applied to a recombinant antibody Escherichia coli fermentation process for the analysis of total free amino acids. We were able to specifically detect and quantify the unfavorable amino acids in such complex samples. Since we observed trace amounts of norvaline and norleucine during all fermentation phases, an obligatory process monitoring should be considered to improve quality of recombinant protein drugs in future. PMID:23306451

  6. Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis.

    PubMed

    van den Boom, Vincent; Maat, Henny; Geugien, Marjan; Rodríguez López, Aida; Sotoca, Ana M; Jaques, Jennifer; Brouwers-Vos, Annet Z; Fusetti, Fabrizia; Groen, Richard W J; Yuan, Huipin; Martens, Anton C M; Stunnenberg, Hendrik G; Vellenga, Edo; Martens, Joost H A; Schuringa, Jan Jacob

    2016-01-12

    Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here, we find that the non-canonical PRC1.1 complex, as identified by mass-spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34(+) cells. Besides a set of genes that is targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3, suggesting a gene-regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls specific genes involved in unique cell biological processes required for leukemic cell viability. PMID:26748712

  7. Snf1/AMP-activated protein kinase activates Arf3p to promote invasive yeast growth via a non-canonical GEF domain

    PubMed Central

    Hsu, Jia-Wei; Chen, Kuan-Jung; Lee, Fang-Jen S.

    2015-01-01

    Active GTP-bound Arf GTPases promote eukaryotic cell membrane trafficking and cytoskeletal remodelling. Arf activation is accelerated by guanine nucleotide-exchange factors (GEFs) using the critical catalytic glutamate in all known Sec7 domain sequences. Yeast Arf3p, a homologue of mammalian Arf6, is required for yeast invasive responses to glucose depletion. Here we identify Snf1p as a GEF that activates Arf3p when energy is limited. SNF1 is the yeast homologue of AMP-activated protein kinase (AMPK), which is a key regulator of cellular energy homeostasis. As activation of Arf3p does not depend on the Snf1p kinase domain, assay of regulatory domain fragments yield evidence that the C-terminal hydrophobic α-helix core of Snf1p is a non-canonical GEF for Arf3p activation. Thus, our study reveals a novel mechanism for regulating cellular responses to energy deprivation, in particular invasive cell growth, through direct Arf activation by Snf1/AMPK. PMID:26198097

  8. 4E-BPs require non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation

    PubMed Central

    Igreja, Cátia; Peter, Daniel; Weiler, Catrin; Izaurralde, Elisa

    2014-01-01

    eIF4E-binding proteins (4E-BPs) are a widespread class of translational regulators that share a canonical (C) eIF4E-binding motif (4E-BM) with eIF4G. Consequently, 4E-BPs compete with eIF4G for binding to the dorsal surface on eIF4E to inhibit translation initiation. Some 4E-BPs contain non-canonical 4E-BMs (NC 4E-BMs), but the contribution of these motifs to the repressive mechanism—and whether these motifs are present in all 4E-BPs—remains unknown. Here, we show that the three annotated Drosophila melanogaster 4E-BPs contain NC 4E-BMs. These motifs bind to a lateral surface on eIF4E that is not used by eIF4G. This distinct molecular recognition mode is exploited by 4E-BPs to dock onto eIF4E–eIF4G complexes and effectively displace eIF4G from the dorsal surface of eIF4E. Our data reveal a hitherto unrecognized role for the NC4E-BMs and the lateral surface of eIF4E in 4E-BP-mediated translational repression, and suggest that bipartite 4E-BP mimics might represent efficient therapeutic tools to dampen translation during oncogenic transformation. PMID:25179781

  9. Structure of 2-methylisoborneol synthase from Streptomyces coelicolor and implications for the cyclization of a non-canonical C-methylated monoterpenoid substrate†

    PubMed Central

    Köksal, Mustafa; Chou, Wayne K. W.; Cane, David E.; Christianson, David W.

    2012-01-01

    The crystal structure of 2-methylisoborneol synthase (MIBS) from Streptomyces coelicolor A3(2) has been determined in complex with substrate analogues geranyl-S-thiolodiphosphate and 2-fluorogeranyl diphosphate at 1.80 Å and 1.95 Å resolution, respectively. This terpenoid cyclase catalyzes the cyclization of the naturally-occuring, non-canonical C-methylated isoprenoid substrate, 2-methylgeranyl diphosphate, to form the bicyclic product 2-methylisoborneol, a volatile C11 homoterpene alcohol with an earthy, musty odor. While MIBS adopts the tertiary structure of a class I terpenoid cyclase, its dimeric quaternary structure differs from that previously observed in dimeric terpenoid cyclases from plants and fungi. The quaternary structure of MIBS is nonetheless similar in some respects to that of dimeric farnesyl diphosphate synthase, which is not a cyclase. The structures of MIBS complexed with substrate analogues provide insights regarding differences in the catalytic mechanism of MIBS and the mechanisms of (+)-bornyl diphosphate synthase and endo-fenchol synthase, plant cyclases that convert geranyl diphosphate into products with closely related bicyclic bornyl skeletons, but distinct structures and stereochemistries. PMID:22455514

  10. PAPERCLIP identifies microRNA targets and a role of CstF64/64tau in promoting non-canonical poly(A) site usage

    PubMed Central

    Hwang, Hun-Way; Park, Christopher Y.; Goodarzi, Hani; Fak, John J.; Mele, Aldo; Moore, Michael J.; Saito, Yuhki; Darnell, Robert B.

    2016-01-01

    Accurate and precise annotation of the 3′ untranslated regions (3′ UTRs) is critical in understanding how mRNAs are regulated by microRNAs (miRNAs) and RNA-binding proteins (RBPs). Here we describe a method, PAPERCLIP (Poly(A) binding Protein-mediated mRNA 3′ End Retrieval by CrossLinking ImmunoPrecipitation), which shows high specificity for the mRNA 3′ ends and compares favorably to existing 3′ end mapping methods. PAPERCLIP uncovers a previously unrecognized role of CstF64/64tau in promoting the usage of a selected group of non-canonical poly(A) sites, the majority of them containing a downstream GUKKU motif. Furthermore, in mouse brain, PAPERCLIP discovers extended 3′ UTR sequences harboring functional miRNA binding sites and reveals developmentally regulated APA shifts including one in Atp2b2 that is evolutionarily conserved in human and results in a gain of a functional binding site of miR-137. PAPERCLIP provides a powerful tool to decipher post-transcriptional regulation of mRNAs through APA in vivo. PMID:27050522

  11. 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

  12. Mesenchymal chemotaxis requires selective inactivation of Myosin II at the leading edge via a non-canonical PLCγ/PKCα pathway

    PubMed Central

    Asokan, Sreeja B.; Johnson, Heath E.; Rahman, Anisur; King, Samantha J.; Rotty, Jeremy D.; Lebedeva, Irina P.; Haugh, Jason M.; Bear, James E.

    2014-01-01

    Summary Chemotaxis, migration towards soluble chemical cues, is critical for processes such as wound healing and immune surveillance, and is exhibited by various cell types from rapidly-migrating leukocytes to slow-moving mesenchymal cells. To interrogate the mechanisms involved in mesenchymal chemotaxis, we observed cell migration in microfluidic chambers that generate stable gradients of the chemoattractant PDGF. Surprisingly, we found that pathways implicated in amoeboid chemotaxis, such as PI3K and mTOR signaling, are dispensable for chemotaxis to PDGF. Instead, we find that local inactivation of Myosin IIA, through a non-canonical Ser1/2 phosphorylation of the regulatory light chain, is essential. This site is phosphorylated by PKCα, which is activated by an intracellular gradient of diacylglycerol generated by PLCγ. Using a combination of TIRF imaging and gradients of activators/inhibitors in the microfluidic chambers, we demonstrate that this signaling pathway and subsequent inhibition of Myosin II activity at the leading edge is required for mesenchymal chemotaxis. PMID:25482883

  13. 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. PMID:26370051

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

    PubMed

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

    2008-06-01

    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

  15. FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway

    PubMed Central

    Asad, M; Wong, M K; Tan, T Z; Choolani, M; Low, J; Mori, S; Virshup, D; Thiery, J P; Huang, R Y-J

    2014-01-01

    Ovarian cancer (OC) can be classified into five biologically distinct molecular subgroups: epithelial-A (Epi-A), Epi-B, mesenchymal (Mes), Stem-A and Stem-B. Among them, Stem-A expresses genes relating to stemness and is correlated with poor clinical prognosis. In this study, we show that frizzled family receptor 7 (FZD7), a receptor for Wnt signalling, is overexpressed in the Stem-A subgroup. To elucidate the functional roles of FZD7, we used an RNA interference gene knockdown approach in three Stem-A cell lines: CH1, PA1 and OV-17R. Si-FZD7 OC cells showed reduced cell proliferation with an increase in the G0/G1 sub-population, with no effect on apoptosis. The cells also displayed a distinctive morphologic change by colony compaction to become more epithelial-like and polarised with smaller internuclear distances and increased z-axis height. Immunofluorescence (IF) staining patterns of pan-cadherin and β-catenin suggested an increase in cadherin-based cell–cell adhesion in si-FZD7 cells. We also observed a significant rearrangement in the actin cytoskeleton and an increase in tensile contractility in si-FZD7 OC cells, as evident by the loss of stress fibres and the redistribution of phospho-myosin light chain (pMLC) from the sites of cell–cell contacts to the periphery of cell colonies. Furthermore, there was reciprocal regulation of RhoA (Ras homolog family member A) and Rac1 (Ras-related C3 botulinum toxin substrate 1 (Rho family, small GTP-binding protein Rac1)) activities upon FZD7 knockdown, with a significant reduction in RhoA activity and a concomitant upregulation in Rac1 activity. These changes in pMLC and RhoA, as well as the increased TopFlash reporter activities in si-FZD7 cells, suggested involvement of the non-canonical Wnt/planar cell polarity (PCP) pathway. Selected PCP pathway genes (cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3), prickle homolog 4 (Drosophila) (PRICKLE4), dishevelled-associated activator of morphogenesis 1 (DAAM1

  16. 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

  17. 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. PMID:27123832

  18. Staurosporine induces chondrogenesis of chick embryo wing bud mesenchyme in monolayer cultures through canonical and non-canonical TGF-β pathways.

    PubMed

    Kim, Hyoin; Kei, Kyungmin; Sonn, Jong Kyung

    2016-01-01

    Staurosporine has been known to induce chondrogenesis in monolayer cultures of mesenchymal cells by dissolving actin stress fibers. The aim of this study was to further elucidate how the alteration of actin filaments by staurosporine induces chondrogenesis. Specifically, we examined whether the transforming growth factor (TGF)-β pathway is implicated. SB505124 strongly suppressed staurosporine-induced chondrogenesis without affecting the drug's action on the actin cytoskeleton. Staurosporine increased the phosphorylation of TGF-β receptor I (TβRI) but had no significant effect on the expression levels of TGF-β1, TGF-β2, TGF-β3, TβRI, TβRII, and TβRIII. Phosphorylation of Smad2 and Smad3 was not increased by staurosporine. However, SB505124 almost completely suppressed the phosphorylation of Smad2 and Smad3. In addition, inhibition of Smad3 blocked staurosporine-induced chondrogenesis. Inhibition of Akt, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) suppressed chondrogenesis induced by staurosporine. Phosphorylation of Akt, p38 MAPK, and JNK was increased by staurosporine. SB505124 reduced the phosphorylation of Akt and p38 MAPK, while it had no effect on the phosphorylation of JNK. The phosphorylation level of extracellular signal-regulated kinase (ERK) was not significantly affected by staurosporine. In addition, inhibition of ERK with PD98059 alone did not induce chondrogenesis. Taken together, these results suggest that staurosporine induces chondrogenesis through TGF-β pathways including canonical Smads and non-canonical Akt and p38 MAPK signaling. PMID:26427712

  19. Desflurane preconditioning protects human umbilical vein endothelial cells against anoxia/reoxygenation by upregulating NLRP12 and inhibiting non-canonical nuclear factor-κB signaling.

    PubMed

    Sun, Zhirong; Lv, Jianing; Zhu, Yun; Song, Dongli; Zhu, Biao; Miao, Changhong

    2015-11-01

    Volatile anesthetics modulate endothelial cell apoptosis and inhibit nuclear factor-κB (NF-κB) signaling. In this study, we aimed to assess whether desflurane preconditioning protects human umbilical vein endothelial cells (HUVECs) agaist anoxia/reoxygenation (A/R) injury. HUVECs were pre-conditioned with desflurane (1.0 MAC) for 30 min, followed by a 15-min washout, then exposed to 60 min anoxia and 60 min reoxygenation (A/R), and incubated with 10 ng/ml tumor necrosis factor (TNF)-α for 60 min. HUVEC viability and apoptosis were measured by MTT assay and annexin V staining, and immunoblot analysis was used to measure the levels of Smac and cellular inhibitor of apoptosis 1 (cIAP1). NF-κB activation was assessed using the NF-κB signaling pathway real‑time PCR array, and the levels of NF-κB inducing kinase (NIK), p52, IκB kinase (IKK)α, p100, RelB and NLR family, pyrin domain containing 12 (NLRP12) were assessed by immunoblot analysis. Desflurane preconditioning attenuated the effects of A/R and/or A/R plus TNF-α on cell viability, decreasing the levels of Smac and enhancing the levels of of cIAP1 (P<0.05). Preconditioning with desflurane also enhanced the mRNA levels of interleukin (IL)-10 and NLRP12 in the cells exposed to A/R by 2.40- and 2.16‑fold, respectively. The HUVECs exposed to A/R had greater levels of NIK and p100 and reduced levels of p52 and IKKα. Desflurance preconditioning further increased p100 levels, decreased the level of NIK, further decreased p52 levels and further reduced IKKα levels. A/R in combination with TNF-α increased the NIK, IKKα, p100 and RelB levels, and this increase was significantly attenuated by desflurance preconditioning (all P<0.05). Desflurane preconditioning enhanced HUVEC survival and protected the cells against A/R injury, and our results suggested that this process involved the upregulation of NLRP12 and the inhibition of non-canonical NF-κB signaling. PMID:26329693

  20. Efficient replication, and evolution of Sindbis virus genomes with non-canonical 3'A/U-rich elements (NC3ARE) in neonatal mice.

    PubMed

    James, Frederick D; Hietala, Katie A; Eldar, Dganit; Guess, Tiffany E; Cone, Cecil; Mundell, Nathan A; Mundall, Nathan; Barnett, Joey V; Raju, Ramaswamy

    2007-12-01

    Sindbis virus (SIN) is a mosquito-transmitted animal RNA virus. We previously reported that SIN genomes lacking a canonical 19 nt 3'CSE undergo novel repair processes in BHK cells to generate a library of stable atypical SIN genomes with non-canonical 3'A/U-rich elements (NC3AREs) adjacent to the 3' poly(A) tail [1]. To determine the stability and evolutionary pressures on the SIN genomes with NC3AREs to regain a 3'CSE, five representative SIN isolates and a wild type SIN were tested in newborn mice. The key findings of this study are: (a) all six SIN isolates, including those that have extensive NC3AREs in the 3'NTRs, replicate well and produce high titer viremia in newborn mice; (b) 7-9 successive passages of these isolates in newborn mice produced comparable levels of viremia; (c) while all isolates produced only small-sized plaques during primary infection in animals, both small- and large-sized plaques were generated in all other passages; (d) polymerase stuttering occurs on select 3' oligo(U) motifs to add more U residues within the NC3AREs; (e) the S3-8 isolate with an internal UAUUU motif in the 3'poly(A) tail maintains this element even after 9 passages in animals; (f) despite differences in 3'NTRs and variable tissue distribution, all SIN isolates appear to produce similar tissue pathology in infected animals. Competition experiments with wt SIN and atypical SIN isolates in BHK cells show dominance of wt SIN. As shown for BHK cells in culture, the 3'CSE of the SIN genome is not required for virus replication and genome stability in live animals. Since the NC3AREs of atypical SIN genomes are not specific to SIN replicases, alternate RNA motifs of alphavirus genome must confer specificity in template selection. These studies fulfill the need to confirm the long-term viability of atypical SIN genomes in newborn mice and offer a basis for exploring the use of atypical SIN genomes in biotechnology. PMID:17616797

  1. Comparative integromics on non-canonical WNT or planar cell polarity signaling molecules: transcriptional mechanism of PTK7 in colorectal cancer and that of SEMA6A in undifferentiated ES cells.

    PubMed

    Katoh, Masuko; Katoh, Masaru

    2007-09-01

    Non-canonical WNT and planar cell polarity (PCP) are overlapping but distinct signaling pathways, which control convergent extension, neural tube closure, orientation of cilia and sensory hair cells, axon guidance, and cell motility. Non-canonical WNT signals, regulated by the interaction of WNT, WNT antagonist, Frizzled and ROR2, are transduced to JNK, ROCK, PKC, MAP3K7, and NFAT signaling cascades. PCP signals, regulated by the interaction of VANGL-PRICKLE complex, CELSR and Frizzled-DVL complex, are transduced to JNK, ROCK, and other uncharacterized signaling cascades. PTK7 signaling, regulated by SEMA6 and Plexin-A family members, affects PCP pathway through VANGL. Here, integrative genomic analyses on WNT5A, WNT5B, WNT11, FZD3, FZD6, ROR1, ROR2, RYK, CELSR1, CELSR2, CELSR3, VANGL1, VANGL2, PRICKLE1, PRICKLE2, PTK7, SEMA6A, SEMA6B, SEMA6C and SEMA6D were carried out. PTK7 and SEMA6A were expressed in undifferentiated embryonic stem (ES) cells, SEMA6A in endodermal progenitors, CELSR1, VANGL1 and PTK7 in gastrointestinal tumors. CELSR2, PRICKLE2 and SEMA6C were expressed in fetal brain, CELSR2, PRICKLE1 and SEMA6A in adult brain, WNT5A and CELSR3 in adult brain tumors. These facts indicate class switches of non-canonical WNT or PCP signaling molecules during embryogenesis and carcinogenesis. TCF/LEF-, SP1-, and 5 bHLH-binding sites within human PTK7 promoter were conserved in chimpanzee, rhesus monkey, mouse, and rat PTK7 orthologs, which explained the mechanism of PTK7 upregulation in colorectal cancer. NANOG-, SOX2-, and POU5F1 (OCT3/OCT4)-binding sites within intron 1 of the human SEMA6A gene were conserved in chimpanzee, rhesus monkey, mouse, and rat SEMA6A orthologs, which explained the mechanism of SEMA6A upregulation in undifferentiated ES cells. Most of non-canonical WNT or PCP signaling molecules, except PTK7 and SEMA6A, were not frequently expressed in undifferentiated human ES cells. Non-canonical WNT or PCP signaling pathway, activated to orchestrate

  2. GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts

    PubMed Central

    Zoppi, Nicoletta; Chiarelli, Nicola; Cinquina, Valeria; Ritelli, Marco; Colombi, Marina

    2015-01-01

    Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFβ signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFβ signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the αvβ3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPARγ activity, rescued canonical TGFβ signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder. PMID:26376865

  3. GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts.

    PubMed

    Zoppi, Nicoletta; Chiarelli, Nicola; Cinquina, Valeria; Ritelli, Marco; Colombi, Marina

    2015-12-01

    Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFβ signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFβ signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the αvβ3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPARγ activity, rescued canonical TGFβ signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder. PMID:26376865

  4. 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

  5. Canonical and Non-canonical Reelin Signaling.

    PubMed

    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

  6. TNFα Modulates Fibroblast Growth Factor Receptor 2 Gene Expression through the pRB/E2F1 Pathway: Identification of a Non-Canonical E2F Binding Motif

    PubMed Central

    D’Amici, Sirio; Ceccarelli, Simona; Vescarelli, Enrica; Romano, Ferdinando; Frati, Luigi; Marchese, Cinzia; Angeloni, Antonio

    2013-01-01

    Interactions between epithelium and mesenchyme during wound healing are not fully understood, but Fibroblast Growth Factors (FGFs) and their receptors FGFRs are recognized as key elements. FGFR2 gene encodes for two splicing transcript variants, FGFR2-IIIb or Keratinocyte Growth Factor Receptor (KGFR) and FGFR2-IIIc, which differ for tissue localization and ligand specificity. Proinflammatory cytokines play an essential role in the regulation of epithelial-mesenchymal interactions, and have been indicated to stimulate FGFs production. Here we demonstrated that upregulation of FGFR2 mRNA and protein expression is induced by the proinflammatory cytokines Tumor Necrosis Factor-α, Interleukin-1β and Interleukin 2. Furthermore, we found that TNFα determines FGFR2 transcriptional induction through activation of pRb, mediated by Raf and/or p38 pathways, and subsequent release of the transcription factor E2F1. Experiments based on FGFR2 promoter serial deletions and site-directed mutagenesis allowed us to identify a minimal responsive element that retains the capacity to be activated by E2F1. Computational analysis indicated that this element is a non-canonical E2F responsive motif. Thus far, the molecular mechanisms of FGFR2 upregulation during wound healing or in pathological events are not known. Our data suggest that FGFR2 expression can be modulated by local recruitment of inflammatory cytokines. Furthermore, since alterations in FGFR2 expression have been linked to the pathogenesis of certain human cancers, these findings could also provide elements for diagnosis and potential targets for novel therapeutic approaches. PMID:23613863

  7. 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

  8. 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

    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 b(562) 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

  9. 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

    Karamitros, Timokratis; Harrison, Ian; 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

  10. Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways

    PubMed Central

    Ma, Xiaojun; Aoki, Tomohiro; Narumiya, Shuh

    2016-01-01

    While there is mounting evidence that interleukin (IL)-23-IL-17 axis plays a critical role in the pathogenesis of various autoimmune diseases, much remains to be elucidated on how IL-23 is induced in the pathological processes. IL-23 is a heterodimer composed of p19 and p40, the latter being shared with IL-12. We previously reported that prostaglandin (PG) E2 promotes CD40-mediated induction of Il23a (p19) expression through its E receptor subtype 4 (EP4) receptor in splenic dendritic cells (DCs). Here, we have analyzed signaling pathways regulating Il23a induction in the cross talk between EP4 and CD40 in bone marrow-derived DCs. We found that PGE2 synergistically induced Il23a transcription with CD40 signaling. An EP4 agonist, but not agonists of EP1, EP2, or EP3, reproduced this action. Stimulation of CD40 with an agonist antibody evoked biphasic induction of Il23a expression, with the early phase peaking at 1 h and the late phase peaking at 12 h and lasting up to 36 h after stimulation, whereas induction by lipopolysaccharide or tumor necrosis factor-α was transient. The early phase induction by CD40 stimulation was absent in DCs derived from Nfkb1-deficient mice, and the late phase induction was eliminated by RNA interference of nuclear factor-kappa B (NF-κB) p100 subunit. Further, cAMP response element-binding protein (CREB) depletion completely eliminated the induction of Il23a by CD40 stimulation. The addition of the EP4 agonist amplified the induction in both phases through the cAMP-protein kinase A (PKA) pathway. These results suggest that Il23a expression in DCs is synergistically triggered by the PG E2-EP4-cAMP-PKA pathway and canonical/non-canonical NF-κB pathways and CREB activated by CD40 stimulation. PMID:26189370

  11. A Role for the Non-Canonical Wnt-β-Catenin and TGF-β Signaling Pathways in the Induction of Tolerance during the Establishment of a Salmonella enterica Serovar Enteritidis Persistent Cecal Infection in Chickens

    PubMed Central

    Kogut, Michael H.; Arsenault, Ryan J.

    2015-01-01

    Non-typhoidal Salmonella enterica induce an early pro-inflammatory response in chickens. However, the response is short-lived, asymptomatic of disease, resulting in a persistent colonization of the ceca, and fecal shedding of bacteria. The underlying mechanisms that control this persistent infection of chickens by Salmonella are unknown. Recently, we found an expansion of the Treg population and subsequent increased in vitro immunosuppressive functions of the CD4+CD25+ cells isolated from the ceca of the Salmonella-infected chickens by day 4 post-infection that increased steadily throughout the course of the 14 days of infection, whereas the number of CD4+CD25+ cells in the non-infected controls remained steady throughout the study. CD4+CD25+ cells from cecal tonsils of S. enteritidis-infected birds had greater expression of IL-10 mRNA content than the CD4+CD25+ cells from the non-infected controls at all the time points studied. These results suggest the development of a tolerogenic immune response in the cecum of Salmonella-infected chickens may contribute to the persistance of Salmonella cecal colonization. Using a chicken-specific kinome peptide immune array, we have analyzed the signaling pathways altered during the establishment of this tolerogenic state. This analysis has revealed a role for the non-canonical Wnt signaling pathway in the cecum at 4 days post-infection. Infection induced the significant (p < 0.01) phosphorylation of the G-protein-coupled transmembrane protein, Frizzled 1 (FZD1), resulting in an influx of intracellular Ca2+ and the phosphorylation of the Ca2+-dependent effector molecules calcium/calmodulin-dependent kinase II (CamKII), β-catenin, protein kinase C, and the activation of the transcription factor, NFAT. Nuclear translocation of NFAT resulted in a significant increase in the expression of the anti-inflammatory cytokines IL-10 and TGF-β. Increased expression of TGF-β4 mRNA activates the TGF-β signaling pathway that

  12. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization.

    PubMed

    Downey, Charlene M; Aghaei, Mehrnoosh; Schwendener, Reto A; Jirik, Frank R

    2014-01-01

    The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a murine agonist of the stimulator of interferon genes (STING), appears to target the tumor vasculature primarily as a result of stimulating pro-inflammatory cytokine production from tumor-associated macrophages (TAMs). Since there were relatively few reports of DMXAA effects in genetically-engineered mutant mice (GEMM), and models of non-small cell lung cancer (NSCLC) in particular, we examined both the effectiveness and macrophage dependence of DMXAA in various NSCLC models. The DMXAA responses of primary adenocarcinomas in K-rasLA1/+ transgenic mice, as well as syngeneic subcutaneous and metastatic tumors, generated by a p53R172HΔg/+; K-rasLA1/+ NSCLC line (344SQ-ELuc), were assessed both by in vivo bioluminescence imaging as well as by histopathology. Macrophage-dependence of DMXAA effects was explored by clodronate liposome-mediated TAM depletion. Furthermore, a comparison of the vascular structure between subcutaneous tumors and metastases was carried out using micro-computed tomography (micro-CT). Interestingly, in contrast to the characteristic hemorrhagic necrosis produced by DMXAA in 344SQ-ELuc subcutaneous tumors, this agent failed to cause hemorrhagic necrosis of either 344SQ-ELuc-derived metastases or autochthonous K-rasLA1/+ NSCLCs. In addition, we found that clodronate liposome-mediated depletion of TAMs in 344SQ-ELuc subcutaneous tumors led to non-hemorrhagic necrosis due to tumor feeding-vessel occlusion. Since NSCLC were comprised exclusively of TAMs with anti-inflammatory M2-like phenotype, the ability of DMXAA to re-educate M2-polarized macrophages was examined. Using various macrophage phenotypic markers, we found that the STING agonists, DMXAA and the non-canonical endogenous cyclic dinucleotide, 2'3'-cGAMP, were both capable of re-educating M2 cells towards an M1 phenotype. Our findings demonstrate that the choice of preclinical model and the anatomical site of a

  13. DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′3′-cGAMP, Induces M2 Macrophage Repolarization

    PubMed Central

    Downey, Charlene M.; Aghaei, Mehrnoosh; Schwendener, Reto A.; Jirik, Frank R.

    2014-01-01

    The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a murine agonist of the stimulator of interferon genes (STING), appears to target the tumor vasculature primarily as a result of stimulating pro-inflammatory cytokine production from tumor-associated macrophages (TAMs). Since there were relatively few reports of DMXAA effects in genetically-engineered mutant mice (GEMM), and models of non-small cell lung cancer (NSCLC) in particular, we examined both the effectiveness and macrophage dependence of DMXAA in various NSCLC models. The DMXAA responses of primary adenocarcinomas in K-rasLA1/+ transgenic mice, as well as syngeneic subcutaneous and metastatic tumors, generated by a p53R172HΔg/+; K-rasLA1/+ NSCLC line (344SQ-ELuc), were assessed both by in vivo bioluminescence imaging as well as by histopathology. Macrophage-dependence of DMXAA effects was explored by clodronate liposome-mediated TAM depletion. Furthermore, a comparison of the vascular structure between subcutaneous tumors and metastases was carried out using micro-computed tomography (micro-CT). Interestingly, in contrast to the characteristic hemorrhagic necrosis produced by DMXAA in 344SQ-ELuc subcutaneous tumors, this agent failed to cause hemorrhagic necrosis of either 344SQ-ELuc-derived metastases or autochthonous K-rasLA1/+ NSCLCs. In addition, we found that clodronate liposome-mediated depletion of TAMs in 344SQ-ELuc subcutaneous tumors led to non-hemorrhagic necrosis due to tumor feeding-vessel occlusion. Since NSCLC were comprised exclusively of TAMs with anti-inflammatory M2-like phenotype, the ability of DMXAA to re-educate M2-polarized macrophages was examined. Using various macrophage phenotypic markers, we found that the STING agonists, DMXAA and the non-canonical endogenous cyclic dinucleotide, 2′3′-cGAMP, were both capable of re-educating M2 cells towards an M1 phenotype. Our findings demonstrate that the choice of preclinical model and the anatomical site of a

  14. 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.

  15. 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…

  16. On homological dimensions

    SciTech Connect

    Gerko, A A

    2001-08-31

    For finite modules over a local ring the general problem is considered of finding an extension of the class of modules of finite projective dimension preserving various properties. In the first section the concept of a suitable complex is introduced, which is a generalization of both a dualizing complex and a suitable module. Several properties of the dimension of modules with respect to such complexes are established. In particular, a generalization of Golod's theorem on the behaviour of G{sub K}-dimension with respect to a suitable module K under factorization by ideals of a special kind is obtained and a new form of the Avramov-Foxby conjecture on the transitivity of G-dimension is suggested. In the second section a class of modules containing modules of finite CI-dimension is considered, which has some additional properties. A dimension constructed in the third section characterizes the Cohen-Macaulay rings in precisely the same way as the class of modules of finite projective dimension characterizes regular rings and the class of modules of finite CI-dimension characterizes complete intersections.

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

    PubMed Central

    Cerutti, Andrea; Cols, Montserrat; Puga, Irene

    2012-01-01

    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. PMID:22868664

  18. Non-canonical Progesterone Signaling in Granulosa Cell Function

    PubMed Central

    Peluso, John J.; Pru, James K.

    2014-01-01

    It has been known for over three decades that progesterone (P4) suppresses follicle growth. It has been assumed that P4 acts directly on granulosa cells of developing follicles to slow their development, since P4 inhibits both mitosis and apoptosis of cultured granulosa cells. However, granulosa cells of developing follicles of mice, rats, monkeys and humans do not express the A or B form of the classic nuclear receptor for progesterone (PGR). In contrast, these granulosa cells express other progesterone binding proteins, one of which is referred to as Progesterone Receptor Membrane Component 1 (PGRMC1). PGRMC1 specifically binds P4 with high affinity and mediates P4’s anti-mitotic and anti-apoptotic action as evidenced by the lack of these P4-dependent effects in PGRMC1-depleted cells. In addition, mice in which PGRMC1 is conditionally depleted in granulosa cells show diminished follicle development. While the mechanism through which P4 activation of PGRMC1 affects granulosa cell function is not well defined, it appears that PGRMC1 controls granulosa cell function in part by regulating gene expression in T cell specific transcription factor/lymphoid enhancer factor (Tcf/Lef)-dependent manner. Clinically, altered PGRMC1 expression has been correlated with premature ovarian failure/insufficiency, polycystic ovarian syndrome and infertility. These collective studies provide strong evidence that PGRMC1 functions as a receptor for P4 in granulosa cells and that altered expression results in compromised reproductive capacity. Ongoing studies seek to define the components of the signal transduction cascade through which P4-activation of PGRMC1 results in the regulation of granulosa cell function. PMID:24516175

  19. Non-canonical transit peptide for import into the chloroplast.

    PubMed

    Miras, Stéphane; Salvi, Daniel; Ferro, Myriam; Grunwald, Didier; Garin, Jérôme; Joyard, Jacques; Rolland, Norbert

    2002-12-01

    The large majority of plastid proteins are nuclear-encoded and, thus, must be imported within these organelles. Unlike most of the outer envelope proteins, targeting of proteins to all other plastid compartments (inner envelope membrane, stroma, and thylakoid) is strictly dependent on the presence of a cleavable transit sequence in the precursor N-terminal region. In this paper, we describe the identification of a new envelope protein component (ceQORH) and demonstrate that its subcellular localization is limited to the inner membrane of the chloroplast envelope. Immunopurification, microsequencing of the natural envelope protein and cloning of the corresponding full-length cDNA demonstrated that this protein is not processed in the N-terminal region during its targeting to the inner envelope membrane. Transient expression experiments in plant cells were performed with truncated forms of the ceQORH protein fused to the green fluorescent protein. These experiments suggest that neither the N-terminal nor the C-terminal are essential for chloroplastic localization of the ceQORH protein. These observations are discussed in the frame of the endosymbiotic theory of chloroplast evolution and suggest that a domain of the ceQORH bacterial ancestor may have evolved so as to exclude the general requirement of an N-terminal plastid transit sequence. PMID:12368288

  20. Non-canonical progesterone signaling in granulosa cell function.

    PubMed

    Peluso, John J; Pru, James K

    2014-05-01

    It has been known for over 3 decades that progesterone (P4) suppresses follicle growth. It has been assumed that P4 acts directly on granulosa cells of developing follicles to slow their development, as P4 inhibits both mitosis and apoptosis of cultured granulosa cells. However, granulosa cells of developing follicles of mice, rats, monkeys, and humans do not express the A or B isoform of the classic nuclear receptor for P4 (PGR). By contrast, these granulosa cells express other P4 binding proteins, one of which is referred to as PGR membrane component 1 (PGRMC1). PGRMC1 specifically binds P4 with high affinity and mediates P4's anti-mitotic and anti-apoptotic action as evidenced by the lack of these P4-dependent effects in PGRMC1-depleted cells. In addition, mice in which PGRMC1 is conditionally depleted in granulosa cells show diminished follicle development. While the mechanism through which P4 activation of PGRMC1 affects granulosa cell function is not well defined, it appears that PGRMC1 controls granulosa cell function in part by regulating gene expression in T-cell-specific transcription factor/lymphoid enhancer factor-dependent manner. Clinically, altered PGRMC1 expression has been correlated with premature ovarian failure/insufficiency, polycystic ovarian syndrome, and infertility. These collective studies provide strong evidence that PGRMC1 functions as a receptor for P4 in granulosa cells and that altered expression results in compromised reproductive capacity. Ongoing studies seek to define the components of the signal transduction cascade through which P4 activation of PGRMC1 results in the regulation of granulosa cell function. PMID:24516175

  1. 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)

  2. 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)

  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. 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.

  5. 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.

  6. 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:…

  7. 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,…

  8. Big Mysteries: Extra Dimensions

    ScienceCinema

    Lincoln, Don

    2014-08-07

    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.

  9. 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…

  10. 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…

  11. Dimensions of Delinquency.

    ERIC Educational Resources Information Center

    Wunderlich, Richard A.

    1985-01-01

    In response to research questioning the utility of the Jesness Inventory in predicting and differentiating delinquency, this study isolated the personality dimensions of 422 adjudicated, noninstitutionalized adolescents by item level factor analysis. The resulting three factors--Mistrust, Social Pessimism, and Hypersensitivity--were compared with…

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Extra Dimensions and ``Branes''

    NASA Astrophysics Data System (ADS)

    Sundrum, Raman

    2011-04-01

    We do not yet know the nature of fundamental physics above the weak scale, but we are about to probe it this decade. It may come in the form of a few new weakly-coupled particles, captured by ordinary Feynman diagrams in standard spacetime, or alternatively in the form of large ``towers'' of new elementary or composite states, requiring a different set of concepts and analytic tools. Extra spatial dimensions provide the simplest, but very rich, class of such possibilities. I will explain how extra-dimensions can provide an elegant and intuitive geometrization of subtle physics, in particular flowing from the powerful AdS/CFT correspondence. This geometrization allows one to ``view'' central issues ranging from electroweak, grand unified, strongly-coupled, flavor, supersymmetry, or collider physics, in terms of the overlap of extra-dimensional wavefunctions, the curvature (``warping'') of the higher dimensional spacetime, and ``branes'' (3-dimensional defects). I will illustrate the kind of physics and experimental signals that flow from the most plausible extra-dimensional scenarios.

  17. Supergravity in twelve dimension

    NASA Astrophysics Data System (ADS)

    Choi, Kang-Sin

    2015-09-01

    We consider supergravity in twelve dimension, whose dimensional reduction yields eleven-dimensional, IIA, and IIB supergravities. This also provides the effective field theory of F-theory. We must take one direction as a compact circle, so that the Poincaré symmetry and the zero-mode field contents are identical to those of eleven-dimensional supergravity. We also have a tower of massive Kaluza-Klein states to be viewed as the wrapping modes of M2-branes. The twelfth dimension decompactifies only if other two directions are compactified on a torus, restoring different ten dimensional Poincaré symmetry of IIB supergravity, whose missing graviton is provided by components of the rank three tensor field. This condition prevents us from violating the condition on the maximal number of real supercharges, which should be thirty-two. The self-duality condition of the IIB four-form fields is understood from twelve-dimensional Hodge duality. In this framework T-duality is re-interpreted as taking different compactification routes.

  18. Normal human CD4(+) helper T cells express Kv1.1 voltage-gated K(+) channels, and selective Kv1.1 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway.

    PubMed

    Fellerhoff-Losch, Barbara; Korol, Sergiy V; Ganor, Yonatan; Gu, Songhai; Cooper, Itzik; Eilam, Raya; Besser, Michal; Goldfinger, Meidan; Chowers, Yehuda; Wank, Rudolf; Birnir, Bryndis; Levite, Mia

    2016-03-01

    TNFα is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFα secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFα medications. TNFα is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFα secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFα secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.09 ± 22.17 %), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.12 ± 3.04 %); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFα production and secretion by normal human T cells, without elevating IFNγ, IL-4 and IL-10; (6) intact Ca(2+) channels are required for DTX-induced TNFα secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFα secretion; (8) DTX-K activates NFκB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells

  19. 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.

  20. Phenomenology of Extra Dimensions

    SciTech Connect

    Hewett, J.L.; /SLAC

    2006-11-07

    If the structure of spacetime is different than that readily observed, gravitational physics, particle physics and cosmology are all immediately affected. The physics of extra dimensions offers new insights and solutions to fundamental questions arising in these fields. Novel ideas and frameworks are continuously born and evolved. They make use of string theoretical features and tools and they may reveal if and how the 11-dimensional string theory is relevant to our four-dimensional world. We have outlined some of the experimental observations in particle and gravitational physics as well as astrophysical and cosmological considerations that can constrain or confirm these scenarios. These developing ideas and the wide interdisciplinary experimental program that is charted out to investigate them mark a renewed effort to describe the dynamics behind spacetime. We look forward to the discovery of a higher dimensional spacetime.

  1. Correlation dimension Wonderland theorems

    NASA Astrophysics Data System (ADS)

    Carvalho, Silas L.; de Oliveira, César R.

    2016-06-01

    Existence of generic sets of self-adjoint operators, related to correlation dimensions of spectral measures, is investigated in separable Hilbert spaces. Typical results say that, given an orthonormal basis, the set of operators whose corresponding spectral measures are both 0-lower and 1-upper correlation dimensional is generic. The proofs rely on details of the relations among Fourier transform of spectral measures and Hausdorff and packing measures on the real line. Then such results are naturally combined with the Wonderland theorem. Applications are to classes of discrete one-dimensional Schrödinger operators and general (bounded) self-adjoint operators as well. Physical consequences include a proof of exotic dynamical behavior of singular continuous spectrum in some settings.

  2. 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.

  3. 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.

  4. 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?

  5. Beta function and anomalous dimensions

    SciTech Connect

    Pica, Claudio; Sannino, Francesco

    2011-06-01

    We demonstrate that it is possible to determine the coefficients of an all-orders beta-function linear in the anomalous dimensions using as data the 2-loop coefficients together with the first one of the anomalous dimensions which are universal. The beta function allows us to determine the anomalous dimension of the fermion masses at the infrared fixed point, and the resulting values compare well with the lattice determinations.

  6. 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

  7. 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

  8. 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.

  9. The Hidden Dimensions of Art.

    ERIC Educational Resources Information Center

    Klein, Bruce

    1982-01-01

    Describes an art program for preschool children that includes four social dimensions of art in order to heighten aesthetic perception, improve artistic creativity, and nurture self-esteem. The social dimensions are children having power, children acting on norms legitimate in their own eyes, children functioning "nonestrangedly," and children…

  10. How Many Dimensions are There?

    NASA Astrophysics Data System (ADS)

    Rowlands, Peter

    Dimensionality has been a much discussed subject since Minkowski formalized special relativity by extending 3D space to 4D space-time. However, there has never been any consensus on the number of dimensions that nature requires and there has been no explanation of why dimensions are needed at all. It is proposed here that dimensions originate in the theory of numbers, that extending the number of dimensions beyond the 3 required by Euclidean space necessarily requires a fundamental change in the meaning of the concept, and that, although various algebraic techniques allow such extension of dimensionality, the structures required always ensure that the number of dimensions and their fundamental characteristics remain ambiguous, leaving the final question unanswerable.

  11. Dimension of spatially embedded networks

    NASA Astrophysics Data System (ADS)

    Daqing, Li; Kosmidis, Kosmas; Bunde, Armin; Havlin, Shlomo

    2011-06-01

    The dimension of a system is one of the most fundamental quantities to characterize its structure and basic physical properties. Diffusion and vibrational excitations, for example, as well as the universal features of a system near a critical point depend crucially on its dimension. However, in the theory of complex networks the concept of dimension has been rarely discussed. Here we study models for spatially embedded networks and show how their dimension can be determined. Our results indicate that networks characterized by a broad distribution of link lengths have a dimension higher than that of the embedding space. We illustrate our findings using the global airline network and the Internet and argue that although these networks are embedded in two-dimensional space they should be regarded as systems with dimension close to 3 and 4.5, respectively. We show that the network dimension is a key concept to understand not only network topology, but also dynamical processes on networks, such as diffusion and critical phenomena including percolation.

  12. Increasing the dimensions of metrology

    NASA Astrophysics Data System (ADS)

    Maurer, Wilhelm; Blaesing-Bangert, Carola; Paul, Hans-Helmut

    1990-06-01

    In any process that generates or measures pattern-placement (overlay), these parameters need to be regarded at least as two-dimensional. We show this on our procedure bringing a mask repeater under statistical process control SPC). In order to increase the accuracy of the overlay measurement process itself, plate bending has to be included as a third dimension. By taking the third dimension into account, the LMS 2000 Metrology System significantly reduces the maximum uncertainity of measurement results.

  13. 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.

  14. 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.

  15. CORDIC algorithms in four dimensions

    NASA Astrophysics Data System (ADS)

    Delosme, Jean-Marc; Hsiao, Shen-Fu

    1990-11-01

    CORDIC algorithms offer an attractive alternative to multiply-and-add based algorithms for the implementation of two-dimensional rotations preserving either norm: (x2 + 2) or (x2 _ y2)/2 Indeed these norms whose computation is a significant part of the evaluation of the two-dimensional rotations are computed much more easily by the CORDIC algorithms. However the part played by norm computations in the evaluation of rotations becomes quickly small as the dimension of the space increases. Thus in spaces of dimension 5 or more there is no practical alternative to multiply-and-add based algorithms. In the intermediate region dimensions 3 and 4 extensions of the CORDIC algorithms are an interesting option. The four-dimensional extensions are particularly elegant and are the main object of this paper.

  16. 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.

  17. 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.

  18. Dimensions for Defining the Curriculum

    ERIC Educational Resources Information Center

    Fensham, Peter J.

    1977-01-01

    Seven dimensions for characterizing a curriculum in higher education are suggested. They include: prior knowledge; institutional response to prior knowledge; primary teaching mode; rates of learning; styles of learning; content openness; and assessment. This characterization is applied specifically to chemistry departments. (LBH)

  19. Dimensions of Interpersonal Relationships Revisited.

    ERIC Educational Resources Information Center

    Wiemann, John M.; Krueger, Dorothy Lenk

    The ways in which people described their own interpersonal relationships were examined along the universally acknowledged relational dimensions control and affiliation. A total of 216 undergraduate communication students wrote about one of three types of relationships they had: best liked friend of the opposite sex, (60), best liked friend of the…

  20. Chaotic Hierarchy in High Dimensions

    NASA Astrophysics Data System (ADS)

    Postnov, D. E.; Balanov, A. G.; Sosnovtseva, O. V.; Mosekilde, E.

    The paper suggests a new mechanism for the development of higher-order chaos in accordance with the concept of a chaotic hierarchy. A discrete-time model is proposed which demonstrates how the creation of coexisting chaotic attractors combined with boundary crises can produce a continued growth of the Lyapunov dimension of the resulting chaotic behavior.

  1. Manpower Training; Some Cost Dimensions.

    ERIC Educational Resources Information Center

    Young, Stanley

    Some of the dimensions of the relative financial contribution of the cooperating parties in manpower institutional training as established under the Manpower Development and Training Act of 1962 were explored. This analysis will provide some perspective to those who must finally decide the question of relative financial contribution, or provide…

  2. Investigation of a Creativity Dimension.

    ERIC Educational Resources Information Center

    Murphy, Richard T.

    This thesis provides evidence for the existence of a creativity dimension containing figural and verbal subfactors which is independent of intelligence and marginally related to school achievement. The original data of Wallach and Kogan, as well as the data from the Ward, Cropley and Maslany and Wallach and Wing studies were reanalyzed using…

  3. Charged polymers in high dimensions

    NASA Technical Reports Server (NTRS)

    Kantor, Yacov

    1990-01-01

    A Monte Carlo study of charged polymers with either homogeneously distributed frozen charges or with mobile charges has been performed in four and five space dimensions. The results are consistent with the renormalization-group predictions and contradict the predictions of Flory-type theory. Introduction of charge mobility does not modify the behavior of the polymers.

  4. Robust large dimension terahertz cloaking.

    PubMed

    Liang, Dachuan; Gu, Jianqiang; Han, Jiaguang; Yang, Yuanmu; Zhang, Shuang; Zhang, Weili

    2012-02-14

    A large scale homogenous invisibility cloak functioning at terahertz frequencies is reported. The terahertz invisibility device features a large concealed volume, low loss, and broad bandwidth. In particular, it is capable of hiding objects with a dimension nearly an order of magnitude larger than that of its lithographic counterpart, but without involving complex and time-consuming cleanroom processing. PMID:22253094

  5. Huygens's secondary-sources dimensions.

    PubMed

    Romero, J A; Hernández, L

    2007-04-01

    Using a vectorial formulation, we show that Huygens's secondary-sources density is constant in plane waves, and it depends only on the wavelength. We also illustrate that Huygens's secondary sources, which act as emitters of secondary wavelets, have a finite dimension equal to 3 pi/2k(2). PMID:17361294

  6. The Dimensions of Residential Segregation.

    ERIC Educational Resources Information Center

    Massey, Douglas S.; Denton, Nancy A.

    1988-01-01

    Evaluates 20 potential indicators of residential segregation using census data on Hispanics, Blacks, Asians, and non-Hispanic Whites in 60 U.S. metropolitan areas. Factor-analyzes the results to select a single best indicator for each of five dimensions of residential segregation. Contains 69 references and 22 statistical formulas. (SV)

  7. Effective dimension in flocking mechanisms

    SciTech Connect

    Baglietto, Gabriel; Albano, Ezequiel V.

    2011-03-24

    Even in its minimal representation (Vicsek Model, VM [T. Vicsek, A. Czirok, E. Ben-Jacob, I. Cohen and O. Shochet. Phys. Rev. Lett. 75, 1226 (1995).]), the widespread phenomenon of flocking raises intriguing questions to the statistical physicists. While the VM is very close to the better understood XY Model because they share many symmetry properties, a major difference arises by the fact that the former can sustain long-range order in two dimensions, while the latter can not. Aiming to contribute to the understanding of this feature, by means of extensive numerical simulations of the VM, we study the network structure of clusters showing that they can also sustain purely orientational, mean-field-like, long-range order. We identify the reason of this capability with the key concept of ''effective dimension.'' In fact, by analyzing the behavior of the average path length and the mean degree, we show that this dimension is very close to four, which coincides with the upper critical dimension of the XY Model, where orientational order is also of a mean-field nature. We expect that this methodology could be generalized to other types of dynamical systems.

  8. 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…

  9. The Hidden Dimensions of Databases.

    ERIC Educational Resources Information Center

    Jacso, Peter

    1994-01-01

    Discusses methods of evaluating commercial online databases and provides examples that illustrate their hidden dimensions. Topics addressed include size, including the number of records or the number of titles; the number of years covered; and the frequency of updates. Comparisons of Readers' Guide Abstracts and Magazine Article Summaries are…

  10. 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 European…

  11. Double Semions in Arbitrary Dimension

    NASA Astrophysics Data System (ADS)

    Freedman, Michael H.; Hastings, Matthew B.

    2016-03-01

    We present a generalization of the double semion topological quantum field theory to higher dimensions, as a theory of {d-1} dimensional surfaces in a d dimensional ambient space. We construct a local Hamiltonian that is a sum of commuting projectors and analyze the excitations and the ground state degeneracy. Defining a consistent set of local rules requires the sign structure of the ground state wavefunction to depend not just on the number of disconnected surfaces, but also upon their higher Betti numbers through the semicharacteristic. For odd d the theory is related to the toric code by a local unitary transformation, but for even d the dimension of the space of zero energy ground states is in general different from the toric code and for even {d > 2} it is also in general different from that of the twisted {Z_2} Dijkgraaf-Witten model.

  12. 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.

  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. 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.

  15. BMS modules in three dimensions

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

    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 nonunitary representations. To support this dichotomy, we also point out that the ultrarelativistic and nonrelativistic limits of generic 𝒲 algebras differ in the structure of their nonlinear terms.

  16. Accessible solitons of fractional dimension

    NASA Astrophysics Data System (ADS)

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

    2016-05-01

    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.

  17. Critical dimensions for chiral bosons

    SciTech Connect

    Mezincescu, L.; Nepomechie, R.I.

    1988-05-15

    We give the Lagrangian formulation of a Bose model in 1+1 dimensions which describes a free chiral Lie-algebra-valued current. This model is a non-Abelian generalization of the chiral scalar model of Siegel. Both the Abelian and non-Abelian actions have a gauge invariance, which becomes anomalous when the models are quantized. The condition that this anomaly be canceled coincides with the string no-ghost condition.

  18. Tsallis information dimension of complex networks

    NASA Astrophysics Data System (ADS)

    Zhang, Qi; Luo, Chuanhai; Li, Meizhu; Deng, Yong; Mahadevan, Sankaran

    2015-02-01

    The fractal and self-similarity properties are revealed in many complex networks. The information dimension is a useful method to describe the fractal and self-similarity properties of the complex networks. In order to show the influence of different parts in the complex networks to the information dimension, we have proposed a new information dimension based on the Tsallis entropy namely the Tsallis information dimension. The proposed information dimension is changed according to the scale which is described by the nonextensivity parameter q, and it is inverse with the nonextensivity parameter q. The existing information dimension is a special case of the Tsallis information dimension when q = 1. The Tsallis information dimension is a generalized information dimension of the complex networks.

  19. Quantum cosmology near two dimensions

    NASA Astrophysics Data System (ADS)

    Bautista, Teresa; Dabholkar, Atish

    2016-08-01

    We consider a Weyl-invariant formulation of gravity with a cosmological constant in d -dimensional spacetime and show that near two dimensions the classical action reduces to the timelike Liouville action. We show that the renormalized cosmological term leads to a nonlocal quantum momentum tensor which satisfies the Ward identities in a nontrivial way. The resulting evolution equations for an isotropic, homogeneous universe lead to slowly decaying vacuum energy and power-law expansion. We outline the implications for the cosmological constant problem, inflation, and dark energy.

  20. 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. PMID:23679650

  1. 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.

  2. Equientangled bases in arbitrary dimensions

    SciTech Connect

    Karimipour, V.; Memarzadeh, L.

    2006-01-15

    For the space of two identical systems of arbitrary dimensions, we introduce a continuous family of bases with the following properties: (i) the bases are orthonormal (ii) in each basis, all the states have the same values of entanglement, and (iii) they continuously interpolate between the product basis and the maximally entangled basis. The states thus constructed may find applications in many areas related to the quantum information science including quantum cryptography, optimal Bell tests, and the investigation of the enhancement of channel capacity due to entanglement.

  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. 16 CFR 1508.3 - Dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Dimensions. 1508.3 Section 1508.3 Commercial... FULL-SIZE BABY CRIBS § 1508.3 Dimensions. Full-size baby cribs shall have dimensions as follows: (a) Interior. The interior dimensions shall be 71±1.6 centimeters (28±5/8 inches) wide as measured between...

  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... FULL-SIZE BABY CRIBS § 1508.3 Dimensions. Full-size baby cribs shall have dimensions as follows: (a) Interior. The interior dimensions shall be 71±1.6 centimeters (28±5/8 inches) wide as measured between...

  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. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Standard dimensions. 241.5 Section 241..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules and regulations in this part the error on a dimension is mentioned, this error shall be determined...

  8. 15 CFR 241.5 - Standard dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Standard dimensions. 241.5 Section 241..., VEGETABLES AND OTHER DRY COMMODITIES, AND FOR CRANBERRIES § 241.5 Standard dimensions. Whenever in the rules and regulations in this part the error on a dimension is mentioned, this error shall be determined...

  9. Bulk charges in eleven dimensions

    NASA Astrophysics Data System (ADS)

    Hawking, S. W.; Taylor-Robinson, M. M.

    1998-07-01

    Eleven dimensional supergravity has electric type currents arising from the Chern-Simon and anomaly terms in the action. However the bulk charge integrates to zero for asymptotically flat solutions with topological trivial spatial sections. We show that by relaxing the boundary conditions to generalisations of the ALE and ALF boundary conditions in four dimensions one can obtain static solutions with a bulk charge. Solutions involving anomaly terms preserve between 1/16 and 1/4 of the supersymmetries but Chern-Simons fluxes generally break all of the remaining supersymmetry. One can introduce membranes with the same sign of charge into these backgrounds. This raises the possibility that these generalized membranes might decay quantum mechanically to leave just a bulk distribution of charge. Alternatively and more probably, a bulk distribution of charge can decay into a collection of singly charged membranes. Dimensional reductions of these solutions lead to novel representations of extreme black holes in four dimensions with up to four charges. We discuss how the eleven-dimensional Kaluza-Klein monopole wrapped around a space with non-zero first Pontryagin class picks up an electric charge proportional to the Pontryagin number.

  10. Fractal Dimensions of Macromolecular Structures

    PubMed Central

    Todoroff, Nickolay; Kunze, Jens; Schreuder, Herman; Hessler, Gerhard; Baringhaus, Karl-Heinz; Schneider, Gisbert

    2014-01-01

    Quantifying the properties of macromolecules is a prerequisite for understanding their roles in biochemical processes. One of the less-explored geometric features of macromolecules is molecular surface irregularity, or ‘roughness’, which can be measured in terms of fractal dimension (D). In this study, we demonstrate that surface roughness correlates with ligand binding potential. We quantified the surface roughnesses of biological macromolecules in a large-scale survey that revealed D values between 2.0 and 2.4. The results of our study imply that surface patches involved in molecular interactions, such as ligand-binding pockets and protein-protein interfaces, exhibit greater local fluctuations in their fractal dimensions than ‘inert’ surface areas. We expect approximately 22 % of a protein’s surface outside of the crystallographically known ligand binding sites to be ligandable. These findings provide a fresh perspective on macromolecular structure and have considerable implications for drug design as well as chemical and systems biology. PMID:26213587

  11. A comparison of correlation and Lyapunov dimensions

    NASA Astrophysics Data System (ADS)

    Chlouverakis, Konstantinos E.; Sprott, J. C.

    2005-01-01

    This paper investigates the relation between the correlation ( D2) and the Kaplan-Yorke dimension ( DKY) of three-dimensional chaotic flows. Besides the Kaplan-Yorke dimension, a new Lyapunov dimension ( DΣ), derived using a polynomial interpolation instead of a linear one, is compared with DKY and D2. Various systems from the literature are used in this analysis together with some special cases that span a range of dimension 2 < DKY ≤ 3. A linear regression to the data produces a new fitted Lyapunov dimension of the form Dfit = α - βλ1/ λ3, where λ1 and λ3 are the largest and smallest Lyapunov exponents, respectively. This form correlates better with the correlation dimension D2 than do either DKY or DΣ. Additional forms of the fitted dimension are investigated to improve the fit to D2, and the results are discussed and interpreted with respect to the Kaplan-Yorke conjecture.

  12. 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.

  13. 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.

  14. 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. PMID:26431004

  15. Grand Unification in Higher Dimensions

    SciTech Connect

    Hall, Lawrence J.; Nomura, Yasunori

    2002-12-10

    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^2theta_w = 0.2313 \\pm 0.0004, which fits the data with extraordinary accuracy. The compactification scale and the strong coupling scale are determined to be M_c \\simeq 5 x 10^14 GeV and M_s \\simeq 1 x 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^+pi^0, 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 mu -> e and tau -> mu 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.

  16. Estimate for the fractal dimension of the Apollonian gasket in d dimensions.

    PubMed

    Farr, R S; Griffiths, E

    2010-06-01

    We adapt a recent theory for the random close packing of polydisperse spheres in three dimensions [R. S. Farr and R. D. Groot, J. Chem. Phys. 131, 244104 (2009)] in order to predict the Hausdorff dimension dA of the Apollonian gasket in dimensions 2 and above. Our approximate results agree with published values in two and three dimensions to within 0.05% and 0.6%, respectively, and we provide predictions for dimensions 4-8. PMID:20866417

  17. Dimensioning of Aeronautical Satellite Services

    NASA Astrophysics Data System (ADS)

    Holzbock, M.; Jahn, A.; Werner, M.

    2002-01-01

    This paper will provide a generalised baseline for a systematic AirCom design process and address in particular the dimensioning of satellite systems for aeronautical services. These services will roll out soon in medium- and long-haul aircraft. The offered services will range from low rate telephony, internet access, and streaming applications for video and audio. The aggregate bit rates on up- and downlink will certainly be statistically time-dependent and asymmetric in forward and backward direction. A tool will be described that is able to model this traffic. Furthermore the dimensioning of satellite constellations can be done. Due to the stochastic nature of the traffic, multi-service models for the traffic generation of different services will be described. Furthermore, the traffic will be affected by the available bit rate and shaping or blocking will equalize the peak loads. If fleets with many aircraft are considered, aeronautical traffic models must be based on actual aircraft routes, flight schedules, location and time of day, as well as seats per aircraft and type of aircraft (charter, business etc.). The regionally distributed traffic has to be served by several satellites and appropriate sharing of the serving satellites may spread the traffic in hot zones and yield a better load distribution. When aeronautical services will spread out, the capacity demand will grow quickly and the capacity of existing Ku-band GEO satellites will soon be exceeded. Changing to higher frequency bands will provide large spectrum portions and smaller spotbeams will allow better frequency reuse. Even constellations with non-geostationary satellites could be re-advent to serve better the higher latitude regions. Then, another mobility component for the fast changing satellite topology need to be addressed, and routing issues of the traffic must be considered. The paper will describe solutions for the mapping of satellites and traffic demand as well as routing algorithms

  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. Space: The Hunt for Hidden Dimensions

    SciTech Connect

    Hewett, JoAnne

    2006-04-25

    Extra dimensions of space may be present in our universe. Their discovery would dramatically change our view of the cosmos and would prompt many questions. How do they hide? What is their shape? How many are there? How big are they? Do particles and forces feel their presence? This lecture will explain the concept of dimensions and show that current theoretical models predict the existence of extra spatial dimensions which could be in the discovery reach of present and near-term experiments. The manner by which these additional dimensions reveal their existence will be described. Searches for modifications of the gravitational force, astrophysical effects, and collider signatures already constrain the size of extra dimensions and will be summarized. Once new dimensions are discovered, the technology by which the above questions can be answered will be discussed.

  20. 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.

  1. 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.

  2. Percolation transitions in two dimensions.

    PubMed

    Feng, Xiaomei; Deng, Youjin; Blöte, Henk W J

    2008-09-01

    We investigate bond- and site-percolation models on several two-dimensional lattices numerically, by means of transfer-matrix calculations and Monte Carlo simulations. The lattices include the square, triangular, honeycomb kagome, and diced lattices with nearest-neighbor bonds, and the square lattice with nearest- and next-nearest-neighbor bonds. Results are presented for the bond-percolation thresholds of the kagome and diced lattices, and the site-percolation thresholds of the square, honeycomb, and diced lattices. We also include the bond- and site-percolation thresholds for the square lattice with nearest- and next-nearest-neighbor bonds. We find that corrections to scaling behave according to the second temperature dimension X_{t2}=4 predicted by the Coulomb gas theory and the theory of conformal invariance. In several cases there is evidence for an additional term with the same exponent, but modified by a logarithmic factor. Only for the site-percolation problem on the triangular lattice does such a logarithmic term appear to be small or absent. The amplitude of the power-law correction associated with X_{t2}=4 is found to be dependent on the orientation of the lattice with respect to the cylindrical geometry of the finite systems. PMID:18851022

  3. Percolation transitions in two dimensions

    NASA Astrophysics Data System (ADS)

    Feng, Xiaomei; Deng, Youjin; Blöte, Henk W. J.

    2008-09-01

    We investigate bond- and site-percolation models on several two-dimensional lattices numerically, by means of transfer-matrix calculations and Monte Carlo simulations. The lattices include the square, triangular, honeycomb kagome, and diced lattices with nearest-neighbor bonds, and the square lattice with nearest- and next-nearest-neighbor bonds. Results are presented for the bond-percolation thresholds of the kagome and diced lattices, and the site-percolation thresholds of the square, honeycomb, and diced lattices. We also include the bond- and site-percolation thresholds for the square lattice with nearest- and next-nearest-neighbor bonds. We find that corrections to scaling behave according to the second temperature dimension Xt2=4 predicted by the Coulomb gas theory and the theory of conformal invariance. In several cases there is evidence for an additional term with the same exponent, but modified by a logarithmic factor. Only for the site-percolation problem on the triangular lattice does such a logarithmic term appear to be small or absent. The amplitude of the power-law correction associated with Xt2=4 is found to be dependent on the orientation of the lattice with respect to the cylindrical geometry of the finite systems.

  4. Invariant imbedding in two dimensions

    SciTech Connect

    Faber, V.; Seth, D.L.; Wing, G.M.

    1988-01-01

    J. Corones has noted that the doubling and addition formulas of invariant imbedding can be extended conceptually to very general situations. All that is needed is a black box ''process'' with n ''ports.'' The /ital i/th port has vector input I/sub i/ and vector output J/sub i/. Addition formulas result when two or more of these processes are joined together to form a new process in some regular way. For example, four congruent squares can be juxtaposed to form a larger square. At each join, the output of one process becomes the input of the other and vice versa. (We always suppose the join to occur at one or more ports.) Addition formulas result from the combination of these shared quantities. Corones has thus pointed out that invariant imbedding is not, as is sometimes asserted, an inherently one-dimensional (1-D) method, but works conceptually in any number of dimensions; some previous work that is conceptually along these lines, with references to other such works, can be found in Refs. 2-4. The details can, of course, become very complicated. We shall show that the method is computationally feasible for certain two-dimensional (2-D) problems. To conform to the thrust of these proceedings, we shall usually phrase our discussions in terms of transport theory rather than speaking of more abstract processes. 7 refs., 13 figs.

  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. 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

  7. Magnetogenesis and the dynamics of internal dimensions

    NASA Astrophysics Data System (ADS)

    Giovannini, Massimo

    2000-12-01

    The dynamical evolution of internal spacelike dimensions breaks the invariance of Maxwell's equations under Weyl rescaling of the (conformally flat) four-dimensional metric. Depending upon the number and upon the dynamics of internal dimensions large scale magnetic fields can be created. The requirements coming from magnetogenesis together with the other cosmological constraints are examined under the assumption that the internal dimensions either grow or shrink (in conformal time) prior to a radiation-dominated epoch. If the internal dimensions are growing, the magnitude of the generated magnetic fields can seed the galactic dynamo mechanism.

  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. 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

  10. A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels.

    PubMed

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

    2016-02-25

    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

  11. 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

    2015-12-01

    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. PMID:26490960

  12. "Canonical and non-canonical actions of GRK5 in the heart".

    PubMed

    Traynham, Christopher J; Hullmann, Jonathan; Koch, Walter J

    2016-03-01

    As the average world-wide lifespan continues to increase, heart failure (HF) has dramatically increased in incidence leading to the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) play a prominent role in regulation of cardiovascular function. GPCRs are effectively "turned off" by GPCR kinases (GRKs) in a process known as "desensitization". GRKs 2 and 5 are highly expressed in the heart, and known to be upregulated in HF. Over the last 20years, the role of GRK2 in HF has been widely studied. However, until recently, the role of GRK5 in cardiac pathophysiology had yet to be elucidated. In the present review, we will focus on GRK5's role in the myocardium in normal physiology, and its apparent critical role in the progression of HF. Further, we will also present potential therapeutic strategies (i.e. small molecule inhibition, gene therapy) that may have potential in combating the deleterious effects of GRK5 in HF. PMID:26829117

  13. A Non-canonical Pathway from Cochlea to Brain Signals Tissue-damaging Noise

    PubMed Central

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

    2015-01-01

    Summary 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, that 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 we term auditory nociception. PMID:25639244

  14. Production of Non-Canonical Sentences in Agrammatic Aphasia: Limits in Representation or Rule Application?

    ERIC Educational Resources Information Center

    Burchert, Frank; Meissner, Nadine; De Bleser, Ria

    2008-01-01

    The study reported here compares two linguistically informed hypotheses on agrammatic sentence production, the TPH [Friedmann, N., & Grodzinsky, Y. (1997). "Tense and agreement in agrammatic production: Pruning the syntactic tree." "Brain and Language," 56, 397-425.] and the DOP [Bastiaanse, R., & van Zonneveld, R. (2005). "Sentence production…

  15. Non-canonical manifestations of familial Mediterranean fever: a changing paradigm.

    PubMed

    Rigante, Donato; Lopalco, Giuseppe; Tarantino, Giusyda; Compagnone, Adele; Fastiggi, Michele; Cantarini, Luca

    2015-09-01

    Paroxysmal crises of fever and systemic inflammation herald familial Mediterranean fever (FMF), considered as the archetype of all inherited systemic autoinflammatory diseases. Inflammatory bouts are characterized by short-term and self-limited abdominal, thoracic, and/or articular symptoms which subside spontaneously. Erysipelas-like findings, orchitis, and different patterns of myalgia may appear in a minority of patients. In recent years, many non-classical manifestations have been reported in the clinical context of FMF, such as vasculitides and thrombotic manifestations, neurologic and sensory organ abnormalities, gastrointestinal diseases, and even macrophage activation syndrome. As FMF left unrecognized and untreated is ominously complicated by the occurrence of AA-amyloidosis, it is highly desirable that diagnosis of this autoinflammatory disorder with its multiple clinical faces can be contemplated at whatever age and brought forward. PMID:25761640

  16. Non-canonical actions of Nogo-A and its receptors.

    PubMed

    Seiler, Stefanie; Di Santo, Stefano; Widmer, Hans Rudolf

    2016-01-15

    Nogo-A is a myelin associated protein and one of the most potent neurite growth inhibitors in the central nervous system. Interference with Nogo-A signaling has thus been investigated as therapeutic target to promote functional recovery in CNS injuries. Still, the finding that Nogo-A presents a fairly ubiquitous expression in many types of neurons in different brain regions, in the eye and even in the inner ear suggests for further functions besides the neurite growth repression. Indeed, a growing number of studies identified a variety of functions including regulation of neuronal stem cells, modulation of microglial activity, inhibition of angiogenesis and interference with memory formation. Aim of the present commentary is to draw attention on these less well-known and sometimes controversial roles of Nogo-A. Furthermore, we are addressing the role of Nogo-A in neuropathological conditions such as ischemic stroke, schizophrenia and neurodegenerative diseases. PMID:26348872

  17. Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40.

    PubMed

    Janowski, Robert; Heinz, Gitta A; Schlundt, Andreas; Wommelsdorf, Nina; Brenner, Sven; Gruber, Andreas R; Blank, Michael; Buch, Thorsten; Buhmann, Raymund; Zavolan, Mihaela; Niessing, Dierk; Heissmeyer, Vigo; Sattler, Michael

    2016-01-01

    The RNA-binding protein Roquin is required to prevent autoimmunity. Roquin controls T-helper cell activation and differentiation by limiting the induced expression of costimulatory receptors such as tumor necrosis factor receptor superfamily 4 (Tnfrs4 or Ox40). A constitutive decay element (CDE) with a characteristic triloop hairpin was previously shown to be recognized by Roquin. Here we use SELEX assays to identify a novel U-rich hexaloop motif, representing an alternative decay element (ADE). Crystal structures and NMR data show that the Roquin-1 ROQ domain recognizes hexaloops in the SELEX-derived ADE and in an ADE-like variant present in the Ox40 3'-UTR with identical binding modes. In cells, ADE-like and CDE-like motifs cooperate in the repression of Ox40 by Roquin. Our data reveal an unexpected recognition of hexaloop cis elements for the posttranscriptional regulation of target messenger RNAs by Roquin. PMID:27010430

  18. The MST/Hippo Pathway and Cell Death: A Non-Canonical Affair

    PubMed Central

    Fallahi, Emma; O’Driscoll, Niamh A.; Matallanas, David

    2016-01-01

    The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders. PMID:27322327

  19. Non-canonical RAN Translation of CGG Repeats Has Canonical Requirements.

    PubMed

    Cox, Diana C; Cooper, Thomas A

    2016-04-21

    Repeat expansions cause dominantly inherited neurological disorders. In this issue of Molecular Cell, Kearse et al. (2016) examine the requirements for RAN translation of the CGG repeats that cause fragile X-associated tremor/ataxia syndrome, revealing similarities and differences with canonical translation. PMID:27105111

  20. Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation

    PubMed Central

    Carrero, Zunamys I.; Kollareddy, Madhusudhan; Chauhan, Krishna M.; Ramakrishnan, Gopalakrishnan; Martinez, Luis A.

    2016-01-01

    Mutations in the tumor suppressor gene TP53 contribute to the development of approximately half of all human cancers. One mechanism by which mutant p53 (mtp53) acts is through interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with the erythroblastosis virus E26 oncogene homologue 2 (ETS2), an ETS transcription factor, and increases its protein stability. To study the mechanism underlying ETS2 degradation, we knocked down ubiquitin ligases known to interact with ETS2. We observed that knockdown of the constitutive photomorphogenesis protein 1 (COP1) and its binding partner De-etiolated 1 (DET1) significantly increased ETS2 stability, and conversely, their ectopic expression led to increased ETS2 ubiquitination and degradation. Surprisingly, we observed that DET1 binds to ETS2 independently of COP1, and we demonstrated that mutation of multiple sites required for ETS2 degradation abrogated the interaction between DET1 and ETS2. Furthermore, we demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Mechanistically, we show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. Our study reveals a hitherto unknown function in which DET1 mediates the interaction with the substrates of its cognate ubiquitin ligase complex and provides an explanation for the ability of mtp53 to protect ETS2. PMID:26871468

  1. 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

    2015-03-01

    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. PMID:25639244

  2. A Non-canonical RNA Silencing Pathway Promotes mRNA Degradation in Basal Fungi

    PubMed Central

    Nicolás, Francisco E.; Vila, Ana; Moxon, Simon; Dalmay, Tamas; Torres-Martínez, Santiago; Garre, Victoriano; Ruiz-Vázquez, Rosa M.

    2015-01-01

    The increasing knowledge on the functional relevance of endogenous small RNAs (esRNAs) as riboregulators has stimulated the identification and characterization of these molecules in numerous eukaryotes. In the basal fungus Mucor circinelloides, an emerging opportunistic human pathogen, esRNAs that regulate the expression of many protein coding genes have been described. These esRNAs share common machinery for their biogenesis consisting of an RNase III endonuclease Dicer, a single Argonaute protein and two RNA-dependent RNA polymerases. We show in this study that, besides participating in this canonical dicer-dependent RNA interference (RNAi) pathway, the rdrp genes are involved in a novel dicer-independent degradation process of endogenous mRNAs. The analysis of esRNAs accumulated in wild type and silencing mutants demonstrates that this new rdrp-dependent dicer-independent regulatory pathway, which does not produce sRNA molecules of discrete sizes, controls the expression of target genes promoting the specific degradation of mRNAs by a previously unknown RNase. This pathway mainly regulates conserved genes involved in metabolism and cellular processes and signaling, such as those required for heme biosynthesis, and controls responses to specific environmental signals. Searching the Mucor genome for candidate RNases to participate in this pathway, and functional analysis of the corresponding knockout mutants, identified a new protein, R3B2. This RNase III-like protein presents unique domain architecture, it is specifically found in basal fungi and, besides its relevant role in the rdrp-dependent dicer-independent pathway, it is also involved in the canonical dicer-dependent RNAi pathway, highlighting its crucial role in the biogenesis and function of regulatory esRNAs. The involvement of RdRPs in RNA degradation could represent the first evolutionary step towards the development of an RNAi mechanism and constitutes a genetic link between mRNA degradation and post-transcriptional gene silencing. PMID:25875805

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

    DOE PAGESBeta

    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 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

  4. 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.

  5. 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. PMID:27133313

  6. 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.

  7. 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...

  8. The core spliceosome as target and effector of non-canonical ATM signaling

    PubMed Central

    Tresini, Maria; Warmerdam, Daniël O.; Kolovos, Petros; Snijder, Loes; Vrouwe, Mischa G.; Demmers, Jeroen A.A.; van IJcken, Wilfred F.J.; Grosveld, Frank G.; Medema, René H.; Hoeijmakers, Jan H.J.; Mullenders, Leon H.F.; Vermeulen, Wim; Marteijn, Jurgen A.

    2015-01-01

    In response to DNA damage tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signaling pathways coordinate these processes, partly by propagating gene expression-modulating signals. DNA damage influences not only abundance of mRNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centered on the signaling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM which signals to further impede spliceosome organization and augment UV-triggered alternative splicing at genome-wide level. Our findings define the R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells and highlight a key role for spliceosome displacement in this process. PMID:26106861

  9. 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

  10. 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

  11. Canonical and non-canonical Wnt signaling control the regeneration of amputated rodent vibrissae follicles.

    PubMed

    Yuan, Yan-Ping; Huang, Keng; Xu, Yan-Min; Chen, Xian-Cai; Li, Hai-Hong; Cai, Bo-Zhi; Liu, Yang; Zhang, Huan; Li, Yu; Lin, Chang-Min

    2016-02-01

    Although mammals are notoriously poor at regeneration compared with many lower-order species, the hair follicle, particular to mammals, is capable of regeneration following partial amputation. The detailed internal mechanism of this phenomenon is still unclear. Development and regrowth of the hair follicle depends on dermal-epidermal interaction within the hair follicle. Previous studies have shown that Wnt/β-catenin, Shh, Bmp, PDGF, TGF and Notch signals all take part in the development and growth of the hair follicle, and the Wnt/β-catenin signaling additionally plays an indispensable role in hair follicle morphogenesis and regrowth. In this study, we investigated the localization, as well as, protein levels of Wnt/β-catenin signaling molecules during amputated whisker follicle regeneration. PMID:26742765

  12. [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. PMID:15859448

  13. Mitoconfusion: Non-canonical functioning of dynamism factors in static mitochondria of the heart

    PubMed Central

    Song, Moshi; Dorn, Gerald W.

    2015-01-01

    Mitochondrial fitness is central to heart health. In many cell types mitochondria are dynamic, interconnected filamentous networks. By comparison, mitochondria of healthy post-mitotic adult cardiomyocytes are shortened, round, hypo-dynamic organelles. Mitochondrial networks are absent in cardiomyocytes; fission, fusion, and organelle mobility are not normally observed. Nevertheless, mitochondrial fission factor Drp1 and fusion factors Mfn1, Mfn2, and Opa1 are abundant and indispensable in adult hearts. Here, we review recent insights into roles for mitochondrial dynamics factors not strictly related to morphometric remodeling, advancing the argument that fission and fusion of cardiomyocyte mitochondria supports surveillance, sequestration, and mitophagic removal of damaged organelles. PMID:25651174

  14. Identification of a broad family of lipid A late acyltransferases with non-canonical substrate specificity

    PubMed Central

    Rubin, Erica J.; O’Brien, John P.; Ivanov, Petko L.; Brodbelt, Jennifer S.; Trent, M. Stephen

    2014-01-01

    Summary Most gram-negative organisms produce lipopolysaccharide (LPS), a complex macromolecule anchored to the bacterial membrane by the lipid A moiety. Lipid A is synthesized via the Raetz pathway, a conserved nine-step enzymatic process first characterized in Escherichia coli. The Epsilonproteobacterium Helicobacter pylori uses the Raetz pathway to synthesize lipid A; however, only eight of nine enzymes in the pathway have been identified in this organism. Here, we identify the missing acyltransferase, Jhp0255, which transfers a secondary acyl chain to the 3′-linked primary acyl chain of lipid A, an activity similar to that of E. coli LpxM. This enzyme, reannotated as LpxJ due to limited sequence similarity with LpxM, catalyzes addition of a C12:0 or C14:0 acyl chain to the 3′-linked primary acyl chain of lipid A, complementing an E. coli LpxM mutant. Enzymatic assays demonstrate that LpxJ and homologs in Campylobacter jejuni and Wolinella succinogenes can act before the 2′ secondary acyltransferase, LpxL, as well as the 3-deoxy-D-manno-octulosonic acid (Kdo) transferase, KdtA. Ultimately, LpxJ is one member of a large class of acyltransferases found in a diverse range of organisms that lack an E. coli LpxM homolog, suggesting that LpxJ participates in lipid A biosynthesis in place of an LpxM homolog. PMID:24372821

  15. A non-canonical caleosin from Arabidopsis efficiently epoxidizes physiological unsaturated fatty acids with complete stereoselectivity.

    PubMed

    Blée, Elizabeth; Flenet, Martine; Boachon, Benoît; Fauconnier, Marie-Laure

    2012-10-01

    In plants, epoxygenated fatty acids (EFAs) are constituents of oil seeds as well as defence molecules and components of biopolymers (cutin, suberin). While the pleiotropic biological activities of mammalian EFAs have been well documented, there is a paucity of information on the physiological relevance of plant EFAs and their biosynthesis. Potential candidates for EFA formation are caleosin-type peroxygenases which catalyze the epoxidation of unsaturated fatty acids in the presence of hydroperoxides as co-oxidants. However, the caleosins characterized so far, which are mostly localized in seeds, are poor epoxidases. In sharp contrast, quantitative RT-PCR analysis revealed that PXG4, a class II caleosin gene, is expressed in roots, stems, leaves and flowers of Arabidopsis. Expressed in yeast, PXG4 encodes a calcium-dependent membrane-associated hemoprotein able to catalyze typical peroxygenase reactions. Moreover, we show here that purified recombinant PXG4 is an efficient fatty acid epoxygenase, catalyzing the oxidation of cis double bonds of unsaturated fatty acids. Physiological linoleic and linolenic acids proved to be the preferred substrates for PXG4; they are oxidized into the different positional isomers of the monoepoxides and into diepoxides. An important regioselectivity was observed; the C-12,13 double bond of these unsaturated fatty acids being the least favored unsaturation epoxidized by PXG4, linolenic acid preferentially yielded the 9,10-15,16-diepoxide. Remarkably, PXG4 catalyzes exclusively the formation of (R),(S)-epoxide enantiomers, which is the absolute stereochemistry of the epoxides found in planta. These findings pave the way for the study of the functional role of EFAs and caleosins in plants. PMID:22913587

  16. Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation.

    PubMed

    Carrero, Zunamys I; Kollareddy, Madhusudhan; Chauhan, Krishna M; Ramakrishnan, Gopalakrishnan; Martinez, Luis A

    2016-03-15

    Mutations in the tumor suppressor gene TP53 contribute to the development of approximately half of all human cancers. One mechanism by which mutant p53 (mtp53) acts is through interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with the erythroblastosis virus E26 oncogene homologue 2 (ETS2), an ETS transcription factor, and increases its protein stability. To study the mechanism underlying ETS2 degradation, we knocked down ubiquitin ligases known to interact with ETS2. We observed that knockdown of the constitutive photomorphogenesis protein 1 (COP1) and its binding partner De-etiolated 1 (DET1) significantly increased ETS2 stability, and conversely, their ectopic expression led to increased ETS2 ubiquitination and degradation. Surprisingly, we observed that DET1 binds to ETS2 independently of COP1, and we demonstrated that mutation of multiple sites required for ETS2 degradation abrogated the interaction between DET1 and ETS2. Furthermore, we demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Mechanistically, we show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. Our study reveals a hitherto unknown function in which DET1 mediates the interaction with the substrates of its cognate ubiquitin ligase complex and provides an explanation for the ability of mtp53 to protect ETS2. PMID:26871468

  17. The MST/Hippo Pathway and Cell Death: A Non-Canonical Affair.

    PubMed

    Fallahi, Emma; O'Driscoll, Niamh A; Matallanas, David

    2016-01-01

    The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders. PMID:27322327

  18. 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

  19. Dopaminergic neurons inhibit striatal output via non-canonical release of GABA

    PubMed Central

    Tritsch, Nicolas X.; Ding, Jun B.; Sabatini, Bernardo L.

    2012-01-01

    The substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) contain the two largest populations of dopamine (DA)-releasing neurons in the mammalian brain. These neurons extend elaborate projections in striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output via the release of DA to promote and reinforce motor action1–4. Here we show that activation of DA neurons in striatal slices rapidly inhibits action potential firing in both direct-and indirect-pathway striatal projection neurons (SPNs) through vesicular release of the inhibitory transmitter γ-aminobutyric acid (GABA). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for DA. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms employed by DA neurons to influence basal ganglia circuits, reveal a novel substrate whose transport is dependent on VMAT2, and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons. PMID:23034651

  20. Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation

    PubMed Central

    Gualdoni, Guido A.; Lingscheid, Tilman; Schmetterer, Klaus G.; Hennig, Annika; Steinberger, Peter; Zlabinger, Gerhard J.

    2015-01-01

    Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca++-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation, and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1α and IL-1β secretion upon LPS stimulation. Interference with Ca++-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin’s inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1β levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma. PMID:26152605

  1. Iterative tyrosine phosphorylation controls non-canonical domain utilization in Crk.

    PubMed

    Sriram, G; Jankowski, W; Kasikara, C; Reichman, C; Saleh, T; Nguyen, K-Q; Li, J; Hornbeck, P; Machida, K; Liu, T; Li, H; Kalodimos, C G; Birge, R B

    2015-08-01

    Crk, the prototypical member of a class of Src homology-2 (SH2) and Src homology-3 (SH3) domain containing proteins that controls the coordinated assembly of signaling complexes, is regulated by phosphorylation of Y221 in the linker region, which forms an intramolecular SH2-pY221 auto-clamp to interrupt SH2-N-terminal SH3 domain (SH3N) signaling. Here, we show using LC-MS/MS and by generating phospho-specific antibodies that, iteratively with Y221, the Crk C-terminal SH3 domain (SH3C) is routinely phosphorylated on Y239 and/or Y251 by several extracellular stimuli known to engage Crk. Although phosphorylation at Y221 auto-inhibits the Crk SH2, phosphorylation of the SH3C generates an unconventional phosphoSH3C-SH3N unit in which the SH3N is fully functional to bind polyproline type II ligands and the phosphoSH3C binds de novo to other SH2 domains. Using high-throughput SH2 domain profiling, artificial neural network and position-specific scoring matrix-based bioinformatics approaches, and unbiased mass spectometry, we found that the phosphoSH3C binds several SH2 domain containing proteins, including specific non-receptor tyrosine kinases-Abl via pY251 and C-terminal Src kinase via pY239. Functionally, we show that the phosphoSH3C modulates the Abl-mediated phenotypes of cell spreading and motility. Together, these studies describe a versatile mechanism wherein phosphorylation of Crk at Y221 is not an off switch but redirects signaling from the SH2-SH3N axis to a phosphoSH3C-SH3N axis, with the SH3N as a common denominator. PMID:25381819

  2. Micromagnetics at submicron dimensions (abstract)

    NASA Astrophysics Data System (ADS)

    Slonczewski, J. C.

    1997-04-01

    We represent the state of a circa 10-nm thick submicron dimensioned magnetic film with a superposition of two-dimensional (2D) magnetic pseudovortices. The effective intervortex exchange-stiffness potential and local magnetization angle at a complex distance z=x+iy from the kth vortex center are given by the real and imaginary parts respectively, of the function -wklnz. Each of the four corners of the rectangle has a stationary quarter vortex with negative winding (wk=-1). Two mobile semivortices with winding wk=+1 and N and S magnetic poles lie at general positions X1 and X2, respectively, along edges of the rectangle. The approximate boundary condition of vanishing M-component normal to each edge is satisfied by repeated reflections which generate a periodic extension of this vortex array to a lattice filling all of a 2D space. The internal energy V(X1,X2) is principally composed of the inter vortex exchange stiffness. Given this function, numerical evaluation of the integrated moment m=m(X1,X2) provides the functional dependence of V on m as parametrized by (X1,X2). The function V(X1,X2) has four equal minima representing states with the N and S vortices located at diagonally opposite corners, in agreement with direct numerical simulations. Therefore, the predicted hysteresis behavior of our vortex model has significantly more complex transitions than those of a uniaxial single-domain particle having only two minima. Our employment of but two variables, rather than the continuum of straightforward micromagnetics, makes possible a more insightful analysis of the smallscale structures used in storage and memory.

  3. Prehension Synergies in Three Dimensions

    PubMed Central

    Shim, Jae Kun; Latash, Mark L.; Zatsiorsky, Vladimir M.

    2010-01-01

    The goal of this study was to investigate the conjoint changes of digit forces/moments in 3 dimensions during static prehension under external torques acting on the object in one plane. The experimental paradigm was similar to holding a book vertically in the air where the center of mass of the book is located farther from the hand than the points of digit contacts. Three force and 3 moment components from each digit were recorded during static prehension of a customized handle. Subjects produced forces and moments in all 3 directions, although the external torques were exerted on the handheld object about only the Z-axis. The 3-dimensional response to a 2-dimensional task was explained by the cause– effect chain effects prompted by the noncollinearity of the normal forces of the thumb and the 4 fingers (represented by the “virtual finger”). Because the forces are not collinear (not along the same line), they generate moments of force about X- and Y-axes that are negated by the finger forces along the Y- and X-directions. The magnitudes of forces produced by lateral fingers (index and little) with longer moment arms were larger compared with the central fingers (middle and ring). At the virtual finger (an imaginary digit whose mechanical action is equivalent to the summed action of the 4 fingers) level, the relative contribution of different fractions of the resistive moment produced by subjects did not depend on the torque magnitude. We conclude that the CNS 1) solves a planar prehension task by producing forces and moments in all 3 directions, 2) uses mechanical advantage of fingers, and 3) shares the total torque among finger forces and moments in a particular way disregarding the torque magnitude. PMID:15456799

  4. 49 CFR 178.360-3 - Dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Dimensions. 178.360-3 Section 178.360-3 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY... Specifications for Packagings for Class 7 (Radioactive) Materials § 178.360-3 Dimensions. (a) The inside...

  5. An Inventory of Listening Competency Dimensions

    ERIC Educational Resources Information Center

    Wolvin, Andrew D.; Cohen, Steven D.

    2012-01-01

    This article proposes the use of a one-page listening inventory sheet that helps students explore five dimensions of listening competency: cognitive, affective, behavioral, contextual, and ethical. After crafting their own responses, students will have the opportunity to engage in a class discussion about the impact of various dimensions of…

  6. 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…

  7. 49 CFR 178.360-3 - Dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Dimensions. 178.360-3 Section 178.360-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Packagings for Class 7 (Radioactive) Materials § 178.360-3 Dimensions. (a) The inside diameter of the...

  8. 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…

  9. 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…

  10. 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…

  11. 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…

  12. The SYMLOG Dimensions and Small Group Conflict.

    ERIC Educational Resources Information Center

    Wall, Victor D., Jr.; Galanes, Gloria J.

    1986-01-01

    Explores the potential usefulness of R.F. Bales' systematic method for the multiple level observation of groups (SYMLOG) by testing the predictive capability of the three SYMLOG dimensions and the amount of member dispersion on each dimension with the amounts of conflict, reported satisfaction, styles of conflict management, and quality of…

  13. 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…

  14. Physics of Extra Dimensions Final Report

    SciTech Connect

    Csaba Csaki

    2007-12-19

    We provide the final report for Csaba Csaki's OJI project on "Physics of extra dimensions". It includes the summary of results of higgsless electroweak symmetry breaking, gauge-higgs unification, AdS/QCD and holographic technicolor, and chiral lattice theories from warped extra dimensions.

  15. Dimensions of Family Coping with Head Injury.

    ERIC Educational Resources Information Center

    Kosciulek, John F.

    1994-01-01

    Examined dimensions underlying family coping with head injury. Data from 150 families with a member with a head injury identified 3 dimensions of coping: individual-to-family versus family-to-community coping; family-respite versus head-injury-focused coping; and cognitive versus behavioral coping. Findings have implications for family stress and…

  16. World View: The Second Hidden Dimension.

    ERIC Educational Resources Information Center

    Skow, Lisa; And Others

    Proposing that world view is a dimension of culture which lies below the surface of human behavior at the level of the subconscious, this paper argues that this often ignored dimension of culture profoundly influences human communication. The paper is divided into two sections. First, world view is defined and its importance in explaining how…

  17. On the dimension of projected polyhedra

    SciTech Connect

    Bales, E.; Oosten, M.

    1994-12-31

    We establish several results relating the dimension of a polyhedron to that of its projections on various subspaces. In particular, we give necessary and sufficient conditions for a polyhedron to have the same dimension as its projection, and for the facet of a polyhedron to project into a facet of the projected polyhedron.

  18. 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.

  19. Is cosmic censorship restored in higher dimensions?

    NASA Astrophysics Data System (ADS)

    Mkenyeleye, M. D.; Goswami, Rituparno; Maharaj, Sunil D.

    2015-07-01

    In this paper we extend the analysis of gravitational collapse of spherically symmetric generalized Vaidya spacetimes to higher dimensions, in the context of the cosmic censorship conjecture. We present the sufficient conditions on the generalized Vaidya mass function that will generate a locally naked singular end state. Our analysis here generalizes all the earlier works on collapsing higher dimensional generalized Vaidya spacetimes. With specific examples, we show the existence of classes of mass functions that lead to a naked singularity in four dimensions, which gets covered on transition to higher dimensions. Hence for these classes of mass function cosmic censorship gets restored in higher dimensions and the transition to higher dimensions restricts the set of initial data that results in a naked singularity.

  20. [Cognitive dimensions used in rating work performance].

    PubMed

    Yanagizawa, Saori

    2008-12-01

    This study explored the cognitive dimensions used by individuals in judging work performance based on the individual scale methodology of Hayashi, Ohashi, & Hirooka (1983). The participants were fifteen undergraduate students and nine workers. First, the participants described the characteristics of eight high performers and eight low performers whom they had worked with. Second, from these characteristics, they selected twenty characteristics that they considered as determinants in judging whether performers are superior or inferior. Third, using an individual scale consisting of the selected characteristics, they rated sixteen high performers and sixteen low performers. Factor analyses were conducted for each participant's ratings on the individual scale. The results suggested that three or four dimensions were generally used in judging performers, although there were individual differences in the number of dimensions used. Undergraduate students judged performers using more cognitive dimensions than workers did. The contents of the cognitive dimensions were relevant to technical skill, work attitude, cognitive ability, motivation, interpersonal competence, leadership, and personality. Undergraduate students used fewer cognitive ability dimensions and more personality dimensions than workers used. PMID:19172909

  1. Correlation of heart external dimensions with body external dimensions of human foetuses.

    PubMed

    Nowak, Dariusz; Boziłow, Władimir; Wałek, Sebastian

    2003-02-01

    In an evaluation of foetal hearts in II and III pregnancy semester, correlation with exterior foetal dimensions should be taken into consideration. It is interesting also if all exterior heart dimensions are correlated at the same level with overall body dimensions. The subject of examination was 204 foetuses of both sexes, including 106 males and 98 females, in 5th and 6th month of foetal life. Foetuses were fixed for minimum 3 months in 9% formalin solution. They were taken from natural abortions, without exterior features of developmental malformations. Examined material was evaluated in month groups of morphological age. The number of foetuses in different groups was various. Exterior heart dimensions were considered: height, width, heart depth, and also heart circumference in coronary sulcus (atrial-ventricular). Exterior dimensions of foetuses were: vertex-plantare, vertex-tubulare. All exterior dimensions of heart are closely and strongly correlated with both exterior dimensions of foetuses. PMID:12769177

  2. 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.

  3. Topological mass generation in 3 + 1 dimensions

    SciTech Connect

    Allen, T.J.; Bowick, M.J.; Lahiri, A. . Dept. of Physics)

    1991-03-07

    In this paper, the 4-dimensional theory of a 1-form Abelian gauge field A coupled to a 2-form (antisymmetric tensor) potential B. The two gauge invariances of the theory admit a coupling mB F where F is the field strength (F = dA) of A. It is shown that this theory is a unitary, renormalizable theory of a massive spin-one field with no additional degrees of freedom. In this sense, it is a generalization to four dimensions of topological mechanisms in two dimensions (the Schwinger model) and three dimensions (Chern-Simons theory). The issue of spontaneous symmetry breaking is also examined.

  4. 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.

  5. Faces of root polytopes in all dimensions.

    PubMed

    Szajewska, Marzena

    2016-07-01

    In this paper the root polytopes of all finite reflection groups W with a connected Coxeter-Dynkin diagram in {\\bb R}^n are identified, their faces of dimensions 0 ≤ d ≤ n - 1 are counted, and the construction of representatives of the appropriate W-conjugacy class is described. The method consists of recursive decoration of the appropriate Coxeter-Dynkin diagram [Champagne et al. (1995). Can. J. Phys. 73, 566-584]. Each recursion step provides the essentials of faces of a specific dimension and specific symmetry. The results can be applied to crystals of any dimension and any symmetry. PMID:27357848

  6. 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

  7. 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.

  8. Testing dimension and nonclassicality in communication networks

    NASA Astrophysics Data System (ADS)

    Bowles, Joseph; Brunner, Nicolas; Pawłowski, Marcin

    2015-08-01

    We consider networks featuring preparation, transformation, and measurement devices, in which devices exchange communication via mediating physical systems. We investigate the problem of testing the dimension of the mediating systems in the device-independent scenario, that is, based on observable data alone. A general framework for tackling this problem is presented, considering both classical and quantum systems. These methods can then also be used to certify the nonclassicality of the mediating systems, given an upper bound on their dimension. Several case studies are reported, which illustrate the relevance of the framework. These examples also show that, for fixed dimension, quantum systems largely outperform classical ones. Moreover, the use of a transformation device considerably improves noise tolerance when compared to simple prepare-and-measure networks. These results suggest that the classical simulation of quantum systems becomes costly in terms of dimension, even for simple networks.

  9. 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.

  10. Randomness in fractals, connectivity dimensions, and percolation

    NASA Astrophysics Data System (ADS)

    Perreau, M.; Levy, J. C. S.

    1989-10-01

    The structural properties of random fractals embedded in a d-dimensional Euclidean space are studied by means of transfer-matrix formalism of fractal sets. For d=1, both global and local approaches have been investigated, leading to the definition of a subdimension that is different from the fractal dimension and depends on the probability distribution. This subdimension is shown to be identical for the global and local approaches; then, the scaling corrections involved in this subdimension are the same for both these approaches. For d>1, only the local approach can be generalized, characterizing the connectivity properties of these structures. There are exactly d subdimensions called connectivity dimensions that prove to be useful to describe percolation properties of these fractals. Several percolation thresholds are shown, and the fractal dimension of the sets at the percolation threshold are related to the connectivity dimensions.

  11. A dimension map for molecular aggregates.

    PubMed

    Jian, Cuiying; Tang, Tian; Bhattacharjee, Subir

    2015-05-01

    A pair of gyradius ratios, defined from the principal radii of gyration, are used to generate a dimension map that describes the geometry of molecular aggregates in water and in organic solvents. Molecular dynamics simulations were performed on the aggregation of representative biomolecules and polyaromatic compounds to demonstrate application of the dimension map. It was shown that molecular aggregate data on the dimension map were bounded by two boundary curves, and that the map could be separated into three regions representing three groups of structures: one-dimensional rod-like structures; two-dimensional planar structures or short-cylinder-like structures; and three-dimensional sphere-like structures. Examining the location of the aggregates on the dimension map and how the location changes with solvent type and solute material parameter provides a simple yet effective way to infer the aggregation manner and to study solubility and mechanism of aggregation. PMID:25768393

  12. Loop quantum cosmology in 2 +1 dimension

    NASA Astrophysics Data System (ADS)

    Zhang, Xiangdong

    2014-12-01

    As a first step to generalize the structure of loop quantum cosmology to the theories with the spacetime dimension other than four, the isotropic model of loop quantum cosmology in 2 +1 dimension is studied in this paper. We find that the classical big bang singularity is again replaced by a quantum bounce in the model. The similarities and differences between the (2 +1 )-dimensional model and the (3 +1 )-dimensional one are also discussed.

  13. Bar dimensions and bar shapes in estuaries

    NASA Astrophysics Data System (ADS)

    Leuven, Jasper; Kleinhans, Maarten; Weisscher, Steven; van der Vegt, Maarten

    2016-04-01

    Estuaries cause fascinating patterns of dynamic channels and shoals. Intertidal sandbars are valuable habitats, whilst channels provide access to harbors. We still lack a full explanation and classification scheme for the shapes and dimensions of bar patterns in natural estuaries, in contrast with bars in rivers. Analytical physics-based models suggest that bar length in estuaries increases with flow velocity, tidal excursion length or estuary width, depending on which model. However, these hypotheses were never validated for lack of data and experiments. We present a large dataset and determine the controls on bar shape and dimensions in estuaries, spanning bar lengths from centimeters (experiments) to 10s of kilometers length. First, we visually identified and classified 190 bars, measured their dimensions (width, length, height) and local braiding index. Data on estuarine geometry and tidal characteristics were obtained from governmental databases and literature on case studies. We found that many complex bars can be seen as simple elongated bars partly cut by mutually evasive ebb- and flood-dominated channels. Data analysis shows that bar dimensions scale with estuary dimensions, in particular estuary width. Breaking up the complex bars in simple bars greatly reduced scatter. Analytical bar theory overpredicts bar dimensions by an order of magnitude in case of small estuarine systems. Likewise, braiding index depends on local width-to-depth ratio, as was previously found for river systems. Our results suggest that estuary dimensions determine the order of magnitude of bar dimensions, while tidal characteristics modify this. We will continue to model bars numerically and experimentally. Our dataset on tidal bars enables future studies on the sedimentary architecture of geologically complex tidal deposits and enables studying effects of man-induced perturbations such as dredging and dumping on bar and channel patterns and habitats.

  14. 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.

  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. Dimensions of emotion in expressive musical performance.

    PubMed

    Vines, Bradley W; Krumhansl, Carol L; Wanderley, Marcelo M; Dalca, Ioana M; Levitin, Daniel J

    2005-12-01

    This paper explores the dimensions of emotion conveyed by music. Participants rated emotion terms after seeing and/or hearing recordings of clarinet performances that varied in expressive content. A factor analysis revealed four independent dimensions of emotion. Changes to the clarinetists' expressive intentions did not significantly affect emotions conveyed by sound. It was largely through the visual modality that expressive intentions influenced the experience for observers. PMID:16597804

  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. Spectral dimension of a quantum universe

    SciTech Connect

    Modesto, Leonardo; Nicolini, Piero

    2010-05-15

    In this paper, we calculate in a transparent way the spectral dimension of a quantum spacetime, considering a diffusion process propagating on a fluctuating manifold. To describe the erratic path of the diffusion, we implement a minimal length by averaging the graininess of the quantum manifold in the flat space case. As a result we obtain that, for large diffusion times, the quantum spacetime behaves like a smooth differential manifold of discrete dimension. On the other hand, for smaller diffusion times, the spacetime looks like a fractal surface with a reduced effective dimension. For the specific case in which the diffusion time has the size of the minimal length, the spacetime turns out to have a spectral dimension equal to 2, suggesting a possible renormalizable character of gravity in this regime. For smaller diffusion times, the spectral dimension approaches zero, making any physical interpretation less reliable in this extreme regime. We extend our result to the presence of a background field and curvature. We show that in this case the spectral dimension has a more complicated relation with the diffusion time, and conclusions about the renormalizable character of gravity become less straightforward with respect to what we found with the flat space analysis.

  19. Cross-cultural generalizability of personality dimensions: relating indigenous and imported dimensions in two cultures.

    PubMed

    Katigbak, M S; Church, A T; Akamine, T X

    1996-01-01

    The cross-cultural generalizability of personality dimensions was investigated by (a) identifying indigenous Philippine dimensions, (b) testing the cross-cultural replicability of the NEO 5-factor model (P. T. Costa & R.R. McCrae, 1992), and (c) relating Philippine and Western dimensions in Philippine and U.S. samples of college students. Filipino self-ratings (N = 536) on indigenous items were factor analyzed, and 6 Philippine dimensions were obtained. Conclusions about the replicability of the 5-factor model in the Philippines (N = 432) depended on whether exploratory, Procrustes, or confirmatory factor methods were used. In regression and joint factor analyses, moderate to strong associations were found between the Philippine dimensions and (a) dimensions from the 5-factor model in both Philippine (N = 387) and U.S. (N = 610) samples, and (b) the Tellegen model (A. Tellegen, 1985; A. Tellegen & N.G. Waller, in press) in a U.S. sample (N = 603). PMID:8558409

  20. Cosmic string evolution in higher dimensions

    SciTech Connect

    Avgoustidis, A.; Shellard, E.P.S.

    2005-06-15

    We obtain the equations of motion for cosmic strings in extensions of the 3+1 Friedmann-Robertson-Walker (FRW) model with extra dimensions. From these we derive a generalization of the velocity-dependent one-scale model for cosmic string network evolution which we apply, first, to a higher-dimensional isotropic D+1 FRW model and, second, to a 3+1 FRW model with static flat extra dimensions. In the former case the string network does not achieve a scaling regime because of the diminishing rate of string intersections (D>3), but this can be avoided in the latter case by considering compact, small extra dimensions, for which there is a reduced but still appreciable string intercommuting probability. We note that the velocity components lying in the three expanding dimensions are Hubble damped, whereas those in the static extra dimensions are only very weakly damped. This leads to the pathological possibility, in principle, that string motion in the three infinite dimensions can come to a halt preventing the strings from intersecting, with the result that scaling is not achieved and the strings irreversibly dominate the early universe. We note criteria by which this can be avoided, notably if the spatial structure of the network becomes essentially three-dimensional, as is expected for string networks produced in brane inflation. Applying our model to a brane inflation setting, we find scaling solutions in which the effective 3D string motion does not necessarily stop, but it is slowed down because of the excitations trapped in the extra dimensions. These effects are likely to influence cosmic string network evolution for a long period after formation and we discuss their more general implications.

  1. A modified holographic dark energy model with infrared infinite extra dimension(s)

    NASA Astrophysics Data System (ADS)

    Gong, Yungui; Li, Tianjun

    2010-01-01

    We propose a modified holographic dark energy (MHDE) model with the Hubble scale as the infrared (IR) cutoff. Introducing the infinite extra dimension(s) at very large distance scale, we consider the black hole mass in higher dimensions as the ultraviolet cutoff. Thus, we can probe the effects of the IR infinite extra dimension(s). As a concrete example, we consider the Dvali-Gabadadze-Porrati (DGP) model and its generalization. We find that the DGP model is dual to the MHDE model in five dimensions, and the ΛCDM model is dual to the MHDE model in six dimensions. Fitting the MHDE model to the observational data, we obtain that Ωm0=0.269-0.027+0.030, Ωk0=0.003-0.012+0.011, and the number of the spatial dimensions is N=4.78-0.44+0.68. The best fit value of N implies that there might exist two IR infinite extra dimensions.

  2. Control of a continuous response dimension by a continuous stimulus dimension1

    PubMed Central

    Wildemann, Donald G.; Holland, James G.

    1972-01-01

    Pigeons were trained to respond to stimuli from a continuous stimulus dimension (tonal frequency) with response values from a continuous response dimension. Both the number of points of correspondence and problem difficulty were varied. After training, subjects were tested with stimulus values intermediate to those trained. During these test tones, subjects emitted only those response values reinforced during training. The study suggested that if there are fast and efficient methods to obtain control of a continuous response dimension by a continuous stimulus dimension, these methods must depend on factors other than simple generalization. PMID:16811635

  3. 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

  4. 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.

  5. 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.

  6. Quantum spectral dimension in quantum field theory

    NASA Astrophysics Data System (ADS)

    Calcagni, Gianluca; Modesto, Leonardo; Nardelli, Giuseppe

    2016-03-01

    We reinterpret the spectral dimension of spacetimes as the scaling of an effective self-energy transition amplitude in quantum field theory (QFT), when the system is probed at a given resolution. This picture has four main advantages: (a) it dispenses with the usual interpretation (unsatisfactory in covariant approaches) where, instead of a transition amplitude, one has a probability density solving a nonrelativistic diffusion equation in an abstract diffusion time; (b) it solves the problem of negative probabilities known for higher-order and nonlocal dispersion relations in classical and quantum gravity; (c) it clarifies the concept of quantum spectral dimension as opposed to the classical one. We then consider a class of logarithmic dispersion relations associated with quantum particles and show that the spectral dimension dS of spacetime as felt by these quantum probes can deviate from its classical value, equal to the topological dimension D. In particular, in the presence of higher momentum powers it changes with the scale, dropping from D in the infrared (IR) to a value dSUV ≤ D in the ultraviolet (UV). We apply this general result to Stelle theory of renormalizable gravity, which attains the universal value dSUV = 2 for any dimension D.

  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. Estimation of large-scale dimension densities.

    PubMed

    Raab, C; Kurths, J

    2001-07-01

    We propose a technique to calculate large-scale dimension densities in both higher-dimensional spatio-temporal systems and low-dimensional systems from only a few data points, where known methods usually have an unsatisfactory scaling behavior. This is mainly due to boundary and finite-size effects. With our rather simple method, we normalize boundary effects and get a significant correction of the dimension estimate. This straightforward approach is based on rather general assumptions. So even weak coherent structures obtained from small spatial couplings can be detected with this method, which is impossible by using the Lyapunov-dimension density. We demonstrate the efficiency of our technique for coupled logistic maps, coupled tent maps, the Lorenz attractor, and the Roessler attractor. PMID:11461376

  9. Estimation of large-scale dimension densities

    NASA Astrophysics Data System (ADS)

    Raab, Corinna; Kurths, Jürgen

    2001-07-01

    We propose a technique to calculate large-scale dimension densities in both higher-dimensional spatio-temporal systems and low-dimensional systems from only a few data points, where known methods usually have an unsatisfactory scaling behavior. This is mainly due to boundary and finite-size effects. With our rather simple method, we normalize boundary effects and get a significant correction of the dimension estimate. This straightforward approach is based on rather general assumptions. So even weak coherent structures obtained from small spatial couplings can be detected with this method, which is impossible by using the Lyapunov-dimension density. We demonstrate the efficiency of our technique for coupled logistic maps, coupled tent maps, the Lorenz attractor, and the Roessler attractor.

  10. Maximum stabilizer dimension for nonproduct states

    SciTech Connect

    Walck, Scott N.; Lyons, David W.

    2007-08-15

    Composite quantum states can be classified by how they behave under local unitary transformations. Each quantum state has a stabilizer subgroup and a corresponding Lie algebra, the structure of which is a local unitary invariant. In this paper, we study the structure of the stabilizer subalgebra for n-qubit pure states, and find its maximum dimension to be n-1 for nonproduct states of three qubits and higher. The n-qubit Greenberger-Horne-Zeilinger state has a stabilizer subalgebra that achieves the maximum possible dimension for pure nonproduct states. The converse, however, is not true: We show examples of pure 4-qubit states that achieve the maximum nonproduct stabilizer dimension, but have stabilizer subalgebra structures different from that of the n-qubit GHZ state.

  11. Control of a Continuous Response Dimension by a Continuous Stimulus Dimension.

    ERIC Educational Resources Information Center

    Wildemann, Donald G.; Holland, James G.

    Pigeons were trained to respond to stimuli from a continuous stimulus dimension (tonal frequency) with response values from continuous response dimension. Both the number of points of correspondence and problem difficulty were varied. Following training, subjects were tested with stimulus values intermediate to those trained. During these test…

  12. Dimension Theory for Invariant Measures of Endomorphisms

    NASA Astrophysics Data System (ADS)

    Shu, Lin

    2010-08-01

    We establish the exact dimensional property of an ergodic hyperbolic measure for a C 2 non-invertible but non-degenerate endomorphism on a compact Riemannian manifold without boundary. Based on this, we give a new formula of Lyapunov dimension of ergodic measures and show it coincides with the dimension of hyperbolic ergodic measures in a setting of random endomorphisms. Our results extend several well known theorems of Barreira et al. (Ann Math 149:755-783, 1999) and Ledrappier and Young [Commun Math Phys 117(4):529-548, 1988] for diffeomorphisms to the case of endomorphisms.

  13. The pore dimensions of gramicidin A.

    PubMed Central

    Smart, O S; Goodfellow, J M; Wallace, B A

    1993-01-01

    The ion channel forming peptide gramicidin A adopts a number of distinct conformations in different environments. We have developed a new method to analyze and display the pore dimensions of ion channels. The procedure is applied to two x-ray crystal structures of gramicidin that adopt distinct antiparallel double helical dimer conformations and a nuclear magnetic resonance (NMR) structure for the beta6.3 NH2-terminal to NH2-terminal dimer. The results are discussed with reference to ion conductance properties and dependence of pore dimensions on the environment. Images FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 PMID:7508762

  14. 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…

  15. New Dimensions for the Multicultural Education Course

    ERIC Educational Resources Information Center

    Gay, Richard

    2011-01-01

    For the past sixteen years, the Five Dimensions of Multicultural Education, as proposed by James A. Banks (1995), have been accepted in many circles as the primary conceptual framework used in teaching multicultural education courses: content integration, the knowledge construction process, prejudice reduction, an equity pedagogy and an empowering…

  16. Shaving Ceramic Tiles To Final Dimensions

    NASA Technical Reports Server (NTRS)

    Shaw, Ernest

    1992-01-01

    Combination of template and routing tool cuts ceramic tiles to final dimensions. Template guides router along precisely defined planes to accurately and uniformly shave chamfers on edge of tiles. Legs of template temporarily bonded to workpiece by double-backed adhesive tape. Adaptable to in-situ final machining of other nominally flat, narrow surfaces.

  17. Content Validation of the Purpose Dimension.

    ERIC Educational Resources Information Center

    LaPlante, Marilyn J.; Jewett, Ann E.

    1987-01-01

    The article reports on LaPlante's research (1973) on evaluation of the purpose dimension of the Purpose Process Curriculum Framework, which established a set of criteria for evaluating the framework and demonstrated that the Delphi technique is appropriate for study of physical education curriculum. (CB)

  18. Dimensions of Black Suicide: A Theoretical Model.

    ERIC Educational Resources Information Center

    Davis, Robert; Short, James F., Jr.

    This paper develops a theoretical model of sucide, based on the theory of "external restraints" proposed by previous researchers, A.F. Henry and J.F. Short, Jr., and applies the model to a study of black suicides in Orleans Parish, Louisiana. The focus of the study is on the complexity of relationships between dimensions of black suicide and the…

  19. Affective Dimensions of Adult Literacy Development.

    ERIC Educational Resources Information Center

    Durgunoglu, Aydin Y.

    To investigate affective dimensions of adult literacy development more systematically, researchers conducted a qualitative comparative analysis of four women participating in an adult literacy program in Istanbul, Turkey. The contrastive study chose two participants who completed the course; each was matched with a participant who had dropped out.…

  20. The Emotional Dimensions of Urban Teacher Change

    ERIC Educational Resources Information Center

    McCaughtry, Nate; Martin, Jeffrey; Kulinna, Pamela Hodges; Cothran, Donetta

    2006-01-01

    This study used an emotional geographies theoretical framework to analyze the emotional dimensions of urban teacher change. Fifteen urban physical education teachers involved in a comprehensive curriculum reform project were interviewed and observed multiple times across one school year. Data were analyzed using inductive analysis, and…

  1. 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.

  2. 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…

  3. 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.

  4. 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…

  5. 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…

  6. Fractal Dimensions and Entropies of Meragi Songs

    NASA Astrophysics Data System (ADS)

    Aydemir, Adnan; Gündüz, Güngör

    Melodies can be treated as time series systems with the pitches (or frequencies of the notes) representing the values in subsequent intervals. The pattern of a melody can be revealed in a scattering diagram where pitches represent vertices, and the directed pathways which connect the former pitches to the next ones signify the relations established during the performance. The pathways form a pattern which is called animal diagram (or lattice animal) in the vocabulary of graph theory. The slopes of pathways can be used to characterize an animal diagram and thus to characterize a melody; and the scattering diagram can be used to find out the fractal dimension . In addition, the entropy , the maximum entropy , and the negentropy (or the order) of melodies can be determined. The analysis of Meragi songs in terms of fractal dimension and entropy was carried out in this work. It was found out that there is not a correlation between the fractal dimension and the entropy ; therefore, the fractal dimension and the entropy each characterizes different aspects of Meragi songs.

  7. 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…

  8. Forms and Dimensions of Civic Involvement

    ERIC Educational Resources Information Center

    Wang, Yan; Jackson, Golden

    2005-01-01

    This research assesses (a) students' perceptions of civic involvement from either a charity or social justice perspective, and (b) the relationship among six dimensions of civic involvement (Knowledge, Skill, Efficacy, Value, Responsibility, and Commitment) for developing a charity or social justice perspective. Pre- and post-course analysis…

  9. 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…

  10. 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…

  11. Dimensions of Marriage Happiness: A Research Note

    ERIC Educational Resources Information Center

    Marini, Margaret Mooney

    1976-01-01

    In an earlier article, Orden and Bradburn (1968) presented a model for the structure of marital happiness which consisted of two independent dimensions, one of marital satisfactions and the other of marital tensions. Further examination of their data suggests that their measures of satisfactions and tensions were only two of a larger number of…

  12. Dimensions of Women's Health across the Lifespan

    ERIC Educational Resources Information Center

    Vamos, Cheryl A.; Vamos, Sandra D.

    2008-01-01

    Objective: This teaching strategy provides students with an opportunity to promote women's health literacy via construction of a creative health information booklet. Students will be able to: (1) Identify health issues that affect women during one particular lifespan stage; (2) Categorize issues according to the seven dimensions of health; (3)…

  13. 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…

  14. Counseling Gay Men with AIDS: Human Dimensions.

    ERIC Educational Resources Information Center

    Barret, Robert L.

    1989-01-01

    Provides case material that demonstrates the emotional response of homosexual men to Acquired Immune Deficiency Syndrome (AIDS). Discusses denial, anger, rage, guilt, and shame experienced by these men with an emphasis on the human dimensions of AIDS. Concludes that most powerful contribution of counselors is their willingness to "be with" persons…

  15. 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, Learning…

  16. 49 CFR 178.360-3 - Dimensions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Dimensions. 178.360-3 Section 178.360-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications...

  17. 49 CFR 178.360-3 - Dimensions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Dimensions. 178.360-3 Section 178.360-3 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) SPECIFICATIONS FOR PACKAGINGS Specifications...

  18. Three Dimensions of Oppositionality in Youth

    ERIC Educational Resources Information Center

    Stringaris, Argyris; Goodman, Robert

    2009-01-01

    Background: Oppositional defiant disorder (ODD) in youth is a strong predictor of mental illness yet the wide range of associations with psychiatric disorders remains largely unexplained. The aim of this study was to investigate whether the identification of irritable, headstrong and hurtful dimensions within youth oppositionality would clarify…

  19. 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...

  20. 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...

  1. 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...

  2. 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…

  3. 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…

  4. 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…

  5. A note on unparticle in lower dimensions

    NASA Astrophysics Data System (ADS)

    Gaete, Patricio; Spallucci, Euro

    2008-10-01

    Using the gauge-invariant but path-dependent variables formalism, we examine the effect of the space time dimensionality on a physical observable in the unparticle scenario. We explicitly show that long-range forces between particles mediated by unparticles are still present whenever we go over into lower dimensions.

  6. Integrable theories in any dimension: a perspective

    SciTech Connect

    Alvarez, Orlando; Ferreira, L. A.

    1999-07-13

    We review the developments of a recently proposed approach to study integrable theories in any dimension. The basic idea consists in generalizing the zero curvature representation for two-dimensional integrable models to space-times of dimension d+1 by the introduction of a d-form connection. The method has been used to study several theories of physical interest, like self-dual Yang-Mills theories, Bogomolny equations, non-linear sigma models and Skyrme-type models. The local version of the generalized zero curvature involves a Lie algebra and a representation of it, leading to a number of conservation laws equal to the dimension of that representation. We discuss the conditions a given theory has to satisfy in order for its associated zero curvature to admit an infinite dimensional (reducible) representation. We also present the theory in the more abstract setting of the space of loops, which gives a deeper understanding and a more simple formulation of integrability in any dimension.

  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. Improving Contact Prediction along Three Dimensions

    PubMed Central

    Pagnani, Andrea; Aurell, Erik

    2014-01-01

    Correlation patterns in multiple sequence alignments of homologous proteins can be exploited to infer information on the three-dimensional structure of their members. The typical pipeline to address this task, which we in this paper refer to as the three dimensions of contact prediction, is to (i) filter and align the raw sequence data representing the evolutionarily related proteins; (ii) choose a predictive model to describe a sequence alignment; (iii) infer the model parameters and interpret them in terms of structural properties, such as an accurate contact map. We show here that all three dimensions are important for overall prediction success. In particular, we show that it is possible to improve significantly along the second dimension by going beyond the pair-wise Potts models from statistical physics, which have hitherto been the focus of the field. These (simple) extensions are motivated by multiple sequence alignments often containing long stretches of gaps which, as a data feature, would be rather untypical for independent samples drawn from a Potts model. Using a large test set of proteins we show that the combined improvements along the three dimensions are as large as any reported to date. PMID:25299132

  9. 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.

  10. 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…

  11. School Furniture Dimensions: Standing and Reaching.

    ERIC Educational Resources Information Center

    Department of Education and Science, London (England).

    Performance of school children in regard to their standing and reach postures are described with dimensions given on the limits of their performance only. The facts of task performances are presented for the following tasks--(1) seeing into a shelf, (2) reaching into a shelf, (3) drawing on a vertical surface, (4) sitting or standing while…

  12. 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.

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

    DOEpatents

    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.

  14. Autism Spectrum Disorder: Defining Dimensions and Subgroups.

    PubMed

    Ousley, Opal; Cermak, Tracy

    2014-03-01

    Autism spectrum disorder (ASD) is a behaviorally defined neurodevelopmental disorder associated with the presence of social-communication deficits and restricted and repetitive behaviors. In the latest conceptualization of ASD, these two behavioral dimensions represent the core defining features of ASD, whereas associated dimensions, such as intellectual and language ability, provide a means for describing the ASD heterogeneity. In addition, the characterization of ASD subgroups, defined by the presence of known medical, genetic, or other psychiatric disorders, furthers our understanding of ASD heterogeneity. This paper reviews the history of autism, describes its core defining features, and provides an overview of the clinically and etiologically relevant subgroups that add to the complexity of this condition. PMID:25072016

  15. Brane modeling in warped extra-dimension

    NASA Astrophysics Data System (ADS)

    Ahmed, Aqeel; Grzadkowski, Bohdan

    2013-01-01

    Five-dimensional scenarios with infinitesimally thin branes replaced by appropriate configurations of a scalar field were considered. A possibility of periodic extra dimension was discussed in the presence on non-minimal scalar-gravity coupling and a generalized Gibbons-Kallosh-Linde sum rule was found. In order to avoid constraints imposed by periodicity, a non-compact spacial extra dimension was introduced. A five dimensional model with warped geometry and two thin branes mimicked by a scalar profile was constructed and discussed. In the thin brane limit the model corresponds to a set-up with two positive-tension branes. The presence of two branes allows to address the issue of the hierarchy problem which could be solved by the standard warping of the four dimensional metric provided the Higgs field is properly localized. Stability of the background solution was discussed and verified in the presence of the most general perturbations of the metric and the scalar field.

  16. Resurgence of the cusp anomalous dimension

    NASA Astrophysics Data System (ADS)

    Dorigoni, Daniele; Hatsuda, Yasuyuki

    2015-09-01

    We revisit the strong coupling limit of the cusp anomalous dimension in planar N=4 super Yang-Mills theory. It is known that the strong coupling expansion is asymptotic and non-Borel summable. As a consequence, the cusp anomalous dimension receives non-perturbative corrections, and the complete strong coupling expansion should be a resurgent transseries. We reveal that the perturbative and non-perturbative parts in the transseries are closely interrelated. Solving the Beisert-Eden-Staudacher equation systematically, we analyze in detail the large order behavior in the strong coupling pertur- bative expansion and show that the non-perturbative information is indeed encoded there. An ambiguity of (lateral) Borel resummations of the perturbative expansion is precisely canceled by the contributions from the non-perturbative sectors, and the final result is real and unambiguous.

  17. 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.

  18. Autism Spectrum Disorder: Defining Dimensions and Subgroups

    PubMed Central

    Cermak, Tracy

    2014-01-01

    Autism spectrum disorder (ASD) is a behaviorally defined neurodevelopmental disorder associated with the presence of social-communication deficits and restricted and repetitive behaviors. In the latest conceptualization of ASD, these two behavioral dimensions represent the core defining features of ASD, whereas associated dimensions, such as intellectual and language ability, provide a means for describing the ASD heterogeneity. In addition, the characterization of ASD subgroups, defined by the presence of known medical, genetic, or other psychiatric disorders, furthers our understanding of ASD heterogeneity. This paper reviews the history of autism, describes its core defining features, and provides an overview of the clinically and etiologically relevant subgroups that add to the complexity of this condition. PMID:25072016

  19. 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.

  20. 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.

  1. Spatiotemporal accessible solitons in fractional dimensions

    NASA Astrophysics Data System (ADS)

    Zhong, Wei-Ping; Belić, Milivoj R.; Malomed, Boris A.; Zhang, Yiqi; Huang, Tingwen

    2016-07-01

    We report solutions for solitons of the "accessible" type in globally nonlocal nonlinear media of fractional dimension (FD), viz., for self-trapped modes in the space of effective dimension 2

  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. Scattering of Massless Particles in Arbitrary Dimensions

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

    We present a compact formula for the complete tree-level S-matrix of pure Yang-Mills and gravity theories in arbitrary spacetime dimensions. The new formula for the scattering of n particles is given by an integral over the positions of n points on a sphere restricted to satisfy a dimension-independent set of equations. The integrand is constructed using the reduced Pfaffian of a 2n ×2n matrix, Ψ, that depends on momenta and polarization vectors. In its simplest form, the gravity integrand is a reduced determinant which is the square of the Pfaffian in the Yang-Mills integrand. Gauge invariance is completely manifest as it follows from a simple property of the Pfaffian.

  4. 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

  5. Spatiotemporal accessible solitons in fractional dimensions.

    PubMed

    Zhong, Wei-Ping; Belić, Milivoj R; Malomed, Boris A; Zhang, Yiqi; Huang, Tingwen

    2016-07-01

    We report solutions for solitons of the "accessible" type in globally nonlocal nonlinear media of fractional dimension (FD), viz., for self-trapped modes in the space of effective dimension 2

  6. 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.

  7. Modeling rotating stars in two dimensions

    NASA Astrophysics Data System (ADS)

    Rieutord, M.

    2013-09-01

    In this lecture I present the way stars can be modeled in two dimensions and especially the fluid flows that are driven by rotation. I discuss some of the various ways of taking into account turbulence and conclude this contribution by a short presentation of some of the first results obtained with the ESTER code on the modeling of interferometrically observed fast rotating early-type stars.

  8. Signals for Extra Dimensions at CLIC

    SciTech Connect

    Rizzo, Thomas G.

    2001-08-28

    A brief overview is presented of the signatures for several different models with extra dimensions at CLIC, an e{sup +}e{sup -} linear collider with a center of mass energy of 3-5 TeV and an integrated luminosity of order 1 ab{sup -1}. In all cases the search reach for the resulting new physic signatures is found to be in the range of {approx} 15-80 TeV.

  9. 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.

  10. Dimensional reduction without continuous extra dimensions

    SciTech Connect

    Chamseddine, Ali H.; Froehlich, J.; Schubnel, B.; Wyler, D.

    2013-01-15

    We describe a novel approach to dimensional reduction in classical field theory. Inspired by ideas from noncommutative geometry, we introduce extended algebras of differential forms over space-time, generalized exterior derivatives, and generalized connections associated with the 'geometry' of space-times with discrete extra dimensions. We apply our formalism to theories of gauge- and gravitational fields and find natural geometrical origins for an axion- and a dilaton field, as well as a Higgs field.

  11. Baryon currents in QCD with compact dimensions

    SciTech Connect

    Lucini, B.; Patella, A.; Pica, C.

    2007-06-15

    On a compact space with nontrivial cycles, for sufficiently small values of the radii of the compact dimensions, SU(N) gauge theories coupled with fermions in the fundamental representation spontaneously break charge conjugation, time reversal, and parity. We show at one loop in perturbation theory that a physical signature for this phenomenon is a nonzero baryonic current wrapping around the compact directions. The persistence of this current beyond the perturbative regime is checked by lattice simulations.

  12. tt * geometry in 3 and 4 dimensions

    NASA Astrophysics Data System (ADS)

    Cecotti, Sergio; Gaiotto, Davide; Vafa, Cumrun

    2014-05-01

    We consider the vacuum geometry of supersymmetric theories with 4 supercharges, on a flat toroidal geometry. The 2 dimensional vacuum geometry is known to be captured by the tt * geometry. In the case of 3 dimensions, the parameter space is ( T 2 × ) N and the vacuum geometry turns out to be a solution to a generalization of monopole equations in 3 N dimensions where the relevant topological ring is that of line operators. We compute the generalization of the 2d cigar amplitudes, which lead to S 2 × S 1 or S 3 partition functions which are distinct from the supersymmetric partition functions on these spaces, but reduce to them in a certain limit. We show the sense in which these amplitudes generalize the structure of 3d Chern-Simons theories and 2d RCFT's. In the case of 4 dimensions the parameter space is of the form X M,N = ( T 3 × ) M × T 3 N , and the vacuum geometry is a solution to a mixture of generalized monopole equations and generalized instanton equations (known as hyper-holomorphic connections). In this case the topological rings are associated to surface operators. We discuss the physical meaning of the generalized Nahm transforms which act on all of these geometries.

  13. 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.

  14. 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. PMID:27214902

  15. White dwarf stars in D dimensions

    NASA Astrophysics Data System (ADS)

    Chavanis, P.-H.

    2007-07-01

    We derive the mass-radius relation of relativistic white dwarf stars (modeled as a self-gravitating degenerate Fermi gas at T=0) in a D-dimensional universe and study the influence of the dimension of space on the laws of physics when we combine quantum mechanics, special relativity, and gravity. We exhibit characteristic dimensions D=1, D=2, D=3, D=(3+17)/2, D=4, D=2(1+2) and show that quantum mechanics cannot balance gravitational collapse for D≥4. This is similar to a result found by Ehrenfest (1917) at the atomic level for Coulomb forces (in Bohr’s model) and for the Kepler problem. This makes the dimension of our universe D=3 very particular with possible implications regarding the anthropic principle. We discuss some historic aspects concerning the discovery of the Chandrasekhar (1931) limiting mass in relation to previous investigations by Anderson (1929) and Stoner (1930). We also propose different derivations of the stability limits of polytropic distributions and consider their application to classical and relativistic white dwarf stars.

  16. General quantum key distribution in higher dimension

    NASA Astrophysics Data System (ADS)

    Xiong, Zhao-Xi; Shi, Han-Duo; Wang, Yi-Nan; Jing, Li; Lei, Jin; Mu, Liang-Zhu; Fan, Heng

    2012-01-01

    We study a general quantum key distribution protocol in higher dimension. In this protocol, quantum states in arbitrary g+1 (1≤g≤d) out of all d+1 mutually unbiased bases in a d-dimensional system can be used for the key encoding. This provides a natural generalization of the quantum key distribution in higher dimension and recovers the previously known results for g=1 and d. In our investigation, we study Eve's attack by two slightly different approaches. One is considering the optimal cloner of Eve, and the other, defined as the optimal attack, is maximizing Eve's information. We derive results for both approaches and show the deviation of the optimal cloner from the optimal attack. With our systematic investigation of the quantum key distribution protocols in higher dimension, one may balance the security gain and the implementation cost by changing the number of bases in the key encoding. As a side product, we also prove the equivalency between the optimal phase covariant quantum cloning machine and the optimal cloner for the g=d-1 quantum key distribution.

  17. 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.

  18. 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.

  19. Determination of sex by armbone dimensions.

    PubMed

    Aye, Victor Omakoji

    2010-06-15

    Sex determination is a vital part of the medico-legal system but can be difficult in cases where the body is damaged. The purpose of this study was to develop a technique for sex determination from three arm-bone dimensions (wrist circumference, arm length and arm span). This knowledge can be applied in cases of mass disaster, homicide and events such as sports. Data were collected for 95 Nigerian male students and 90 Nigerian female students using physical anthropometry. Discriminant function presented the wrist dimension as the dominant contributor in this study. Combination equations for both the wrist and arm-span dimensions correctly classified sex (male/female) with an accuracy rate of 84.9%. On cross-validation, sex was also established with the same 84.9% accuracy rate. Sex determination was higher in males. Sexual dimorphism was established in this study, although the wrist circumference was more distinct than arm span; a combination of both generated sex with an accuracy prediction rate of 84.9%. PMID:20395082

  20. 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.

  1. Unconscious evaluation of faces on social dimensions.

    PubMed

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

    2012-11-01

    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 that they are likely to be interpretations arising from interactions between the face stimuli and observer-specific traits. Monocularly viewed faces that varied independently along two social dimensions of trust and dominance were rendered invisible by continuous flash suppression (CFS) when a flashing pattern was presented to the other eye. Participants pressed a button as soon as they saw the face emerge from suppression to indicate whether the previously hidden face was located slightly to the left or right of central fixation. Dominant and untrustworthy faces took significantly longer time to emerge (T2E) compared with neutral faces. A control experiment showed these findings could not reflect delayed motor responses to conscious faces. Finally, we showed that participants' self-reported propensity to trust was strongly predictive of untrust avoidance (i.e., difference in T2E for untrustworthy vs neutral faces) as well as dominance avoidance (i.e., difference in T2E for dominant vs neutral faces). Dominance avoidance was also correlated with submissive behavior. We suggest that such prolongation of suppression for threatening faces may result from a passive fear response, leading to slowed visual perception. PMID:22468670

  2. 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.

  3. Trainlets: Dictionary Learning in High Dimensions

    NASA Astrophysics Data System (ADS)

    Sulam, Jeremias; Ophir, Boaz; Zibulevsky, Michael; Elad, Michael

    2016-06-01

    Sparse representations has shown to be a very powerful model for real world signals, and has enabled the development of applications with notable performance. Combined with the ability to learn a dictionary from signal examples, sparsity-inspired algorithms are often achieving state-of-the-art results in a wide variety of tasks. Yet, these methods have traditionally been restricted to small dimensions mainly due to the computational constraints that the dictionary learning problem entails. In the context of image processing, this implies handling small image patches. In this work we show how to efficiently handle bigger dimensions and go beyond the small patches in sparsity-based signal and image processing methods. We build our approach based on a new cropped wavelet decomposition, which enables a multi-scale analysis with virtually no border effects. We then employ this as the base dictionary within a double sparsity model to enable the training of adaptive dictionaries. To cope with the increase of training data, while at the same time improving the training performance, we present an Online Sparse Dictionary Learning (OSDL) algorithm to train this model effectively, enabling it to handle millions of examples. This work shows that dictionary learning can be up-scaled to tackle a new level of signal dimensions, obtaining large adaptable atoms that we call trainlets.

  4. Groupwise Dimension Reduction via Envelope Method

    PubMed Central

    Guo, Zifang; Li, Lexin; Lu, Wenbin; Li, Bing

    2016-01-01

    The family of sufficient dimension reduction (SDR) methods that produce informative combinations of predictors, or indices, are particularly useful for high dimensional regression analysis. In many such analyses, it becomes increasingly common that there is available a priori subject knowledge of the predictors; e.g., they belong to different groups. While many recent SDR proposals have greatly expanded the scope of the methods’ applicability, how to effectively incorporate the prior predictor structure information remains a challenge. In this article, we aim at dimension reduction that recovers full regression information while preserving the predictor group structure. Built upon a new concept of the direct sum envelope, we introduce a systematic way to incorporate the group information in most existing SDR estimators. As a result, the reduction outcomes are much easier to interpret. Moreover, the envelope method provides a principled way to build a variety of prior structures into dimension reduction analysis. Both simulations and real data analysis demonstrate the competent numerical performance of the new method. PMID:26973362

  5. 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. PMID:1960272

  6. 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. PMID:23588506

  7. 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.

  8. Statistically interacting quantum gases in D dimensions

    NASA Astrophysics Data System (ADS)

    Potter, Geoffrey G.

    Chapter 1. Exact and explicit results are derived for the thermodynamic properties (isochores, isotherms, isobars, response functions, speed of sound) of a quantum gas in dimensions D ≥ 1 and with fractional exclusion statistics 0 ≤ g ≤ 1 connecting bosons (g = 0) and fermions (g = 1). In D = 1 the results are equivalent to those of the Calogero-Sutherland model, a gas with long-range two-body interaction. Emphasis is given to the crossover between boson-like and fermion-like features, caused by aspects of the statistical interaction that mimic long-range attraction and short-range repulsion. A phase transition along the isobar occurs at a nonzero temperature in all dimensions. The T-dependence of the speed of sound is in simple relation to isochores and isobars. The effects of soft container walls are accounted for rigorously for the case of a pure power-law potential. Chapter 2. The exact thermodynamics (isochores, isotherms, isobars, response functions, speed of sound) is worked out for a statistically interacting quantum gas in D dimensions. The results in D = 1 are those of the thermodynamic Bethe ansatz for the Nonlinear Schrodinger model, a gas with repulsive two-body contact potential. In all dimensions the ideal boson and fermion gases are recovered in the weak-coupling and strong-coupling limits, respectively. For all nonzero couplings ideal fermion gas behavior emerges for D >> 1 and, in the limit D → infinity, a phase transition occurs at T > 0. Significant deviations from ideal quantum gas behavior are found for intermediate coupling and finite D . Chapter 3. Methodology previously developed in the framework of the coordinate Bethe ansatz applied to integrable quantum gas models is employed to calculate some ground-state properties and elementary excitations for quantum gas models in D = 1 dimensions with statistical interactions that are not equivalent to dynamical interactions. The focus in this comparative study is on modifications of the

  9. Quantum Gravity in More than Four Dimensions.

    NASA Astrophysics Data System (ADS)

    Vaz, Cenalo

    Ever since its inception, Einstein's general relativity has been considered a most remarkable theory. It is generally believed today, that the classical theory is well understood. Nevertheless, in the pursuit of a deeper understanding of physics in terms of a 'grand' unification of forces, one would like to quantize the theory, thus bringing it under the known forces of nature. We will address the possibility that space-time is of dimension greater that four. In the pursuit of Einstein's dream of a unification of physical interactions, many interesting ideas have been developed. Beginning with Weyl and Kaluza, we have progressed to strings and superstrings. The thing that is common to all these theories is the requirement of a space-time of more than four dimensions. To explain the apparent dimensionality of space-time, the extra dimensions are thought to form some compact manifold of extremely small characteristic size. While Kaluza's theory implicitly assumes that Einstein's gravity is classically correct in any number of dimensions, superstring phenomenology may suggest otherwise. Generalizations to Einstein's gravity are indicated, and the gravitational Casimir energy is explicitly approximated on a background configuration M^4 times S^6, on a ten dimensional space-time. Weyl invariance is particularly interesting to the quantum gravitationalist. One finds that energy momentum tensor of the Weyl invariant quantum field picks up an anomalous trace, which is related to particle production by the curved background. We therefore compute the conformal anomaly for a conformally coupled scalar field and consider some of its consequences. We then suggest that the conformal anomaly, when combined with the perfect fluid hypothesis, can be used to determine the complete energy momentum tensor of the quantum field in certain backgrounds. Christensen has suggested that by imposing some 'natural' conditions to be obeyed by the renormalized stress tensor, one could avoid most

  10. One universal extra dimension in PYTHIA

    NASA Astrophysics Data System (ADS)

    ElKacimi, M.; Goujdami, D.; Przysiezniak, H.; Skands, P.

    2010-01-01

    The Universal Extra Dimensions model has been implemented in the PYTHIA generator from version 6.4.18 onwards, in its minimal formulation with one TeV -1-sized extra dimension. The additional possibility of gravity-mediated decays, through a variable number of eV -1-sized extra dimensions into which only gravity extends, is also available. The implementation covers the lowest lying Kaluza-Klein (KK) excitations of Standard Model particles, except for the excitations of the Higgs fields, with the mass spectrum calculated at one loop. 2→2 tree-level production cross sections and unpolarized KK number conserving 2-body decays are included. Mixing between iso-doublet and -singlet KK excitations is neglected thus far, and is expected to be negligible for all but the top sector. New version summaryProgram title: PYTHIA Version number: 6.420 Catalogue identifier: ACTU_v2_1 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ACTU_v2_1.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 79 362 No. of bytes in distributed program, including test data, etc.: 590 900 Distribution format: tar.gz Programming language: Fortran 77 Computer: CERN lxplus and any other machine with a Fortran 77 compiler Operating system: Linux Red Hat RAM: about 800 K words Word size: 32 bits Classification: 11.2 Catalogue identifier of previous version: ACTU_v2_0 Journal reference of previous version: Comput. Phys. Comm. 135 (2001) 238 Does the new version supersede the previous version?: Yes Nature of problem: At high energy collisions between elementary particles, physics beyond the Standard Model is searched for. Many models are being investigated, namely extra-dimensional models. Solution method: The Universal Extra Dimension model is implemented in the PYTHIA event generator. Reasons for new version

  11. Gender differences in dimensions of anxiety sensitivity.

    PubMed

    Stewart, S H; Taylor, S; Baker, J M

    1997-01-01

    Anxiety sensitivity (AS) is the fear of anxiety-related sensations arising from beliefs that these sensations have harmful physical, psychological, or social consequences. AS is measured using the Anxiety Sensitivity Index (ASI), a 16-item self-report questionnaire. Little is known about the origins of AS, although social learning experiences (including sex-role socialization experiences) may be important. The present study examined whether there were gender differences in: (a) the lower- or higher-order factor structure of the ASI; and/or (b) pattern of ASI factor scores. The ASI was completed by 818 university students (290 males; 528 females). Separate principal components analyses on the ASI items of the total sample, males, and females revealed nearly identical lower-order three-factor structures for all groups, with factors pertaining to fears about the anticipated (a) physical, (b) psychological, and (c) social consequences of anxiety. Separate principal components analyses on the lower-order factor scores of the three samples revealed similar unidimensional higher-order solutions for all groups. Gender x AS dimension analyses on ASI lower-order factor scores showed that: females scored higher than males only on the physical concerns factor; females scored higher on the physical concerns factor relative to their scores on the social and psychological concerns factors; and males scored higher on the social and psychological concerns factors relative to their scores on the physical concerns factor. Finally, females scored higher than males on the higher-order factor representing the global AS construct. The present study provides further support for the empirical distinction of the three lower-order dimensions of AS, and additional evidence for the theoretical hierarchical structure of the ASI. Results also suggest that males and females differ on these various AS dimensions in ways consistent with sex role socialization practices. PMID:9168341

  12. 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.

  13. 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.

  14. Singlet fission in reduced dimensions of crystals

    NASA Astrophysics Data System (ADS)

    Teichen, Paul; Eaves, Joel

    2014-03-01

    In some molecular systems the decay of an initially excited singlet into two independent triplets, a process called singlet fission, is highly efficient. Organic crystals are among the most promising candidates for increasing yields in next-generation photovoltaics. Although excitons are known to exist in reduced dimensions of crystals the role of dimensionality in the entanglement of two triplets born out of singlet fission remains unclear. We develop a quantum lattice model for singlet fission to examine the role of quantum entanglement and exciton delocalization.

  15. Large Extra Dimension and Dark Matter Detection

    SciTech Connect

    Qin Bo; Starkman, Glenn D.; Silk, Joseph

    2008-01-03

    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.

  16. Finite element radiation transport in one dimension

    SciTech Connect

    Painter, J.F.

    1997-05-09

    A new physics package solves radiation transport equations in one space dimension, multiple energy groups and directions. A discontinuous finite element method discretizes radiation intensity with respect to space and angle, and a continuous finite element method discretizes electron temperature `in space. A splitting method solves the resulting linear equations. This is a one-dimensional analog of Kershaw and Harte`s two-dimensional package. This package has been installed in a two-dimensional inertial confinement fusion code, and has given excellent results for both thermal waves and highly directional radiation. In contrast, the traditional discrete ordinate and spherical harmonic methods show less accurate results in both cases.

  17. Fractal dimension in nonhyperbolic chaotic scattering

    NASA Technical Reports Server (NTRS)

    Lau, Yun-Tung; Finn, John M.; Ott, Edward

    1991-01-01

    In chaotic scattering there is a Cantor set of input-variable values of zero Lebesgue measure (i.e., zero total length) on which the scattering function is singular. For cases where the dynamics leading to chaotic scattering is nonhyperbolic (e.g., there are Kolmogorov-Arnol'd-Moser tori), the nature of this singular set is fundamentally different from that in the hyperbolic case. In particular, for the nonhyperbolic case, although the singular set has zero total length, strong evidence is presented to show that its fractal dimension is 1.

  18. 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.

  19. Wavelet frames and admissibility in higher dimensions

    SciTech Connect

    Fuehr, H.

    1996-12-01

    This paper is concerned with the relations between discrete and continuous wavelet transforms on {ital 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 L{sup 2}({bold R}{sup {ital k}}) 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. {copyright} {ital 1996 American Institute of Physics.}

  20. 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.

  1. A new string in ten dimensions?

    NASA Astrophysics Data System (ADS)

    Sethi, Savdeep

    2013-09-01

    I suggest the possibility of a new string in ten dimensions. Evidence for this string is presented both from orientifold physics and from K-theory, along with a mystery concerning the M-theory description. Motivated by this possibility, some novel aspects of decoupling limits in heterotic/type I theories are described; specifically, the decoupled theory on type I D-strings is argued to be three-dimensional rather than two-dimensional. These decoupled theories provide the matrix model definitions of the heterotic/type I strings.

  2. 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.

  3. 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.

  4. Charged balanced black rings in five dimensions

    NASA Astrophysics Data System (ADS)

    Kleihaus, Burkhard; Kunz, Jutta; Schnülle, Kirsten

    2011-05-01

    We present balanced black ring solutions of pure Einstein-Maxwell theory in five dimensions. The solutions are asymptotically flat, and their tension and gravitational self-attraction are balanced by the repulsion due to rotation and electrical charge. Hence the solutions are free of conical singularities and possess a regular horizon which exhibits the ring topology S×S. We discuss the global charges and the horizon properties of the solutions and show that they satisfy a Smarr relation. We construct these black rings numerically, restricting to the case of black rings with a rotation in the direction of the S and large black rings. We compare these to the blackfold results.

  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. Generalized Efimov Effect in One Dimension.

    PubMed

    Moroz, Sergej; D'Incao, José P; Petrov, Dmitry S

    2015-10-30

    We study a one-dimensional quantum problem of two particles interacting with a third one via a scale-invariant subcritically attractive inverse square potential, which can be realized, for example, in a mixture of dipoles and charges confined to one dimension. We find that above a critical mass ratio, this version of the Calogero problem exhibits the generalized Efimov effect, the emergence of discrete scale invariance manifested by a geometric series of three-body bound states with an accumulation point at zero energy. PMID:26565445

  7. Exploring dimensions of access to medical care.

    PubMed

    Andersen, R M; McCutcheon, A; Aday, L A; Chiu, G Y; Bell, R

    1983-01-01

    This paper examines the dimensions of the access concept with particular attention to the extent to which more parsimonious indicators of access can be developed. This process is especially useful to health policy makers, planners and researchers in need of cost-effective social indicators of access to monitor the need for and impact of innovative health care programs. Three stages of data reduction are used in the analysis, resulting in a reduced set of key indicators of the concept. Implication for subsequent data collection and measurement of access are discussed. PMID:6841113

  8. 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.

  9. 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...

  10. 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...

  11. 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…

  12. 33 CFR Appendix I to Subpart A of... - Vessel Dimensions

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Vessel Dimensions I Appendix I to... Subpart A of Part 401—Vessel Dimensions Structures are located at a number of Seaway locks which, when... of 23.2 m. For vessels that have a beam width less than this and that have dimensions exceeding...

  13. 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…

  14. Logical Rules and the Classification of Integral-Dimension Stimuli

    ERIC Educational Resources Information Center

    Little, Daniel R.; Nosofsky, Robert M.; Donkin, Christopher; Denton, Stephen E.

    2013-01-01

    A classic distinction in perceptual information processing is whether stimuli are composed of separable dimensions, which are highly analyzable, or integral dimensions, which are processed holistically. Previous tests of a set of logical-rule models of classification have shown that separable-dimension stimuli are processed serially if the…

  15. 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…

  16. 24 CFR 3280.110 - Minimum room dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 5 2011-04-01 2011-04-01 false Minimum room dimensions. 3280.110... Minimum room dimensions. The gross floor area required by § 3280.110 (a) and (b) shall have no clear horizontal dimension less than 5 feet except as permitted by § 3280.102(a)....

  17. 33 CFR 401.3 - Maximum vessel dimensions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Maximum vessel dimensions. 401.3... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.3 Maximum vessel dimensions..., and having dimensions that do not exceed the limits set out in the block diagram in appendix I of...

  18. 33 CFR Appendix I to Subpart A of... - Vessel Dimensions

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Vessel Dimensions I Appendix I to... Subpart A of Part 401—Vessel Dimensions Structures are located at a number of Seaway locks which, when... of 23.2 m. For vessels that have a beam width less than this and that have dimensions exceeding...

  19. 33 CFR 401.3 - Maximum vessel dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Maximum vessel dimensions. 401.3... TRANSPORTATION SEAWAY REGULATIONS AND RULES Regulations Condition of Vessels § 401.3 Maximum vessel dimensions..., and having dimensions that do not exceed the limits set out in the block diagram in appendix I of...

  20. 24 CFR 3280.110 - Minimum room dimensions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Minimum room dimensions. 3280.110... Minimum room dimensions. The gross floor area required by § 3280.110 (a) and (b) shall have no clear horizontal dimension less than 5 feet except as permitted by § 3280.102(a)....

  1. 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...

  2. 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...

  3. 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...

  4. Interactive Dimensions in the Construction of Mental Representations for Text

    ERIC Educational Resources Information Center

    Rapp, David N.; Taylor, Holly A.

    2004-01-01

    To detail the structure and format of memory for texts, researchers have examined whether readers monitor separate text dimensions for space, time, and characters. The authors proposed that the interactivity between these individual dimensions may be as critical to the construction of complex mental models as the discrete dimensions themselves. In…

  5. Electrophysiological Markers of Visual Dimension Changes and Response Changes

    ERIC Educational Resources Information Center

    Tollner, Thomas; Gramann, Klaus; Muller, Hermann J.; Kiss, Monika; Eimer, Martin

    2008-01-01

    In cross-dimensional visual search tasks, target discrimination is faster when the previous trial contained a target defined in the same visual dimension as the current trial. The dimension-weighting account (DWA; A. Found & H. J. Muller, 1996) explains this intertrial facilitation by assuming that visual dimensions are weighted at an early…

  6. 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…

  7. NLO BFKL and Anomalous Dimensions of Light-Ray Operators

    SciTech Connect

    Balitsky, Ian

    2014-01-01

    The anomalous dimensions of light-ray operators of twist two are obtained by analytical continuation of the anomalous dimensions of corresponding local operators. I demonstrate that the asymptotics of these anomalous dimensions at the "BFKL point" j → 1 can be obtained by comparing the light-cone operator expansion with the high-energy expansion in Wilson lines.

  8. 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. PMID:25997539

  9. 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.

  10. Unparticles and anomalous dimensions in the cuprates

    NASA Astrophysics Data System (ADS)

    Karch, Andreas; Limtragool, Kridsanaphong; Phillips, Philip W.

    2016-03-01

    Motivated by the overwhelming evidence some type of quantum criticality underlies the power-law for the optical conductivity and T-linear resistivity in the cuprates, we demonstrate here how a scale-invariant or unparticle sector can lead to a unifying description of the observed scaling forms. We adopt the continuous mass formalism or multi band (flavor) formalism of the unparticle sector by letting various microscopic parameters be mass-dependent. In particular, we show that an effective mass that varies with the flavor index as well as a running band edge and lifetime capture the AC and DC transport phenomenology of the cuprates. A key consequence of the running mass is that the effective dynamical exponent can differ from the underlying bare critical exponent, thereby providing a mechanism for realizing the fractional values of the dynamical exponent required in a previous analysis [1]. We also predict that regardless of the bare dynamical exponent, z, a non-zero anomalous dimension for the current is required. Physically, the anomalous dimension arises because the charge depends on the flavor, mass or energy. The equivalent phenomenon in a d + 1 gravitational construction is the running of the charge along the radial direction. The nature of the superconducting instability in the presence of scale invariant stuff shows that the transition temperature is not necessarily a monotonic function of the pairing interaction.

  11. Hamiltonian quantum computer in one dimension

    NASA Astrophysics Data System (ADS)

    Wei, Tzu-Chieh; Liang, John C.

    2015-12-01

    Quantum computation can be achieved by preparing an appropriate initial product state of qudits and then letting it evolve under a fixed Hamiltonian. The readout is made by measurement on individual qudits at some later time. This approach is called the Hamiltonian quantum computation and it includes, for example, the continuous-time quantum cellular automata and the universal quantum walk. We consider one spatial dimension and study the compromise between the locality k and the local Hilbert space dimension d . For geometrically 2-local (i.e., k =2 ), it is known that d =8 is already sufficient for universal quantum computation but the Hamiltonian is not translationally invariant. As the locality k increases, it is expected that the minimum required d should decrease. We provide a construction of a Hamiltonian quantum computer for k =3 with d =5 . One implication is that simulating one-dimensional chains of spin-2 particles is BQP-complete (BQP denotes "bounded error, quantum polynomial time"). Imposing translation invariance will increase the required d . For this we also construct another 3-local (k =3 ) Hamiltonian that is invariant under translation of a unit cell of two sites but that requires d to be 8.

  12. General gauge mediation in five dimensions

    SciTech Connect

    McGarrie, Moritz; Russo, Rodolfo

    2010-08-01

    We use the ''general gauge mediation'' (GGM) formalism to describe a five-dimensional setup with an S{sup 1}/Z{sub 2} orbifold. We first consider a model independent supersymmetry breaking hidden sector on one boundary and generic chiral matter on another. Using the definition of GGM, the effects of the hidden sector are contained in a set of global symmetry current correlator functions and is mediated through the bulk. We find the gaugino, sfermion and hyperscalar mass formulas for minimal and generalized messengers in different regimes of a large, small and intermediate extra dimension. Then we use the five-dimensional GGM formalism to construct a model in which an SU(5) Intriligator, Seiberg and Shih (ISS) model is located on the hidden boundary. We weakly gauge a global symmetry of the ISS model and associate it with the bulk vector superfield. Compared to four-dimensional GGM, there is a natural way to adjust the gaugino versus sfermion mass ratio by a factor (Ml){sup 2}, where M is a characteristic mass scale of the supersymmetry breaking sector and l is the length of the extra dimension.

  13. 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.

  14. Single cell correlation fractal dimension of chromatin

    PubMed Central

    Récamier, Vincent; Izeddin, Ignacio; Bosanac, Lana; Dahan, Maxime; Proux, Florence; Darzacq, Xavier

    2014-01-01

    Chromatin is a major nuclear component, and it is an active matter of debate to understand its different levels of spatial organization, as well as its implication in gene regulation. Measurements of nuclear chromatin compaction were recently used to understand how DNA is folded inside the nucleus and to detect cellular dysfunctions such as cancer. Super-resolution imaging opens new possibilities to measure chromatin organization in situ. Here, we performed a direct measure of chromatin compaction at the single cell level. We used histone H2B, one of the 4 core histone proteins forming the nucleosome, as a chromatin density marker. Using photoactivation localization microscopy (PALM) and adaptive optics, we measured the three-dimensional distribution of H2B with nanometric resolution. We computed the distribution of distances between every two points of the chromatin structure, namely the Ripley K(r) distribution. We found that the K(r) distribution of H2B followed a power law, leading to a precise measurement of the correlation fractal dimension of chromatin of 2.7. Moreover, using photoactivable GFP fused to H2B, we observed dynamic evolution of chromatin sub-regions compaction. As a result, the correlation fractal dimension of chromatin reported here can be interpreted as a dynamically maintained non-equilibrium state. PMID:24637833

  15. Tracking sperm in three-dimensions.

    PubMed

    Corkidi, G; Taboada, B; Wood, C D; Guerrero, A; Darszon, A

    2008-08-15

    Sperm motility, crucial for fertilization, has been mostly studied in two dimensions (2D) by recording their swimming trajectories near a flat surface. However, spermatozoa swim in three-dimensions (3D) to find eggs, with their speed being the main impediment to track them under realistic conditions. Here, we describe a novel method allowing 3D tracking and analysis of the trajectories of multiple free-swimming sperm. The system uses a piezo-electric device displacing a large focal distance objective mounted on a microscope to acquire 70 image stacks per second, each stack composed of 60 images that span a depth of 100 microm. With this method, 3D paths of multiple sperm in the same field could be visualized simultaneously during 1 s. Within the same sample we found that surface-confined sperm swam 25% slower, produced 3-fold fewer circular revolutions per second, and had trajectories of 134% greater radius of curvature than those sperm swimming freely in 3D. PMID:18555013

  16. 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. PMID:26280268

  17. Sufficient dimension reduction with additional information.

    PubMed

    Hung, Hung; Liu, Chih-Yen; Horng-Shing Lu, Henry

    2016-07-01

    Sufficient dimension reduction is widely applied to help model building between the response [Formula: see text] and covariate [Formula: see text] In some situations, we also collect additional covariate [Formula: see text] that has better performance in predicting [Formula: see text], but has a higher obtaining cost, than [Formula: see text] While constructing a predictive model for [Formula: see text] based on [Formula: see text] is straightforward, this strategy is not applicable since [Formula: see text] is not available for future observations in which the constructed model is to be applied. As a result, the aim of the study is to build a predictive model for [Formula: see text] based on [Formula: see text] only, where the available data is [Formula: see text] A naive method is to conduct analysis using [Formula: see text] directly, but ignoring [Formula: see text] can cause the problem of inefficiency. On the other hand, it is not trivial to utilize the information of [Formula: see text] to infer [Formula: see text], either. In this article, we propose a two-stage dimension reduction method for [Formula: see text] that is able to utilize the information of [Formula: see text] In the breast cancer data, the risk score constructed from the two-stage method can well separate patients with different survival experiences. In the Pima data, the two-stage method requires fewer components to infer the diabetes status, while achieving higher classification accuracy than the conventional method. PMID:26704765

  18. Weak homological dimensions and biflat Koethe algebras

    SciTech Connect

    Pirkovskii, A Yu

    2008-06-30

    The homological properties of metrizable Koethe algebras {lambda}(P) are studied. A criterion for an algebra A={lambda}(P) to be biflat in terms of the Koethe set P is obtained, which implies, in particular, that for such algebras the properties of being biprojective, biflat, and flat on the left are equivalent to the surjectivity of the multiplication operator A otimes-hat A{yields}A. The weak homological dimensions (the weak global dimension w.dg and the weak bidimension w.db) of biflat Koethe algebras are calculated. Namely, it is shown that the conditions w.db {lambda}(P)<=1 and w.dg {lambda}(P)<=1 are equivalent to the nuclearity of {lambda}(P); and if {lambda}(P) is non-nuclear, then w.dg {lambda}(P)=w.db {lambda}(P)=2. It is established that the nuclearity of a biflat Koethe algebra {lambda}(P), under certain additional conditions on the Koethe set P, implies the stronger estimate db {lambda}(P), where db is the (projective) bidimension. On the other hand, an example is constructed of a nuclear biflat Koethe algebra {lambda}(P) such that db {lambda}(P)=2 (while w.db {lambda}(P)=1). Finally, it is shown that many biflat Koethe algebras, while not being amenable, have trivial Hochschild homology groups in positive degrees (with arbitrary coefficients). Bibliography: 37 titles.

  19. 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.

  20. 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.