Science.gov

Sample records for non-canonical dimension

  1. Refining inflation using non-canonical scalars

    SciTech Connect

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

    2012-08-01

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

  2. 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

  3. 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.

  4. 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

  5. Non-canonical WNT signalling in the lung.

    PubMed

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

    2015-11-01

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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Novel perspectives on non-canonical inflammasome activation

    PubMed Central

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

    2015-01-01

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

  11. Unsaturated fatty acids induce non-canonical autophagy

    PubMed Central

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

    2015-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Nandi, Debottam; Shankaranarayanan, S.

    2016-10-01

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

  13. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

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

  15. 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

  16. 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

  17. Constitutive non-canonical NFκB signaling in pancreatic cancer cells

    PubMed Central

    Wharry, Catherine E.; Haines, Kathleen M.; Carroll, Richard G.; May, Michael J.

    2010-01-01

    Constitutive classical NFκB activation has been implicated in the development of pancreatic cancer, and inhibition of classical NFκB signaling sensitizes pancreatic cancer cells to apoptosis. However, the role of the more recently described non-canonical NFκB pathway has not been specifically addressed in pancreatic cancer. The non-canonical pathway requires stabilization of NIK and IKKα-dependent phosphorylation and processing of NFκB2/p100 to p52. This leads to the activation of p52-RelB heterodimers that regulate genes encoding lymphoid-specific chemokines and cytokines. We performed qRT-PCR to detect gene expression in a panel of pancreatic ductal adenocarcinoma cell lines (BxPC-3, PCA-2, PANC-1, Capan-1, Hs-766T, AsPC-1, MiaPACA-2) and found only modest elevation of classical NFκB-dependent genes. In contrast, each of the tumor cell lines displayed dramatically elevated levels of subsets of the non-canonical NFκB target genes CCL19, CCL21, CXCL12, CXCL13 and BAFF. Consistent with activation of the non-canonical pathway, p52 and RelB co-localized in adenocarcinoma cells in sections of pancreatic tumor tissue, and each of the tumor cell lines displayed elevated p52 levels. Furthermore, p52 and RelB co-immunoprecipitated from pancreatic cancer cells and immunoblotting revealed that NIK was stabilized and p100 was constitutively phosphorylated in a subset of the cell lines. Finally, stable overexpression of dominant negative IKKα significantly inhibited non-canonical target gene expression in BxPC-3 cells. These findings therefore demonstrate that the non-canonical NFκB pathway is constitutively active and functional in pancreatic cancer cells. PMID:19502791

  18. Power spectra beyond the slow roll approximation in theories with non-canonical kinetic terms

    SciTech Connect

    De Bruck, Carsten van; Robinson, Mathew E-mail: app11mrr@sheffield.ac.uk

    2014-08-01

    We derive analytical expressions for the power spectra at the end of inflation in theories with two inflaton fields and non-canonical kinetic terms. We find that going beyond the slow-roll approximation is necessary and that the nature of the non-canonical terms have an important impact on the final power spectra at the end of inflation. We study five models numerically and find excellent agreement with our analytical results. Our results emphasise the fact that going beyond the slow-roll approximation is important in times of high-precision data coming from cosmological observations.

  19. Non-canonical NF-κB signaling in rheumatoid arthritis: Dr Jekyll and Mr Hyde?

    PubMed

    Noort, Ae R; Tak, Paul P; Tas, Sander W

    2015-01-01

    The nuclear factor-κB (NF-κB) family of transcription factors is essential for the expression of pro-inflammatory cytokines, but can also induce regulatory pathways. NF-κB can be activated via two distinct pathways: the classical or canonical pathway, and the alternative or non-canonical pathway. It is well established that the canonical NF-κB pathway is essential both in acute inflammatory responses and in chronic inflammatory diseases, including rheumatoid arthritis (RA). Although less extensively studied, the non-canonical NF-κB pathway is not only central in lymphoid organ development and adaptive immune responses, but is also thought to play an important role in the pathogenesis of RA. Importantly, this pathway appears to have cell type-specific functions and, since many different cell types are involved in the pathogenesis of RA, it is difficult to predict the net overall contribution of the non-canonical NF-κB pathway to synovial inflammation. In this review, we describe the current understanding of non-canonical NF-κB signaling in various important cell types in the context of RA and consider the relevance to the pathogenesis of the disease. In addition, we discuss current drugs targeting this pathway, as well as future therapeutic prospects. PMID:25774937

  20. Agonistic and Antagonistic Roles for TNIK and MINK in Non-Canonical and Canonical Wnt Signalling

    PubMed Central

    Mikryukov, Alexander; Moss, Tom

    2012-01-01

    Wnt signalling is a key regulatory factor in animal development and homeostasis and plays an important role in the establishment and progression of cancer. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical ß-catenin pathway and a non-canonical pathway controlling planar cell polarity and convergent extension. Interference between these pathways is an important determinant of cellular and phenotypic responses, but is poorly understood. Here we show that TNIK (Traf2 and Nck-interacting kinase) and MINK (Misshapen/NIKs-related kinase) MAP4K signalling kinases are integral components of both canonical and non-canonical pathways in Xenopus. xTNIK and xMINK interact and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology (CNH) Domain fragments that are suppressive. The catalytic activity of the Kinase domain fragments of both xTNIK and xMINK mediate non-canonical signalling. However, while the Kinase domain fragments of xTNIK also mediate canonical signalling, the analogous fragments derived from xMINK strongly antagonize this signalling. Our data suggest that the proteolytic cleavage of xTNIK and xMINK determines their respective activities and is an important factor in controlling the balance between canonical and non-canonical Wnt signalling in vivo. PMID:22984420

  1. Both Canonical and Non-Canonical Wnt Signaling Independently Promote Stem Cell Growth in Mammospheres

    PubMed Central

    Many, Alexander M.; Brown, Anthony M. C.

    2014-01-01

    The characterization of mammary stem cells, and signals that regulate their behavior, is of central importance in understanding developmental changes in the mammary gland and possibly for targeting stem-like cells in breast cancer. The canonical Wnt/β-catenin pathway is a signaling mechanism associated with maintenance of self-renewing stem cells in many tissues, including mammary epithelium, and can be oncogenic when deregulated. Wnt1 and Wnt3a are examples of ligands that activate the canonical pathway. Other Wnt ligands, such as Wnt5a, typically signal via non-canonical, β-catenin-independent, pathways that in some cases can antagonize canonical signaling. Since the role of non-canonical Wnt signaling in stem cell regulation is not well characterized, we set out to investigate this using mammosphere formation assays that reflect and quantify stem cell properties. Ex vivo mammosphere cultures were established from both wild-type and Wnt1 transgenic mice and were analyzed in response to manipulation of both canonical and non-canonical Wnt signaling. An increased level of mammosphere formation was observed in cultures derived from MMTV-Wnt1 versus wild-type animals, and this was blocked by treatment with Dkk1, a selective inhibitor of canonical Wnt signaling. Consistent with this, we found that a single dose of recombinant Wnt3a was sufficient to increase mammosphere formation in wild-type cultures. Surprisingly, we found that Wnt5a also increased mammosphere formation in these assays. We confirmed that this was not caused by an increase in canonical Wnt/β-catenin signaling but was instead mediated by non-canonical Wnt signals requiring the receptor tyrosine kinase Ror2 and activity of the Jun N-terminal kinase, JNK. We conclude that both canonical and non-canonical Wnt signals have positive effects promoting stem cell activity in mammosphere assays and that they do so via independent signaling mechanisms. PMID:25019931

  2. 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.

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

    PubMed Central

    Lawrence, Cortney L.; Baldwin, Albert S.

    2016-01-01

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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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

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

    PubMed

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

    2016-03-21

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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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

  17. Widespread occurrence of non-canonical transcription termination by human RNA polymerase III

    PubMed Central

    Orioli, Andrea; Pascali, Chiara; Quartararo, Jade; Diebel, Kevin W.; Praz, Viviane; Romascano, David; Percudani, Riccardo; van Dyk, Linda F.; Hernandez, Nouria; Teichmann, Martin; Dieci, Giorgio

    2011-01-01

    Human RNA polymerase (Pol) III-transcribed genes are thought to share a simple termination signal constituted by four or more consecutive thymidine residues in the coding DNA strand, just downstream of the RNA 3′-end sequence. We found that a large set of human tRNA genes (tDNAs) do not display any T≥4 stretch within 50 bp of 3′-flanking region. In vitro analysis of tDNAs with a distanced T≥4 revealed the existence of non-canonical terminators resembling degenerate T≥5 elements, which ensure significant termination but at the same time allow for the production of Pol III read-through pre-tRNAs with unusually long 3′ trailers. A panel of such non-canonical signals was found to direct transcription termination of unusual Pol III-synthesized viral pre-miRNA transcripts in gammaherpesvirus 68-infected cells. Genome-wide location analysis revealed that human Pol III tends to trespass into the 3′-flanking regions of tDNAs, as expected from extensive terminator read-through. The widespread occurrence of partial termination suggests that the Pol III primary transcriptome in mammals is unexpectedly enriched in 3′-trailer sequences with the potential to contribute novel functional ncRNAs. PMID:21421562

  18. 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

  19. 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

  20. Study of parametrized dark energy models with a general non-canonical scalar field

    NASA Astrophysics Data System (ADS)

    Mamon, Abdulla Al; Das, Sudipta

    2016-03-01

    In this paper, we consider various dark energy models in the framework of a non-canonical scalar field with a Lagrangian density of the form {L}(φ , X)=f(φ )X{left(X/M^{4_{Pl}}right) }^{α -1} - V(φ ), which provides the standard canonical scalar field model for α =1 and f(φ )=1. In this particular non-canonical scalar field model, we carry out the analysis for α =2. We then obtain cosmological solutions for constant as well as variable equation of state parameter (ω _{φ }(z)) for dark energy. We also perform the data analysis for three different functional forms of ω _{φ }(z) by using the combination of SN Ia, BAO, and CMB datasets. We have found that for all the choices of ω _{φ }(z), the SN Ia + CMB/BAO dataset favors the past decelerated and recent accelerated expansion phase of the universe. Furthermore, using the combined dataset, we have observed that the reconstructed results of ω _{φ }(z) and q(z) are almost choice independent and the resulting cosmological scenarios are in good agreement with the Λ CDM model (within the 1σ confidence contour). We have also derived the form of the potentials for each model and the resulting potentials are found to be a quartic potential for constant ω _{φ } and a polynomial in φ for variable ω _{φ }.

  1. 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

  2. Environmental PCR survey to determine the distribution of a non-canonical genetic code in uncultivable oxymonads.

    PubMed

    de Koning, Audrey P; Noble, Geoffrey P; Heiss, Aaron A; Wong, Jensen; Keeling, Patrick J

    2008-01-01

    The universal genetic code is conserved throughout most living systems, but a non-canonical code where TAA and TAG encode glutamine has evolved in several eukaryotes, including oxymonad protists. Most oxymonads are uncultivable, so environmental RT-PCR and PCR was used to examine the distribution of this rare character. A total of 253 unique isolates of four protein-coding genes were sampled from the hindgut community of the cockroach, Cryptocercus punctulatus, an environment rich in diversity from two of the five subgroups of oxymonad, saccinobaculids and polymastigids. Four alpha-tubulins were found with non-canonical glutamine codons. Environmental RACE confirmed that these and related genes used only TGA as stop codons, as expected for the non-canonical code, whereas other genes used TAA or TAG as stop codons, as expected for the universal code. We characterized alpha-tubulin from manually isolated Saccinobaculus ambloaxostylus, confirming it uses the universal code and suggesting, by elimination, that the non-canonical code is used by a polymastigid. HSP90 and EF-1alpha phylogenies also showed environmental sequences falling into two distinct groups, and are generally consistent with previous hypotheses that polymastigids and Streblomastix are closely related. Overall, we propose that the non-canonical genetic code arose once in a common ancestor of Streblomastix and a subgroup of polymastigids. PMID:18211267

  3. Environmental PCR survey to determine the distribution of a non-canonical genetic code in uncultivable oxymonads.

    PubMed

    de Koning, Audrey P; Noble, Geoffrey P; Heiss, Aaron A; Wong, Jensen; Keeling, Patrick J

    2008-01-01

    The universal genetic code is conserved throughout most living systems, but a non-canonical code where TAA and TAG encode glutamine has evolved in several eukaryotes, including oxymonad protists. Most oxymonads are uncultivable, so environmental RT-PCR and PCR was used to examine the distribution of this rare character. A total of 253 unique isolates of four protein-coding genes were sampled from the hindgut community of the cockroach, Cryptocercus punctulatus, an environment rich in diversity from two of the five subgroups of oxymonad, saccinobaculids and polymastigids. Four alpha-tubulins were found with non-canonical glutamine codons. Environmental RACE confirmed that these and related genes used only TGA as stop codons, as expected for the non-canonical code, whereas other genes used TAA or TAG as stop codons, as expected for the universal code. We characterized alpha-tubulin from manually isolated Saccinobaculus ambloaxostylus, confirming it uses the universal code and suggesting, by elimination, that the non-canonical code is used by a polymastigid. HSP90 and EF-1alpha phylogenies also showed environmental sequences falling into two distinct groups, and are generally consistent with previous hypotheses that polymastigids and Streblomastix are closely related. Overall, we propose that the non-canonical genetic code arose once in a common ancestor of Streblomastix and a subgroup of polymastigids.

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

    PubMed

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

    2016-05-17

    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.

  5. 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

  6. 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

  7. 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.

  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. 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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    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

  12. Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4+ T Cells

    PubMed Central

    Dongre, Anushka; Surampudi, Lalitha; Lawlor, Rebecca G.; Fauq, Abdul H.; Miele, Lucio; Golde, Todd E.; Minter, Lisa M.; Osborne, Barbara A.

    2014-01-01

    Cleavage of the Notch receptor via a γ-secretase, results in 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. This canonical Notch signaling pathway has been documented to influence T cell development and function. However, the mechanistic details underlying this process remain obscure. In addition to RBP-Jκ, the intra-cellular domain of Notch also interacts with other proteins in the cytoplasm and nucleus, giving rise to the possibility of an alternate, RBP-Jκ independent Notch pathway. However, the contribution of such RBP-Jκ independent, “non-canonical” Notch signaling in regulating peripheral T cell responses is unknown. In this report, we specifically demonstrate the requirement of Notch1 for regulating signal strength and signaling events distal to the T cell receptor in peripheral CD4+ T cells. By using mice with a conditional deletion in Notch1 or RBP-Jκ, we show that Notch1 regulates activation and proliferation of CD4+ T cells independently of RBP-Jκ. Furthermore, differentiation to TH1 and iTreg lineages although Notch dependent, is RBP-Jκ independent. Our striking observations demonstrate that many of the cell-intrinsic functions of Notch occur independently of RBP-Jκ. Such non-canonical regulation of these processes likely occurs through NF-κ B. This reveals a previously unknown, novel role of non-canonical Notch signaling in regulating peripheral T cell responses. PMID:24611064

  13. 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

  14. 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.

  15. TGFβ1 rapidly activates Src through a non-canonical redox signaling mechanism

    PubMed Central

    Zhang, Hongqiao; Davies, Kelvin J. A.; Forman, Henry Jay

    2015-01-01

    Transforming growth factor-β1 (TGF-β) is involved in multiple cellular processes through Src activation. In the canonical pathway, Src activation is initiated by pTyr530 dephosphorylation followed by a conformational change allowing Tyr419 auto-phosphorylation. A non-canonical pathway in which oxidation of cysteine allows bypassing of pTyr530 dephosphorylation has been reported. Here, we examined how TGF-β activates Src in H358 cells, a small cell lung carcinoma cell line. TGF-β increased Src Tyr419 phosphorylation, but surprisingly, Tyr530 phosphorylation was increased rather than decreased. Vanadate, a protein tyrosine phosphatase inhibitor, stimulated Src activation itself, but rather than inhibiting Src activation by TGF-β, activation by vanadate was additive with TGF-β showing that pTyr530 dephosphorylation was not required. Thus, the involvement of the non-canonical oxidative activation was suspected. TGF-β increased extracellular H2O2 transiently while GSH-ester and catalase abrogated Src activation by TGF-β. Apocynin, a NADPH oxidase inhibitor, inhibited TGF-β-stimulated H2O2 production. Furthermore, mutation of cysteines to alanine, 248C/A, 277C/A, or 501C/A abrogated, while 490C/A significantly reduced, TGF-β-mediated Src activation. Taken together, the results indicate that TGF-β-mediated Src activation operates largely through a redox dependent mechanism, resulting from enhanced H2O2 production through an NADPH oxidase and that cysteines 248, 277, 490, and 501 are critical for this activation. PMID:25585026

  16. 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.

  17. 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.

  18. Canonical and non-canonical barriers facing antimiR cancer therapeutics.

    PubMed

    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 describes 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.

  19. 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

  20. 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

  1. 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

  2. The Non-Canonical Role of Aurora-A in DNA Replication

    PubMed Central

    Tsunematsu, Takaaki; Arakaki, Rieko; Yamada, Akiko; Ishimaru, Naozumi; Kudo, Yasusei

    2015-01-01

    Aurora-A is a well-known mitotic kinase that regulates mitotic entry, spindle formation, and chromosome maturation as a canonical role. During mitosis, Aurora-A protein is stabilized by its phosphorylation at Ser51 via blocking anaphase-promoting complex/cyclosome-mediated proteolysis. Importantly, overexpression and/or hyperactivation of Aurora-A is involved in tumorigenesis via aneuploidy and genomic instability. Recently, the novel function of Aurora-A for DNA replication has been revealed. In mammalian cells, DNA replication is strictly regulated for preventing over-replication. Pre-replication complex (pre-RC) formation is required for DNA replication as an initiation step occurring at the origin of replication. The timing of pre-RC formation depends on the protein level of geminin, which is controlled by the ubiquitin–proteasome pathway. Aurora-A phosphorylates geminin to prevent its ubiquitin-mediated proteolysis at the mitotic phase to ensure proper pre-RC formation and ensuing DNA replication. In this review, we introduce the novel non-canonical role of Aurora-A in DNA replication. PMID:26380219

  3. 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

  4. Processing of visually evoked innate fear by a non-canonical thalamic pathway.

    PubMed

    Wei, Pengfei; Liu, Nan; Zhang, Zhijian; Liu, Xuemei; Tang, Yongqiang; He, Xiaobin; Wu, Bifeng; Zhou, Zheng; Liu, Yaohan; Li, Juan; Zhang, Yi; Zhou, Xuanyi; Xu, Lin; Chen, Lin; Bi, Guoqiang; Hu, Xintian; Xu, Fuqiang; Wang, Liping

    2015-01-01

    The ability of animals to respond to life-threatening stimuli is essential for survival. Although vision provides one of the major sensory inputs for detecting threats across animal species, the circuitry underlying defensive responses to visual stimuli remains poorly defined. Here, we investigate the circuitry underlying innate defensive behaviours elicited by predator-like visual stimuli in mice. Our results demonstrate that neurons in the superior colliculus (SC) are essential for a variety of acute and persistent defensive responses to overhead looming stimuli. Optogenetic mapping revealed that SC projections to the lateral posterior nucleus (LP) of the thalamus, a non-canonical polymodal sensory relay, are sufficient to mimic visually evoked fear responses. In vivo electrophysiology experiments identified a di-synaptic circuit from SC through LP to the lateral amygdale (Amg), and lesions of the Amg blocked the full range of visually evoked defensive responses. Our results reveal a novel collicular-thalamic-Amg circuit important for innate defensive responses to visual threats. PMID:25854147

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

    PubMed Central

    Fischer, Ute; Schäuble, Nico; Schütz, Sabina; Altvater, Martin; Chang, Yiming; Boulos Faza, Marius; 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. DOI: http://dx.doi.org/10.7554/eLife.05745.001 PMID:25895666

  6. 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.

  7. 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

  8. The cardiac connexome: Non-canonical functions of connexin43 and their role in cardiac arrhythmias.

    PubMed

    Leo-Macias, Alejandra; Agullo-Pascual, Esperanza; Delmar, Mario

    2016-02-01

    Connexin43 is the major component of gap junctions, an anatomical structure present in the cardiac intercalated disc that provides a low-resistance pathway for direct cell-to-cell passage of electrical charge. Recent studies have shown that in addition to its well-established function as an integral membrane protein that oligomerizes to form gap junctions, Cx43 plays other roles that are independent of channel (or perhaps even hemi-channel) formation. This article discusses non-canonical functions of Cx43. In particular, we focus on the role of Cx43 as a part of a protein interacting network, a connexome, where molecules classically defined as belonging to the mechanical junctions, the gap junctions and the sodium channel complex, multitask and work together to bring about excitability, electrical and mechanical coupling between cardiac cells. Overall, viewing Cx43 as a multi-functional protein, beyond gap junctions, opens a window to better understand the function of the intercalated disc and the pathological consequences that may result from changes in the abundance or localization of Cx43 in the intercalated disc subdomain. PMID:26673388

  9. 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.

  10. K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.

    PubMed

    Wang, Man-Tzu; Holderfield, Matthew; Galeas, Jacqueline; Delrosario, Reyno; To, Minh D; Balmain, Allan; McCormick, Frank

    2015-11-19

    K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein.

  11. A non-canonical DNA structure enables homologous recombination in various genetic systems.

    PubMed

    Masuda, Tokiha; Ito, Yutaka; Terada, Tohru; Shibata, Takehiko; Mikawa, Tsutomu

    2009-10-30

    Homologous recombination, which is critical to genetic diversity, depends on homologous pairing (HP). HP is the switch from parental to recombinant base pairs, which requires expansion of inter-base pair spaces. This expansion unavoidably causes untwisting of the parental double-stranded DNA. RecA/Rad51-catalyzed ATP-dependent HP is extensively stimulated in vitro by negative supercoils, which compensates for untwisting. However, in vivo, double-stranded DNA is relaxed by bound proteins and thus is an unfavorable substrate for RecA/Rad51. In contrast, Mhr1, an ATP-independent HP protein required for yeast mitochondrial homologous recombination, catalyzes HP without the net untwisting of double-stranded DNA. Therefore, we questioned whether Mhr1 uses a novel strategy to promote HP. Here, we found that, like RecA, Mhr1 induced the extension of bound single-stranded DNA. In addition, this structure was induced by all evolutionarily and structurally distinct HP proteins so far tested, including bacterial RecO, viral RecT, and human Rad51. Thus, HP includes the common non-canonical DNA structure and uses a common core mechanism, independent of the species of HP proteins. We discuss the significance of multiple types of HP proteins. PMID:19729448

  12. Composition and Activity of the Non-canonical Gram-positive SecY2 Complex*

    PubMed Central

    Bandara, Mikaila; Corey, Robin A.; Martin, Remy; Skehel, J. Mark; Blocker, Ariel J.; Jenkinson, Howard F.; Collinson, Ian

    2016-01-01

    The accessory Sec system in Streptococcus gordonii DL1 is a specialized export system that transports a large serine-rich repeat protein, Hsa, to the bacterial surface. The system is composed of core proteins SecA2 and SecY2 and accessory Sec proteins Asp1–Asp5. Similar to canonical SecYEG, SecY2 forms a channel for translocation of the Hsa adhesin across the cytoplasmic membrane. Accessory Sec proteins Asp4 and Asp5 have been suggested to work alongside SecY2 to form the translocon, similar to the associated SecY, SecE, and SecG of the canonical system (SecYEG). To test this theory, S. gordonii secY2, asp4, and asp5 were co-expressed in Escherichia coli. The resultant complex was subsequently purified, and its composition was confirmed by mass spectrometry to be SecY2-Asp4-Asp5. Like SecYEG, the non-canonical complex activates the ATPase activity of the SecA motor (SecA2). This study also shows that Asp4 and Asp5 are necessary for optimal adhesion of S. gordonii to glycoproteins gp340 and fibronectin, known Hsa binding partners, as well as for early stage biofilm formation. This work opens new avenues for understanding the structure and function of the accessory Sec system. PMID:27551046

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

    PubMed Central

    Beerman, Rebecca W.; Jongens, Thomas A.

    2011-01-01

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

  14. 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

  15. 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

  16. 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

  17. Novel Bioinformatics Method for Identification of Genome-Wide Non-Canonical Spliced Regions Using RNA-Seq Data

    PubMed Central

    Ziyar, Ahdad; Li, Philip; Wright, Zachary; Menon, Rajasree; Omenn, Gilbert S.; Cavalcoli, James D.; Kaufman, Randal J.; Sartor, Maureen A.

    2014-01-01

    Setting During endoplasmic reticulum (ER) stress, the endoribonuclease (RNase) Ire1α initiates removal of a 26 nt region from the mRNA encoding the transcription factor Xbp1 via an unconventional mechanism (atypically within the cytosol). This causes an open reading frame-shift that leads to altered transcriptional regulation of numerous downstream genes in response to ER stress as part of the unfolded protein response (UPR). Strikingly, other examples of targeted, unconventional splicing of short mRNA regions have yet to be reported. Objective Our goal was to develop an approach to identify non-canonical, possibly very short, splicing regions using RNA-Seq data and apply it to ER stress-induced Ire1α heterozygous and knockout mouse embryonic fibroblast (MEF) cell lines to identify additional Ire1α targets. Results We developed a bioinformatics approach called the Read-Split-Walk (RSW) pipeline, and evaluated it using two Ire1α heterozygous and two Ire1α-null samples. The 26 nt non-canonical splice site in Xbp1 was detected as the top hit by our RSW pipeline in heterozygous samples but not in the negative control Ire1α knockout samples. We compared the Xbp1 results from our approach with results using the alignment program BWA, Bowtie2, STAR, Exonerate and the Unix “grep” command. We then applied our RSW pipeline to RNA-Seq data from the SKBR3 human breast cancer cell line. RSW reported a large number of non-canonical spliced regions for 108 genes in chromosome 17, which were identified by an independent study. Conclusions We conclude that our RSW pipeline is a practical approach for identifying non-canonical splice junction sites on a genome-wide level. We demonstrate that our pipeline can detect novel splice sites in RNA-Seq data generated under similar conditions for multiple species, in our case mouse and human. PMID:24991935

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

    NASA Astrophysics Data System (ADS)

    Finley, James P.; Hirao, Kimihiko

    2000-09-01

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

  19. 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.

  20. Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling.

    PubMed

    Scholz, Beate; Korn, Claudia; Wojtarowicz, Jessica; Mogler, Carolin; Augustin, Iris; Boutros, Michael; Niehrs, Christof; Augustin, Hellmut G

    2016-01-11

    The WNT signaling enhancer R-spondin3 (RSPO3) is prominently expressed in the vasculature. Correspondingly, embryonic lethality of Rspo3-deficient mice is caused by vessel remodeling defects. Yet the mechanisms underlying vascular RSPO3 function remain elusive. Inducible endothelial Rspo3 deletion (Rspo3-iECKO) resulted in perturbed developmental and tumor vascular remodeling. Endothelial cell apoptosis and vascular pruning led to reduced microvessel density in Rspo3-iECKO mice. Rspo3-iECKO mice strikingly phenocopied the non-canonical WNT signaling-induced vascular defects of mice deleted for the WNT secretion factor Evi/Wls. An endothelial screen for RSPO3 and EVI/WLS co-regulated genes identified Rnf213, Usp18, and Trim30α. RNF213 targets filamin A and NFAT1 for proteasomal degradation attenuating non-canonical WNT/Ca(2+) signaling. Likewise, USP18 and TRIM5α inhibited NFAT1 activation. Consequently, NFAT protein levels were decreased in endothelial cells of Rspo3-iECKO mice and pharmacological NFAT inhibition phenocopied Rspo3-iECKO mice. The data identify endothelial RSPO3-driven non-canonical WNT/Ca(2+)/NFAT signaling as a critical maintenance pathway of the remodeling vasculature.

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

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

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

  2. 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.

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

    PubMed Central

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

    2014-01-01

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

  4. 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

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

    PubMed Central

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

    2016-01-01

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

  6. 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.

  7. A non-canonical function of sortase enables site-specific conjugation of small molecules to lysine residues in proteins**

    PubMed Central

    Bellucci, Joseph J.; Bhattacharyya, Jayanta

    2014-01-01

    We provide the first demonstration that isopeptide ligation, a non-canonical activity of the enzyme sortase A, can be used to modify recombinant proteins. This reaction was used in vitro to conjugate small molecules to a peptide, an engineered targeting protein, and a full-length monoclonal antibody with an exquisite level of control over the site of conjugation. Attachment to the protein substrate occurred exclusively through isopeptide bonds at a lysine ε-amino group within a specific amino acid sequence. This reaction allows more than one molecule to be site-specifically conjugated to a protein at internal sites, thereby overcoming significant limitations of the canonical native peptide ligation reaction catalyzed by sortase A. Our method provides a unique chemical ligation procedure that is orthogonal to existing methods, supplying a new method to site-specifically modify lysine residues that will be a valuable addition to the protein conjugation toolbox. PMID:25363491

  8. 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.

  9. An Unprecedented Non-canonical Nuclear Genetic Code with All Three Termination Codons Reassigned as Sense Codons.

    PubMed

    Záhonová, Kristína; Kostygov, Alexei Y; Ševčíková, Tereza; Yurchenko, Vyacheslav; Eliáš, Marek

    2016-09-12

    A limited number of non-canonical genetic codes have been described in eukaryotic nuclear genomes. Most involve reassignment of one or two termination codons as sense ones [1-4], but no code variant is known that would have reassigned all three termination codons. Here, we describe such a variant that we discovered in a clade of trypanosomatids comprising nominal Blastocrithidia species. In these protists, UGA has been reassigned to encode tryptophan, while UAG and UAA (UAR) have become glutamate encoding. Strikingly, UAA and, less frequently, UAG also serve as bona fide termination codons. The release factor eRF1 in Blastocrithidia contains a substitution of a conserved serine residue predicted to decrease its affinity to UGA, which explains why this triplet can be read as a sense codon. However, the molecular basis for the dual interpretation of UAR codons remains elusive. Our findings expand the limits of comprehension of one of the fundamental processes in molecular biology.

  10. 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

  11. An Unprecedented Non-canonical Nuclear Genetic Code with All Three Termination Codons Reassigned as Sense Codons.

    PubMed

    Záhonová, Kristína; Kostygov, Alexei Y; Ševčíková, Tereza; Yurchenko, Vyacheslav; Eliáš, Marek

    2016-09-12

    A limited number of non-canonical genetic codes have been described in eukaryotic nuclear genomes. Most involve reassignment of one or two termination codons as sense ones [1-4], but no code variant is known that would have reassigned all three termination codons. Here, we describe such a variant that we discovered in a clade of trypanosomatids comprising nominal Blastocrithidia species. In these protists, UGA has been reassigned to encode tryptophan, while UAG and UAA (UAR) have become glutamate encoding. Strikingly, UAA and, less frequently, UAG also serve as bona fide termination codons. The release factor eRF1 in Blastocrithidia contains a substitution of a conserved serine residue predicted to decrease its affinity to UGA, which explains why this triplet can be read as a sense codon. However, the molecular basis for the dual interpretation of UAR codons remains elusive. Our findings expand the limits of comprehension of one of the fundamental processes in molecular biology. PMID:27593378

  12. 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

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

    PubMed Central

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

    2013-01-01

    A core component of the α-proteobacterial general stress response (GSR) is the extracytoplasmic function (ECF) sigma factor EcfG, exclusively present in this taxonomic class. Half of the completed α-proteobacterial genome sequences contain two or more copies of genes encoding σEcfG-like sigma factors, with the primary copy typically located adjacent to genes coding for a cognate anti-sigma factor (NepR) and two-component response regulator (PhyR). So far, the widespread occurrence of additional, non-canonical σEcfG copies has not satisfactorily been explained. This study explores the hierarchical relation between Rhizobium etli σEcfG1 and σEcfG2, canonical and non-canonical σEcfG proteins, respectively. Contrary to reports in other species, we find that σEcfG1 and σEcfG2 act in parallel, as nodes of a complex regulatory network, rather than in series, as elements of a linear regulatory cascade. We demonstrate that both sigma factors control unique yet also shared target genes, corroborating phenotypic evidence. σEcfG1 drives expression of rpoH2, explaining the increased heat sensitivity of an ecfG1 mutant, while katG is under control of σEcfG2, accounting for reduced oxidative stress resistance of an ecfG2 mutant. We also identify non-coding RNA genes as novel σEcfG targets. We propose a modified model for GSR regulation in R. etli, in which σEcfG1 and σEcfG2 function largely independently. Based on a phylogenetic analysis and considering the prevalence of α-proteobacterial genomes with multiple σEcfG copies, this model may also be applicable to numerous other species. PMID:24311555

  14. 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.

  15. 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

  16. Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation.

    PubMed

    Choudhary, Sanjeev; Kalita, Mridul; Fang, Ling; Patel, Kershaw V; Tian, Bing; Zhao, Yingxin; Edeh, Chukwudi B; Brasier, Allan R

    2013-05-17

    The NF-κB transcription factor mediates the inflammatory response through distinct (canonical and non-canonical) signaling pathways. The mechanisms controlling utilization of either of these pathways are largely unknown. Here we observe that TNF stimulation induces delayed NF-κB2/p100 processing and investigate the coupling mechanism. TNF stimulation induces TNF-associated factor-1 (TRAF-1) that directly binds NF-κB-inducing kinase (NIK) and stabilizes it from degradation by disrupting its interaction with TRAF2·cIAP2 ubiquitin ligase complex. We show that TRAF1 depletion prevents TNF-induced NIK stabilization and reduces p52 production. To further examine the interactions of TRAF1 and NIK with NF-κB2/p100 processing, we mathematically modeled TRAF1·NIK as a coupling signaling complex and validated computational inference by siRNA knockdown to show non-canonical pathway activation is dependent not only on TRAF1 induction but also NIK stabilization by forming TRAF1·NIK complex. Thus, these integrated computational-experimental studies of TNF-induced TRAF1 expression identified TRAF1·NIK as a central complex linking canonical and non-canonical pathways by disrupting the TRAF2-cIAP2 ubiquitin ligase complex. This feed-forward kinase pathway is essential for the activation of non-canonical pathway. PMID:23543740

  17. The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway.

    PubMed

    Abe, Takashi; Yamazaki, Daisuke; Murakami, Satoshi; Hiroi, Makoto; Nitta, Yohei; Maeyama, Yuko; Tabata, Tetsuya

    2014-12-01

    The Rac-Cofilin pathway is essential for cytoskeletal remodeling to control axonal development. Rac signals through the canonical Rac-Pak-LIMK pathway to suppress Cofilin-dependent axonal growth and through a Pak-independent non-canonical pathway to promote outgrowth. Whether this non-canonical pathway converges to promote Cofilin-dependent F-actin reorganization in axonal growth remains elusive. We demonstrate that Sickie, a homolog of the human microtubule-associated protein neuron navigator 2, cell-autonomously regulates axonal growth of Drosophila mushroom body (MB) neurons via the non-canonical pathway. Sickie was prominently expressed in the newborn F-actin-rich axons of MB neurons. A sickie mutant exhibited axonal growth defects, and its phenotypes were rescued by exogenous expression of Sickie. We observed phenotypic similarities and genetic interactions among sickie and Rac-Cofilin signaling components. Using the MARCM technique, distinct F-actin and phospho-Cofilin patterns were detected in developing axons mutant for sickie and Rac-Cofilin signaling regulators. The upregulation of Cofilin function alleviated the axonal defect of the sickie mutant. Epistasis analyses revealed that Sickie suppresses the LIMK overexpression phenotype and is required for Pak-independent Rac1 and Slingshot phosphatase to counteract LIMK. We propose that Sickie regulates F-actin-mediated axonal growth via the non-canonical Rac-Cofilin pathway in a Slingshot-dependent manner.

  18. 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…

  19. Lipopolysaccharide-induced Activation of NF-κB Non-Canonical Pathway Requires BCL10 Serine 138 and NIK Phosphorylations

    PubMed Central

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

    2010-01-01

    Background and Aims B-cell lymphoma / leukemia (BCL)-10 and reactive oxygen species mediate two pathways of NF-κB (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-κB activation, including nuclear RelB and p52 and phospho- and total NF-κB 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-IκBα 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-κB 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. PMID:20466000

  20. 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.

  1. 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

  2. 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.

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

    PubMed Central

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

    2014-01-01

    Engineering antibodies to utilize non-canonical amino acids (NCAA) should greatly expand the utility of an already important biological reagent. In particular, introducing crosslinking reagents into antibody complementarity determining regions (CDRs) should provide a means to covalently crosslink residues at the antibody–antigen interface. Unfortunately, finding the optimum position for crosslinking two proteins is often a matter of iterative guessing, even when the interface is known in atomic detail. Computer-aided antibody design can potentially greatly restrict the number of variants that must be explored in order to identify successful crosslinking sites. We have therefore used Rosetta to guide the introduction of an oxidizable crosslinking NCAA, l-3,4-dihydroxyphenylalanine (l-DOPA), into the CDRs of the anti-protective antigen scFv antibody M18, and have measured crosslinking to its cognate antigen, domain 4 of the anthrax protective antigen. Computed crosslinking distance, solvent accessibility, and interface energetics were three factors considered that could impact the efficiency of l-DOPA-mediated crosslinking. In the end, 10 variants were synthesized, and crosslinking efficiencies were generally 10% or higher, with the best variant crosslinking to 52% of the available antigen. The results suggest that computational analysis can be used in a pipeline for engineering crosslinking antibodies. The rules learned from l-DOPA crosslinking of antibodies may also be generalizable to the formation of other crosslinked interfaces and complexes. PMID:23680795

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

    PubMed

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

    2015-07-10

    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 (FLU(TPR)) at 1.45-Å resolution and the complex of the dimeric domain of GluTR bound to FLU(TPR) at 2.4-Å resolution. Three non-canonical TPR motifs of each FLU(TPR) form a concave surface and clamp the helix bundle in the C-terminal dimeric domain of GluTR. We demonstrate that a 2:2 FLU(TPR)-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.

  5. 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

  6. The non-canonical effect of N-acetyl-D-glucosamine kinase on the formation of neuronal dendrites.

    PubMed

    Lee, HyunSook; Cho, Sun-Jung; Moon, Il Soo

    2014-03-01

    N-acetylglucosamine kinase (GlcNAc kinase or NAGK; EC 2.7.1.59) is a N-acetylhexosamine kinase that belong to the sugar kinase/heat shock protein 70/actin superfamily. In this study, we investigated both the expression and function of NAGK in neurons. Immunohistochemistry of rat brain sections showed that NAGK was expressed at high levels in neurons but at low levels in astrocytes. Immunocytochemistry of rat hippocampal dissociate cultures confirmed these findings and showed that NAGK was also expressed at low levels in oligodendrocytes. Furthermore, several NAGK clusters were observed in the nucleoplasm of both neuron and glia. The overexpression of EGFP- or RFP (DsRed2)-tagged NAGK in rat hippocampal neurons (DIV 5-9) increased the complexity of dendritic architecture by increasing the numbers of primary dendrites and dendritic branches. In contrast, knockdown of NAGK by shRNA resulted in dendrite degeneration, and this was prevented by the co-expression of RFP-tagged NAGK. These results suggest that the upregulation of dendritic complexity is a non-canonical function of NAGK.

  7. 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

  8. Allosteric Regulation of Serine Protease HtrA2 through Novel Non-Canonical Substrate Binding Pocket

    PubMed Central

    Singh, Nitu; Gadewal, Nikhil; Chaganti, Lalith K.; Sastry, G. Madhavi; Bose, Kakoli

    2013-01-01

    HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucidated. Although allostery has been found in some of its homologs, it has not been characterized in HtrA2 so far. Here, with an in silico and biochemical approach we have shown that allostery does regulate HtrA2 activity. Our studies identified a novel non-canonical selective binding pocket in HtrA2 which initiates signal propagation to the distal active site through a complex allosteric mechanism. This non-classical binding pocket is unique among HtrA family proteins and thus unfolds a novel mechanism of regulation of HtrA2 activity and hence apoptosis. PMID:23457469

  9. Evidence for possible non-canonical pathway(s) driven early-onset colorectal cancer in India

    PubMed Central

    Raman, Ratheesh; Kotapalli, Viswakalyan; Adduri, Raju; Gowrishankar, Swarnalata; Bashyam, Leena; Chaudhary, Ajay; Vamsy, Mohana; Patnaik, Sujith; Srinivasulu, Mukta; Sastry, Regulagadda; Rao, Subramanyeshwar; Vasala, Anjayneyulu; Kalidindi, NarasimhaRaju; Pollack, Jonathan; Murthy, Sudha; Bashyam, Murali

    2012-01-01

    Two genetic instability pathways viz. chromosomal instability, driven primarily by APC mutation induced deregulated Wnt signaling, and microsatellite instability (MSI) caused by mismatch repair (MMR) inactivation, together account for greater than 90% of late-onset colorectal cancer. Our understanding of early-onset sporadic CRC is however comparatively limited. In addition, most seminal studies have been performed in the western population and analyses of tumorigenesis pathway(s) causing CRC in developing nations have been rare. We performed a comparative analysis of early and late-onset CRC from India with respect to common genetic aberrations including Wnt, KRAS and p53 (constituting the classical CRC progression sequence) in addition to MSI. Our results revealed the absence of Wnt and MSI in a significant proportion of early-onset as against late-onset CRC in India. In addition, KRAS mutation frequency was significantly lower in early-onset CRC indicating that a significant proportion of CRC in India may follow tumorigenesis pathways distinct from the classical CRC progression sequence. Our study has therefore revealed the possible existence of non-canonical tumorigenesis pathways in early-onset CRC in India. PMID:23168910

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

    PubMed

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

    2013-10-01

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

  11. 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

  12. 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.

  13. The Legionella pneumophila GTPase Activating Protein LepB Accelerates Rab1 Deactivation by a Non-canonical Hydrolytic Mechanism*

    PubMed Central

    Mishra, Ashwini K.; Del Campo, Claudia M.; Collins, Robert E.; Roy, Craig R.; Lambright, David G.

    2013-01-01

    GTPase activating proteins (GAPs) from pathogenic bacteria and eukaryotic host organisms deactivate Rab GTPases by supplying catalytic arginine and glutamine fingers in trans and utilizing the cis-glutamine in the DXXGQ motif of the GTPase for binding rather than catalysis. Here, we report the transition state mimetic structure of the Legionella pneumophila GAP LepB in complex with Rab1 and describe a comprehensive structure-based mutational analysis of potential catalytic and recognition determinants. The results demonstrate that LepB does not simply mimic other GAPs but instead deploys an expected arginine finger in conjunction with a novel glutamic acid finger, which forms a salt bridge with an indispensible switch II arginine that effectively locks the cis-glutamine in the DXXGQ motif of Rab1 in a catalytically competent though unprecedented transition state configuration. Surprisingly, a heretofore universal transition state interaction with the cis-glutamine is supplanted by an elaborate polar network involving critical P-loop and switch I serines. LepB further employs an unusual tandem domain architecture to clamp a switch I tyrosine in an open conformation that facilitates access of the arginine finger to the hydrolytic site. Intriguingly, the critical P-loop serine corresponds to an oncogenic substitution in Ras and replaces a conserved glycine essential for the canonical transition state stereochemistry. In addition to expanding GTP hydrolytic paradigms, these observations reveal the unconventional dual finger and non-canonical catalytic network mechanisms of Rab GAPs as necessary alternative solutions to a major impediment imposed by substitution of the conserved P-loop glycine. PMID:23821544

  14. No tail co-operates with non-canonical Wnt signaling to regulate posterior body morphogenesis in zebrafish

    PubMed Central

    Marlow, Florence; Gonzalez, Encina M.; Yin, Chunyue; Rojo, Concepcion; Solnica-Krezel, Lilianna

    2016-01-01

    Summary The vertebrate posterior body is formed by a combination of the gastrulation movements that shape the head and anterior trunk and posterior specific cell behaviors. Here, we investigated whether genes that regulate cell movements during gastrulation [no tail (ntl)/brachyury, knypek (kny) and pipetail (ppt)/wnt5] interact to regulate posterior body morphogenesis. Both kny;ntl and ppt;ntl double mutant embryos exhibit synergistic trunk and tail shortening by early segmentation. Gene expression analysis in the compound mutants indicates that anteroposterior germ-layer patterning is largely normal and that the tail elongation defects are not due to failure to specify or maintain posterior tissues. Moreover, ntl interacts with ppt and kny to synergistically regulate the posterior expression of the gene encoding bone morphogenetic protein 4 (bmp4) but not of other known T-box genes, fibroblast growth factor genes or caudal genes. Examination of mitotic and apoptotic cells indicates that impaired tail elongation is not simply due to decreased cell proliferation or increased cell death. Cell tracing in ppt;ntl and kny;ntl mutants demonstrates that the ventral derived posterior tailbud progenitors move into the tailbud. However, gastrulation-like convergence and extension movements and cell movements within the posterior tailbud are impaired. Furthermore, subduction movements of cells into the mesendoderm are reduced in kny;ntl and ppt;ntl mutants. We propose that Ntl and the non-canonical Wnt pathway components Ppt and Kny function in parallel, partially redundant pathways to regulate posterior body development. Our work initiates the genetic dissection of posterior body morphogenesis and links genes to specific tail-forming movements. Moreover, we provide genetic evidence for the notion that tail development entails a continuation of mechanisms regulating gastrulation together with mechanisms unique to the posterior body. PMID:14660439

  15. Metabolic engineering of monoterpene biosynthesis in tomato fruits via introduction of the non-canonical substrate neryl diphosphate.

    PubMed

    Gutensohn, Michael; Nguyen, Thuong T H; McMahon, Richard D; Kaplan, Ian; Pichersky, Eran; Dudareva, Natalia

    2014-07-01

    Recently it was shown that monoterpenes in tomato trichomes (Solanum lycopersicum) are synthesized by phellandrene synthase 1 (PHS1) from the non-canonical substrate neryl diphosphate (NPP), the cis-isomer of geranyl diphosphate (GPP). As PHS1 accepts both NPP and GPP substrates forming different monoterpenes, it was overexpressed in tomato fruits to test if NPP is also available in a tissue highly active in carotenoid production. However, transgenic fruits overexpressing PHS1 produced only small amounts of GPP-derived PHS1 monoterpene products, indicating the absence of endogenous NPP. Therefore, NPP formation was achieved by diverting the metabolic flux from carotenoids via expression of tomato neryl diphosphate synthase 1 (NDPS1). NDPS1 transgenic fruits produced NPP-derived monoterpenes, including nerol, neral and geranial, while displaying reduced lycopene content. NDPS1 co-expression with PHS1 resulted in a monoterpene blend, including β-phellandrene, similar to that produced from NPP by PHS1 in vitro and in trichomes. Unexpectedly, PHS1×NDPS1 fruits showed recovery of lycopene levels compared to NDPS1 fruits, suggesting that redirection of metabolic flux is only partially responsible for the reduction in carotenoids. In vitro assays demonstrated that NPP serves as an inhibitor of geranylgeranyl diphosphate synthase, thus its consumption by PHS1 leads to recovery of lycopene levels. Monoterpenes produced in PHS1×NDPS1 fruits contributed to direct plant defense negatively affecting feeding behavior of the herbivore Helicoverpa zea and displaying antifungal activity against Botrytis cinerea. These results show that NPP-derived terpenoids can be produced in plant tissues; however, NPP has to be consumed to avoid negative impacts on plant metabolism.

  16. 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.

  17. 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

  18. Structure of Human Cytomegalovirus UL141 Binding to TRAIL-R2 Reveals Novel, Non-canonical Death Receptor Interactions

    PubMed Central

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

    2013-01-01

    The TRAIL (TNF-related apoptosis inducing ligand) death receptors (DRs) of the tumor necrosis factor receptor superfamily (TNFRSF) can promote apoptosis and regulate antiviral immunity by maintaining immune homeostasis during infection. In turn, human cytomegalovirus (HCMV) expresses immunomodulatory proteins that down-regulate cell surface expression of TNFRSF members as well as poliovirus receptor-related proteins in an effort to inhibit host immune effector pathways that would lead to viral clearance. The UL141 glycoprotein of human cytomegalovirus inhibits host defenses by blocking cell surface expression of TRAIL DRs (by retention in ER) and poliovirus receptor CD155, a nectin-like Ig-fold molecule. Here we show that the immunomodulatory function of HCMV UL141 is associated with its ability to bind diverse proteins, while utilizing at least two distinct binding sites to selectively engage TRAIL DRs or CD155. Binding studies revealed high affinity interaction of UL141 with both TRAIL-R2 and CD155 and low affinity binding to TRAIL-R1. We determined the crystal structure of UL141 bound to TRAIL-R2 at 2.1 Å resolution, which revealed that UL141 forms a homodimer that engages two TRAIL-R2 monomers 90° apart to form a heterotetrameric complex. Our structural and biochemical data reveal that UL141 utilizes its Ig-domain to facilitate non-canonical death receptor interactions while UL141 partially mimics the binding site of TRAIL on TRAIL-R2, which we found to be distinct from that of CD155. Moreover, UL141 also binds to an additional surface patch on TRAIL-R2 that is distinct from the TRAIL binding site. Therefore, the breadth of UL141-mediated effects indicates that HCMV has evolved sophisticated strategies to evade the immune system by modulating multiple effector pathways. PMID:23555243

  19. 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

  20. 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

  1. No tail co-operates with non-canonical Wnt signaling to regulate posterior body morphogenesis in zebrafish.

    PubMed

    Marlow, Florence; Gonzalez, Encina M; Yin, Chunyue; Rojo, Concepcion; Solnica-Krezel, Lilianna

    2004-01-01

    The vertebrate posterior body is formed by a combination of the gastrulation movements that shape the head and anterior trunk and posterior specific cell behaviors. Here, we investigated whether genes that regulate cell movements during gastrulation [no tail (ntl)/brachyury, knypek (kny) and pipetail (ppt)/wnt5] interact to regulate posterior body morphogenesis. Both kny;ntl and ppt;ntl double mutant embryos exhibit synergistic trunk and tail shortening by early segmentation. Gene expression analysis in the compound mutants indicates that anteroposterior germ-layer patterning is largely normal and that the tail elongation defects are not due to failure to specify or maintain posterior tissues. Moreover, ntl interacts with ppt and kny to synergistically regulate the posterior expression of the gene encoding bone morphogenetic protein 4 (bmp4) but not of other known T-box genes, fibroblast growth factor genes or caudal genes. Examination of mitotic and apoptotic cells indicates that impaired tail elongation is not simply due to decreased cell proliferation or increased cell death. Cell tracing in ppt;ntl and kny;ntl mutants demonstrates that the ventral derived posterior tailbud progenitors move into the tailbud. However, gastrulation-like convergence and extension movements and cell movements within the posterior tailbud are impaired. Furthermore, subduction movements of cells into the mesendoderm are reduced in kny;ntl and ppt;ntl mutants. We propose that Ntl and the non-canonical Wnt pathway components Ppt and Kny function in parallel, partially redundant pathways to regulate posterior body development. Our work initiates the genetic dissection of posterior body morphogenesis and links genes to specific tail-forming movements. Moreover, we provide genetic evidence for the notion that tail development entails a continuation of mechanisms regulating gastrulation together with mechanisms unique to the posterior body.

  2. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway.

    PubMed

    Lynch, Jennifer; Fay, Joanna; Meehan, Maria; Bryan, Kenneth; Watters, Karen M; Murphy, Derek M; Stallings, Raymond L

    2012-05-01

    Transforming growth factor-β (TGF-β) signaling regulates many diverse cellular activities through both canonical (SMAD-dependent) and non-canonical branches, which includes the mitogen-activated protein kinase (MAPK), Rho-like guanosine triphosphatase and phosphatidylinositol-3-kinase/AKT pathways. Here, we demonstrate that miR-335 directly targets and downregulates genes in the TGF-β non-canonical pathways, including the Rho-associated coiled-coil containing protein (ROCK1) and MAPK1, resulting in reduced phosphorylation of downstream pathway members. Specifically, inhibition of ROCK1 and MAPK1 reduces phosphorylation levels of the motor protein myosin light chain (MLC) leading to a significant inhibition of the invasive and migratory potential of neuroblastoma cells. Additionally, miR-335 targets the leucine-rich alpha-2-glycoprotein 1 (LRG1) messenger RNA, which similarly results in a significant reduction in the phosphorylation status of MLC and a decrease in neuroblastoma cell migration and invasion. Thus, we link LRG1 to the migratory machinery of the cell, altering its activity presumably by exerting its effect within the non-canonical TGF-β pathway. Moreover, we demonstrate that the MYCN transcription factor, whose coding sequence is highly amplified in a particularly clinically aggressive neuroblastoma tumor subtype, directly binds to a region immediately upstream of the miR-335 transcriptional start site, resulting in transcriptional repression. We conclude that MYCN contributes to neuroblastoma cell migration and invasion, by directly downregulating miR-335, resulting in the upregulation of the TGF-β signaling pathway members ROCK1, MAPK1 and putative member LRG1, which positively promote this process. Our results provide novel insight into the direct regulation of TGF-β non-canonical signaling by miR-335, which in turn is downregulated by MYCN.

  3. 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

  4. 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

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

    PubMed Central

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

    2016-01-01

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

  6. 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

  7. 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.

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

    PubMed

    Saldanha-Araujo, Felipe; Haddad, Rodrigo; Farias, Kelen C R Malmegrim de; 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

    2012-06-01

    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.

  9. WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1.

    PubMed

    Vassallo, I; Zinn, P; Lai, M; Rajakannu, P; Hamou, M-F; Hegi, M E

    2016-01-01

    Glioblastoma is the most aggressive primary brain tumor in adults and due to the invasive nature cannot be completely removed. The WNT inhibitory factor 1 (WIF1), a secreted inhibitor of WNTs, is systematically downregulated in glioblastoma and acts as strong tumor suppressor. The aim of this study was the dissection of WIF1-associated tumor-suppressing effects mediated by canonical and non-canonical WNT signaling. We found that WIF1 besides inhibiting the canonical WNT pathway selectively downregulates the WNT/calcium pathway associated with significant reduction of p38-MAPK (p38-mitogen-activated protein kinase) phosphorylation. Knockdown of WNT5A, the only WNT ligand overexpressed in glioblastoma, phenocopied this inhibitory effect. WIF1 expression inhibited cell migration in vitro and in an orthotopic brain tumor model, in accordance with the known regulatory function of the WNT/Ca(2+) pathway on migration and invasion. In search of a mediator for this function differential gene expression profiles of WIF1-expressing cells were performed. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA and key positive regulator of invasion, emerged as the top downregulated gene. Indeed, knockdown of MALAT1 reduced migration in glioblastoma cells, without effect on proliferation. Hence, loss of WIF1 enhances the migratory potential of glioblastoma through WNT5A that activates the WNT/Ca(2+) pathway and MALAT1. These data suggest the involvement of canonical and non-canonical WNT pathways in glioblastoma promoting key features associated with this deadly disease, proliferation on one hand and invasion on the other. Successful targeting will require a dual strategy affecting both canonical and non-canonical WNT pathways.

  10. 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

  11. 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

  12. Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs

    PubMed Central

    Adhikari, Rajan P.; Kort, Thomas; Shulenin, Sergey; Kanipakala, Tulasikumari; Ganjbaksh, Nader; Roghmann, Mary-Claire; Holtsberg, Frederick W.; Aman, M. Javad

    2015-01-01

    S. aureus vaccine development has proven particularly difficult. The conventional approach to achieve sterile immunity through opsonophagocytic killing has been largely unsuccessful. S. aureus is highly toxigenic and a great body of evidence suggests that a successful future vaccine for this organism should target extracellular toxins which are responsible for host tissue destruction and immunosuppression. Major staphylococcal toxins are alpha toxin (a single subunit hemolysin) along with a group of bicomponent pore-forming toxins (BCPFT), namely Panton-Valentine leukocidin (PVL), gamma hemolysins (HlgCB and AB), LukAB and LukED. In our previous report, an attenuated mutant of LukS-PV (PVL- S subunit) named as “LukS-mut9” elicited high immunogenic response as well as provided a significant protection in a mouse sepsis model. Recent discovery of PVL receptors shows that mice lack receptors for this toxin, thus the reported protection of mice with the PVL vaccine may relate to cross protective responses against other homologous toxins. This manuscript addresses this issue by demonstrating that polyclonal antibody generated by LukS-mut9 can neutralize other canonical and non-canonical leukotoxin pairs. In this report, we also demonstrated that several potent toxins can be created by non-canonical pairing of subunits. Out of 5 pairs of canonical and 8 pairs of non-canonical toxins tested, anti-LukS-mut9 polyclonal antibodies neutralized all except for LukAB. We also studied the potential hemolytic activities of canonical and noncanonical pairs among biocomponent toxins and discovered that a novel non-canonical pair consisting of HlgA and LukD is a highly toxic combination. This pair can lyse RBC from different species including human blood far better than alpha hemolysin. Moreover, to follow-up our last report, we explored the correlation between the levels of pre-existing antibodies to new sets of leukotoxins subunits and clinical outcomes in adult patients with S

  13. 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

  14. The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes

    PubMed Central

    Indrieri, Alessia; Conte, Ivan; Chesi, Giancarlo; Romano, Alessia; Quartararo, Jade; Tatè, Rosarita; Ghezzi, Daniele; Zeviani, Massimo; Goffrini, Paola; Ferrero, Ileana; Bovolenta, Paola; Franco, Brunella

    2013-01-01

    Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial-dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holo-cytochrome c-type synthase (HCCS) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders. PMID:23239471

  15. 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

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

    PubMed Central

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

    2013-01-01

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

  17. 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

  18. 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

  19. 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.

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

    PubMed Central

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

    2014-01-01

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

  1. 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

  2. The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3(+) lymphocyte-primed multipotent precursors.

    PubMed

    Xiao, Jing; Zhou, Haibo; Wu, Ning; Wu, Li

    2016-09-01

    The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a(-)CD8α(+)conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3(+) lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging.

  3. The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

    PubMed Central

    Xiao, Jing; Zhou, Haibo; Wu, Ning; Wu, Li

    2016-01-01

    The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a−CD8α+conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3+ lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging. PMID:26051474

  4. Methylation-associated silencing of SFRP1 with an 8p11-12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers

    PubMed Central

    Yang, Zeng-Quan; Liu, Gang; Bollig-Fischer, Aliccia; Haddad, Ramsi; Tarca, Adi L; Ethier, Stephen P.

    2009-01-01

    Recently we analyzed the 8p11-12 genomic region for copy number and gene expression changes in a panel of human breast cancer cell lines and primary specimens. We found that SFRP1 (Secreted frizzled related protein 1) is frequently under expressed even in breast tumors with copy number increases in this genomic region. SFRP1 encodes a WNT signaling antagonist, and plays a role in the development of multiple solid tumor types. In this study, we analyzed methylation-associated silencing of the SFRP1 gene in breast cancer cells with the 8p11-12 amplicon, and investigated the tumor suppressor properties of SFRP1 in breast cancer cells. SFRP1 expression was markedly reduced in both the breast cancer cell lines and primary tumor specimens relative to normal primary human mammary epithelial cells even when SFRP1 is amplified. Suppression of SFRP1 expression in breast cancer cells with an SFRP1 gene amplification is associated with SFRP1 promoter methylation. Furthermore, restoration of SFRP1 expression suppressed the growth of breast cancer cells in monolayer, and inhibited anchorage independent growth. We also examined the releationship between the silencing of SFRP1 gene and WNT signaling in breast cancer. Ectopic SFRP1 expression in breast cancer cells suppressed both canonical and non-canonical WNT signaling pathways, and SFRP1 expression was negatively associated with the expression of a subset of WNT responsive genes including RET and MSX2. Thus, down-regulation of SFRP1 can be triggered by epigenetic and/or genetic events and may contribute to the tumorigenesis of human breast cancer through both canonical and non-canonical WNT signaling pathways. PMID:19569235

  5. 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

  6. Identification of canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor.

    PubMed

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

    2013-07-01

    Signaling of interleukin 23 (IL-23) via the IL-23 receptor (IL-23R) and the shared IL-12 receptor β1 (IL-12Rβ1) controls innate and adaptive immune responses and is involved in the differentiation and expansion of IL-17-producing CD4(+) T helper (TH17) cells. Activation of signal transducer and activator of transcription 3 (STAT3) appears to be the major signaling pathway of IL-23, and STAT binding sites were predicted in the IL-23R but not in the IL-12Rβ1 chain. Using site-directed mutagenesis and deletion variants of the murine and human IL-23R, we showed that the predicted STAT binding sites (pYXXQ; including Tyr-504 and Tyr-626 in murine IL-23R and Tyr-484 and Tyr-611 in human IL-23R) mediated STAT3 activation. Furthermore, we identified two uncommon STAT3 binding/activation sites within the murine IL-23R. First, the murine IL-23R carried the Y(542)PNFQ sequence, which acts as an unusual Src homology 2 (SH2) domain-binding protein activation site of STAT3. Second, we identified a non-canonical, phosphotyrosine-independent STAT3 activation motif within the IL-23R. A third predicted site, Tyr-416 in murine and Tyr-397 in human IL-23R, is involved in the activation of PI3K/Akt and the MAPK pathway leading to STAT3-independent proliferation of Ba/F3 cells upon stimulation with IL-23. In contrast to IL-6-induced short term STAT3 phosphorylation, cellular activation by IL-23 resulted in a slower but long term STAT3 phosphorylation, indicating that the IL-23R might not be a major target of negative feedback inhibition by suppressor of cytokine signaling (SOCS) proteins. In summary, we characterized IL-23-dependent signal transduction with a focus on STAT3 phosphorylation and identified canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the IL-23R.

  7. The Impact of Canonical and Non-canonical El Niño on Atlantic Tropical Cyclone Activity: High-resolution Tropical Channel Model Simulations

    NASA Astrophysics Data System (ADS)

    Patricola, C. M.; Chang, P.; Saravanan, R.

    2013-12-01

    Tropical Pacific sea surface temperature (SST) variability during the El Niño-Southern Oscillation (ENSO) influences seasonal Atlantic tropical cyclone activity by modulating vertical wind shear and tropospheric temperature in the tropical Atlantic, with warmer than average SST during El Niño suppressing Atlantic tropical cyclones. The location of maximum SST warming during El Niño varies from the East Pacific (canonical) to Central Pacific (non-canonical/Modoki). This study investigates how the location and magnitude of maximum tropical Pacific warming impacts Atlantic tropical cyclones, and through what mechanisms. Climate simulations are performed to supplement observationally based studies, which yield conflicting results and rely on a relatively short data record that is complicated by factors other than ENSO, such as Atlantic SST variability. The simulations are run with the Weather Research and Forecasting (WRF) model configured as a tropical channel model at a relatively fine horizontal resolution of 27 km compared to the current generation of global climate models that typically use a 50 - 100 km grid. Monthly climatological SST is prescribed in the control simulation, and mechanistic experiments are forced by tropical Pacific SST patterns characteristic of Central Pacific and East Pacific El Niño. Seasonal accumulated cyclone energy is used to evaluate the response in Atlantic tropical cyclone activity to Central and East Pacific El Niño, and the response in atmospheric conditions relevant for tropical cyclones is diagnosed using a genesis potential index.

  8. A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation.

    PubMed

    Zha, Zhengyu; Han, Xiaoran; Smith, Matthew D; Liu, Yang; Giguère, Patrick M; Kopanja, Dragana; Raychaudhuri, Pradip; Siderovski, David P; Guan, Kun-Liang; Lei, Qun-Ying; Xiong, Yue

    2015-06-01

    G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of α, β, and γ subunits (Gαβγ). Here, we report that G protein β subunits (Gβ) bind to DDB1 and that Gβ2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR results in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from Gβ2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gβ protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling.

  9. 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

  10. Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS.

    PubMed

    Korlimarla, Aruna; Bhandary, Lekhana; Prabhu, Jyothi S; Shankar, Hema; Sankaranarayanan, Hari; Kumar, Pravin; Remacle, Jose; Natarajan, Dipa; Sridhar, T S

    2013-06-01

    The breast cancer type 1 susceptibility gene (BRCA1) is a tumor suppressor gene, mutations or loss of which lead to genomic instability and breast cancer. BRCA1 protein is part of a large multi-protein complex involved in a variety of DNA repair and transcription regulatory functions. At least four splice variants have been described and these differ in their function and tissue and spatio-temporal expression patterns. Structural analysis has revealed the presence of two nuclear localization signals (NLS) located in exon 11 of BRCA1. Interestingly, a splice variant of the protein that lacks both of the known NLS still manages to gain entry to the nucleus. While there is experimental proof for the translocation of these proteins by binding to other established nuclear proteins, we examined the possibility of a hitherto unidentified NLS in this particular variant. In this paper, we present evidence for the existence of a previously unreported non-canonical NLS contained within the first 39 amino acids of exon 11. A fusion protein with this 39mer and a reporter green fluorescent protein translocated into the nucleus when it was expressed in breast epithelial cells. We demonstrate the presence of a hitherto unreported noncanonical NLS in exon 11a of BRCA1. This NLS might aid proteins that were encoded by splice variants and lack the canonical NLS to localize to the nucleus. PMID:23666596

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

    PubMed Central

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

    2016-01-01

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

  12. 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

  13. 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

  14. 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.

  15. 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

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

    PubMed Central

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

    2014-01-01

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

  17. 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

  18. 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

  19. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2014-05-20

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

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

    PubMed

    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

  3. 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

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

    PubMed Central

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

    2016-01-01

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

  5. Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

    PubMed Central

    Allache, Redouane; Lachance, Stéphanie; Guyot, Marie Claude; De Marco, Patrizia; Merello, Elisa; Justice, Monica J.; Capra, Valeria; Kibar, Zoha

    2014-01-01

    Wnt signaling has been classified as canonical Wnt/β-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor–related protein Lrp6 is crucial for the activation of the Wnt/β-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26m1Jus) and in human NTDs. We demonstrate that Skax26m1Jus represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6Skax26-Jus genetically interacts with a PCP mutant (Vangl2Lp) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells’ polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process. PMID:24203697

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

    PubMed

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

    2009-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. 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

  9. 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

  10. 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

  11. 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

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

    PubMed

    Ma, Xiaojun; Aoki, Tomohiro; Narumiya, Shuh

    2016-03-01

    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.

  13. Non-canonical interleukin 23 receptor complex assembly: p40 protein recruits interleukin 12 receptor β1 via site II and induces p19/interleukin 23 receptor interaction via site III.

    PubMed

    Schröder, Jutta; Moll, Jens M; Baran, Paul; Grötzinger, Joachim; Scheller, Jürgen; Floss, Doreen M

    2015-01-01

    IL-23, composed of the cytokine subunit p19 and the soluble α receptor subunit p40, binds to a receptor complex consisting of the IL-23 receptor (IL-23R) and the IL-12 receptor β1 (IL-12Rβ1). Complex formation was hypothesized to follow the "site I-II-III" architectural paradigm, with site I of p19 being required for binding to p40, whereas sites II and III of p19 mediate binding to IL-12Rβ1 and IL-23R, respectively. Here we show that the binding mode of p19 to p40 and of p19 to IL-23R follow the canonical site I and III paradigm but that interaction of IL-23 to IL-12Rβ1 is independent of site II in p19. Instead, binding of IL-23 to the cytokine binding module of IL-12Rβ1 is mediated by domains 1 and 2 of p40 via corresponding site II amino acids of IL-12Rβ1. Moreover, domains 2 and 3 of p40 were sufficient for complex formation with p19 and to induce binding of p19 to IL-23R. The Fc-tagged fusion protein of p40_D2D3/p19 did, however, not act as a competitive IL-23 antagonist but, at higher concentrations, induced proliferation via IL-23R but independent of IL-12Rβ1. On the basis of our experimental validation, we propose a non-canonical topology of the IL-23·IL-23R·IL-12Rβ1 complex. Furthermore, our data help to explain why p40 is an antagonist of IL-23 and IL-12 signaling and show that site II of p19 is dispensable for IL-23 signaling.

  14. 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

  15. 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

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

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

  17. 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

  18. 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

  19. Dimension stone

    USGS Publications Warehouse

    Dolley, T.P.

    2003-01-01

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

  20. 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.

  1. 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

  2. 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…

  3. Dimension control of Superradiance

    NASA Astrophysics Data System (ADS)

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

    2016-05-01

    We develop a theory for quantum dipole-dipole coupling when the electromagnetic fields are confined to an open line, open plane, or open space, commensurate with experimental capability for collective atomic effects subject to dimensional confinement. Our mathematical model naturally interpolates for all real dimension between one dimension for the line to three dimensions for open space. We show how superradiant emission can be controlled by dimensional confinement, including near-field and dipole-orientation effects, and we propose a two-dimensional confinement experiment to test our theory's efficacy. University of Michigan.

  4. 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)

  5. 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…

  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. 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…

  8. 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…

  9. 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.

  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. Big Mysteries: Extra Dimensions

    ScienceCinema

    Lincoln, Don

    2016-07-12

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

  12. 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,…

  13. Tensor sufficient dimension reduction

    PubMed Central

    Zhong, Wenxuan; Xing, Xin; Suslick, Kenneth

    2015-01-01

    Tensor is a multiway array. With the rapid development of science and technology in the past decades, large amount of tensor observations are routinely collected, processed, and stored in many scientific researches and commercial activities nowadays. The colorimetric sensor array (CSA) data is such an example. Driven by the need to address data analysis challenges that arise in CSA data, we propose a tensor dimension reduction model, a model assuming the nonlinear dependence between a response and a projection of all the tensor predictors. The tensor dimension reduction models are estimated in a sequential iterative fashion. The proposed method is applied to a CSA data collected for 150 pathogenic bacteria coming from 10 bacterial species and 14 bacteria from one control species. Empirical performance demonstrates that our proposed method can greatly improve the sensitivity and specificity of the CSA technique. PMID:26594304

  14. 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.

  15. Infinitely Large New Dimensions

    SciTech Connect

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

    1999-07-29

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

  16. Bond percolation in higher dimensions

    NASA Astrophysics Data System (ADS)

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

    2013-07-01

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

  17. Dimensions of E-Learning.

    ERIC Educational Resources Information Center

    Khan, Badrul H.

    2002-01-01

    Considers factors that must be weighed in creating effective electronic learning environments and presents a basic framework for Web-based or electronic learning. Highlights include the institutional dimension; the pedagogical dimension; technological dimension; interface design; evaluation; management; resource support; and ethical…

  18. 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.

  19. 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.

  20. Infinitely Large New Dimensions

    SciTech Connect

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

    2000-01-24

    We construct intersecting brane configurations in anitde Sitter (AdS) space which localize gravity to the intersection region, generalizing the trapping of gravity to any number n of infinite extra dimensions. Since the 4D Planck scale M{sub Pl} is determined by the fundamental Planck scale M{sub *} and the AdS radius L via the familiar relation M{sup 2}{sub Pl}{approx}M{sup 2+n}{sub *}L{sup n} , we get two kinds of theories with TeV scale quantum gravity and submillimeter deviations from Newton's law. With M{sub *}{approx}TeV and L{approx}submillimeter , we recover the phenomenology of theories with large extra dimensions. Alternatively, if M{sub *}{approx}L{sup -1}{approx}M{sub Pl} , and our 3-brane is at a distance of {approx}100M{sup -1}{sub Pl} from the intersection, we obtain a theory with an exponential determination of the weak/Planck hierarchy. (c) 2000 The American Physical Society.

  1. 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.

  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. Dimensions of systems biology.

    PubMed

    Huang, S; Wikswo, J

    2006-01-01

    Systems biology, possibly the latest sub-discipline of biology, has arisen as a result of the shockwave of genomic and proteomic data that has appeared in the past few years. However, despite ubiquitous initiatives that carry this label, there is no precise definition of systems biology other than the implication of a new, all-encompassing, multidisciplinary endeavor. Here we propose that systems biology is more than the integration of biology with methods of the physical and computational sciences, and also more than the expansion of the single-pathway approach to embracing genome-scale networks. It is the discipline that specifically addresses the fundamental properties of the complexity that living systems represent. To facilitate the discussion, we dissect and project the multifaceted systems complexity of living organisms into five dimensions: (1) molecular complexity; (2) structural complexity; (3) temporal complexity; (4) abstraction and emergence; and (5) algorithmic complexity. This "five-dimensional space" may provide a framework for comparing, classifying, and complementing the vast diversity of existing systems biology programs and their goals, and will also give a glimpse of the magnitude of the scientific problems associated with unraveling the ultimate mysteries of life.

  4. 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

  5. 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

  6. 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?

  7. Anomalous dimensions of conformal baryons

    NASA Astrophysics Data System (ADS)

    Pica, Claudio; Sannino, Francesco

    2016-10-01

    We determine the anomalous dimensions of baryon operators for the three-color theory as functions of the number of massless flavors within the conformal window to the maximum known order in perturbation theory. We show that the anomalous dimension of the baryon is controllably small, within the δ expansion, for a wide range of number of flavors. We also find that this is always smaller than the anomalous dimension of the fermion mass operator. These findings challenge the partial compositeness paradigm.

  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. Dimensioning, Tolerancing, and Machine Finishes.

    ERIC Educational Resources Information Center

    Adams, George C.

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

  10. Dimensions of Organizational Task Environments.

    ERIC Educational Resources Information Center

    Dess, Gregory G.; Beard, Donald W.

    1984-01-01

    Reducing Aldrich's codification of organizational task environments from six to three dimensions--munificence (capacity), complexity (homogeneity-heterogeneity, concentration-dispersion), and dynamism (stability-instability, turbulence), the authors use interim and factor analytical techniques to explore each dimension's viability and draw…

  11. Dimensions of temperament: an analysis.

    PubMed

    Lorr, M; Stefic, E C

    1976-01-01

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

  12. Timbre Dimensions for Musical Control

    NASA Astrophysics Data System (ADS)

    Giese, Gregory Roy

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

  13. 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.

  14. 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.

  15. 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.

  16. Classical Liquids in Fractal Dimension.

    PubMed

    Heinen, Marco; Schnyder, Simon K; Brady, John F; Löwen, Hartmut

    2015-08-28

    We introduce fractal liquids by generalizing classical liquids of integer dimensions d=1,2,3 to a noninteger dimension dl. The particles composing the liquid are fractal objects and their configuration space is also fractal, with the same dimension. Realizations of our generic model system include microphase separated binary liquids in porous media, and highly branched liquid droplets confined to a fractal polymer backbone in a gel. Here, we study the thermodynamics and pair correlations of fractal liquids by computer simulation and semianalytical statistical mechanics. Our results are based on a model where fractal hard spheres move on a near-critical percolating lattice cluster. The predictions of the fractal Percus-Yevick liquid integral equation compare well with our simulation results.

  17. Personality dimensions of opiate addicts.

    PubMed

    Vukov, M; Baba-Milkic, N; Lecic, D; Mijalkovic, S; Marinkovic, J

    1995-02-01

    A survey of 80 opiate addicts included in a detoxification program was conducted at the Institute on Addictions in Belgrade. In addition to a dependence diagnosis and mental disorders based on DSM-III-R, we applied a Tridimensional Personality Questionnaire (TPQ) that measures the 3 major personality dimensions: novelty-seeking (NS), harm avoidance (HA) and reward dependence (RD). When compared with a control group (a sample of Yugoslav undergraduate students), the opiate addicts demonstrate significantly high NS dimension as well as significant divergences of HA and RD subscales. The surveyed opiate addicts demonstrate a high percentage of personality disorders specifically in cluster B. The personality dimensions of opiate addicts showed certain temperament traits, such as: impulsiveness, shyness with strangers, fear of uncertainty and dependence. NS, HA and RD determined by temperament specifics may be an etiological factor in forming of a personality disorder, an affective disorder as well as of a drug choice.

  18. 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.

  19. 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.

  20. Critical dimension: MEMS road map

    NASA Astrophysics Data System (ADS)

    Poulingue, Marc; Knutrud, Paul

    2007-03-01

    The use of Micro-Electro-Mechanical Systems (MEMS) technology in mechanical, biotechnology, optical, communications, and ink jet is growing. Critical dimensions in MEMS devices are getting smaller and processes are constantly facing new metrology challenges. This paper will examine some critical dimension metrology needs and challenges for MEMS using resist-on-silicon structures. It is shown that the use of automated optical CD metrology can meet emerging measurement requirements while bringing the advantages of a non-destructive, high throughput and precise methodology.

  1. 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…

  2. Dimension independence in exterior algebra.

    PubMed Central

    Hawrylycz, M

    1995-01-01

    The identities between homogeneous expressions in rank 1 vectors and rank n - 1 covectors in a Grassmann-Cayley algebra of rank n, in which one set occurs multilinearly, are shown to represent a set of dimension-independent identities. The theorem yields an infinite set of nontrivial geometric identities from a given identity. PMID:11607520

  3. The Visuospatial Dimension of Writing

    ERIC Educational Resources Information Center

    Olive, Thierry; Passerault, Jean-Michel

    2012-01-01

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

  4. The 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…

  5. Heat conduction in three dimensions

    NASA Technical Reports Server (NTRS)

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

    1980-01-01

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

  6. Critical gravity in four dimensions.

    PubMed

    Lü, H; Pope, C N

    2011-05-01

    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. PMID:21635082

  7. 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.

  8. Critical gravity in four dimensions.

    PubMed

    Lü, H; Pope, C N

    2011-05-01

    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.

  9. Double Semions in Arbitrary Dimension

    NASA Astrophysics Data System (ADS)

    Freedman, Michael H.; Hastings, Matthew B.

    2016-10-01

    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.

  10. Turing patterns in three dimensions

    NASA Astrophysics Data System (ADS)

    Shoji, Hiroto; Yamada, Kohtaro; Ueyama, Daishin; Ohta, Takao

    2007-04-01

    We investigate three-dimensional Turing patterns in two-component reaction diffusion systems. The FitzHugh-Nagumo equation, the Brusselator, and the Gray-Scott model are solved numerically in three dimensions. Several interconnected structures of domains as well as lamellar, hexagonal, and spherical domains are obtained as stable motionless equilibrium patterns. The relative stability of these structures is studied analytically based on the reduction approximation. The relation with the microphase-separated structures in block copolymers is also discussed.

  11. 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.

  12. Supergravity Theory from Ten Dimensions.

    NASA Astrophysics Data System (ADS)

    Romans, Larry James

    1985-12-01

    This work is concerned with the study of several ten-dimensional field theories intimately associated with superstring theories, and possibilities for obtaining realistic four-dimensional theories from them. Three chapters follow the N = 2b supergravity from ten to five, then to four dimensions. First of all, compactifications to five dimensions on various manifolds are studied. Then the entire mass spectrum for the compactification on S('5) is derived using techniques of harmonic analysis on spheres. A particular set of modes corresponds to a gauged maximal supergravity theory in five dimensions; this theory, with Yang-Mills group SO(6), is constructed in detail. By a process similar to analytic continuation, noncompact versions of this theory are also obtained, gauging all the semisimple real forms of SO(6). One particular form, with gauge group SO*(6) (DBLTURN) SU(3,1), compactifies to flat four-dimensional spacetime and offers attractive phenomenological possibilities. The final chapter is concerned with candidates for effective low-energy theories for N = 1 superstrings with gauge group SO(32) or E(,8) x E(,8). These effective theories contain curvature squared terms, and require unusual gravitational interactions to cancel anomalies. The field equations are derived and found to admit compactifications to flat four dimensional spacetime, with the possibility of accommodating many phenomenological considerations.

  13. 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.

  14. Turing patterns in three dimensions.

    PubMed

    Shoji, Hiroto; Yamada, Kohtaro; Ueyama, Daishin; Ohta, Takao

    2007-04-01

    We investigate three-dimensional Turing patterns in two-component reaction diffusion systems. The FitzHugh-Nagumo equation, the Brusselator, and the Gray-Scott model are solved numerically in three dimensions. Several interconnected structures of domains as well as lamellar, hexagonal, and spherical domains are obtained as stable motionless equilibrium patterns. The relative stability of these structures is studied analytically based on the reduction approximation. The relation with the microphase-separated structures in block copolymers is also discussed. PMID:17500983

  15. 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.

  16. 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.

  17. 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.

  18. Localized instanton in four dimensions

    NASA Astrophysics Data System (ADS)

    O'brien, G. M.; Tchrakian, D. H.

    1987-02-01

    A family of generalized Yang-Mills- (GYM) Higgs (H) systems is proposed as phenomenological models giving rise to localized instantons in four dimensions. An argument in favor of the (qualified) uniqueness of this system, which features a fundamental-representation Higgs field, is given. Two ``radial'' Ansa$auml-tze are made, and the compatibility of one of them with the field equation is analyzed in detail. It is suggested that such GYMH systems can be used in the computation of the confining potential.

  19. Random flights through spaces of different dimensions

    NASA Astrophysics Data System (ADS)

    Reimberg, Paulo H. F.; Abramo, L. Raul

    2015-01-01

    We shall study random flights that start in a space of one given dimension and, after performing a definite number of steps, continue to develop in a space of higher dimension. We show that if the difference of the dimension of spaces is even, then the probability density describing the composite flight can be expressed as marginalizations of the probability density associated to a random flight in the space of less dimensions. This dimensional reduction is a consequence of Gegenbauer addition theorem.

  20. 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...

  1. 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...

  2. Quantum Dimension and Quantum Projective Spaces

    NASA Astrophysics Data System (ADS)

    Matassa, Marco

    2014-09-01

    We show that the family of spectral triples for quantum projective spaces introduced by D'Andrea and Dąbrowski, which have spectral dimension equal to zero, can be reconsidered as modular spectral triples by taking into account the action of the element K_{2rho} or its inverse. The spectral dimension computed in this sense coincides with the dimension of the classical projective spaces. The connection with the well known notion of quantum dimension of quantum group theory is pointed out.

  3. 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…

  4. 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...

  5. 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...

  6. Reflections from the fourth dimension

    NASA Astrophysics Data System (ADS)

    Lefranc, Marc

    2013-01-01

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

  7. 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

  8. Tan relations in one dimension

    SciTech Connect

    Barth, Marcus Zwerger, Wilhelm

    2011-10-15

    We derive exact relations that connect the universal C/k{sup 4}-decay of the momentum distribution at large k with both thermodynamic properties and correlation functions of two-component Fermi gases in one dimension with contact interactions. The relations are analogous to those obtained by Tan in the three-dimensional case and are derived from an operator product expansion of the one- and two-particle density matrix. They extend earlier results by Olshanii and Dunjko (2003) for the bosonic Lieb-Liniger gas. As an application, we calculate the pair distribution function at short distances and the dimensionless contact in the limit of infinite repulsion. The ground state energy approaches a universal constant in this limit, a behavior that also holds in the three-dimensional case. In both one and three dimensions, a Stoner instability to a saturated ferromagnet for repulsive fermions with zero range interactions is ruled out at any finite coupling. - Highlights: > We derive universal relations for the two-component, contact-interacting 1D Fermi gas. > These relations connect the tail of the momentum distribution to thermodynamic properties. > There is no saturated ferromagnetism at finite, repulsive couplings for the 3D model.

  9. International dimensions of Colombian violence.

    PubMed

    Franco, S

    2000-01-01

    Violence is the main public health problem in Colombia, as demonstrated by current homicide rates (the highest in the world), the strong effect of violence on the health care sector, and the forceful displacement of citizens, among other factors. This violence has international dimensions and consequences: inequity resulting from the political-economic system and increased by the neoliberal adjustments; the international traffic of drugs and weapons; exile and forceful displacement of persons into bordering countries; and frequent violations of human rights and humanitarian international rights. The international community can play a role in the search for a solution to this problem, as the author discusses in terms of contributions made in the past and those that could be made in the near future. Colombian violence can be viewed as a problem, a message, and a challenge for international public health, and the author suggests specific areas in which international public health could contribute to the study and solution of this complex situation.

  10. 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.

  11. 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.

  12. Ethical Dimensions and Filial Caregiving

    PubMed Central

    McCarty, Ellen F.; Hendricks, Constance S.; Hendricks, Denisha L.; McCarty, Kathleen M.

    2013-01-01

    The elderly are growing rapidly today as life expectancy increases. As this longevity has increased, so has the need for filial caregivers. While much has been written about caregiving stress, little has been written regarding the ethical dimensions of filial responsibility and daughter and son caregivers’ perceptions of responsibility and moral demands. This paper will address the concept of family caregiving and contextual family characteristics. Family characteristics will expand awareness of the interrelationship value between the nature of the prior filial relationship, image of caregiving, and ethical views that underscore acceptance of the filial obligation. An explanation of both the interview process and selected measurements that speak to ethical perspective, sense of caregiving image, and expectations of filial caregiving will also be addressed. Therefore, the purpose of this paper is to elucidate how adult children may be helped in an anticipatory and proactive manner as more and more adult children take on parent care for longer durations of time. PMID:23459516

  13. 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

  14. 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...

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

    PubMed Central

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

    2016-01-01

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

  16. The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

    PubMed Central

    Wang, Chu-An

    2015-01-01

    It has been shown in many clinical studies that the level of vascular endothelial growth factor-C (VEGF-C) positively correlates with lymph node metastasis. Nevertheless, beyond the canonical role of VEGF-C in stimulating lymphangiogenesis and thus promoting lymph node/distant metastasis, emerging evidence indicates that expression of VEGF-C contributes to various aspects of carcinogenicity via autocrine regulation. The newly identified functions of VEGF-C include but are not limited to proliferation, migration, invasion, and chemo-resistance. Besides tumor cell autocrine regulation, VEGF-C can also modulate the immune system such that tumor cells more easily escape immune surveillance. Therefore, understanding the functional roles and regulatory mechanisms related to the VEGF-C axis may lead to alternative strategies for cancer treatment. This mini-review will focus on summarizing recent discoveries regarding the unconventional functions of VEGF-C in cancer progression. PMID:25888649

  17. 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

  18. 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

  19. A non-canonical function of topoisomerase II in disentangling dysfunctional telomeres.

    PubMed

    Germe, Thomas; Miller, Kyle; Cooper, Julia Promisel

    2009-09-16

    The decatenation activity of topoisomerase II (Top2), which is widely conserved within the eukaryotic domain, is essential for chromosomal segregation in mitosis. It is less clear, however, whether Top2 performs the same function uniformly across the whole genome, and whether all its functions rely on decatenation. In the fission yeast, Schizosaccharomyces pombe, telomeres are bound by Taz1, which promotes smooth replication fork progression through the repetitive telomeric sequences. Hence, replication forks stall at taz1 Delta telomeres. This leads to telomeric entanglements at low temperatures (

  20. Unsaturated fatty acid-induced non-canonical autophagy: unusual? or unappreciated?

    PubMed Central

    Bankaitis, Vytas A

    2015-01-01

    The breakdown of cellular components via autophagy is crucial for cellular homeostasis. In this issue of The EMBO Journal, Niso-Santano et al (2015) report the important observation that feeding cells with saturated or unsaturated fatty acids triggers mechanistically distinct autophagic responses. Feeding cells saturated fatty acid induced the canonical, BECN1/PI3K-dependent autophagy pathway. Conversely, the unsaturated fatty acid oleate triggered autophagic responses that were independent of the BECN1/PI3K complex, but that required a functional Golgi system. PMID:25762589

  1. 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

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

    DOE PAGES

    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

  3. 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

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

    PubMed

    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. 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.

  6. 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.

  7. 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

  8. A Non-Canonical Role for β-Secretase in the Retina.

    PubMed

    Qian, Qingwen; Mitter, Sayak K; Pay, S Louise; Qi, Xiaoping; Rickman, Catherine Bowes; Grant, Maria B; Boulton, Michael E

    2016-01-01

    It has long been established that β-Secretase (BACE) plays a critical role in the formation of amyloid plaques in Alzheimer's Disease patients, but it is only recently that the importance of β-secretases in retinal pathophysiology has been recognized. BACE expression is elevated in response to stress, and downregulation results in lysosomal abnormalities and mitochondrial changes. Inhibition of BACE can lead to reduced retinal function, retinal thinning, lipofuscin accumulation and vascular dysfunction in mice. Furthermore, BACE inhibition accelerates choroidal neovascularization (CNV) in mice. We propose that BACE plays an important role in retinal homeostasis and that BACE upregulation in response to stress is a protective measure. PMID:26427429

  9. 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

  10. 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…

  11. 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

  12. Interferon gamma induces protective non-canonical signaling pathways in primary neurons.

    PubMed

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

    2015-10-01

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

  13. 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.

  14. [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.

  15. 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

  16. 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.

  17. Changes in fractal dimension during aggregation.

    PubMed

    Chakraborti, Rajat K; Gardner, Kevin H; Atkinson, Joseph F; Van Benschoten, John E

    2003-02-01

    Experiments were performed to evaluate temporal changes in the fractal dimension of aggregates formed during flocculation of an initially monodisperse suspension of latex microspheres. Particle size distributions and aggregate geometrical information at different mixing times were obtained using a non-intrusive optical sampling and digital image analysis technique, under variable conditions of mixing speed, coagulant (alum) dose and particle concentration. Pixel resolution required to determine aggregate size and geometric measures including the fractal dimension is discussed and a quantitative measure of accuracy is developed. The two-dimensional fractal dimension was found to range from 1.94 to 1.48, corresponding to aggregates that are either relatively compact or loosely structured, respectively. Changes in fractal dimension are explained using a conceptual model, which describes changes in fractal dimension associated with aggregate growth and changes in aggregate structure. For aggregation of an initially monodisperse suspension, the fractal dimension was found to decrease over time in the initial stages of floc formation.

  18. 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.

  19. The international dimensions of neuroethics.

    PubMed

    Lombera, Sofia; Illes, Judy

    2009-08-01

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

  20. 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.

  1. Higgs bosons in extra dimensions

    NASA Astrophysics Data System (ADS)

    Quiros, Mariano

    2015-04-01

    In this paper, motivated by the recent discovery of a Higgs-like boson at the Large Hadron Collider (LHC) with a mass mH≃125 GeV, we review different models where the hierarchy problem is solved by means of a warped extra dimension. In the Randall-Sundrum (RS) model electroweak observables provide very strong bounds on the mass of KK modes which motivates extensions to overcome this problem. Two extensions are briefly discussed. One particular extension is based on the deformation of the metric such that it strongly departs from the AdS5 structure in the IR region while it goes asymptotically to AdS5 in the UV brane. This model has the IR brane close to a naked metric singularity (which is outside the physical interval) characteristic of soft-walls constructions. The proximity of the singularity provides a strong wave function renormalization for the Higgs field which suppresses the T and S parameters. The second class of considered extensions are based on the introduction of an extra gauge group in the bulk such that the custodial SU(2)R symmetry is gauged and protects the T parameter. By further enlarging the bulk gauge symmetry one can find models where the Higgs is identified with the fifth component of gauge fields and for which the Higgs potential along with the Higgs mass can be dynamically determined by the Coleman-Weinberg mechanism.

  2. 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.

  3. 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.

  4. What dimensions underlie cluster B personality disorders?

    PubMed

    Looper, K J; Paris, J

    2000-01-01

    This report presents a conceptual model of the relationships between personality dimensions and the four personality disorders listed in the B cluster on axis II. The hypothesis will be developed that while impulsivity is the common dimension underlying all four disorders, differences between the categories reflect the severity of impulsive traits, interactions with other personality dimensions, the effects of gender, and the influence of culture. Clinical and research implications of the model are then described.

  5. 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.

  6. 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

  7. 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.

  8. 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…

  9. 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…

  10. 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…

  11. 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…

  12. 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…

  13. 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...

  14. 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...

  15. 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…

  16. 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…

  17. 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.

  18. [Vertical dimension in the Begg technic].

    PubMed

    Demange, C; Dion, J G

    1989-01-01

    This data of 25 treated cases in BEGG technic show, with RICKETTS analysis, a small augmentation of vertical dimensions during treatment. During retention, four of five factors improved. No correlation have been found between increase rate of vertical dimensions, treatment duration, and initial typology.

  19. Positioner with long travel in two dimensions

    DOEpatents

    Trumper, David L.; Williams, Mark E.

    1997-12-23

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

  20. Expressing n dimensions as n-1

    NASA Astrophysics Data System (ADS)

    Laubenstein, John

    2009-03-01

    The IWPD Scale Metrics team has explored a different conceptualization of multiple dimensions through a model expressing n dimensions as n -- 1. This is achieved by aligning time and a spatial dimension along the same orientation. We have shown that time and distance along the same axis in combination with a scalar is equivalent to two orthogonal dimensions. Scale Metrics is simply a different conceptualization of multi-dimensions; however, it requires a change in the modeling of gravitation since time is no longer considered to be orthogonal to the three spatial dimensions. A model for Scale Metrics gravity has been developed and in the process a quantum theory of gravitation emerges. Why entertain IWPD Scale Metrics? Because the Standard Model has not been successful in the unification of GR with QT. A new model of gravitation built on a foundation of quantum concepts (as opposed to a quantum fix to an inherently classical geometric theory) may be of benefit in the ultimate search for the unification of gravitation with quantum theory. Further, since Scale Metrics provides nothing more than a different way to conceptualize multiple dimensions in a manner that is equivalent to 4 vectors -- it replaces nothing, but rather serves only to complement past and current achievements while providing a new view of quantum gravitation.

  1. 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

  2. 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

  3. 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.

  4. 49 CFR 178.360-3 - Dimensions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Packagings for Class 7 (Radioactive) Materials § 178.360-3 Dimensions. (a) The inside diameter of the vessel... wall thickness and length in accordance with the following: Inside diameter maximum Inches Cm...

  5. 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.

  6. Thinking in Two Dimensions: Simple Multiplicative Relations

    ERIC Educational Resources Information Center

    Hutson, Barbara A.; Clark, Richard M.

    1976-01-01

    In order to study developmental and task-related factors in ability to coordinate two dimensions, a simple multiplicative relations matrix task was presented to 51 children in kindergarten and grades 1 and 2. (MS)

  7. Cardiac Dimensions in Elite Young Track Athletes.

    ERIC Educational Resources Information Center

    Tharp, Gerald D.; And Others

    1986-01-01

    The study compared young sprint and distance runners for changes in cardiac dimensions with increased age or increased body surface area. Results, which run counter to generalizations stated for adult athletes, are detailed. (Author/MT)

  8. BOX DIMENSIONS OF α-FRACTAL FUNCTIONS

    NASA Astrophysics Data System (ADS)

    Akhtar, Md. Nasim; Prasad, M. Guru Prem; Navascués, M. A.

    2016-08-01

    The box dimension of the graph of non-affine, continuous, nowhere differentiable function fα which is a fractal analogue of a continuous function f corresponding to a certain iterated function system (IFS), is investigated in the present paper. The estimates for box dimension of the graph of α-fractal function fα for equally spaced as well as arbitrary data sets are found.

  9. 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.

  10. 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.

  11. Rotating Black Holes in Higher Dimensions

    NASA Astrophysics Data System (ADS)

    Kleihaus, Burkhard; Kunz, Jutta; Navarro-Lérida, Francisco

    2008-03-01

    The properties of higher-dimensional black holes can differ significantly from those of black holes in four dimensions, since neither the uniqueness theorem, nor the staticity theorem or the topological censorship theorem generalize to higher dimensions. We first discuss black holes of Einstein-Maxwell theory and Einstein-Maxwell-Chern-Simons theory with spherical horizon topology. Here new types of stationary black holes are encountered. We then discuss nonuniform black strings and present evidence for a horizon topology changing transition.

  12. [Personality dimensions and cerebral evoked potential].

    PubMed

    Camposano, S; Alvarez, C; Lolas, F

    1994-12-01

    Eysenck's personality theory postulates 3 orthogonal dimensions of personality: extraversion (E), neuroticism (N) and psychoticism (P), predicting conductual and physiological predispositions to suffer mental illness. Biological bases of Eysenck's personality traits have been documented electrophysiologically. Psychoticism, the latest described dimension, is controverted, since there is some evidence of common factors with the other two. In order to assess the relation between Eysenck's dimensions and sensorial reactivity and information encoding processes we studied 20 healthy young subjects (mean age 28.5 years) with flash visual cortical evoked potentials (VEP, 3 intensities, peak to peak amplitude of III, IV-V-VI, VII components), and auditory cognitive evoked potentials (odd ball paradigm, P300 latency). There was a positive correlation between N and P dimensions (Spearman, r = 0.52), between N and VEP amplitude at high intensity (r = 0.58) and a negative correlation between E and P300 latency (r = 0.58). In short we found that P is not an independent dimension, but is related to sensorial reactivity. E dimension was related to encoding processes supporting Eysenck's observations about memory and learning differences.

  13. 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.

  14. 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.

  15. Resolving statistical uncertainty in correlation dimension estimation.

    PubMed

    Borovkova, Svetlana; Rosa, Rodolfo; Sardonini, Laura

    2011-06-01

    In this paper we propose a novel method for obtaining standard errors and confidence intervals for the correlation dimension estimated on an observed chaotic time series. This method is based on the U-Statistics theory and an ingenious combination of the moving block and parametric bootstrap procedures. We test the method on the basis of computer simulations for both clean and noisy series. We show that the distribution of the correlation dimension estimate obtained by our method agrees very well with the "true" distribution obtained by the Monte Carlo simulation. One of the main advantage of our method is the ability to estimate the distribution (and hence, the standard error) of the correlation dimension estimate using only one observed time series. PMID:21721766

  16. 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.

  17. Mineral resource of the month: dimension stone

    USGS Publications Warehouse

    Dolley, Thomas P.

    2012-01-01

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

  18. The Spectral Dimension of Generic Trees

    NASA Astrophysics Data System (ADS)

    Durhuus, Bergfinnur; Jonsson, Thordur; Wheater, John F.

    2007-09-01

    We define generic ensembles of infinite trees. These are limits as N→∞ of ensembles of finite trees of fixed size N, defined in terms of a set of branching weights. Among these ensembles are those supported on trees with vertices of a uniformly bounded order. The associated probability measures are supported on trees with a single spine and Hausdorff dimension d h =2. Our main result is that the spectral dimension of the ensemble average is d s =4/3, and that the critical exponent of the mass, defined as the exponential decay rate of the two-point function along the spine, is 1/3.

  19. Multigravity from a discrete extra dimension

    NASA Astrophysics Data System (ADS)

    Deffayet, C.; Mourad, J.

    2004-06-01

    Multigravity theories are constructed from the discretization of the extra dimension of five-dimensional gravity. Using an ADM decomposition, the discretization is performed while maintaining the four-dimensional diffeomorphism invariance on each site. We relate the Goldstone bosons used to realize nonlinearly general covariance in discretized gravity to the shift fields of the higher-dimensional metric. We investigate the scalar excitations of the resulting theory and show the absence of ghosts and massive modes; this is due to a local symmetry inherited from the reparametrization invariance along the fifth dimension.

  20. Cosmic censorship in higher dimensions. II

    SciTech Connect

    Mahajan, Ashutosh; Goswami, Rituparno; Joshi, Pankaj S.

    2005-07-15

    Generalizing earlier results on dust collapse in higher dimensions, we show here that cosmic censorship can be restored in some classes of gravitational collapse models with tangential pressure present, if we take the spacetime dimension to be N{>=}6. This is under conditions to be motivated physically, such as smoothness of initial data from which the collapse develops. The models considered here with nonzero pressure include the Einstein cluster spacetimes which have been earlier studied extensively. Our work provides a step towards an understanding of the cosmic censorship conjecture and the necessary conditions for its validity.

  1. Microscopic Primordial Black Holes and Extra Dimensions

    SciTech Connect

    Conley, John A.; Wizansky, Tommer

    2006-11-15

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

  2. FLRW and LTB Cosmology in Extra Dimensions

    SciTech Connect

    Gueham, A.; Mebarki, N.

    2010-10-31

    Two models of 4+1 dimensions are discussed and some new exact solutions are found. Moreover, a dynamical study of a 4+1 homogeneous FLRW model is made. It is shown that the LTB inhomogeneous case leads to a scenario of the universe similar to that of Turok's cyclic model but with different mechanism.

  3. Introduction to Geometric Dimensioning and Tolerancing.

    ERIC Educational Resources Information Center

    Proebstle, Donald C.

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

  4. 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

  5. The Language Dimension of Mathematics Teaching.

    ERIC Educational Resources Information Center

    Barwell, Richard; Leung, Constant; Morgan, Candia; Street, Brian

    2002-01-01

    Explores how to develop children's understanding of mathematical vocabulary. Presents a lesson in which the class works on the concept of dimension, and issues raised by a discussion of applied linguistics and mathematics education. Discussion was stimulated by advice from the National Numeracy Strategy (NNS) vocabulary book. (KHR)

  6. 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…

  7. Dimensions of Nutrition Knowledge among Preadolescent Girls.

    ERIC Educational Resources Information Center

    Moxley, Robert L.; Wimberley, Ronald C.

    1982-01-01

    Examines the underlying dimensionality of a nutrition knowledge test for preadolescent girls. In contrast to the manner in which nutrition knowledge has previously been measured in research, analysis of the results indicates that their nutrition knowledge is multidimensional. The dimensions include "differentiated eating" and "vitamin importance."…

  8. 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…

  9. The Adaptive Dimension in Core Curriculum.

    ERIC Educational Resources Information Center

    Saskatchewan Dept. of Education, Regina.

    The Adaptive Dimension refers to the concept of making adjustments in approved educational programs to accommodate diversity in student learning needs, and to practices undertaken to make the approved core curriculum, instruction, and the learning environment meaningful and appropriate for each student. Adaptation takes into account the shift away…

  10. 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…

  11. 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…

  12. 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…

  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. 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.

  15. 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…

  16. Different lattice geometries with a synthetic dimension

    NASA Astrophysics Data System (ADS)

    Suszalski, Dominik; Zakrzewski, Jakub

    2016-09-01

    The possibility of creating different geometries with the help of an extra synthetic dimension in optical lattices is studied. The additional linear potential together with Raman-assisted tunnelings are used to engineer well-controlled tunnelings between available states. The great flexibility of the system allows us to obtain different geometries of synthetic lattices with the possibility for adding synthetic gauge fields.

  17. 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…

  18. 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…

  19. Traumatic Head Injury: Dimensions of Family Responsivity.

    ERIC Educational Resources Information Center

    Zarski, John J.; And Others

    1988-01-01

    Forty-five parents or spouses of head-injured patients were studied to: (1) determine differences among various family types on clinically relevant dimensions of family functioning, based on Olson's Circumplex model, and (2) establish the validity of three assessment methods. Results showed family functioning to be an important factor in recovery.…

  20. 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…

  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. 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…

  3. 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…

  4. 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…

  5. International Dimensions in Community College Education.

    ERIC Educational Resources Information Center

    Innovation Abstracts, 1984

    1984-01-01

    A cooperative project between community colleges in the Northeast and the Universities Field Staff International (UFSI) which sought to add an international dimension to existing community college curricula is described. Two objectives of the project are listed: to broaden faculty and administrative interest and skills in international studies;…

  6. The Authoritarian Dimension of Entertainment Television.

    ERIC Educational Resources Information Center

    Leckenby, John D.; Surlin, Stuart H.

    Some critics of broadcasting assert that the authoritarian dimension of entertainment television encourages viewer passivity and the uncritical acceptance of negative social values on the part of some viewers. This paper reviews the research on this topic and presents two new studies that tested the authoritarian impact of entertainment…

  7. Renormalization of dimension 6 gluon operators

    NASA Astrophysics Data System (ADS)

    Kim, HyungJoo; Lee, Su Houng

    2015-09-01

    We identify the independent dimension 6 twist 4 gluon operators and calculate their renormalization in the pure gauge theory. By constructing the renormalization group invariant combinations, we find the scale invariant condensates that can be estimated in nonperturbative calculations and used in QCD sum rules for heavy quark systems in medium.

  8. 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…

  9. Science in Primary Schools: The Multicultural Dimension.

    ERIC Educational Resources Information Center

    Peacock, Alan, Ed.

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

  10. Physical Dimensions of College Classroom Environments.

    ERIC Educational Resources Information Center

    Farrenkopf, Toni

    A project was undertaken at two state universities to investigate the physical dimensions of college classroom environments and their effects on student attitudes and the determining factors of such attitudes. The attitudes of 789 undergraduate, introductory psychology students toward 11 college classrooms were surveyed through administration of…

  11. (Super-)Gravity in Three Dimensions

    SciTech Connect

    Bergshoeff, Eric A.

    2009-12-15

    We present a new unitary model of gravity in three dimensions containing a particular combination of terms of higher-order derivatives in the gravitational field. We discuss some properties of this model. In particular, we present the N = 1 supersymmetric extension and discuss the role of the auxiliary scalar in the presence of the higher-derivative terms.

  12. 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...

  13. 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...

  14. 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...

  15. 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.

  16. 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…

  17. 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…

  18. Dimensions of Police Types: A Study of Perspective and Passion.

    ERIC Educational Resources Information Center

    Hochstedler, Ellen

    1981-01-01

    Investigated two dimensions of a typology of police officers: perspective and passion. Test results indicate these dimensions failed to identify the four police types proposed by W.K. Muir relating to dimensions of: the professional, enforcer, reciprocator, and avoider. The four types appear as general characters defined by several dimensions.…

  19. Fractal Dimension Analysis of Putative Martian Coastlines

    NASA Astrophysics Data System (ADS)

    Gianelli, G. A.

    2005-08-01

    Prior research is equivocal on the existence and location of Martian coastlines. This study proposes a novel method of analyzing putative coastlines; fractal dimensions provide a quantitative measurement of the complexity and nature of a fractal. Geological evidence points to a coastline at the elevation of -3790 meters, called the Deuteronilus contact. It is hypothesized that the fractal dimensions of this putative Martian coastline will be comparable to those of Earth shorelines. A topographic map with a contour line at -3790 meters was obtained from the U. S. Geological Survey, reflecting the most recent Mars Orbiter Laser Altimeter data. The map was cropped into sixty and twenty degree segments, and the putative coastline was isolated from extraneous features. A program which used the box-counting method calculated the fractal dimensions of the putative shorelines. The 22 results were tabulated and compared to 17 fractal dimensions of Earth shorelines, collected from published articles. Ranges were 1.07 to 1.66 for Earth and 1.141 to 1.436 for Mars. The mean was 1.28 for the Mars data and 1.22 for the Earth data, a slight difference that asteroid craters could account for. An unpaired t-test could not prove that the two data sets were significantly different. Although the past existence of a coastline at the Deuteronilus contact cannot be definitively proven without on site investigations, the hypothesis that the fractal dimensions of the putative Martian coastline would be comparable to those of Earth's was accepted, thereby substantiating the claims for the existence of a large northern ocean.

  20. Midsagittal dimensions of the prenatal human cranium.

    PubMed

    Eriksen, E; Bach-Petersen, S; van den Eynde, B; Solow, B; Kjaer, I

    1995-01-01

    The purpose of the present study was to analyze the linear dimensions of the cranial base and the anterior facial heights in the median plane of human fetal crania during the second trimester. The distances measured were related to gestational age (GA), crown-rump length (CRL) and maturation stages of the cranial base (MSS). The material comprised midsagittal tissue blocks of the crania from 52 normal human fetuses aged 13 to 22 weeks GA with CRL from 78 to 230 mm and cranial base maturation from MSS 3 to MSS 7. The measurements of the cranial and facial dimensions were performed on radiographs of these tissue blocks. The study confirmed previous observations regarding the dimensional increase in the linear dimensions of the cranial base and the upper facial height in the second trimester. The assessment of absolute changes was further supplemented by an analysis of the percentage changes. This analysis showed that the percentage changes from MSS 3 to MSS 7 of the linear dimensions of the cranial base and the upper facial heights were similar. On the other hand, the percentage increase in the lower anterior facial height during the second trimester was found to be much larger than that of the cranial base and the upper anterior facial height. It is suggested that this is related to the marked increase of the tooth germs during the period and the concurrent growth of the alveolar processes. Standards for normal prenatal cranial dimensions in relation to stages of maturation in the midsagittal cranial base were provided. These data may be of value for use in prenatal diagnostics. PMID:7601913

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

    SciTech Connect

    Stolte, Chris; Hanrahan, Patrick

    2015-07-28

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

  2. Bonnor stars in d spacetime dimensions

    SciTech Connect

    Lemos, Jose P. S.; Zanchin, Vilson T.

    2008-03-15

    Bonnor stars are regular static compact configurations in equilibrium, composed of an extremal dust fluid, i.e., a charged dust fluid where the mass density is equal to the charge density in appropriate units and up to a sign, joined to a suitable exterior vacuum solution, both within Newtonian gravity and general relativity. In four dimensions, these configurations obey the Majumdar-Papapetrou system of equations: in one case, the system is a particular setup of Newtonian gravity coupled to Coulomb electricity and electrically charged matter or fluid, in the other case, the system is a particular setup of general relativity coupled to Maxwell electromagnetism and electrically charged matter or fluid, where the corresponding gravitational potential is a specially simple function of the electric potential field and the fluid, when there is one, is made of extremal dust. Since the Majumdar-Papapetrou system can be generalized to d spacetime dimensions, as has been previously done, and higher-dimensional scenarios can be important in gravitational physics, it is natural to study this type of Bonnor solutions in higher dimensions, d{>=}4. As a preparation, we analyze Newton-Coulomb theory with an electrically charged fluid in a Majumdar-Papapetrou context, in d=n+1 spacetime dimensions, with n being the number of spatial dimensions. We show that within the Newtonian theory, in vacuum, the Majumdar-Papapetrou relation for the gravitational potential in terms of the electric potential, and its related Weyl relation, are equivalent, in contrast to general relativity where they are distinct. We study a class of spherically symmetric Bonnor stars within this theory. Under sufficient compactification they form point mass charged Newtonian singularities. We then study the analogue-type systems in the Einstein-Maxwell theory with an electrically charged fluid. Drawing on our previous work on the d-dimensional Majumdar-Papapetrou system, we restate some properties of this

  3. Three-body correlation functions and recombination rates for bosons in three dimensions and one dimension.

    PubMed

    Haller, E; Rabie, M; Mark, M J; Danzl, J G; Hart, R; Lauber, K; Pupillo, G; Nägerl, H-C

    2011-12-01

    We investigate local three-body correlations for bosonic particles in three dimensions and one dimension as a function of the interaction strength. The three-body correlation function g(3) is determined by measuring the three-body recombination rate in an ultracold gas of Cs atoms. In three dimensions, we measure the dependence of g(3) on the gas parameter in a BEC, finding good agreement with the theoretical prediction accounting for beyond-mean-field effects. In one dimension, we observe a reduction of g(3) by several orders of magnitude upon increasing interactions from the weakly interacting BEC to the strongly interacting Tonks-Girardeau regime, in good agreement with predictions from the Lieb-Liniger model for all strengths of interaction. PMID:22182071

  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. Biological transport processes and space dimension.

    PubMed

    Nadler, W; Stein, D L

    1991-08-01

    We discuss the generic time behavior of reaction-diffusion processes capable of modeling various types of biological transport processes, such as ligand migration in proteins and gating fluctuations in ion channel proteins. The main observable in these two cases, the fraction of unbound ligands and the probability of finding the channel in the closed state, respectively, exhibits an algebraic t-1/2 decay at intermediate times, followed by an exponential cutoff. We provide a simple framework for understanding these observations and explain their ubiquity by showing that these qualitative results are independent of space dimension. We also derive an experimental criterion to distinguish between a one-dimensional process and one whose effective dimension is higher.

  6. The Ising Spin Glass in dimension four

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

    The critical behaviors of the bimodal and Gaussian Ising spin glass (ISG) models in dimension four are studied through extensive numerical simulations, and from an analysis of high temperature series expansion (HTSE) data of Klein et al. (1991). The simulations include standard finite size scaling measurements, thermodynamic limit regime measurements, and analyses which provide estimates of critical exponents without any consideration of the critical temperature. The higher order HTSE series for the bimodal model provide accurate estimates of the critical temperature and critical exponents. These estimates are independent of and fully consistent with the simulation values. Comparisons between ISG models in dimension four show that the critical exponents and the critical constants for dimensionless observables depend on the form of the interaction distribution of the model.

  7. 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.

  8. 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.

  9. Tolerancing of component dimensions in CAD

    NASA Astrophysics Data System (ADS)

    Parkinson, D. B.

    1984-01-01

    Any particular dimension of a manufactured component varies in its value between individual nominally identical components. When several components are to be assembled together, it can happen that in some cases assembly will prove impossible, or that the assembly may not satisfy design specifications. The problem arises to optimize dimensional tolerances to ensure that, for given manufacturing costs, there is an acceptably low risk of the assembly failing to meet the specification. Approaches for solving this problem are discussed. The ability to associate a chosen set of nominal dimensions and dimensional tolerances with a numerical estimate of the risk of unsatisfactory assembly is found to be of considerable value in computer-aided design procedures, where it is necessary to optimize tolerances for minimum overall cost.

  10. 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.

  11. 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

  12. Avatar body dimensions and men's body image.

    PubMed

    Cacioli, Jon-Paul; Mussap, Alexander J

    2014-03-01

    Two online surveys examined the significance of the visual analogues, or 'avatars', men (total N=266) create and use online. Two-dimensional (adiposity×muscle) somatomorphic matrices revealed that avatars are generally thinner than their creator's actual body and similar to their ideal, but more muscular than either their actual or ideal. Men's ratings of the importance of their avatar's appearance correlated with their actual weight and muscle concerns, and disparity between their avatar and actual body dimensions predicted their offline context body change concerns additional to that accounted for by disparity between their ideal and actual bodies. Together with the observation that men also reported higher self-esteem, less social interaction anxiety and less social phobia while online (which correlated with the time they spent online), these results suggest that the physical dimensions of avatars used in social interactions online may serve a compensatory function.

  13. 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

  14. Supersymmetric Janus solutions in four dimensions

    NASA Astrophysics Data System (ADS)

    Bobev, Nikolay; Pilch, Krzysztof; Warner, Nicholas P.

    2014-06-01

    We use maximal gauged supergravity in four dimensions to construct the gravity dual of a class of supersymmetric conformal interfaces in the theory on the worldvolume of multiple M2-branes. We study three classes of examples in which the (1+1)-dimensional defects preserve (4, 4), (0, 2) or (0, 1) supersymmetry. Many of the solutions have the maximally supersymmetric AdS 4 vacuum dual to the = 8 ABJM theory on both sides of the interface. We also find new special classes of solutions including one that interpolates between the maximally supersymmetric vacuum and a conformal fixed point with = 1 supersymmetry and G2 global symmetry. We find another solution that interpolates between two distinct conformal fixed points with = 1 supersymmetry and G2 global symmetry. In eleven dimensions, this G2 to G2 solution corresponds to a domain wall across which a magnetic flux reverses orientation.

  15. 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

  16. Avatar body dimensions and men's body image.

    PubMed

    Cacioli, Jon-Paul; Mussap, Alexander J

    2014-03-01

    Two online surveys examined the significance of the visual analogues, or 'avatars', men (total N=266) create and use online. Two-dimensional (adiposity×muscle) somatomorphic matrices revealed that avatars are generally thinner than their creator's actual body and similar to their ideal, but more muscular than either their actual or ideal. Men's ratings of the importance of their avatar's appearance correlated with their actual weight and muscle concerns, and disparity between their avatar and actual body dimensions predicted their offline context body change concerns additional to that accounted for by disparity between their ideal and actual bodies. Together with the observation that men also reported higher self-esteem, less social interaction anxiety and less social phobia while online (which correlated with the time they spent online), these results suggest that the physical dimensions of avatars used in social interactions online may serve a compensatory function. PMID:24394638

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Spherical gravitational collapse in N dimensions

    NASA Astrophysics Data System (ADS)

    Goswami, Rituparno; Joshi, Pankaj S.

    2007-10-01

    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=ti 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.

  3. 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

  4. Economical quantum cloning in any dimension

    SciTech Connect

    Durt, Thomas; Fiurasek, Jaromir; Cerf, Nicolas J.

    2005-11-15

    The possibility of cloning a d-dimensional quantum system without an ancilla is explored, extending on the economical phase-covariant cloning machine for qubits found in Phys. Rev. A 60, 2764 (1999). We prove the impossibility of constructing an economical version of the optimal universal 1{yields}2 cloning machine in any dimension. We also show, using an ansatz on the generic form of cloning machines, that the d-dimensional 1{yields}2 phase-covariant cloner, which optimally clones all balanced superpositions with arbitrary phases, can be realized economically only in dimension d=2. The used ansatz is supported by numerical evidence up to d=7. An economical phase-covariant cloner can nevertheless be constructed for d>2, albeit with a slightly lower fidelity than that of the optimal cloner requiring an ancilla. Finally, using again an ansatz on cloning machines, we show that an economical version of the 1{yields}2 Fourier-covariant cloner, which optimally clones the computational basis and its Fourier transform, is also possible only in dimension d=2.

  5. Faces of Platonic solids in all dimensions.

    PubMed

    Szajewska, Marzena

    2014-07-01

    This paper considers Platonic solids/polytopes in the real Euclidean space R(n) of dimension 3 ≤ n < ∞. The Platonic solids/polytopes are described together with their faces of dimensions 0 ≤ d ≤ n - 1. Dual pairs of Platonic polytopes are considered in parallel. The underlying finite Coxeter groups are those of simple Lie algebras of types A(n), B(n), C(n), F4, also called the Weyl groups or, equivalently, crystallographic Coxeter groups, and of non-crystallographic Coxeter groups H3, H4. The method consists of recursively decorating the appropriate Coxeter-Dynkin diagram. Each recursion step provides the essential information about faces of a specific dimension. If, at each recursion step, all of the faces are in the same Coxeter group orbit, i.e. are identical, the solid is called Platonic. The main result of the paper is found in Theorem 2.1 and Propositions 3.1 and 3.2. PMID:25970193

  6. Exploring Warped Compactifications of Extra Dimensions

    NASA Astrophysics Data System (ADS)

    Dabholkar, Sujan

    In 1920s, the concept of extra dimensions was considered for the first time to unify gravity and electromagnetism. Since then there have been many developments to understand the unification of fundamental forces using extra dimensions. In this thesis, we study this idea of extra dimensions in higher dimensional gravity theories such as String Theory or Supergravity to make connections with cosmology. We construct a family of non-singular time-dependent solutions of a six-dimensional gravity with a warped geometry. The warp factor is time-dependent and breaks the translation invariance along one of the extra directions. Our solutions have the desired property of homogeneity and isotropy along the non-compact space. These geometries are supported by matter that does not violate the null energy condition. These 6D solutions do not have a closed trapped surface and hence the Hawking-Penrose singularity theorems do not apply to these solutions. These solutions are constructed from 7D locally flat solution by performing Kaluza-Klein reduction. We also study warped compactifications of string/M theory with the help of effective potentials for the construction of de Sitter vacua. The dynamics of the conformal factor of the internal metric is explored to investigate instabilities. The results works the best mainly in the case of a slowly varying warp factor. We also present interesting ideas to find AdS vacua of N=1 flux compactifications using smooth, compact toric manifolds as internal space.

  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. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. VASP- VARIABLE DIMENSION AUTOMATIC SYNTHESIS PROGRAM

    NASA Technical Reports Server (NTRS)

    White, J. S.

    1994-01-01

    VASP is a variable dimension Fortran version of the Automatic Synthesis Program, ASP. The program is used to implement Kalman filtering and control theory. Basically, it consists of 31 subprograms for solving most modern control problems in linear, time-variant (or time-invariant) control systems. These subprograms include operations of matrix algebra, computation of the exponential of a matrix and its convolution integral, and the solution of the matrix Riccati equation. The user calls these subprograms by means of a FORTRAN main program, and so can easily obtain solutions to most general problems of extremization of a quadratic functional of the state of the linear dynamical system. Particularly, these problems include the synthesis of the Kalman filter gains and the optimal feedback gains for minimization of a quadratic performance index. VASP, as an outgrowth of the Automatic Synthesis Program, has the following improvements: more versatile programming language; more convenient input/output format; some new subprograms which consolidate certain groups of statements that are often repeated; and variable dimensioning. The pertinent difference between the two programs is that VASP has variable dimensioning and more efficient storage. The documentation for the VASP program contains a VASP dictionary and example problems. The dictionary contains a description of each subroutine and instructions on its use. The example problems include dynamic response, optimal control gain, solution of the sampled data matrix Riccati equation, matrix decomposition, and a pseudo-inverse of a matrix. This program is written in FORTRAN IV and has been implemented on the IBM 360. The VASP program was developed in 1971.

  17. TEM calibration methods for critical dimension standards

    NASA Astrophysics Data System (ADS)

    Orji, Ndubuisi G.; Dixson, Ronald G.; Garcia-Gutierrez, Domingo I.; Bunday, Benjamin D.; Bishop, Michael; Cresswell, Michael W.; Allen, Richard A.; Allgair, John A.

    2007-03-01

    One of the key challenges in critical dimension (CD) metrology is finding suitable calibration standards. Over the last few years there has been some interest in using features measured with the transmission electron microscope (TEM) as primary standards for linewidth measurements. This is because some modes of TEM can produce lattice-resolved images having scale traceability to the SI (Systeme International d'Unites or International System of Units) definition of length through an atomic lattice constant. As interest in using calibration samples that are closer to the length scales being measured increases, so will the use of these TEM techniques. An area where lattice-traceable images produced by TEM has been used as a primary standard is in critical dimension atomic force microscope (CD-AFM) tip width calibration. Two modes of TEM that produce crystal lattice-traceable images are high resolution transmission electron microscope (HR-TEM) and high angle annular dark field scanning transmission electron microscope (HAADF-STEM). HR-TEM produces lattice-traceable images by interference patterns of the diffracted and transmitted beams rather than the actual atomic columns, while HAADF-STEM produces direct images of the crystal lattice. The difference in how both of these techniques work could cause subtle variations in the way feature edges are defined. In this paper, we present results from width samples measured using HR-TEM and HAADF-STEM. Next we compare the results with measurements taken from the same location by two different CD-AFMs. Both of the CD-AFM instruments used for this work have been calibrated using a single crystal critical dimension reference material (SCCDRM). These standards, developed by the National Institute of Standards and Technology (NIST) and SEMATECH, used HR-TEM for traceable tip-width calibration. Consequently, the present work and the previous SCCDRM work provide a mutual cross-check on the traceability of the width calibration

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Split universal extra dimension and dark matter

    SciTech Connect

    Park, Seong Chan; Shu Jing

    2009-05-01

    Motivated by the recent observation of the high energy electron and positron excesses in cosmic ray by PAMELA and ATIC/PPB-BETS, we suggest an anomaly-free scenario for the universal extra dimension that localizes the standard model quarks and splits the spectrum of Kaluza-Klein (KK) quarks from KK leptons. When the SM quarks are 'well localized' at the boundaries, the most stringent bound of the model (1/R>510 GeV) comes from the resonance search for the Tevatron dijet channels. Even at the early stage of LHC, one can discover the second KK gluon for masses up to 4 TeV.

  4. 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.

  5. Nonlinear models in 2 + epsilon dimensions

    SciTech Connect

    Friedan, D.H.

    1980-08-01

    The general nonlinear scalar model is studied at asymptotically low temperature near two dimensions. The low-temperature expansion is renormalized, and effective algorithms are derived for calculation to all orders in the renormalized expansion. The renormalization group coefficients are calculated in the two-loop approximation, and topological properties of the renormalization group equations are investigated. Special attention is paid to the infrared instabilities of the fixed points, since they provide the continuum limits of the model. The model consists of a scalar field phi on Euclidean 2 + epsilon space whose values phi(x) lie in a finite-dimensional differentiable manifold. 4 figures.

  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.

  7. 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.

  8. 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.

  9. A simple method for estimating the fractal dimension from digital images: The compression dimension

    NASA Astrophysics Data System (ADS)

    Chamorro-Posada, Pedro

    2016-10-01

    The fractal structure of real world objects is often analyzed using digital images. In this context, the compression fractal dimension is put forward. It provides a simple method for the direct estimation of the dimension of fractals stored as digital image files. The computational scheme can be implemented using readily available free software. Its simplicity also makes it very interesting for introductory elaborations of basic concepts of fractal geometry, complexity, and information theory. A test of the computational scheme using limited-quality images of well-defined fractal sets obtained from the Internet and free software has been performed. Also, a systematic evaluation of the proposed method using computer generated images of the Weierstrass cosine function shows an accuracy comparable to those of the methods most commonly used to estimate the dimension of fractal data sequences applied to the same test problem.

  10. Institutional Quality Assessment of Higher Education: Dimensions, Criteria and Indicators

    ERIC Educational Resources Information Center

    Savickiene, Izabela; Pukelis, Kestutis

    2004-01-01

    The article discusses dimensions and criteria, which are used to assess the quality of higher education in different countries. The paper presents dimensions and criteria that could be appropriate for assessment of the quality of higher education at Lithuanian universities. Quality dimensions, assessment criteria and indicators are defined and…

  11. 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...

  12. 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...

  13. 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...

  14. 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…

  15. 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…

  16. 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...

  17. 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...

  18. Pre-Service Teachers' Concept Images on Fractal Dimension

    ERIC Educational Resources Information Center

    Karakus, Fatih

    2016-01-01

    The analysis of pre-service teachers' concept images can provide information about their mental schema of fractal dimension. There is limited research on students' understanding of fractal and fractal dimension. Therefore, this study aimed to investigate the pre-service teachers' understandings of fractal dimension based on concept image. The…

  19. 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)....

  20. 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…

  1. 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)....

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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…

  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. 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

  9. Quantum critical metals in 4 -ɛ dimensions

    NASA Astrophysics Data System (ADS)

    Torroba, Gonzalo; Wang, Huajia

    2014-10-01

    We study the quantum theory of a Fermi surface coupled to a gapless boson scalar in D =4 -ɛ space-time dimensions as a simple model for non-Fermi liquids (NFL) near a quantum phase transition. Our analysis takes into account the full backreaction from Landau damping of the boson, and obtains an RG flow that proceeds through three distinct stages. Above the scale of Landau damping, the Fermi velocity flows to zero, while the coupling evolves according to its classical dimension. Once damping becomes important, its backreaction leads to a crossover regime where dynamic and static damping effects compete and the fermion self-energy does not respect scaling. Below this crossover and having tuned the boson to criticality, the theory flows to a z =3 scalar interacting with an NFL. We finally analyze the IR phases of the theory with arbitrary number of flavors Nc. When Nc is small, the superconducting dome covers the NFL behavior; strikingly, for moderately large Nc, we find that NFL effects become important first, before the onset of superconductivity. A generic prediction of the theory is that the Fermi velocity and quasiparticle residue vanish with a power law ωɛ as the fixed point is approached. These features may be useful for understanding some of the phenomenology of high-Tc materials in a systematic ɛ expansion.

  10. Dynamic glass transition in two dimensions.

    PubMed

    Bayer, M; Brader, J M; Ebert, F; Fuchs, M; Lange, E; Maret, G; Schilling, R; Sperl, M; Wittmer, J P

    2007-07-01

    The question of the existence of a structural glass transition in two dimensions is studied using mode coupling theory (MCT). We determine the explicit d dependence of the memory functional of mode coupling for one-component systems. Applied to two dimensions we solve the MCT equations numerically for monodisperse hard disks. A dynamic glass transition is found at a critical packing fraction phi(c)d=2 approximately equal 0.697 which is above phi(c)d=3 approximately equal 0.516 by about 35%. Phi(c)d scales approximately with phi(rcp)d, the value for random close packing, at least for d=2, 3. Quantities characterizing the local, cooperative "cage motion" do not differ much for d=2 and d=3, and we, e.g., find the Lindemann criterion for the localization length at the glass transition. The final relaxation obeys the superposition principle, collapsing remarkably well onto a Kohlrausch law. The d=2 MCT results are in qualitative agreement with existing results from Monte Carlo and molecular dynamics simulations. The mean-squared displacements measured experimentally for a quasi-two-dimensional binary system of dipolar hard spheres can be described satisfactorily by MCT for monodisperse hard disks over four decades in time provided the experimental control parameter Gamma (which measures the strength of dipolar interactions) and the packing fraction phi are properly related to each other.

  11. 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.

  12. Geographical dimensions and correlates of trust

    SciTech Connect

    Greenberg, M.R. ); Williams, B. )

    1999-04-01

    A sample of 323 residents of New Jersey stratified by neighborhood quality (excellent, good, fair, poor) was gathered to determine if trust in science and technology to protect public health and environment at the societal scale was associated with trust of the local officials, such as the mayor, health officer, developers, mass media, and legislators who are guardians of the local environment. Societal (trust of science and technology) and neighborhood (mayor, health officer) dimensions of trust were found. These societal and neighborhood trust dimensions were weakly correlated. Respondents were divided into fur trust-of-authority groups: high societal-high neighborhood, low societal-low neighborhood, high societal-low neighborhood, and low societal-high neighborhood. High societal-high neighborhood trust respondents were older, had lived in the neighborhoods for many years, were not troubled much by neighborhood or societal environmental threats, and had a strong sense of control over their environment. In strong contrast, low societal-low neighborhood trust respondents were relatively young, typically had lived in their present neighborhood for a short time, were troubled by numerous neighborhood and societal environmental threats, did not practice many personal public health practices, and felt little control over their environment.

  13. Unconventional localization transition in high dimensions

    NASA Astrophysics Data System (ADS)

    Syzranov, S. V.; Gurarie, V.; Radzihovsky, L.

    2015-01-01

    We study noninteracting systems with a power-law quasiparticle dispersion ξk∝kα and a random short-range-correlated potential. We show that, unlike the case of lower dimensions, for d >2 α , there exists a critical disorder strength (set by the bandwidth), at which the system exhibits a disorder-driven quantum phase transition at the bottom of the band that lies in a universality class distinct from the Anderson transition. In contrast to the conventional wisdom, it manifests itself in, e.g., the disorder-averaged density of states. For systems in symmetry classes that permit localization, the striking signature of this transition is a nonanalytic behavior of the mobility edge, which is pinned to the bottom of the band for subcritical disorder and grows for disorder exceeding a critical strength. Focusing on the density of states, we calculate the critical behavior (exponents and scaling functions) at this novel transition, using a renormalization group, controlled by an ɛ =d -2 α expansion. We also apply our analysis to Dirac materials, e.g., Weyl semimetals, where this transition takes place in physically interesting three dimensions.

  14. 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.

  15. Research: the third dimension of librarianship.

    PubMed Central

    Love, E

    1980-01-01

    The rapid accumulation of data through increasingly sophisticated computer technology has created an unprecedented information explosion which might better be called an ignorance explosion. Data gathering emphasizing quantity rather than quality, speed of transmission rather than reliability or relevance, poses a challenge to the future of librarianship. Two concerns are discussed: (1) Relationship of technology to the information age. Librarians must be concerned with the methodology used in data collection, including the value judgments reflected in this activity. (2) Preparation of medical librarianship for the future. The profession will grow only as a result of individual effort, the recognition of people, and an appreciation of human values. Thus far, attempts to evaluate needs focus on technology while neglecting research into the human aspect. The author proposes that dimensions of the total professional model for medical librarianship must include research, as well as education and practice. The need to aid in the development of library researchers at the Ph.D. level through a National Library of Medicine program similar to that offered to researchers by the National Institutes of Health is stressed. By way of federal assistance and scholarships made available through national library associations, library research can become the vital and effective third dimension that will redefine the traditional concept of information storage and service in human terms, thus introducing a new relevance into the area of medical librarianship during the coming decades. PMID:7356492

  16. 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.

  17. 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.

  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. 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.

  20. Stress tensor for GYM in 4 p dimensions and viability of GYM-Higgs in four dimensions

    NASA Astrophysics Data System (ADS)

    O'Brien, G. M.; Tchrakian, D. H.

    1986-02-01

    We present the stress tensor for GYM systems in 4 p dimensions and give a method to compute this tensor density for a GYM-Higgs system in four dimensions. This computation is made explicitly for the first such system and its viability in four Euclidean dimensions is checked. The possibility of extracting phenomenological models from this system is analysed briefly.

  1. BOOK REVIEW: Quantum Physics in One Dimension

    NASA Astrophysics Data System (ADS)

    Logan, David

    2004-05-01

    To a casual ostrich the world of quantum physics in one dimension may sound a little one-dimensional, suitable perhaps for those with an unhealthy obsession for the esoteric. Nothing of course could be further from the truth. The field is remarkably rich and broad, and for more than fifty years has thrown up innumerable challenges. Theorists, realising that the role of interactions in 1D is special and that well known paradigms of higher dimensions (Fermi liquid theory for example) no longer apply, took up the challenge of developing new concepts and techniques to understand the undoubted pecularities of one-dimensional systems. And experimentalists have succeeded in turning pipe dreams into reality, producing an impressive and ever increasing array of experimental realizations of 1D systems, from the molecular to the mesoscopic---spin and ladder compounds, organic superconductors, carbon nanotubes, quantum wires, Josephson junction arrays and so on. Many books on the theory of one-dimensional systems are however written by experts for experts, and tend as such to leave the non-specialist a touch bewildered. This is understandable on both fronts, for the underlying theoretical techniques are unquestionably sophisticated and not usually part of standard courses in many-body theory. A brave author it is then who aims to produce a well rounded, if necessarily partial, overview of quantum physics in one dimension, accessible to a beginner yet taking them to the edge of current research, and providing en route a thorough grounding in the fundamental ideas, basic methods and essential phenomenology of the field. It is of course the brave who succeed in this world, and Thierry Giamarchi does just that with this excellent book, written by an expert for the uninitiated. Aimed in particular at graduate students in theoretical condensed matter physics, and assumimg little theoretical background on the part of the reader (well just a little), Giamarchi writes in a refreshingly

  2. Fractal dimension analyses of lava surfaces and flow boundaries

    NASA Technical Reports Server (NTRS)

    Cleghorn, Timothy F.

    1993-01-01

    An improved method of estimating fractal surface dimensions has been developed. The accuracy of this method is illustrated using artificially generated fractal surfaces. A slightly different from usual concept of linear dimension is developed, allowing a direct link between that and the corresponding surface dimension estimate. These methods are applied to a series of images of lava flows, representing a variety of physical and chemical conditions. These include lavas from California, Idaho, and Hawaii, as well as some extraterrestrial flows. The fractal surface dimension estimations are presented, as well as the fractal line dimensions where appropriate.

  3. High-order central Hermite WENO schemes: Dimension-by-dimension moment-based reconstructions

    NASA Astrophysics Data System (ADS)

    Tao, Zhanjing; Li, Fengyan; Qiu, Jianxian

    2016-08-01

    In this paper, a class of high-order central finite volume schemes is proposed for solving one- and two-dimensional hyperbolic conservation laws. Formulated on staggered meshes, the methods involve Hermite WENO (HWENO) spatial reconstructions, and Lax-Wendroff type discretizations or the natural continuous extension of Runge-Kutta methods in time. Differently from the central Hermite WENO methods we developed previously in Tao et al. (2015) [34], the spatial reconstructions, a core ingredient of the methods, are based on the zeroth-order and the first-order moments of the solution, and are implemented through a dimension-by-dimension strategy when the spatial dimension is higher than one. This leads to much simpler implementation of the methods in higher dimension and better cost efficiency. Meanwhile, the proposed methods have the attractive features of the general central Hermite WENO methods such as being compact in reconstruction and requiring neither flux splitting nor numerical fluxes, while being accurate and essentially non-oscillatory. A collection of one- and two-dimensional numerical examples is presented to demonstrate high resolution and robustness of the methods in capturing smooth and non-smooth solutions.

  4. Crucial dimensions constituting dignity experience in persons living with dementia.

    PubMed

    Tranvåg, Oscar; Petersen, Karin Anna; Nåden, Dagfinn

    2016-07-01

    Dignity is seen as an essential need, fundamental right, and inherent quality of each human being. There is however, a need for increased knowledge on crucial dimensions constituting dignity experience in persons living with dementia. This study explored personal dimensions of life which persons with dementia perceived crucial for experiencing dignity in their daily lives. Based on the findings of eight empirical sub-dimensions, three main dimensions crucial for constituting dignity experience, were identified through hermeneutical interpretation: A historical dignity-dimension, acknowledging one's own life-projects and life-history; an intrapersonal dignity-dimension, recognizing one's own human worth, and living according to internal values; and an interpersonal dignity-dimension, experiencing being part of a caring and confirming communion. Knowledge of dignity preservation should be a crucial foundation for future dementia care.

  5. The limits of chemosensation vary across dimensions

    NASA Astrophysics Data System (ADS)

    Bicknell, Brendan A.; Dayan, Peter; Goodhill, Geoffrey J.

    2015-06-01

    Many biological processes rely on the ability of cells to measure local ligand concentration. However, such measurements are constrained by noise arising from diffusion and the stochastic nature of receptor-ligand interactions. It is thus critical to understand how accurately, in principle, concentration measurements can be made. Previous theoretical work has mostly investigated this in 3D under the simplifying assumption of an unbounded domain of diffusion, but many biological problems involve 2D concentration measurement in bounded domains, for which diffusion behaves quite differently. Here we present a theory of the precision of chemosensation that covers bounded domains of any dimensionality. We find that the quality of chemosensation in lower dimensions is controlled by domain size, suggesting a general principle applicable to many biological systems. Applying the theory to biological problems in 2D shows that diffusion-limited signalling is an efficient mechanism on time scales consistent with behaviour.

  6. The limits of chemosensation vary across dimensions.

    PubMed

    Bicknell, Brendan A; Dayan, Peter; Goodhill, Geoffrey J

    2015-01-01

    Many biological processes rely on the ability of cells to measure local ligand concentration. However, such measurements are constrained by noise arising from diffusion and the stochastic nature of receptor-ligand interactions. It is thus critical to understand how accurately, in principle, concentration measurements can be made. Previous theoretical work has mostly investigated this in 3D under the simplifying assumption of an unbounded domain of diffusion, but many biological problems involve 2D concentration measurement in bounded domains, for which diffusion behaves quite differently. Here we present a theory of the precision of chemosensation that covers bounded domains of any dimensionality. We find that the quality of chemosensation in lower dimensions is controlled by domain size, suggesting a general principle applicable to many biological systems. Applying the theory to biological problems in 2D shows that diffusion-limited signalling is an efficient mechanism on time scales consistent with behaviour. PMID:26088726

  7. How to track protists in three dimensions

    NASA Astrophysics Data System (ADS)

    Drescher, Knut; Leptos, Kyriacos C.; Goldstein, Raymond E.

    2009-01-01

    We present an apparatus optimized for tracking swimming micro-organisms in the size range of 10-1000 μm, in three dimensions (3Ds), far from surfaces, and with negligible background convective fluid motion. Charge coupled device cameras attached to two long working distance microscopes synchronously image the sample from two perpendicular directions, with narrow band dark-field or bright-field illumination chosen to avoid triggering a phototactic response. The images from the two cameras can be combined to yield 3D tracks of the organism. Using additional, highly directional broad-spectrum illumination with millisecond timing control the phototactic trajectories in 3D of organisms ranging from Chlamydomonas to Volvox can be studied in detail. Surface-mediated hydrodynamic interactions can also be investigated without convective interference. Minimal modifications to the apparatus allow for studies of chemotaxis and other taxes.

  8. Mental number space in three dimensions.

    PubMed

    Winter, Bodo; Matlock, Teenie; Shaki, Samuel; Fischer, Martin H

    2015-10-01

    A large number of experimental findings from neuroscience and experimental psychology demonstrated interactions between spatial cognition and numerical cognition. In particular, many researchers posited a horizontal mental number line, where small numbers are thought of as being to the left of larger numbers. This review synthesizes work on the mental association between space and number, indicating the existence of multiple spatial mappings: recent research has found associations between number and vertical space, as well as associations between number and near/far space. We discuss number space in three dimensions with an eye on potential origins of the different number mappings, and how these number mappings fit in with our current knowledge of brain organization and brain-culture interactions. We derive novel predictions and show how this research fits into a general view of cognition as embodied, grounded and situated.

  9. The resurgence of the cusp anomalous dimension

    NASA Astrophysics Data System (ADS)

    Aniceto, Inês

    2016-02-01

    This work addresses the resurgent properties of the cusp anomalous dimension’s strong coupling expansion, obtained from the integral Beisert-Eden-Staudacher (BES) equation. This expansion is factorially divergent, and its first non-perturbative corrections are related to the mass gap of the O(6)σ -model. The factorial divergence can also be analyzed from a resurgence perspective. Building on the work of Basso and Korchemsky, a transseries ansatz for the cusp anomalous dimension is proposed and the corresponding expected large-order behaviour studied. One finds non-perturbative phenomena in both the positive and negative real coupling directions, which need to be included to address the analyticity conditions coming from the BES equation. After checking the resurgence structure of the proposed transseries, it is shown that it naturally leads to an unambiguous resummation procedure, furthermore allowing for a strong/weak coupling interpolation.

  10. Personality dimensions and subjective well-being.

    PubMed

    Chico Librán, Eliseo

    2006-05-01

    This work examines the association between personality dimensions (extraversion and neuroticism) and subjective well-being. Subjective well-being is associated both with extraversion and neuroticism, and currently, neuroticism is generally considered the more important. A total of 368 students from the University of Rovira i Virgili completed the Extraversion and Neuroticism subscales of the revised Eysenck Personality Questionnaire (Eysenck, Eysenck, and Barrett, 1985), the Satisfaction with Life Scale (SWLS; Diener, Emmons, Larsen, and Griffin, 1985), and the Positive and Negative Affect Scale (Watson, Clark, and Tellegen, 1988). Regression analyses revealed the personality variable of neuroticism as one of the most important correlates of subjective well-being. Regression analyses also showed that 44% of the variance of subjective well-being was accounted for by neuroticism, whereas extraversion only explained 8% of the variance.

  11. Personality disorders and dimensions in pathological gambling.

    PubMed

    Odlaug, Brian L; Schreiber, Liana R N; Grant, Jon E

    2012-06-01

    Comorbid DSM-IV Axis II personality disorders appear to be common in pathological gambling (PG) and may contribute to the chronic problems often associated with the disorder. This study sought to examine the relationship between PG, personality disorders, and impulsivity in a sample of pathological gamblers. Personality assessments included the SCID-II, Eysenck Impulsiveness Questionnaire, Tridimensional Personality Questionnaire, and Barratt Impulsiveness Scale. A total of 77 individuals with DSM-IV PG were included in this study, of which 35 (45.5%) met criteria for at least one personality disorder. Specific aspects of impulsivity were associated with certain personality disorders in PG when grouped by cluster, yet the presence of a personality disorder was not positively correlated with gambling severity. It remains unclear how the presence of a personality disorder and aspects of impulsivity may affect treatment outcome. Further exploration of these disorders and dimensions of personality may encourage a more inclusively global treatment approach.

  12. Rotating black lens solution in five dimensions

    SciTech Connect

    Chen Yu; Teo, Edward

    2008-09-15

    It has recently been shown that a stationary, asymptotically flat vacuum black hole in five space-time dimensions with two commuting axial symmetries must have an event horizon with either a spherical, ring or lens-space topology. In this paper, we study the third possibility, a so-called black lens with L(n,1) horizon topology. Using the inverse scattering method, we construct a black-lens solution with the simplest possible rod structure, and possessing a single asymptotic angular momentum. Its properties are then analyzed; in particular, it is shown that there must either be a conical singularity or a naked curvature singularity present in the space-time.

  13. Null structure groups in eleven dimensions

    SciTech Connect

    Cariglia, Marco; Mac Conamhna, Oisin A. P.

    2006-02-15

    We classify all the structure groups which arise as subgroups of the isotropy group (Spin(7)xR{sup 8})xR, of a single null Killing spinor in 11 dimensions. We construct the spaces of spinors fixed by these groups. We determine the conditions under which structure subgroups of the maximal null structure group (Spin(7)xR{sup 8})xR may also be embedded in SU(5), and hence the conditions under which a supersymmetric spacetime admits only null, or both timelike and null, Killing spinors. We discuss how this purely algebraic material will facilitate the direct analysis of the Killing spinor equation of 11 dimensional supergravity, and the classification of supersymmetric spacetimes therein.

  14. Perfect-fluid cosmologies with extra dimensions

    NASA Astrophysics Data System (ADS)

    Gleiser, Reinaldo J.; Diaz, Mario C.

    1988-06-01

    We give an analysis of the solutions of the n-dimensional vacuum Einstein equations with a metric in the form of a direct sum of a Friedmann-Robertson-Walker (FRW) metric and a Kasner-type Euclidean metric. The solutions are interpreted as four-dimensional perfect-fluid cosmological FRW models, using the simple ansatz proposed by Ibán~ez and Verdaguer. We first obtain the general solution for flat models. These are perfect-fluid solutions that can be made compatible with contraction of all the extra dimensions. The general compatibility of the field equations is then discussed. It is found that for n>5 both open and closed models admit a range of perfect-fluid solutions whose qualitative behavior is analyzed.

  15. [The metaphysical dimension of animal ethics].

    PubMed

    Walz, Norbert

    2008-01-01

    Utilitarian ethics recognises animals as moral objects, but it does not attribute an absolute value to human or non-human individuals. Animal ethics according to Regan defines the non-human individual as an inherent value, but concedes that humans should be given precedence over animals if a situation involves a decision between life and death. Such life and death decisions relate to the fundamental structures of biological nature. To individuals these fundamental structures (the paradox of life and death) will necessarily appear absurd. The metaphysical dimension of animal ethics tries to shed light on the connections between life and death, body and mind that underly ethical discussions and searches for alternatives to the natural organisation of life.

  16. Personality dimensions in spotted hyenas (Crocuta crocuta).

    PubMed

    Gosling, S D

    1998-06-01

    Personality ratings of 34 spotted hyenas (Crocuta crocuta) were made by 4 observers who knew the animals well. Analyses suggest that (a) hyena personality traits were rated with generally high reliability; (b) 5 broad dimensions (Assertiveness, Excitability, Human-Directed Agreeableness, Sociability, and Curiosity) captured about 75% of the total variance; (c) this dimensional structure could not be explained in terms of dominance status, sex, age, or appearance; and (d) as expected, female hyenas were more assertive than male hyenas. Comparisons with previous research provide evidence for the cross-species generality of Excitability, Sociability, and especially Assertiveness. Discussion focuses on methodological issues in research on animal personality and on the potential contributions this research can make for understanding the biological and environmental bases of personality.

  17. Laboratory alluvial fans in one dimension.

    PubMed

    Guerit, L; Métivier, F; Devauchelle, O; Lajeunesse, E; Barrier, L

    2014-08-01

    When they reach a flat plain, rivers often deposit their sediment load into a cone-shaped structure called alluvial fan. We present a simplified experimental setup that reproduces, in one dimension, basic features of alluvial fans. A mixture of water and glycerol transports and deposits glass beads between two transparent panels separated by a narrow gap. As the beads, which mimic natural sediments, get deposited in this gap, they form an almost one-dimensional fan. At a moderate sediment discharge, the fan grows quasistatically and maintains its slope just above the threshold for sediment transport. The water discharge determines this critical slope. At leading order, the sediment discharge only controls the velocity at which the fan grows. A more detailed analysis reveals a slight curvature of the fan profile, which relates directly to the rate at which sediments are transported. PMID:25215729

  18. Lattice Green's functions in all dimensions

    NASA Astrophysics Data System (ADS)

    Guttmann, Anthony J.

    2010-07-01

    We give a systematic treatment of lattice Green's functions (LGF) on the d-dimensional diamond, simple cubic, body-centred cubic and face-centred cubic lattices for arbitrary dimensionality d >= 2 for the first three lattices, and for 2 <= d <= 5 for the hyper-fcc lattice. We show that there is a close connection between the LGF of the d-dimensional hyper-cubic lattice and that of the (d - 1)-dimensional diamond lattice. We give constant-term formulations of LGFs for each of these lattices in all dimensions. Through a still under-developed connection with Mahler measures, we point out an unexpected connection between the coefficients of the sc, bcc and diamond LGFs and some Ramanujan-type formulae for 1/π.

  19. Turbulent supersonic convection in three dimensions

    NASA Technical Reports Server (NTRS)

    Malagoli, Andrea; Cattaneo, Fausto; Brummell, Nicholas H.

    1990-01-01

    Previous numerical calculations of two-dimensional, compressible convection are extended to three dimensions, using a higher order Godunov scheme. The results show that the flow readily becomes supersonic in the upper boundary layer, where shock structures form intermittently in the vicinity of the strong downflow lanes. The convection as a whole is strongly time-dependent and evolves on a time scale comparable to the sound crossing time. The motions in the upper layers are characterized by the rapid expansion of the upward-moving fluid elements. In the interior, most of the heat is carried by a small fraction of the fluid residing in strong, highly coherent downflows. The remaining fluid is dominated by small-scale, disorganized turbulent motions.

  20. Dimension reduction method for ODE fluid models

    SciTech Connect

    Tartakovsky, Alexandre M.; Panchenko, Alexander; Ferris, Kim F.

    2011-09-20

    We develop a dimension reduction method for large size ODE systems obtained from a dis- cretization of partial differential equations of viscous fluid flow of nearly constant density. The method is also applicable to other large size classical particle systems with negligibly small variations of concentration. We propose a new computational closure for mesoscale balance equations based on numerical iterative deconvolution. To illustrate the computa- tional advantages of the proposed reduction method we use it to solve a system of Smoothed Particle Hydrodynamic ODEs describing Poiseuille flows driven by uniform and periodic (in space) body forces. For the Poiseuille flow driven by the uniform force the coarse solution was obtained with the zero-order deconvolution. For the flow driven by the periodic body force, the first-order deconvolution was necessary to obtain a sufficiently accurate solution.

  1. Fracture dimensions in frac&pack stimulation

    SciTech Connect

    Fan, Y.; Economides, M.J.

    1995-12-31

    A model is introduced to predict dynamic fracture dimensions in frac&pack stimulation. Design aspects of the two-in-one step treatment techniques, required by soft and high-permeability reservoirs are discussed. A pressure-dependent leakoff model, based on the transient flow of a non-Newtonian fluid displacing a reservoir fluid has been developed and incorporated with fracture mechanics concepts to simulate the entire process of frac&pack treatments including fracture propagation, inflation, proppant packing and closure. Results obtained in this study indicate the considerable difference between traditional fracturing and frac&pack treatments. In the latter, fracture length is much less important than fracture conductivity. This work shows how to terminate the fracture growth at the appropriate time, and how to design frac&packs resulting in fracture widths several times larger than those for traditional fracturing.

  2. Laboratory alluvial fans in one dimension.

    PubMed

    Guerit, L; Métivier, F; Devauchelle, O; Lajeunesse, E; Barrier, L

    2014-08-01

    When they reach a flat plain, rivers often deposit their sediment load into a cone-shaped structure called alluvial fan. We present a simplified experimental setup that reproduces, in one dimension, basic features of alluvial fans. A mixture of water and glycerol transports and deposits glass beads between two transparent panels separated by a narrow gap. As the beads, which mimic natural sediments, get deposited in this gap, they form an almost one-dimensional fan. At a moderate sediment discharge, the fan grows quasistatically and maintains its slope just above the threshold for sediment transport. The water discharge determines this critical slope. At leading order, the sediment discharge only controls the velocity at which the fan grows. A more detailed analysis reveals a slight curvature of the fan profile, which relates directly to the rate at which sediments are transported.

  3. How to track protists in three dimensions.

    PubMed

    Drescher, Knut; Leptos, Kyriacos C; Goldstein, Raymond E

    2009-01-01

    We present an apparatus optimized for tracking swimming micro-organisms in the size range of 10-1000 microm, in three dimensions (3Ds), far from surfaces, and with negligible background convective fluid motion. Charge coupled device cameras attached to two long working distance microscopes synchronously image the sample from two perpendicular directions, with narrow band dark-field or bright-field illumination chosen to avoid triggering a phototactic response. The images from the two cameras can be combined to yield 3D tracks of the organism. Using additional, highly directional broad-spectrum illumination with millisecond timing control the phototactic trajectories in 3D of organisms ranging from Chlamydomonas to Volvox can be studied in detail. Surface-mediated hydrodynamic interactions can also be investigated without convective interference. Minimal modifications to the apparatus allow for studies of chemotaxis and other taxes.

  4. On partially massless theory in 3 dimensions

    SciTech Connect

    Alexandrov, Sergei; Deffayet, Cédric

    2015-03-24

    We analyze the first-order formulation of the ghost-free bigravity model in three-dimensions known as zwei-dreibein gravity. For a special choice of parameters, it was argued to have an additional gauge symmetry and give rise to a partially massless theory. We provide a thorough canonical analysis and identify that whether the theory becomes partially massless depends on the form of the stability condition of the secondary constraint responsible for the absence of the ghost. Generically, it is found to be an equation for a Lagrange multiplier implying that partially massless zwei-dreibein gravity does not exist. However, for special backgrounds this condition is identically satisfied leading to the presence of additional symmetries, which however disappear at quadratic order in perturbations.

  5. Dimensions of biodiversity in the Earth mycobiome.

    PubMed

    Peay, Kabir G; Kennedy, Peter G; Talbot, Jennifer M

    2016-07-01

    Fungi represent a large proportion of the genetic diversity on Earth and fungal activity influences the structure of plant and animal communities, as well as rates of ecosystem processes. Large-scale DNA-sequencing datasets are beginning to reveal the dimensions of fungal biodiversity, which seem to be fundamentally different to bacteria, plants and animals. In this Review, we describe the patterns of fungal biodiversity that have been revealed by molecular-based studies. Furthermore, we consider the evidence that supports the roles of different candidate drivers of fungal diversity at a range of spatial scales, as well as the role of dispersal limitation in maintaining regional endemism and influencing local community assembly. Finally, we discuss the ecological mechanisms that are likely to be responsible for the high heterogeneity that is observed in fungal communities at local scales. PMID:27296482

  6. Ferromagnetism in one dimension: Critical temperature

    NASA Astrophysics Data System (ADS)

    Curilef, S.; Del Pino, L. A.; Orellana, P.

    2005-12-01

    Ferromagnetism in one dimension is a observation which has been reported in a recent work [Gambardella , Nature (London) 416, 301 (2002)], and it is thought that anisotropy barriers are responsible in that relevant effect. In the present work, transitions between two different magnetic ordering phases are obtained as a result of an alternative approach. The critical temperature has been estimated by the Binder method. Ferromagnetic long-range interactions have been included in a special Hamiltonian through a power law that decays at large interparticle distance r as r-α for α⩾0 . If the range of interactions decreases (α→∞) , the trend of the critical temperature disappears, but if the range of interactions increases (α→0) , the trend of the critical temperature approaches to the mean field approximation. The crossover between these two limiting situations is discussed.

  7. Controlling anomalies of vertical dimension and speech.

    PubMed

    Pound, E

    1976-08-01

    In this article, definite ways and means have been discussed for controlling the the verticale dimension of occlusion by using certain tooth-to-tooth and tooth-to-tissue relations that exist in normal speech. The primary emphasis is placed on managing the problems encountered in the most troublesome types of patients--those with Class II occlusions, the tongue thrusters, and those who lisp. It is not easy to identify those patients in whom these problems previously existed after they become edentulous. An Analytical Control Chart has been introduced which can be used to separate these problem patients from the normal ones, and a step-by-step procedure for their management can be followed. Also the phases of this approach which are beneficial in restorative dentistry are reviewed. PMID:789862

  8. Tornado intensity estimated from damage path dimensions.

    PubMed

    Elsner, James B; Jagger, Thomas H; Elsner, Ian J

    2014-01-01

    The Newcastle/Moore and El Reno tornadoes of May 2013 are recent reminders of the destructive power of tornadoes. A direct estimate of a tornado's power is difficult and dangerous to get. An indirect estimate on a categorical scale is available from a post-storm survery of the damage. Wind speed bounds are attached to the scale, but the scale is not adequate for analyzing trends in tornado intensity separate from trends in tornado frequency. Here tornado intensity on a continuum is estimated from damage path length and width, which are measured on continuous scales and correlated to the EF rating. The wind speeds on the EF scale are treated as interval censored data and regressed onto the path dimensions and fatalities. The regression model indicates a 25% increase in expected intensity over a threshold intensity of 29 m s(-1) for a 100 km increase in path length and a 17% increase in expected intensity for a one km increase in path width. The model shows a 43% increase in the expected intensity when fatalities are observed controlling for path dimensions. The estimated wind speeds correlate at a level of .77 (.34, .93) [95% confidence interval] with a small sample of wind speeds estimated independently from a doppler radar calibration. The estimated wind speeds allow analyses to be done on the tornado database that are not possible with the categorical scale. The modeled intensities can be used in climatology and in environmental and engineering applications. Research is needed to understand the upward trends in path length and width. PMID:25229242

  9. The human dimension of program evaluation

    SciTech Connect

    Vine, E.L.

    1993-05-01

    Social science issues play an important role in the evaluation of demand-side management (DSM) programs. In the very early years of DSM program evaluation in the United States, there was a fair amount of social science research applied to the behavioral aspects of energy efficiency. Since the mid-1980s, however, there has been a heavy emphasis on impact evaluation, technical measurement, and engineering methodologies. Although some have articulated the need to integrate behavioral research into energy evaluation, most emphasis has tended to center on the technical/engineering aspects. Increasingly, however, the realization is growing that it is necessary to integrate important behavioral variables into impact evaluation techniques. In addition, it is being further recognized that behavioral research questions are central to a number of critical evaluation issues: e.g., design of samples for evaluation studies, net energy savings, self-selection bias, free riders and free drivers, persistence of energy savings, process evaluation, and market impact evaluation. Finally, it is increasingly being realized that the utilization of evaluation results relies heavily on behavioral factors. Social science researchers should be poised to expect a greatly expanded role of behavioral research in evaluation. As new techniques are developed and perfected, as the results of impact evaluations become more abundant, and as the gap between technical energy savings potential and realized savings becomes more visible, research regarding the ``human dimension`` of program evaluation will be crucial. This paper provides an overview of the human dimension of program evaluation and focuses on key evaluation issues in demand-side management which will require the use of social science research for addressing these issues.

  10. Tornado intensity estimated from damage path dimensions.

    PubMed

    Elsner, James B; Jagger, Thomas H; Elsner, Ian J

    2014-01-01

    The Newcastle/Moore and El Reno tornadoes of May 2013 are recent reminders of the destructive power of tornadoes. A direct estimate of a tornado's power is difficult and dangerous to get. An indirect estimate on a categorical scale is available from a post-storm survery of the damage. Wind speed bounds are attached to the scale, but the scale is not adequate for analyzing trends in tornado intensity separate from trends in tornado frequency. Here tornado intensity on a continuum is estimated from damage path length and width, which are measured on continuous scales and correlated to the EF rating. The wind speeds on the EF scale are treated as interval censored data and regressed onto the path dimensions and fatalities. The regression model indicates a 25% increase in expected intensity over a threshold intensity of 29 m s(-1) for a 100 km increase in path length and a 17% increase in expected intensity for a one km increase in path width. The model shows a 43% increase in the expected intensity when fatalities are observed controlling for path dimensions. The estimated wind speeds correlate at a level of .77 (.34, .93) [95% confidence interval] with a small sample of wind speeds estimated independently from a doppler radar calibration. The estimated wind speeds allow analyses to be done on the tornado database that are not possible with the categorical scale. The modeled intensities can be used in climatology and in environmental and engineering applications. Research is needed to understand the upward trends in path length and width.

  11. Tornado Intensity Estimated from Damage Path Dimensions

    PubMed Central

    Elsner, James B.; Jagger, Thomas H.; Elsner, Ian J.

    2014-01-01

    The Newcastle/Moore and El Reno tornadoes of May 2013 are recent reminders of the destructive power of tornadoes. A direct estimate of a tornado's power is difficult and dangerous to get. An indirect estimate on a categorical scale is available from a post-storm survery of the damage. Wind speed bounds are attached to the scale, but the scale is not adequate for analyzing trends in tornado intensity separate from trends in tornado frequency. Here tornado intensity on a continuum is estimated from damage path length and width, which are measured on continuous scales and correlated to the EF rating. The wind speeds on the EF scale are treated as interval censored data and regressed onto the path dimensions and fatalities. The regression model indicates a 25% increase in expected intensity over a threshold intensity of 29 m s−1 for a 100 km increase in path length and a 17% increase in expected intensity for a one km increase in path width. The model shows a 43% increase in the expected intensity when fatalities are observed controlling for path dimensions. The estimated wind speeds correlate at a level of .77 (.34, .93) [95% confidence interval] with a small sample of wind speeds estimated independently from a doppler radar calibration. The estimated wind speeds allow analyses to be done on the tornado database that are not possible with the categorical scale. The modeled intensities can be used in climatology and in environmental and engineering applications. Research is needed to understand the upward trends in path length and width. PMID:25229242

  12. A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation.

    PubMed

    Morandi, Fabio; Morandi, Barbara; Horenstein, Alberto L; Chillemi, Antonella; Quarona, Valeria; Zaccarello, Gianluca; Carrega, Paolo; Ferlazzo, Guido; Mingari, Maria Cristina; Moretta, Lorenzo; Pistoia, Vito; Malavasi, Fabio

    2015-09-22

    Nucleotide-metabolizing ectoenzymes are endowed with an extracellular catalytic domain, which is involved in regulating the extracellular nucleotide/nucleoside balance. The tumor microenvironment contains high levels of adenosine (ADO) generated by this enzymatic network, thus promoting tumor growth by inhibiting anti-tumor immune responses. ADO inhibition in melanoma murine models limits tumor metastases and restores anti-tumor immune responses. This work investigates the expression and function of ectoenzymes in primary human melanoma cell lines. All of latter cells expressed CD38, CD39, CD73, and CD203a/PC-1, and produced ADO from AMP and NAD(+ )T cell proliferation. Accordingly, phosphorylation of S6 ribosomal protein, p38 and Stat1 was lower in activated memory cells than in naïve CD4(+) T lymphocytes. Melanoma cells also inhibited proliferation of naïve, memory and -to a lesser extent- of effector CD8(+) T cells. These different inhibitory effects correlated with distinct patterns of expression of the ADO receptor A2a and A2b. These results show that primary human melanoma cell lines suppress in vitro T cell proliferation through an adenosinergic pathway in which CD38 and CD73 play a prominent role. PMID:26329660

  13. Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.

    PubMed

    Kumar, Santosh; Mehta, Kapil

    2012-01-01

    Constitutive activation of nuclear factor kappa B (NF-κB) has been linked with carcinogenesis and cancer progression, including metastasis, chemoresistance, and radiation resistance. However, the molecular mechanisms that result in constitutive activation of NF-κB are poorly understood. Here we show that chronic expression of the pro-inflammatory protein tissue transglutaminase (TG2) reprograms the transcription regulatory network in epithelial cells via constitutive activation of NF-κB. TG2-induced NF-κB binds the functional NF-κB binding site in hypoxia-inducible factor-1 (HIF-1α) promoter and results in its increased expression at transcription and protein levels even under normoxic conditions. TG2/NF-κB-induced HIF-1 was deemed essential for increased expression of some transcription repressors, like Zeb1, Zeb2, Snail, and Twist. Unlike tumor necrosis factor-alpha (TNFα), TG2 did not require IκB kinase (IKK) for NF-κB activation. Our data suggest that TG2 binds with IκBα and results in its rapid degradation via a non-proteasomal pathway. Importantly, the catalytically inactive (C277S) mutant form of TG2 was as effective as was wild-type TG2 in activating NF-κB and inducing HIF-1 expression. We also found that TG2 interacted with p65/RelA protein, both in the cytosolic and the nuclear compartment. The TG2/p65(NF-κB) complex binds to the HIF-1 promoter and induced its transcriptional regulation. Inhibition of TG2 or p65/RelA also inhibited the HIF-1α expression and attenuated Zeb1, Zeb2, and Twist expression. To our knowledge, these findings show for the first time a direct link between TG2, NF-κB, and HIF-1α, demonstrating TG2's important role in cancer progression. PMID:23185316

  14. Characterization of a Non-Canonical Signal Peptidase Cleavage Site in a Replication Protein from Tomato Ringspot Virus

    PubMed Central

    Wei, Ting; Chisholm, Joan

    2016-01-01

    The NTB-VPg polyprotein from tomato ringspot virus is an integral membrane replication protein associated with endoplasmic reticulum membranes. A signal peptidase (SPase) cleavage was previously detected in the C-terminal region of NTB-VPg downstream of a 14 amino acid (aa)-long hydrophobic region (termed TM2). However, the exact location of the cleavage site was not determined. Using in vitro translation assays, we show that the SPase cleavage site is conserved in the NTB-VPg protein from various ToRSV isolates, although the rate of cleavage varies from one isolate to another. Systematic site-directed mutagenesis of the NTB-VPg SPase cleavage sites of two ToRSV isolates allowed the identification of sequences that affect cleavage efficiency. We also present evidence that SPase cleavage in the ToRSV-Rasp2 isolate occurs within a GAAGG sequence likely after the AAG (GAAG/G). Mutation of a downstream MAAV sequence to AAAV resulted in SPase cleavage at both the natural GAAG/G and the mutated AAA/V sequences. Given that there is a distance of seven aa between the two cleavage sites, this indicates that there is flexibility in the positioning of the cleavage sites relative to the inner surface of the membrane and the SPase active site. SPase cleavage sites are typically located 3–7 aa downstream of the hydrophobic region. However, the NTB-VPg GAAG/G cleavage site is located 17 aa downstream of the TM2 hydrophobic region, highlighting unusual features of the NTB-VPg SPase cleavage site. A putative 11 aa-long amphipathic helix was identified immediately downstream of the TM2 region and five aa upstream of the GAAG/G cleavage site. Based on these results, we present an updated topology model in which the hydrophobic and amphipathic domains form a long tilted helix or a bent helix in the membrane lipid bilayer, with the downstream cleavage site(s) oriented parallel to the membrane inner surface. PMID:27589230

  15. Non-canonical pathway network modelling and ubiquitination site prediction through homology modelling of NF-κB.

    PubMed

    Ghosh, Sayantan; Febin Prabhu Dass, J

    2016-04-25

    Given the fact that NF-κB stays as a dormant molecule in the cytoplasm in steady state, one common step in all the metabolic activities comprising NF-κB is its activation. Consequently there are two pathways of interest related to NF-κB activation: Canonical and alternate. Both the pathways involve ubiquitination of its repressors, that is to say ubiquitination of I-κB by NEMO/IKK-α/IKK-β complex in case of NF-κB1 and that of p100 by IKK-α homodimer in case of NF-κB2. This paper attempts to figure out the ubiquitination sites in alternate pathway of NF-κB activation using a purely computational approach. We initiated the work by acquiring the genes involved in NF kappa B alternate pathway through Agilent literature search. For this we employed the Cytoscape and STRING database. Secondly, the MSA was built using the sequences obtained through BLAST search, and the results were used to update the original sequence list, which was further refined using HMMER. Structural alignment was achieved via Modeller libraries. The final model has been refined using loop_model and asses_dope functions of Modeller. Ubiquitination site is predicted to be comprised of residues 'SPECLDLLVDS' between sites 178 and 188, both positions inclusive. Unlike the classical pathway, due to absence of parallel studies for p100/RelB, a quality match could not be performed, but future studies are in pipeline to replicate the methodology for NF-κB1 activation and compare the results with existing observations. The study can be used to understand the cofactors involved and ubiquitination sites employed during the activation process during drug designing activities. The methodology can be easily scaled and adapted for classical pathway as well. PMID:26784652

  16. Time-resolved Studies of IsdG Protein Identify Molecular Signposts along the Non-canonical Heme Oxygenase Pathway.

    PubMed

    Streit, Bennett R; Kant, Ravi; Tokmina-Lukaszewska, Monika; Celis, Arianna I; Machovina, Melodie M; Skaar, Eric P; Bothner, Brian; DuBois, Jennifer L

    2016-01-01

    IsdGs are heme monooxygenases that break open the tetrapyrrole, releasing the iron, and thereby allowing bacteria expressing this protein to use heme as a nutritional iron source. Little is currently known about the mechanism by which IsdGs degrade heme, although the products differ from those generated by canonical heme oxygenases. A synthesis of time-resolved techniques, including in proteo mass spectrometry and conventional and stopped-flow UV/visible spectroscopy, was used in conjunction with analytical methods to define the reaction steps mediated by IsdG from Staphylococcus aureus and their time scales. An apparent meso-hydroxyheme (forming with k = 0.6 min(-1), pH 7.4, 10 mm ascorbate, 10 μm IsdG-heme, 22 °C) was identified as a likely common intermediate with the canonical heme oxygenases. Unlike heme oxygenases, this intermediate does not form with added H2O2 nor does it convert to verdoheme and CO. Rather, the next observable intermediates (k = 0.16 min(-1)) were a set of formyloxobilin isomers, similar to the mycobilin products of the IsdG homolog from Mycobacterium tuberculosis (MhuD). These converted in separate fast and slow phases to β-/δ-staphylobilin isomers and formaldehyde (CH2O). Controlled release of this unusual C1 product may support IsdG's dual role as both an oxygenase and a sensor of heme availability in S. aureus. PMID:26534961

  17. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes.

    PubMed

    Viganò, Elena; Diamond, Catherine Emma; Spreafico, Roberto; Balachander, Akhila; Sobota, Radoslaw M; Mortellaro, Alessandra

    2015-01-01

    Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1β. The biologically inactive IL-1β precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown. Here we report that caspase-4 and caspase-5 mediate IL-1α and IL-1β release from human monocytes after LPS stimulation. Although caspase-4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment. We also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion. This one-step pathway requires Syk activity and Ca(2+) flux instigated by CD14/TLR4-mediated LPS internalization. Identification of caspase-4/5 as the key determinants of one-step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock. PMID:26508369

  18. A novel role for MuSK and non-canonical Wnt signaling during segmental neural crest cell migration.

    PubMed

    Banerjee, Santanu; Gordon, Laura; Donn, Thomas M; Berti, Caterina; Moens, Cecilia B; Burden, Steven J; Granato, Michael

    2011-08-01

    Trunk neural crest cells delaminate from the dorsal neural tube as an uninterrupted sheet; however, they convert into segmentally organized streams before migrating through the somitic territory. These neural crest cell streams join the segmental trajectories of pathfinding spinal motor axons, suggesting that interactions between these two cell types might be important for neural crest cell migration. Here, we show that in the zebrafish embryo migration of both neural crest cells and motor axons is temporally synchronized and spatially restricted to the center of the somite, but that motor axons are dispensable for segmental neural crest cell migration. Instead, we find that muscle-specific receptor kinase (MuSK) and its putative ligand Wnt11r are crucial for restricting neural crest cell migration to the center of each somite. Moreover, we find that blocking planar cell polarity (PCP) signaling in somitic muscle cells also results in non-segmental neural crest cell migration. Using an F-actin biosensor we show that in the absence of MuSK neural crest cells fail to retract non-productive leading edges, resulting in non-segmental migration. Finally, we show that MuSK knockout mice display similar neural crest cell migration defects, suggesting a novel, evolutionarily conserved role for MuSK in neural crest migration. We propose that a Wnt11r-MuSK dependent, PCP-like pathway restricts neural crest cells to their segmental path.

  19. Time-Course Gene Expression Profiling Reveals a Novel Role of Non-Canonical WNT Signaling During Neural Induction.

    PubMed

    Huang, Cindy Tzu-Ling; Tao, Yunlong; Lu, Jianfeng; Jones, Jeffrey R; Fowler, Lucas; Weick, Jason P; Zhang, Su-Chun

    2016-01-01

    The process of neuroepithelial differentiation from human pluripotent stem cells (PSCs) resembles in vivo neuroectoderm induction in the temporal course, morphogenesis, and biochemical changes. This in vitro model is therefore well-suited to reveal previously unknown molecular mechanisms underlying neural induction in humans. By transcriptome analysis of cells along PSC differentiation to early neuroepithelia at day 6 and definitive neuroepithelia at day 10, we found downregulation of genes that are associated with TGF-β and canonical WNT/β-CATENIN signaling, confirming the roles of classical signaling in human neural induction. Interestingly, WNT/Ca(2+) signaling was upregulated. Pharmacological inhibition of the downstream effector of WNT/Ca(2+) pathway, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), led to an inhibition of the neural marker PAX6 and upregulation of epidermal marker K18, suggesting that Ca(2+)/CaMKII signaling promotes neural induction by preventing the alternative epidermal fate. In addition, our analyses revealed known and novel expression patterns of genes that are involved in DNA methylation, histone modification, as well as epithelial-mesenchymal transition, highlighting potential roles of those genes and signaling pathways during neural differentiation. PMID:27600186

  20. Time-Course Gene Expression Profiling Reveals a Novel Role of Non-Canonical WNT Signaling During Neural Induction

    PubMed Central

    Huang, Cindy Tzu-Ling; Tao, Yunlong; Lu, Jianfeng; Jones, Jeffrey R.; Fowler, Lucas; Weick, Jason P.; Zhang, Su-Chun

    2016-01-01

    The process of neuroepithelial differentiation from human pluripotent stem cells (PSCs) resembles in vivo neuroectoderm induction in the temporal course, morphogenesis, and biochemical changes. This in vitro model is therefore well-suited to reveal previously unknown molecular mechanisms underlying neural induction in humans. By transcriptome analysis of cells along PSC differentiation to early neuroepithelia at day 6 and definitive neuroepithelia at day 10, we found downregulation of genes that are associated with TGF-β and canonical WNT/β-CATENIN signaling, confirming the roles of classical signaling in human neural induction. Interestingly, WNT/Ca2+ signaling was upregulated. Pharmacological inhibition of the downstream effector of WNT/Ca2+ pathway, Ca2+/calmodulin-dependent protein kinase II (CaMKII), led to an inhibition of the neural marker PAX6 and upregulation of epidermal marker K18, suggesting that Ca2+/CaMKII signaling promotes neural induction by preventing the alternative epidermal fate. In addition, our analyses revealed known and novel expression patterns of genes that are involved in DNA methylation, histone modification, as well as epithelial-mesenchymal transition, highlighting potential roles of those genes and signaling pathways during neural differentiation. PMID:27600186

  1. Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα

    PubMed Central

    Wunderle, Lina; Knopf, Julia D.; Kühnle, Nathalie; Morlé, Aymeric; Hehn, Beate; Adrain, Colin; Strisovsky, Kvido; Freeman, Matthew; Lemberg, Marius K.

    2016-01-01

    Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes. PMID:27264103

  2. Characterization of a Non-Canonical Signal Peptidase Cleavage Site in a Replication Protein from Tomato Ringspot Virus.

    PubMed

    Wei, Ting; Chisholm, Joan; Sanfaçon, Hélène

    2016-01-01

    The NTB-VPg polyprotein from tomato ringspot virus is an integral membrane replication protein associated with endoplasmic reticulum membranes. A signal peptidase (SPase) cleavage was previously detected in the C-terminal region of NTB-VPg downstream of a 14 amino acid (aa)-long hydrophobic region (termed TM2). However, the exact location of the cleavage site was not determined. Using in vitro translation assays, we show that the SPase cleavage site is conserved in the NTB-VPg protein from various ToRSV isolates, although the rate of cleavage varies from one isolate to another. Systematic site-directed mutagenesis of the NTB-VPg SPase cleavage sites of two ToRSV isolates allowed the identification of sequences that affect cleavage efficiency. We also present evidence that SPase cleavage in the ToRSV-Rasp2 isolate occurs within a GAAGG sequence likely after the AAG (GAAG/G). Mutation of a downstream MAAV sequence to AAAV resulted in SPase cleavage at both the natural GAAG/G and the mutated AAA/V sequences. Given that there is a distance of seven aa between the two cleavage sites, this indicates that there is flexibility in the positioning of the cleavage sites relative to the inner surface of the membrane and the SPase active site. SPase cleavage sites are typically located 3-7 aa downstream of the hydrophobic region. However, the NTB-VPg GAAG/G cleavage site is located 17 aa downstream of the TM2 hydrophobic region, highlighting unusual features of the NTB-VPg SPase cleavage site. A putative 11 aa-long amphipathic helix was identified immediately downstream of the TM2 region and five aa upstream of the GAAG/G cleavage site. Based on these results, we present an updated topology model in which the hydrophobic and amphipathic domains form a long tilted helix or a bent helix in the membrane lipid bilayer, with the downstream cleavage site(s) oriented parallel to the membrane inner surface. PMID:27589230

  3. Proteome-wide measurement of non-canonical bacterial mistranslation by quantitative mass spectrometry of protein modifications

    PubMed Central

    Cvetesic, Nevena; Semanjski, Maja; Soufi, Boumediene; Krug, Karsten; Gruic-Sovulj, Ita; Macek, Boris

    2016-01-01

    The genetic code is virtually universal in biology and was likely established before the advent of cellular life. The extent to which mistranslation occurs is poorly understood and presents a fundamental question in basic research and production of recombinant proteins. Here we used shotgun proteomics combined with unbiased protein modification analysis to quantitatively analyze in vivo mistranslation in an E. coli strain with a defect in the editing mechanism of leucyl-tRNA synthetase. We detected the misincorporation of a non-proteinogenic amino acid norvaline on 10% of all measured leucine residues under microaerobic conditions and revealed preferential deployment of a tRNALeu(CAG) isoacceptor during norvaline misincorporation. The strain with the norvalylated proteome demonstrated a substantial reduction in cell fitness under both prolonged aerobic and microaerobic cultivation. Unlike norvaline, isoleucine did not substitute for leucine even under harsh error-prone conditions. Our study introduces shotgun proteomics as a powerful tool in quantitative analysis of mistranslation. PMID:27377007

  4. PreTIS: A Tool to Predict Non-canonical 5’ UTR Translational Initiation Sites in Human and Mouse

    PubMed Central

    Reuter, Kerstin; Helms, Volkhard

    2016-01-01

    Translation of mRNA sequences into proteins typically starts at an AUG triplet. In rare cases, translation may also start at alternative non–AUG codons located in the annotated 5’ UTR which leads to an increased regulatory complexity. Since ribosome profiling detects translational start sites at the nucleotide level, the properties of these start sites can then be used for the statistical evaluation of functional open reading frames. We developed a linear regression approach to predict in–frame and out–of–frame translational start sites within the 5’ UTR from mRNA sequence information together with their translation initiation confidence. Predicted start codons comprise AUG as well as near–cognate codons. The underlying datasets are based on published translational start sites for human HEK293 and mouse embryonic stem cells that were derived by the original authors from ribosome profiling data. The average prediction accuracy of true vs. false start sites for HEK293 cells was 80%. When applied to mouse mRNA sequences, the same model predicted translation initiation sites observed in mouse ES cells with an accuracy of 76%. Moreover, we illustrate the effect of in silico mutations in the flanking sequence context of a start site on the predicted initiation confidence. Our new webservice PreTIS visualizes alternative start sites and their respective ORFs and predicts their ability to initiate translation. Solely, the mRNA sequence is required as input. PreTIS is accessible at http://service.bioinformatik.uni-saarland.de/pretis. PMID:27768687

  5. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways

    PubMed Central

    Zappia, Carlos Daniel; Granja-Galeano, Gina; Fernández, Natalia; Shayo, Carina; Davio, Carlos; Fitzsimons, Carlos P.; Monczor, Federico

    2015-01-01

    Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat inflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with the high morbidity levels of such inflammatory conditions, these receptors are the targets of a vast number of approved drugs, and in many situations their ligands are co-administered. However, this drug association has no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling could affect GR-mediated activity, impacting on its transcriptional outcome. Indeed, our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-protein βγ subunits and a parallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamine and clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation and transrepression in a gene-specific manner. Our work provides a delineation of molecular mechanisms underlying the widespread clinical association of antihistamines and GR agonists, which may contribute to future dosage optimization and reduction of well-described side effects associated with glucocorticoid administration. PMID:26635083

  6. Dbf4 regulates the Cdc5 Polo-like kinase through a distinct non-canonical binding interaction.

    PubMed

    Chen, Ying-Chou; Weinreich, Michael

    2010-12-31

    Cdc7-Dbf4 is a conserved, two-subunit kinase required for initiating eukaryotic DNA replication. Recent studies have shown that Cdc7-Dbf4 also regulates the mitotic exit network (MEN) and monopolar homolog orientation in meiosis I (Matos, J., Lipp, J. J., Bogdanova, A., Guillot, S., Okaz, E., Junqueira, M., Shevchenko, A., and Zachariae, W. (2008) Cell 135, 662-678 and Miller, C. T., Gabrielse, C., Chen, Y. C., and Weinreich, M. (2009) PLoS Genet. 5, e1000498). Both activities likely involve a Cdc7-Dbf4 interaction with Cdc5, the single Polo-like kinase in budding yeast. We previously showed that Dbf4 binds the Cdc5 polo-box domain (PBD) via an ∼40-residue N-terminal sequence, which lacks a PBD consensus binding site (S(pS/pT)(P/X)), and that Dbf4 inhibits Cdc5 function during mitosis. Here we identify a non-consensus PBD binding site within Dbf4 and demonstrate that the PBD-Dbf4 interaction occurs via a distinct PBD surface from that used to bind phosphoproteins. Genetic and biochemical analysis of multiple dbf4 mutants indicate that Dbf4 inhibits Cdc5 function through direct binding. Surprisingly, mutation of invariant Cdc5 residues required for binding phosphorylated substrates has little effect on yeast viability or growth rate. Instead, cdc5 mutants defective for binding phosphoproteins exhibit enhanced resistance to microtubule disruption and an increased rate of spindle elongation. This study, therefore, details the molecular nature of a new type of PBD binding and reveals that Cdc5 targeting to phosphorylated substrates likely regulates spindle dynamics.

  7. Importin α1 Mediates Yorkie Nuclear Import via an N-terminal Non-canonical Nuclear Localization Signal.

    PubMed

    Wang, Shimin; Lu, Yi; Yin, Meng-Xin; Wang, Chao; Wu, Wei; Li, Jinhui; Wu, Wenqing; Ge, Ling; Hu, Lianxin; Zhao, Yun; Zhang, Lei

    2016-04-01

    The Hippo signaling pathway controls organ size by orchestrating cell proliferation and apoptosis. When the Hippo pathway was inactivated, the transcriptional co-activator Yorkie translocates into the nucleus and forms a complex with transcription factor Scalloped to promote the expression of Hippo pathway target genes. Therefore, the nuclear translocation of Yorkie is a critical step in Hippo signaling. Here, we provide evidence that the N-terminal 1-55 amino acids of Yorkie, especially Arg-15, were essential for its nuclear localization. By mass spectrometry and biochemical analyses, we found that Importin α1 can directly interact with the Yorkie N terminus and drive Yorkie into the nucleus. Further experiments show that the upstream component Hippo can inhibit Importin α1-mediated Yorkie nuclear import. Taken together, we identified a potential nuclear localization signal at the N-terminal end of Yorkie as well as a critical role for Importin α1 in Yorkie nuclear import. PMID:26887950

  8. Non-canonical distribution and non-equilibrium transport beyond weak system-bath coupling regime: A polaron transformation approach

    NASA Astrophysics Data System (ADS)

    Xu, Dazhi; Cao, Jianshu

    2016-08-01

    The concept of polaron, emerged from condense matter physics, describes the dynamical interaction of moving particle with its surrounding bosonic modes. This concept has been developed into a useful method to treat open quantum systems with a complete range of system-bath coupling strength. Especially, the polaron transformation approach shows its validity in the intermediate coupling regime, in which the Redfield equation or Fermi's golden rule will fail. In the polaron frame, the equilibrium distribution carried out by perturbative expansion presents a deviation from the canonical distribution, which is beyond the usual weak coupling assumption in thermodynamics. A polaron transformed Redfield equation (PTRE) not only reproduces the dissipative quantum dynamics but also provides an accurate and efficient way to calculate the non-equilibrium steady states. Applications of the PTRE approach to problems such as exciton diffusion, heat transport and light-harvesting energy transfer are presented.

  9. Non-canonical CRP sites control competence regulons in Escherichia coli and many other γ-proteobacteria

    PubMed Central

    Cameron, Andrew D. S.; Redfield, Rosemary J.

    2006-01-01

    Escherichia coli's cAMP receptor protein (CRP), the archetypal bacterial transcription factor, regulates over a hundred promoters by binding 22 bp symmetrical sites with the consensus core half-site TGTGA. However, Haemophilus influenzae has two types of CRP sites, one like E.coli's and one with the core sequence TGCGA that regulates genes required for DNA uptake (natural competence). Only the latter ‘CRP-S’ sites require both CRP and the coregulator Sxy for activation. To our knowledge, the TGTGA and TGCGA motifs are the first example of one transcription factor having two distinct binding-site motifs. Here we show that CRP-S promoters are widespread in the γ-proteobacteria and demonstrate their Sxy-dependence in E.coli. Orthologs of most H.influenzae CRP-S-regulated genes are ubiquitous in the five best-studied γ-proteobacteria families, Enterobacteriaceae, Pasteurellaceae, Pseudomonadaceae, Vibrionaceae and Xanthomonadaceae. Phylogenetic footprinting identified CRP-S sites in the promoter regions of the Enterobacteriaceae, Pasteurellaceae and Vibrionaceae orthologs, and canonical CRP sites in orthologs of genes known to be Sxy-independent in H.influenzae. Bandshift experiments confirmed that E.coli CRP-S sequences are low affinity binding sites for CRP, and mRNA analysis showed that they require CRP, cAMP (CRP's allosteric effector) and Sxy for gene induction. This work suggests not only that the γ-proteobacteria share a common DNA uptake mechanism, but also that, in the three best studied families, their competence regulons share both CRP-S specificity and Sxy dependence. PMID:17068078

  10. Neuronal development and axon growth are altered by glyphosate through a WNT non-canonical signaling pathway.

    PubMed

    Coullery, Romina P; Ferrari, María E; Rosso, Silvana B

    2016-01-01

    The growth and morphological differentiation of neurons are critical events in the establishment of proper neuronal connectivity and functioning. The developing nervous system is highly susceptible to damage caused by exposure to environmental contaminants. Glyphosate-containing herbicides are the most used agrochemicals in the world, particularly on genetically modified plants. Previous studies have demonstrated that glyphosate induces neurotoxicity in mammals. Therefore, its action mechanism on the nervous system needs to be determined. In this study, we report about impaired neuronal development caused by glyphosate exposure. Particularly, we observed that the initial axonal differentiation and growth of cultured neurons is affected by glyphosate since most treated cells remained undifferentiated after 1 day in culture. Although they polarized at 2 days in vitro, they elicited shorter and unbranched axons and they also developed less complex dendritic arbors compared to controls. To go further, we attempted to identify the cellular mechanism by which glyphosate affected neuronal morphology. Biochemical approaches revealed that glyphosate led to a decrease in Wnt5a level, a key factor for the initial neurite development and maturation, as well as inducing a down-regulation of CaMKII activity. This data suggests that the morphological defects would likely be a consequence of the decrease in both Wnt5a expression and CaMKII activity induced by glyphosate. Additionally, these changes might be reflected in a subsequent neuronal dysfunction. Therefore, our findings highlight the importance of establishing rigorous control on the use of glyphosate-based herbicides in order to protect mammals' health.

  11. The RRM Domain of Human Fused in Sarcoma Protein Reveals a Non-Canonical Nucleic Acid Binding Site

    PubMed Central

    Liu, Xuehui; Niu, Chunyan; Ren, Jintao; Zhang, Jiayu; Xie, Xiaodong; Zhu, Haining; Feng, Wei; Gong, Weimin

    2012-01-01

    Fused in sarcoma (FUS) is involved in many processes of RNA metabolism. FUS and another RNA binding protein, TDP-43, are implicated in amyotrophic lateral sclerosis (ALS). It is significant to characterize the RNA recognition motif (RRM) of FUS as its nucleic acid binding properties are unclear. More importantly, abolishing the RNA binding ability of the RRM domain of TDP43 was reported to suppress the neurotoxicity of TDP-43 in Drosophila. The sequence of FUS-RRM varies significantly from canonical RRMs, but the solution structure of FUS-RRM determined by NMR showed a similar overall folding as other RRMs. We found that FUS-RRM directly bound to RNA and DNA and the binding affinity was in the micromolar range as measured by surface plasmon resonance and NMR titration. The nucleic acid binding pocket in FUS-RRM is significantly distorted since several critical aromatic residues are missing. An exceptionally positively charged loop in FUS-RRM, which is not found in other RRMs, is directly involved in the RNA/DNA binding. Substituting the lysine residues in the unique KK loop impaired the nucleic acid binding and altered FUS subcellular localization. The results provide insights into the nucleic acid binding properties of FUS-RRM and its potential relevance to ALS. PMID:23200923

  12. Copper is a potent inhibitor of both the canonical and non-canonical NFκB pathways.

    PubMed

    Kenneth, Niall S; Hucks, George E; Kocab, Andrew J; McCollom, Annie L; Duckett, Colin S

    2014-01-01

    Copper is an essential trace element that plays key roles in many metabolic processes. Homeostatic regulation of intracellular copper is normally tightly controlled, but deregulated copper levels are found in numerous metabolic and neurodegenerative diseases, as well as in a range of neoplasms. There are conflicting reports regarding the exact role of copper in the regulation of NFκB-responsive genes, specifically whether copper leads to increased activation of the NFκB pathways, or downregulation. Here we show that increased intracellular levels of copper, using the ionophore clioquinol, leads to a potent inhibition of NFκB pathways, induced by multiple distinct stimuli. Addition of copper to cells inhibits ubiquitin-mediated degradation of IκBα by preventing its phoshorylation by the upstream IKK complex. Intriguingly, copper-dependent inhibition of NFκB can be reversed by the addition of the reducing agent, N-acetylcysteine (NAC). These results suggest that the oxidative properties of excess copper prevent NFκB activation by blocking IκBα destruction, and that NFκB activity should be assessed in diseases associated with copper excess.

  13. Non-canonical protein-DNA interactions identified by ChIP are not artifacts”: response

    PubMed Central

    2013-01-01

    Background Studies of protein association with DNA on a genome wide scale are possible through methods like ChIP-Chip or ChIP-Seq. Massive problems with false positive signals in our own experiments motivated us to revise the standard ChIP-Chip protocol. Analysis of chromosome wide binding of the alternative sigma factor σ32 in Escherichia coli with this new protocol resulted in detection of only a subset of binding sites found in a previous study by Wade and colleagues. We suggested that the remainder of binding sites detected in the previous study are likely to be false positives. In a recent article the Wade group claimed that our conclusion is wrong and that the disputed sites are genuine σ32 binding sites. They further claimed that the non-detection of these sites in our study was due to low data quality. Results/discussion We respond to the criticism of Wade and colleagues and discuss some general questions of ChIP-based studies. We outline why the quality of our data is sufficient to derive meaningful results. Specific points are: (i) the modifications we introduced into the standard ChIP-Chip protocol do not necessarily result in a low dynamic range, (ii) correlation between ChIP-Chip replicates should not be calculated based on the whole data set as done in transcript analysis, (iii) control experiments are essential for identifying false positives. Suggestions are made how ChIP-based methods could be further optimized and which alternative approaches can be used to strengthen conclusions. Conclusion We appreciate the ongoing discussion about the ChIP-Chip method and hope that it helps other scientist to analyze and interpret their results. The modifications we introduced into the ChIP-Chip protocol are a first step towards reducing false positive signals but there is certainly potential for further optimization. The discussion about the σ32 binding sites in question highlights the need for alternative approaches and further investigation of appropriate methods for verification. PMID:24053571

  14. Importin α1 Mediates Yorkie Nuclear Import via an N-terminal Non-canonical Nuclear Localization Signal.

    PubMed

    Wang, Shimin; Lu, Yi; Yin, Meng-Xin; Wang, Chao; Wu, Wei; Li, Jinhui; Wu, Wenqing; Ge, Ling; Hu, Lianxin; Zhao, Yun; Zhang, Lei

    2016-04-01

    The Hippo signaling pathway controls organ size by orchestrating cell proliferation and apoptosis. When the Hippo pathway was inactivated, the transcriptional co-activator Yorkie translocates into the nucleus and forms a complex with transcription factor Scalloped to promote the expression of Hippo pathway target genes. Therefore, the nuclear translocation of Yorkie is a critical step in Hippo signaling. Here, we provide evidence that the N-terminal 1-55 amino acids of Yorkie, especially Arg-15, were essential for its nuclear localization. By mass spectrometry and biochemical analyses, we found that Importin α1 can directly interact with the Yorkie N terminus and drive Yorkie into the nucleus. Further experiments show that the upstream component Hippo can inhibit Importin α1-mediated Yorkie nuclear import. Taken together, we identified a potential nuclear localization signal at the N-terminal end of Yorkie as well as a critical role for Importin α1 in Yorkie nuclear import.

  15. Salicylic acid receptors activate jasmonic acid signalling through a non-canonical pathway to promote effector-triggered immunity

    PubMed Central

    Liu, Lijing; Sonbol, Fathi-Mohamed; Huot, Bethany; Gu, Yangnan; Withers, John; Mwimba, Musoki; Yao, Jian; He, Sheng Yang; Dong, Xinnian

    2016-01-01

    It is an apparent conundrum how plants evolved effector-triggered immunity (ETI), involving programmed cell death (PCD), as a major defence mechanism against biotrophic pathogens, because ETI-associated PCD could leave them vulnerable to necrotrophic pathogens that thrive on dead host cells. Interestingly, during ETI, the normally antagonistic defence hormones, salicylic acid (SA) and jasmonic acid (JA) associated with defence against biotrophs and necrotrophs respectively, both accumulate to high levels. In this study, we made the surprising finding that JA is a positive regulator of RPS2-mediated ETI. Early induction of JA-responsive genes and de novo JA synthesis following SA accumulation is activated through the SA receptors NPR3 and NPR4, instead of the JA receptor COI1. We provide evidence that NPR3 and NPR4 may mediate this effect by promoting degradation of the JA transcriptional repressor JAZs. This unique interplay between SA and JA offers a possible explanation of how plants can mount defence against a biotrophic pathogen without becoming vulnerable to necrotrophic pathogens. PMID:27725643

  16. Time-Course Gene Expression Profiling Reveals a Novel Role of Non-Canonical WNT Signaling During Neural Induction

    PubMed Central

    Huang, Cindy Tzu-Ling; Tao, Yunlong; Lu, Jianfeng; Jones, Jeffrey R.; Fowler, Lucas; Weick, Jason P.; Zhang, Su-Chun

    2016-01-01

    The process of neuroepithelial differentiation from human pluripotent stem cells (PSCs) resembles in vivo neuroectoderm induction in the temporal course, morphogenesis, and biochemical changes. This in vitro model is therefore well-suited to reveal previously unknown molecular mechanisms underlying neural induction in humans. By transcriptome analysis of cells along PSC differentiation to early neuroepithelia at day 6 and definitive neuroepithelia at day 10, we found downregulation of genes that are associated with TGF-β and canonical WNT/β-CATENIN signaling, confirming the roles of classical signaling in human neural induction. Interestingly, WNT/Ca2+ signaling was upregulated. Pharmacological inhibition of the downstream effector of WNT/Ca2+ pathway, Ca2+/calmodulin-dependent protein kinase II (CaMKII), led to an inhibition of the neural marker PAX6 and upregulation of epidermal marker K18, suggesting that Ca2+/CaMKII signaling promotes neural induction by preventing the alternative epidermal fate. In addition, our analyses revealed known and novel expression patterns of genes that are involved in DNA methylation, histone modification, as well as epithelial-mesenchymal transition, highlighting potential roles of those genes and signaling pathways during neural differentiation. PMID:27600186

  17. Expression and Evolution of the Non-Canonically Translated Yeast Mitochondrial Acetyl-CoA Carboxylase Hfa1p

    PubMed Central

    Suomi, Fumi; Menger, Katja E.; Monteuuis, Geoffray; Naumann, Uta; Kursu, V. A. Samuli; Shvetsova, Antonina; Kastaniotis, Alexander J.

    2014-01-01

    The Saccharomyces cerevisiae genome encodes two sequence related acetyl-CoA carboxylases, the cytosolic Acc1p and the mitochondrial Hfa1p, required for respiratory function. Several aspects of expression of the HFA1 gene and its evolutionary origin have remained unclear. Here, we determined the HFA1 transcription initiation sites by 5′ RACE analysis. Using a novel “Stop codon scanning” approach, we mapped the location of the HFA1 translation initiation site to an upstream AUU codon at position −372 relative to the annotated start codon. This upstream initiation leads to production of a mitochondrial targeting sequence preceding the ACC domains of the protein. In silico analyses of fungal ACC genes revealed conserved “cryptic” upstream mitochondrial targeting sequences in yeast species that have not undergone a whole genome duplication. Our Δhfa1 baker's yeast mutant phenotype rescue studies using the protoploid Kluyveromyces lactis ACC confirmed functionality of the cryptic upstream mitochondrial targeting signal. These results lend strong experimental support to the hypothesis that the mitochondrial and cytosolic acetyl-CoA carboxylases in S. cerevisiae have evolved from a single gene encoding both the mitochondrial and cytosolic isoforms. Leaning on a cursory survey of a group of genes of our interest, we propose that cryptic 5′ upstream mitochondrial targeting sequences may be more abundant in eukaryotes than anticipated thus far. PMID:25503745

  18. A Transposable Element within the Non-canonical Telomerase RNA of Arabidopsis thaliana Modulates Telomerase in Response to DNA Damage

    PubMed Central

    Xu, Hengyi; Nelson, Andrew D. L.; Shippen, Dorothy E.

    2015-01-01

    Long noncoding RNAs (lncRNAs) have emerged as critical factors in many biological processes, but little is known about how their regulatory functions evolved. One of the best-studied lncRNAs is TER, the essential RNA template for telomerase reverse transcriptase. We previously showed that Arabidopsis thaliana harbors three TER isoforms: TER1, TER2 and TER2S. TER1 serves as a canonical telomere template, while TER2 is a novel negative regulator of telomerase activity, induced in response to double-strand breaks (DSBs). TER2 contains a 529 nt intervening sequence that is removed along with 36 nt at the RNA 3’ terminus to generate TER2S, an RNA of unknown function. Here we investigate how A. thaliana TER2 acquired its regulatory function. Using data from the 1,001 Arabidopsis genomes project, we report that the intervening sequence within TER2 is derived from a transposable element termed DSB responsive element (DRE). DRE is found in the TER2 loci of most but not all A. thaliana accessions. By analyzing accessions with (TER2) and without DRE (TER2Δ) we demonstrate that this element is responsible for many of the unique properties of TER2, including its enhanced binding to TERT and telomerase inhibitory function. We show that DRE destabilizes TER2, and further that TER2 induction by DNA damage reflects increased RNA stability and not increased transcription. DRE-mediated changes in TER2 stability thus provide a rapid and sensitive switch to fine-tune telomerase enzyme activity. Altogether, our data shows that invasion of the TER2 locus by a small transposon converted this lncRNA into a DNA damage sensor that modulates telomerase enzyme activity in response to genome assault. PMID:26075395

  19. The Lyapunov dimension and its estimation via the Leonov method

    NASA Astrophysics Data System (ADS)

    Kuznetsov, N. V.

    2016-06-01

    Along with widely used numerical methods for estimating and computing the Lyapunov dimension there is an effective analytical approach, proposed by G.A. Leonov in 1991. The Leonov method is based on the direct Lyapunov method with special Lyapunov-like functions. The advantage of the method is that it allows one to estimate the Lyapunov dimension of invariant sets without localization of the set in the phase space and, in many cases, to get effectively an exact Lyapunov dimension formula. In this work the invariance of the Lyapunov dimension with respect to diffeomorphisms and its connection with the Leonov method are discussed. For discrete-time dynamical systems an analog of Leonov method is suggested. In a simple but rigorous way, here it is presented the connection between the Leonov method and the key related works: Kaplan and Yorke (the concept of the Lyapunov dimension, 1979), Douady and Oesterlé (upper bounds of the Hausdorff dimension via the Lyapunov dimension of maps, 1980), Constantin, Eden, Foiaş, and Temam (upper bounds of the Hausdorff dimension via the Lyapunov exponents and Lyapunov dimension of dynamical systems, 1985-90), and the numerical calculation of the Lyapunov exponents and dimension.

  20. Embedding in higher dimensions causes ambiguity in determining equations from data. Embedding in higher dimensions

    NASA Astrophysics Data System (ADS)

    Vaidya, P. G.; Majumder, S.

    2008-12-01

    A linear system of dimension D can be embedded by D time-delay vectors. However, a nonlinear system often requires more vectors, almost always not more than 2D+1. This paper is regarding the consequence of such an embedding. We encountered this problem in an attempt to obtain a set of equations from the observed data. Our goal was to generate a system which is topologically conjugate to the original system. We found that many a times our efforts led to highly unstable systems. Now, we have an explanation. Embedding in higher dimensions causes a topological foliation and this foliation has a D-dimensional “leaf”. All the data were on this leaf and therefore we were unable to distinguish this foliated system from those where the foliation had collapsed. We illustrate the phenomenon by examples from numerically generated data and suggest possible remedies.