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Sample records for noncanonical wnt11 signaling

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

    OpenAIRE

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

    2008-01-01

    Knowledge of the molecular mechanisms regulating cell ingression, epithelial-mesenchymal transition and migration movements during amniote gastrulation is steadily improving. In the frog and fish embryo, Wnt5 and Wnt11 ligands are expressed around the blastopore and play an important role in regulating cell movements associated with gastrulation. In the chicken embryo, although Wnt5a and Wnt5b are expressed in the primitive streak, the known Wnt11 gene is expressed in paraxial and intermediat...

  2. Wnt-11 signaling leads to down-regulation of the Wnt/β-catenin, JNK/AP-1 and NF-κB pathways and promotes viability in the CHO-K1 cells

    International Nuclear Information System (INIS)

    Railo, Antti; Nagy, Irina I.; Kilpelaeinen, Pekka; Vainio, Seppo

    2008-01-01

    The Wnt family of glycoprotein growth factors controls a number of central cellular processes such as proliferation, differentiation and ageing. All the Wnt proteins analyzed so far either activate or inhibit the canonical β-catenin signaling pathway that regulates transcription of the target genes. In addition, some of them activate noncanonical signaling pathways that involve components such as the JNK, heterotrimeric G proteins, protein kinase C, and calmodulin-dependent protein kinase II, although the precise signaling mechanisms are only just beginning to be revealed. We demonstrate here that Wnt-11 signaling is sufficient to inhibit not only the canonical β-catenin mediated Wnt signaling but also JNK/AP-1 and NF-κB signaling in the CHO cells, thus serving as a noncanonical Wnt ligand in this system. Inhibition of the JNK/AP-1 pathway is mediated in part by the MAPK kinase MKK4 and Akt. Moreover, protein kinase C is involved in the regulation of JNK/AP-1 by Wnt-11, but not of the NF-κB pathway. Consistent with the central role of Akt, JNK and NF-κB in cell survival and stress responses, Wnt-11 signaling promotes cell viability. Hence Wnt-11 is involved in coordination of key signaling pathways

  3. Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

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    Zhao-Jun Liu

    Full Text Available Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM. They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox embryonic fibroblasts (MEFs. Notch1-deficient (Notch1(-/- MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1 in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441, which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1. Functionally, "Notch-activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4 in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.

  4. Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development

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    Silvia Mazzotta

    2016-10-01

    Full Text Available Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

  5. Evidence of non-canonical NOTCH signaling

    DEFF Research Database (Denmark)

    Traustadóttir, Gunnhildur Ásta; Jensen, Charlotte H; Thomassen, Mads

    2016-01-01

    suggested to interact with NOTCH1 and act as an antagonist. This non-canonical interaction is, however controversial, and evidence for a direct interaction, still lacking in mammals. In this study, we elucidated the putative DLK1-NOTCH1 interaction in a mammalian context. Taking a global approach and using...... this interaction to occur between EGF domains 5 and 6 of DLK1 and EGF domains 10-15 of NOTCH1. Thus, our data provide the first evidence for a direct interaction between DLK1 and NOTCH1 in mammals, and substantiate that non-canonical NOTCH ligands exist, adding to the complexity of NOTCH signaling....

  6. Contributions of Noncanonical Smoothened Signaling During Embryonic Development.

    Science.gov (United States)

    Pandit, Tanushree; Ogden, Stacey K

    2017-01-01

    The Sonic Hedgehog (Shh) signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo), is a G protein-coupled receptor (GPCR) that has been demonstrated to signal through at least two effector routes. The first is a G protein-independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fate during early embryonic development. The second, commonly referred to as the noncanonical Smo signal, induces rapid, transcription-independent responses that are essential for establishing and maintaining distinct cell behaviors during development. Herein, we discuss contributions of this noncanonical route during embryonic development. We also highlight important open questions regarding noncanonical Smo signal route selection during development, and consider implications of noncanonical signal corruption in disease.

  7. Contributions of Noncanonical Smoothened Signaling During Embryonic Development

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    Tanushree Pandit

    2017-10-01

    Full Text Available The Sonic Hedgehog (Shh signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo, is a G protein-coupled receptor (GPCR that has been demonstrated to signal through at least two effector routes. The first is a G protein–independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fate during early embryonic development. The second, commonly referred to as the noncanonical Smo signal, induces rapid, transcription-independent responses that are essential for establishing and maintaining distinct cell behaviors during development. Herein, we discuss contributions of this noncanonical route during embryonic development. We also highlight important open questions regarding noncanonical Smo signal route selection during development, and consider implications of noncanonical signal corruption in disease.

  8. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

    DEFF Research Database (Denmark)

    Hönes, G. Sebastian; Rakov, Helena; Logan, John

    2017-01-01

    that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level....

  9. Wnt11b is involved in cilia-mediated symmetry breakage during Xenopus left-right development.

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    Peter Walentek

    Full Text Available Breakage of bilateral symmetry in amphibian embryos depends on the development of a ciliated epithelium at the gastrocoel roof during early neurulation. Motile cilia at the gastrocoel roof plate (GRP give rise to leftward flow of extracellular fluids. Flow is required for asymmetric gene expression and organ morphogenesis. Wnt signaling has previously been involved in two steps, Wnt/ß-catenin mediated induction of Foxj1, a regulator of motile cilia, and Wnt/planar cell polarity (PCP dependent cilia polarization to the posterior pole of cells. We have studied Wnt11b in the context of laterality determination, as this ligand was reported to activate canonical and non-canonical Wnt signaling. Wnt11b was found to be expressed in the so-called superficial mesoderm (SM, from which the GRP derives. Surprisingly, Foxj1 was only marginally affected in loss-of-function experiments, indicating that another ligand acts in this early step of laterality specification. Wnt11b was required, however, for polarization of GRP cilia and GRP morphogenesis, in line with the known function of Wnt/PCP in cilia-driven leftward flow. In addition Xnr1 and Coco expression in the lateral-most GRP cells, which sense flow and generate the first asymmetric signal, was attenuated in morphants, involving Wnt signaling in yet another process related to symmetry breakage in Xenopus.

  10. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells

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    Diez Soraya

    2010-03-01

    Full Text Available Abstract Background Wnt-11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development. We previously reported that Wnt-11 expression is elevated in hormone-independent prostate cancer and that the progression of prostate cancer from androgen-dependent to androgen-independent proliferation correlates with a loss of mutual inhibition between Wnt-11- and androgen receptor-dependent signals. However, the prevalence of increased expression of Wnt-11 in patient tumours and the functions of Wnt-11 in prostate cancer cells were not known. Results Wnt-11 protein levels in prostate tumours were determined by immunohistochemical analysis of prostate tumour tissue arrays. Wnt-11 protein was elevated in 77/117 of tumours when compared with 27 benign prostatic hypertrophy specimens and was present in 4/4 bone metastases. In addition, there was a positive correlation between Wnt-11 expression and PSA levels above 10 ng/ml. Androgen-depleted LNCaP prostate cancer cells form neurites and express genes associated with neuroendocrine-like differentiation (NED, a feature of prostate tumours that have a poor prognosis. Since androgen-depletion increases expression of Wnt-11, we examined the role of Wnt-11 in NED. Ectopic expression of Wnt-11 induced expression of NSE and ASCL1, which are markers of NED, and this was prevented by inhibitors of cyclic AMP-dependent protein kinase, consistent with the known role of this kinase in NED. In contrast, Wnt-11 did not induce NSE expression in RWPE-1 cells, which are derived from benign prostate, suggesting that the role of Wnt-11 in NED is specific to prostate cancer. In addition, silencing of Wnt-11 expression in androgen-depleted LNCaP cells prevented NED and resulted in apoptosis. Silencing of Wnt-11 gene expression in androgen-independent PC3 cells also reduced expression of NSE and increased apoptosis. Finally, silencing of Wnt-11 reduced PC3 cell migration and ectopic

  11. Both canonical and non-canonical Wnt signaling independently promote stem cell growth in mammospheres.

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    Alexander M Many

    Full Text Available 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.

  12. The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo

    Czech Academy of Sciences Publication Activity Database

    Bryja, Vítězslav; Andersson, E.R.; Schambony, A.; Esner, M.; Bryjová, Lenka; Biris, K.K.; Hall, A.C.; Kraft, B.; Čajánek, L.; Yamaguchi, T.P.; Buckingham, M.; Arenas, E.

    2009-01-01

    Roč. 20, č. 3 (2009), s. 924-936 ISSN 1059-1524 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : non-canonical Wnt signaling * Lrp5/6 * mouse Subject RIV: BO - Biophysics Impact factor: 5.979, year: 2009

  13. Contributions of Noncanonical Smoothened Signaling During Embryonic Development

    OpenAIRE

    Pandit, Tanushree; Ogden, Stacey K.

    2017-01-01

    The Sonic Hedgehog (Shh) signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo), is a G protein-coupled receptor (GPCR) that has been demonstrated to signal through at least two effector routes. The first is a G protein–independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fa...

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

    International Nuclear Information System (INIS)

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

    2008-01-01

    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

  15. Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD

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    Baarsma, Hoeke A.; John-Schuster, Gerrit; Heinzelmann, Katharina; Dagouassat, Maylis; Boczkowski, Jorge; Brusselle, Guy G.; Smits, Ron; Yildirim, Ali Ö.

    2017-01-01

    Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT–β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin–driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal–epithelial cross talk in COPD pathogenesis, which is amenable to therapy. PMID:27979969

  16. IFN signaling: how a non-canonical model led to the development of IFN mimetics

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    Howard M Johnson

    2013-07-01

    Full Text Available The classical model of cytokine signaling dominates our view of specific gene activation by cytokines such as the interferons (IFNs. The importance of the model extends beyond cytokines and applies to hormones such as growth hormone (GH and insulin, and growth factors such as epidermal growth factor (EGF and fibroblast growth factor (FGF. According to this model, ligand activates the cell via interaction with the extracellular domain of the receptor. This results in activation of receptor or receptor-associated tyrosine kinases, primarily of the Janus kinase (JAK family, phosphorylation and dimerization of the STAT transcription factors, which dissociate from the receptor cytoplasmic domain and translocate to the nucleus. This view ascribes no further role to the ligand, JAK kinase, or receptor in either specific gene activation or the associated epigenetic events. The presence of dimeric STATs in the nucleus essentially explains it all. Our studies have resulted in the development of a non-canonical, more complex model of IFNγ signaling that is akin to that of steroid hormone/steroid receptor signaling. We have shown that ligand, receptor, activated JAKs and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events. We found that the type I IFN system functions similarly. The fact that GH receptor, insulin receptor, EGF receptor, and FGF receptor undergo nuclear translocation upon ligand binding suggests that they may also function similarly. The steroid hormone/steroid receptor nature of type I and II IFN signaling provides insight into the specificity of signaling by members of cytokine families. The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and

  17. Transforming growth factor β induces bone marrow mesenchymal stem cell migration via noncanonical signals and N-cadherin.

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    Dubon, Maria Jose; Yu, Jinyeong; Choi, Sanghyuk; Park, Ki-Sook

    2018-01-01

    Transforming growth factor-beta (TGF-β) induces the migration and mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) to maintain bone homeostasis during bone remodeling and facilitate the repair of peripheral tissues. Although many studies have reported the mechanisms through which TGF-β mediates the migration of various types of cells, including cancer cells, the intrinsic cellular mechanisms underlying cellular migration, and mobilization of BM-MSCs mediated by TGF-β are unclear. In this study, we showed that TGF-β activated noncanonical signaling molecules, such as Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, via TGF-β type I receptor in human BM-MSCs and murine BM-MSC-like ST2 cells. Inhibition of Rac1 by NSC23766 and Src by PP2 resulted in impaired TGF-β-mediated migration. These results suggested that the Smad-independent, noncanonical signals activated by TGF-β were necessary for migration. We also showed that N-cadherin-dependent intercellular interactions were required for TGF-β-mediated migration using functional inhibition of N-cadherin with EDTA treatment and a neutralizing antibody (GC-4 antibody) or siRNA-mediated knockdown of N-cadherin. However, N-cadherin knockdown did not affect the global activation of noncanonical signals in response to TGF-β. Therefore, these results suggested that the migration of BM-MSCs in response to TGF-β was mediated through N-cadherin and noncanonical TGF-β signals. © 2017 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    vandenBerg, Alysia L.; Sassoon, David A.

    2009-01-01

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

  19. Noncanonical Wnt signaling promotes osteoclast differentiation and is facilitated by the human immunodeficiency virus protease inhibitor ritonavir

    International Nuclear Information System (INIS)

    Santiago, Francisco; Oguma, Junya; Brown, Anthony M.C.; Laurence, Jeffrey

    2012-01-01

    Highlights: ► First demonstration of direct role for noncanonical Wnt in osteoclast differentiation. ► Demonstration of Ryk as a Wnt5a/b receptor in inhibition of canonical Wnt signaling. ► Modulation of noncanonical Wnt signaling by a clinically important drug, ritonavir. ► Establishes a mechanism for an important clinical problem: HIV-associated bone loss. -- Abstract: Wnt proteins that signal via the canonical Wnt/β-catenin pathway directly regulate osteoblast differentiation. In contrast, most studies of Wnt-related effects on osteoclasts involve indirect changes. While investigating bone mineral density loss in the setting of human immunodeficiency virus (HIV) infection and its treatment with the protease inhibitor ritonavir (RTV), we observed that RTV decreased nuclear localization of β-catenin, critical to canonical Wnt signaling, in primary human and murine osteoclast precursors. This occurred in parallel with upregulation of Wnt5a and Wnt5b transcripts. These Wnts typically stimulate noncanonical Wnt signaling, and this can antagonize the canonical Wnt pathway in many cell types, dependent upon Wnt receptor usage. We now document RTV-mediated upregulation of Wnt5a/b protein in osteoclast precursors. Recombinant Wnt5b and retrovirus-mediated expression of Wnt5a enhanced osteoclast differentiation from human and murine monocytic precursors, processes facilitated by RTV. In contrast, canonical Wnt signaling mediated by Wnt3a suppressed osteoclastogenesis. Both RTV and Wnt5b inhibited canonical, β-catenin/T cell factor-based Wnt reporter activation in osteoclast precursors. RTV- and Wnt5-induced osteoclast differentiation were dependent upon the receptor-like tyrosine kinase Ryk, suggesting that Ryk may act as a Wnt5a/b receptor in this context. This is the first demonstration of a direct role for Wnt signaling pathways and Ryk in regulation of osteoclast differentiation, and its modulation by a clinically important drug, ritonavir. These studies

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  1. GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells.

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    Jason E Cain

    Full Text Available Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1(-/-UB mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3(-/- mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1(-/-UB mice. Indeed, constitutive expression of GLI3 repressor via the Gli3(Delta699 allele in Ptc1(-/-UB mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret.

  2. Canonical and Non-Canonical NF-κB Signaling Promotes Breast Cancer Tumor-Initiating Cells

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    Kendellen, Megan F.; Bradford, Jennifer W.; Lawrence, Cortney L.; Clark, Kelly S.; Baldwin, Albert S.

    2014-01-01

    Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors, and the development of metastases. TICs have been identified in various tumors, including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the NF-κB family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition (EMT) and by upregulating the expression of the inflammatory cytokines IL-1β and IL-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. PMID:23474754

  3. The Alternative Splicing Regulator Tra2b Is Required for Somitogenesis and Regulates Splicing of an Inhibitory Wnt11b Isoform

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    Darwin S. Dichmann

    2015-02-01

    Full Text Available Alternative splicing is pervasive in vertebrates, yet little is known about most isoforms or their regulation. transformer-2b (tra2b encodes a splicing regulator whose endogenous function is poorly understood. Tra2b knockdown in Xenopus results in embryos with multiple defects, including defective somitogenesis. Using RNA sequencing, we identify 142 splice changes (mostly intron retention and exon skipping, 89% of which are not in current annotations. A previously undescribed isoform of wnt11b retains the last intron, resulting in a truncated ligand (Wnt11b-short. We show that this isoform acts as a dominant-negative ligand in cardiac gene induction and pronephric tubule formation. To determine the contribution of Wnt11b-short to the tra2b phenotype, we induce retention of intron 4 in wnt11b, which recapitulates the failure to form somites but not other tra2b morphant defects. This alternative splicing of a Wnt ligand adds intricacy to a complex signaling pathway and highlights intron retention as a regulatory mechanism.

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

    Energy Technology Data Exchange (ETDEWEB)

    Samarzija, Ivana [Friedrich Miescher Institute for Biomedical Research, Basel (Switzerland); Sini, Patrizia [Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Macclesfield (United Kingdom); Schlange, Thomas [Bayer Schering Pharma AG, Wuppertal (Germany); MacDonald, Gwen [Friedrich Miescher Institute for Biomedical Research, Basel (Switzerland); Hynes, Nancy E., E-mail: Nancy.Hynes@fmi.ch [Friedrich Miescher Institute for Biomedical Research, Basel (Switzerland)

    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.

  5. Inhibitory Effect of 1,8-Cineol on β-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC

    Directory of Open Access Journals (Sweden)

    Anna Roettger

    2017-05-01

    Full Text Available ObjectivesHead and neck squamous cell carcinoma (HNSCC is one of the most common tumors worldwide. The high mortality rates have not changed during the last three decades, and thus there is an enormous need for innovative therapy approaches. Several recent studies suggest an important role of the Wnt/β-catenin signaling pathway in the tumorigenesis of HNSCC. We analyzed the effect of the monoterpene oxide 1,8-cineol on the regulation of the Wnt/β-catenin signaling pathway and the cellular progression of different HNSCC cell lines.MethodsPermanent HNSCC cell lines were exposed to varying concentrations and times of 1,8-cineol. Regulation and activity profiles of the Wnt/β-catenin signaling cascade were analyzed using Western hybridization experiments, MTT assays, real-time PCR-based epithelial to mesenchymal transition array, and immunohistochemistry.ResultsExposure of different cell lines to 1,8-cineol treatment resulted in a dose-dependent inhibition of proliferation and a decreased activity of the WNT/β-catenin pathway. We can show the inhibition of glycogen synthase kinase 3 (GSK-3α/β (Ser-9/21 as well as a corresponding decreased endolysosomal localization, leading to a decreased β-catenin activity. Furthermore, we can show that exposure to cineol functionally results in a reduced expression of WNT11.ConclusionIn this work, we demonstrate for the first time that 1,8-cineol acts as an inhibitor of the Wnt/β-catenin activity in HNSCC via a decreased inhibition of GSK-3, which lead to reduced levels of WNT11 and a dose-dependent decrease of the cellular progression. Our data represent a new mechanism of 1,8-cineol activity, which may lead to novel molecular targets and treatment approaches of this natural drug.

  6. Inhibitory Effect of 1,8-Cineol on β-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC.

    Science.gov (United States)

    Roettger, Anna; Bruchhage, Karl-Ludwig; Drenckhan, Maren; Ploetze-Martin, Kirsten; Pries, Ralph; Wollenberg, Barbara

    2017-01-01

    Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumors worldwide. The high mortality rates have not changed during the last three decades, and thus there is an enormous need for innovative therapy approaches. Several recent studies suggest an important role of the Wnt/β-catenin signaling pathway in the tumorigenesis of HNSCC. We analyzed the effect of the monoterpene oxide 1,8-cineol on the regulation of the Wnt/β-catenin signaling pathway and the cellular progression of different HNSCC cell lines. Permanent HNSCC cell lines were exposed to varying concentrations and times of 1,8-cineol. Regulation and activity profiles of the Wnt/β-catenin signaling cascade were analyzed using Western hybridization experiments, MTT assays, real-time PCR-based epithelial to mesenchymal transition array, and immunohistochemistry. Exposure of different cell lines to 1,8-cineol treatment resulted in a dose-dependent inhibition of proliferation and a decreased activity of the WNT/β-catenin pathway. We can show the inhibition of glycogen synthase kinase 3 (GSK-3)α/β (Ser-9/21) as well as a corresponding decreased endolysosomal localization, leading to a decreased β-catenin activity. Furthermore, we can show that exposure to cineol functionally results in a reduced expression of WNT11. In this work, we demonstrate for the first time that 1,8-cineol acts as an inhibitor of the Wnt/β-catenin activity in HNSCC via a decreased inhibition of GSK-3, which lead to reduced levels of WNT11 and a dose-dependent decrease of the cellular progression. Our data represent a new mechanism of 1,8-cineol activity, which may lead to novel molecular targets and treatment approaches of this natural drug.

  7. Unterschiede und Gemeinsamkeiten der nicht-kanonischen Wnt-Liganden Wnt5a und Wnt11

    OpenAIRE

    Wallkamm, Veronika

    2014-01-01

    Die nicht-kanonischen Zweige des Wnt-Signalnetzwerkes sind Regulatoren der konvergenten Extension während der Xenopus Gastrulation. Dabei übernehmen die nicht-kanonischen Wnt-Liganden Wnt5a und Wnt11 nicht-redundante Aufgaben.

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

    NARCIS (Netherlands)

    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|info:eu-repo/dai/nl/107536129; 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 signalling pathways coordinate these processes, partly by propagating gene-expression-modulating signals. DNA damage influences not only the

  9. Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Joseph L. Regan

    2017-12-01

    Full Text Available Summary: Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs. To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH-positive CSCs. Canonical GLI-dependent Hedgehog signaling is a negative regulator of WNT signaling in normal intestine and intestinal tumors. Here, we show that Hedgehog signaling in colon CSCs is autocrine SHH-dependent, non-canonical PTCH1 dependent, and GLI independent. In addition, using small-molecule inhibitors and RNAi against SHH-palmitoylating Hedgehog acyltransferase (HHAT, we demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival. : Colon cancer is a heterogeneous tumor driven by a subpopulation(s of therapy-resistant cancer stem cells (CSCs. Regan et al. use 3D culture models to demonstrate that CSC survival is regulated by non-canonical, SHH-dependent, PTCH1-dependent Hedgehog signaling, which acts as a positive regulator of WNT signaling to block CSC differentiation. Keywords: WNT pathway, non-canonical Hedgehog signaling, cancer stem cell, colon cancer, cancer organoid, PTCH1, HHAT, SHH

  10. Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases.

    Science.gov (United States)

    Ackers, Ian; Malgor, Ramiro

    2018-01-01

    Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation.

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

    Science.gov (United States)

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

    2014-12-20

    Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UBs) in mutants emerge as doublets from the intermediate mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the glial cell line-derived neurotrophic factor (Gdnf) expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in the mesoderm with an inducible Cre at E7.5 results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before the formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role of Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  12. Wnt11 Is Required for Oriented Migration of Dermogenic Progenitor Cells from the Dorsomedial Lip of the Avian Dermomyotome

    Science.gov (United States)

    Morosan-Puopolo, Gabriela; Balakrishnan-Renuka, Ajeesh; Yusuf, Faisal; Chen, Jingchen; Dai, Fangping; Zoidl, Georg; Lüdtke, Timo H.-W.; Kispert, Andreas; Theiss, Carsten; Abdelsabour-Khalaf, Mohammed; Brand-Saberi, Beate

    2014-01-01

    The embryonic origin of the dermis in vertebrates can be traced back to the dermomyotome of the somites, the lateral plate mesoderm and the neural crest. The dermal precursors directly overlying the neural tube display a unique dense arrangement and are the first to induce skin appendage formation in vertebrate embryos. These dermal precursor cells have been shown to derive from the dorsomedial lip of the dermomyotome (DML). Based on its expression pattern in the DML, Wnt11 is a candidate regulator of dorsal dermis formation. Using EGFP-based cell labelling and time-lapse imaging, we show that the Wnt11 expressing DML is the source of the dense dorsal dermis. Loss-of-function studies in chicken embryos show that Wnt11 is indeed essential for the formation of dense dermis competent to support cutaneous appendage formation. Our findings show that dermogenic progenitors cannot leave the DML to form dense dorsal dermis following Wnt11 silencing. No alterations were noticeable in the patterning or in the epithelial state of the dermomyotome including the DML. Furthermore, we show that Wnt11 expression is regulated in a manner similar to the previously described early dermal marker cDermo-1. The analysis of Wnt11 mutant mice exhibits an underdeveloped dorsal dermis and strongly supports our gene silencing data in chicken embryos. We conclude that Wnt11 is required for dense dermis and subsequent cutaneous appendage formation, by influencing the cell fate decision of the cells in the DML. PMID:24671096

  13. Leptin upregulates VEGF in breast cancer via canonic and non-canonical signaling pathways and NFκB/HIF-1α activation

    Science.gov (United States)

    Gonzalez-Perez, Ruben R.; Guo, Shanchun; Watters, Amber; Zhou, Weiqiang; Leibovich, Samuel J.

    2010-01-01

    High levels of VEGF and leptin are strongly linked to worse prognosis of breast cancer. Leptin signalling up-regulates VEGF in human and mouse mammary tumor cells (MT), but the specific molecular mechanisms are largely unknown. Pharmacologic and genetic approaches were used to dissect the mechanism of leptin regulation of VEGF protein and mRNA in MT (4T1, EMT6 and MMT). A series of VEGF-promoter Luc-reporters (full-length and transcription factor-binding deletions) were transfected into MT to analyze leptin regulation of VEGF transcription. Deletion analysis of VEGF promoter and RNA knockdown shows that HIF-1α and NFκB are essentials for leptin regulation of VEGF. Leptin activation of HIF-1α was mainly linked to canonic (MAPK, PI-3K) and non-canonic (PKC, JNK and p38 MAP) signalling pathways. Leptin non-canonic signalling pathways (JNK, p38 MAP and to less extent PKC) were linked to NFκB activation. SP1 was involved in leptin regulation of VEGF in 4T1 cells. AP1 was not involved and AP2 repressed leptin-induced increase of VEGF. Overall, these data suggest that leptin signalling regulates VEGF mainly through HIF-1α and NFκB. These results delineate a comprehensive mechanism for leptin regulation of VEGF in MT. Disruption of leptin signalling could be used as a novel way to treat breast cancer. PMID:20466060

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

    Science.gov (United States)

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

    2015-12-26

    To investigate the effect of secreted frizzled-related proteins (sFRPs) on CXC chemokine expression in human mesenchymal stem cells (hMSCs). 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. 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 sFRP1-induced

  15. The Role of Canonical and Non-Canonical Hedgehog Signaling in Tumor Progression in a Mouse Model of Small Cell Lung Cancer

    Science.gov (United States)

    Szczepny, Anette; Rogers, Samuel; Jayasekara, W. Samantha N.; Park, Kwon; McCloy, Rachael A.; Cochrane, Catherine R.; Ganju, Vinod; Cooper, Wendy A.; Sage, Julien; Peacock, Craig D.; Cain, Jason E.; Burgess, Andrew; Watkins, D. Neil

    2017-01-01

    Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability. PMID:28581526

  16. Concise Review: Reprogramming, Behind the Scenes: Noncanonical Neural Stem Cell Signaling Pathways Reveal New, Unseen Regulators of Tissue Plasticity With Therapeutic Implications.

    Science.gov (United States)

    Poser, Steven W; Chenoweth, Josh G; Colantuoni, Carlo; Masjkur, Jimmy; Chrousos, George; Bornstein, Stefan R; McKay, Ronald D; Androutsellis-Theotokis, Andreas

    2015-11-01

    Interest is great in the new molecular concepts that explain, at the level of signal transduction, the process of reprogramming. Usually, transcription factors with developmental importance are used, but these approaches give limited information on the signaling networks involved, which could reveal new therapeutic opportunities. Recent findings involving reprogramming by genetic means and soluble factors with well-studied downstream signaling mechanisms, including signal transducer and activator of transcription 3 (STAT3) and hairy and enhancer of split 3 (Hes3), shed new light into the molecular mechanisms that might be involved. We examine the appropriateness of common culture systems and their ability to reveal unusual (noncanonical) signal transduction pathways that actually operate in vivo. We then discuss such novel pathways and their importance in various plastic cell types, culminating in their emerging roles in reprogramming mechanisms. We also discuss a number of reprogramming paradigms (mouse induced pluripotent stem cells, direct conversion to neural stem cells, and in vivo conversion of acinar cells to β-like cells). Specifically for acinar-to-β-cell reprogramming paradigms, we discuss the common view of the underlying mechanism (involving the Janus kinase-STAT pathway that leads to STAT3-tyrosine phosphorylation) and present alternative interpretations that implicate STAT3-serine phosphorylation alone or serine and tyrosine phosphorylation occurring in sequential order. The implications for drug design and therapy are important given that different phosphorylation sites on STAT3 intercept different signaling pathways. We introduce a new molecular perspective in the field of reprogramming with broad implications in basic, biotechnological, and translational research. Reprogramming is a powerful approach to change cell identity, with implications in both basic and applied biology. Most efforts involve the forced expression of key transcription

  17. wnt3a but not wnt11 supports self-renewal of embryonic stem cells

    International Nuclear Information System (INIS)

    Singla, Dinender K.; Schneider, David J.; LeWinter, Martin M.; Sobel, Burton E.

    2006-01-01

    wnt proteins (wnts) promote both differentiation of midbrain dopaminergic cells and self-renewal of haematopoietic stem cells. Mouse embryonic stem (ES) cells can be maintained and self-renew on mouse feeder cell layers or in media containing leukemia inhibitory factor (LIF). However, the effects of wnts on ES cells self-renewal and differentiation are not clearly understood. In the present study, we found that conditioned medium prepared from L cells expressing wnt3a can replace feeder cell layers and medium containing LIF in maintaining ES cells in the proliferation without differentiation (self-renewal) state. By contrast, conditioned medium from NIH3T3 cells expressing wnt11 did not. Alkaline phosphatase staining and compact colony formation were used as criteria of cells being in the undifferentiated state. ES cells maintained in medium conditioned by Wnt3a expressing cells underwent freezing and thawing while maintaining properties seen with LIF maintained ES cells. Purified wnt3a did not maintain self-renewal of ES cells for prolonged intervals. Thus, other factors in the medium conditioned by wnt3a expressing cells may have contributed to maintenance of ES cells in a self-renewal state. Pluripotency of ES cells was determined with the use of embryoid bodies in vitro. PD98059, a MEK specific inhibitor, promoted the growth of undifferentiated ES cells maintained in conditioned medium from wnt3a expressing cells. By contrast, the P38 MAPK inhibitor SB230580 did not, suggesting a role for the MEK pathway in self-renewal and differentiation of ES cells maintained in the wnt3a cell conditioned medium. Thus, our results show that conditioned medium from wnt3a but not wnt11 expressing cells can maintain ES cells in self-renewal and in a pluripotent state

  18. Prediction of non-canonical polyadenylation signals in human genomic sequences based on a novel algorithm using a fuzzy membership function.

    Science.gov (United States)

    Kamasawa, Masami; Horiuchi, Jun-Ichi

    2009-05-01

    Computational prediction of polyadenylation signals (PASes) is essential for analysis of alternative polyadenylation that plays crucial roles in gene regulations by generating heterogeneity of 3'-UTR of mRNAs. To date, several algorithms that are mostly based on machine learning methods have been developed to predict PASes. Accuracies of predictions by those algorithms have improved significantly for the last decade. However, they are designed primarily for prediction of the most canonical AAUAAA and its common variant AUUAAA whereas other variants have been ignored in their predictions despite recent studies indicating that non-canonical variants of AAUAAA are more important in the polyadenylation process than commonly recognized. Here we present a new algorithm "PolyF" employing fuzzy logic to confer an advance in computational PAS prediction--enable prediction of the non-canonical variants, and improve the accuracies for the canonical A(A/U)UAAA prediction. PolyF is a simple computational algorithm that is composed of membership functions defining sequence features of downstream sequence element (DSE) and upstream sequence element (USE), together with an inference engine. As a result, PolyF successfully identified the 10 single-nucleotide variants with approximately the same or higher accuracies compared to those for A(A/U)UAAA. PolyF also achieved higher accuracies for A(A/U)UAAA prediction than those by commonly known PAS finder programs, Polyadq and Erpin. Incorporating the USE into the PolyF algorithm was found to enhance prediction accuracies for all the 12 PAS hexamers compared to those using only the DSE, suggesting an important contribution of the USE in the polyadenylation process.

  19. A TNF-p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs.

    Science.gov (United States)

    Mukherjee, Tapas; Chatterjee, Budhaditya; Dhar, Atika; Bais, Sachendra S; Chawla, Meenakshi; Roy, Payel; George, Anna; Bal, Vineeta; Rath, Satyajit; Basak, Soumen

    2017-12-01

    Lymphotoxin-beta receptor (LTβR) present on stromal cells engages the noncanonical NF-κB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-κB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation per se also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naïve lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LTβR-stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IκBδ. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized Nfkb2 -/- mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses. © 2017 The Authors.

  20. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

    Science.gov (United States)

    Katoh, Masaru

    2017-01-01

    Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers

  1. Noncanonical Hamiltonian mechanics

    International Nuclear Information System (INIS)

    Litteljohn, R.G.

    1986-01-01

    Noncanonical variables in Hamiltonian mechanics were first used by Lagrange in 1808. In spite of this, most work in Hamiltonian mechanics has been carried out in canonical variables, up to this day. One reason for this is that noncanonical coordinates are seldom needed for mechanical problems based on Lagrangians of the form L = T - V, where T is the kinetic energy and V is the potential energy. Of course, such Lagrangians arise naturally in celestial mechanics, and as a result they form the paradigms of nineteenth-century mechanics and have become enshrined in all the mechanics textbooks. Certain features of modern problems, however, lead to the use of noncanonical coordinates. Among these are issues of gauge invariance and singular Lagrange a Poisson structures. In addition, certain problems, like the flow of magnetic-field lines in physical space, are naturally formulated in terms of noncanonical coordinates. None of these features is present in the nineteenth-century paradigms of mechanics, but they do arise in problems involving particle motion in the presence of magnetic fields. For example, the motion of a particle in an electromagnetic wave is an important one in plasma physics, but the usual Hamiltonian formulation is gauge dependent. For this problem, noncanonical approaches based on Lagrangians in phase space lead to powerful computational techniques which are gauge invariant. In the limit of strong magnetic fields, particle motion becomes 'guiding-center motion'. Guiding-center motion is also best understood in terms of noncanonical coordinates. Finally the flow of magnetic-field lines through physical space is a Hamiltonian system which is best understood with noncanonical coordinates. No doubt many more systems will arise in the future for which these noncanonical techniques can be applied. (author)

  2. A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain.

    Science.gov (United States)

    Ishimoto, Hiroshi; Wang, Zhe; Rao, Yi; Wu, Chun-Fang; Kitamoto, Toshihiro

    2013-01-01

    The biological actions of steroid hormones are mediated primarily by their cognate nuclear receptors, which serve as steroid-dependent transcription factors. However, steroids can also execute their functions by modulating intracellular signaling cascades rapidly and independently of transcriptional regulation. Despite the potential significance of such "non-genomic" steroid actions, their biological roles and the underlying molecular mechanisms are not well understood, particularly with regard to their effects on behavioral regulation. The major steroid hormone in the fruit fly Drosophila is 20-hydroxy-ecdysone (20E), which plays a variety of pivotal roles during development via the nuclear ecdysone receptors. Here we report that DopEcR, a G-protein coupled receptor for ecdysteroids, is involved in activity- and experience-dependent plasticity of the adult central nervous system. Remarkably, a courtship memory defect in rutabaga (Ca²⁺/calmodulin-responsive adenylate cyclase) mutants was rescued by DopEcR overexpression or acute 20E feeding, whereas a memory defect in dunce (cAMP-specific phosphodiestrase) mutants was counteracted when a loss-of-function DopEcR mutation was introduced. A memory defect caused by suppressing dopamine synthesis was also restored through enhanced DopEcR-mediated ecdysone signaling, and rescue and phenocopy experiments revealed that the mushroom body (MB)--a brain region central to learning and memory in Drosophila--is critical for the DopEcR-dependent processing of courtship memory. Consistent with this finding, acute 20E feeding induced a rapid, DopEcR-dependent increase in cAMP levels in the MB. Our multidisciplinary approach demonstrates that DopEcR mediates the non-canonical actions of 20E and rapidly modulates adult conditioned behavior through cAMP signaling, which is universally important for neural plasticity. This study provides novel insights into non-genomic actions of steroids, and opens a new avenue for genetic

  3. A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain.

    Directory of Open Access Journals (Sweden)

    Hiroshi Ishimoto

    Full Text Available The biological actions of steroid hormones are mediated primarily by their cognate nuclear receptors, which serve as steroid-dependent transcription factors. However, steroids can also execute their functions by modulating intracellular signaling cascades rapidly and independently of transcriptional regulation. Despite the potential significance of such "non-genomic" steroid actions, their biological roles and the underlying molecular mechanisms are not well understood, particularly with regard to their effects on behavioral regulation. The major steroid hormone in the fruit fly Drosophila is 20-hydroxy-ecdysone (20E, which plays a variety of pivotal roles during development via the nuclear ecdysone receptors. Here we report that DopEcR, a G-protein coupled receptor for ecdysteroids, is involved in activity- and experience-dependent plasticity of the adult central nervous system. Remarkably, a courtship memory defect in rutabaga (Ca²⁺/calmodulin-responsive adenylate cyclase mutants was rescued by DopEcR overexpression or acute 20E feeding, whereas a memory defect in dunce (cAMP-specific phosphodiestrase mutants was counteracted when a loss-of-function DopEcR mutation was introduced. A memory defect caused by suppressing dopamine synthesis was also restored through enhanced DopEcR-mediated ecdysone signaling, and rescue and phenocopy experiments revealed that the mushroom body (MB--a brain region central to learning and memory in Drosophila--is critical for the DopEcR-dependent processing of courtship memory. Consistent with this finding, acute 20E feeding induced a rapid, DopEcR-dependent increase in cAMP levels in the MB. Our multidisciplinary approach demonstrates that DopEcR mediates the non-canonical actions of 20E and rapidly modulates adult conditioned behavior through cAMP signaling, which is universally important for neural plasticity. This study provides novel insights into non-genomic actions of steroids, and opens a new avenue for

  4. Coactosin-like protein CLP/Cotl1 suppresses breast cancer growth through activation of IL-24/PERP and inhibition of non-canonical TGFβ signaling.

    Science.gov (United States)

    Xia, L; Xiao, X; Liu, W L; Song, Y; Liu, T J J; Li, Y J; Zacksenhaus, E; Hao, X J; Ben-David, Y

    2018-01-18

    Coactosin-like protein (CLP, or Cotl1), is an F-actin-binding protein, whose role in cancer is largely unknown. Here we show that CLP/Cotl1 is highly expressed in a rat epithelial breast cancer cell line (FE1.3) compared with its mesenchymal counterpart (FE1.2). Knockdown of CLP/Cotl1 in FE1.3 cells increased cell proliferation, whereas its overexpression in FE1.2 cells inhibited proliferation in culture and reduced tumor growth in xenograft assays in mice. Mechanistically, we identified two major pathways through which CLP/Cotl1 exerts its suppressive effects. First, CLP/Cotl1 re-expression in FE1.2 and in human MCF7 breast cancer cells induced expression of the growth-suppressor gene interleukin-24 (IL-24), which independently of p53 upregulates the tumor-suppressor genes p53 apoptosis effector related to PMP-22 (PERP) and p21 cip1 . Second, overexpression of CLP/Cotl1 potentiated the growth-suppressive effect of transforming growth factor-β1 (TGFβ1), leading to downregulation of TGFβ-responsive genes vascular growth factor A/B (VEGFA/VEGFB), hypoxia inducing factor 1α (HIF-1α) and trombospondin 1 (TSP1), which mediate various hallmarks of cancer progression including angiogenesis, invasion and metastasis. CLP/Cotl1 inhibited TGFβ signaling via a non-canonical signaling involving IL-24-instigated inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) phosphorylation and subsequent post-transcriptional downregulation of SMAD2 and SMAD4. We also showed that CLP/COTL1 expression sensitizes breast cancer cells to chemotherapeutic drugs, and this was further enhanced by addition of exogenous TGFβ1. CLP/Cotl1 expression is lost in many human malignancies including prostate, uterine and breast cancers. Thus, our results uncover a novel tumor-suppressor role for CLP/Cotl1 and identify the downstream effectors interleukin 24 (IL-24)/PERP and IL-24/MAPK/ERK/TGFβ as potential targets for precision therapy.

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

    Science.gov (United States)

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

    2015-12-04

    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.

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

    Directory of Open Access Journals (Sweden)

    Ting Wei

    Full Text Available 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.

  7. Wnt5a and Wnt11 are essential for second heart field progenitor development

    OpenAIRE

    Cohen, Ethan David; Miller, Mayumi F.; Wang, Zichao; Moon, Randall T.; Morrisey, Edward E.

    2012-01-01

    Wnt/β-catenin has a biphasic effect on cardiogenesis, promoting the induction of cardiac progenitors but later inhibiting their differentiation. Second heart field progenitors and expression of the second heart field transcription factor Islet1 are inhibited by the loss of β-catenin, indicating that Wnt/β-catenin signaling is necessary for second heart field development. However, expressing a constitutively active β-catenin with Islet1-Cre also inhibits endogenous Islet1 expression, reflectin...

  8. STAT3 cooperates with the non-canonical NF-κB signaling to regulate pro-labor genes in the human placenta.

    Science.gov (United States)

    Yu, L J; Wang, B; Parobchak, N; Roche, N; Rosen, T

    2015-05-01

    Our recent studies have shown that constitutively activated non-canonical RelB/NF-κB2 (p52) in the human placenta positively regulates the pro-labor genes CRH and COX-2. STAT3 regulates NF-κB2 (p100) processing to active p52, and in turn, nuclear activation of RelB/p52, by directly binding to p100/p52 in a variety of cancer cells. In the current study, we tested the hypothesis that STAT3 is involved in regulation of pro-labor genes by associating with RelB/p52 heterodimers in the human placenta. We used a variety of techniques including immunohistochemical staining, gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, RT-qPCR, and immunofluorescence assays in primary culture of cytotrophoblast and placental tissues. We found that knockdown of STAT3 led to down-regulation of both CRH and COX-2 in a dose-dependent manner. By using chromatin immunoprecipitation, we further showed that interaction of RelB with the CRH or COX-2 gene promoters decreased when STAT3 was depleted. Immunofluorescence demonstrated co-localization of STAT3 with RelB or p100/p52 in both the cytoplasm and nucleus of term cytotrophoblasts. Collectively, these results suggest that STAT3 constitutes part of the RelB/p52-containing activator complex that positively regulates pro-labor genes in the human placenta. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling inDrosophilaaxon guidance.

    Science.gov (United States)

    Kannan, Ramakrishnan; Cox, Eric; Wang, Lei; Kuzina, Irina; Gu, Qun; Giniger, Edward

    2018-01-17

    Notch signaling is required for the development and physiology of nearly every tissue in metazoans. Much of Notch signaling is mediated by transcriptional regulation of downstream target genes, but Notch controls axon patterning in Drosophila by local modulation of Abl tyrosine kinase signaling, via direct interactions with the Abl co-factors Disabled and Trio. Here, we show that Notch-Abl axonal signaling requires both of the proteolytic cleavage events that initiate canonical Notch signaling. We further show that some Notch protein is tyrosine phosphorylated in Drosophila , that this form of the protein is selectively associated with Disabled and Trio, and that relevant tyrosines are essential for Notch-dependent axon patterning but not for canonical Notch-dependent regulation of cell fate. Based on these data, we propose a model for the molecular mechanism by which Notch controls Abl signaling in Drosophila axons. © 2018. Published by The Company of Biologists Ltd.

  10. Initial conditions for noncanonical inflation

    International Nuclear Information System (INIS)

    Franche, Paul; Underwood, Bret; Wissanji, Alisha; Gwyn, Rhiannon

    2010-01-01

    We investigate the dynamics of homogeneous phase space for single-field models of inflation. Inflationary trajectories are formally attractors in phase space, but since in practice not all initial conditions lead to them, some degree of fine-tuning is required for successful inflation. We explore how the dynamics of noncanonical inflation, which is driven by the potential energy but has additional kinetic terms that are powers of the kinetic energy, can play a role in ameliorating the initial-conditions fine-tuning problem. We present an analysis of inflationary phase space based on the dynamical behavior of the scalar field. This allows us to construct the flow of trajectories, finding that they generically decay towards the inflationary solution at a steeper angle for noncanonical kinetic terms, in comparison to canonical kinetic terms, so that a larger fraction of the initial-conditions space leads to inflation. Thus, noncanonical kinetic terms can be important for removing the initial conditions fine-tuning problem of some small-field inflation models.

  11. Zebrafish models of non-canonical Wnt/planar cell polarity signalling: fishing for valuable insight into vertebrate polarized cell behavior.

    Science.gov (United States)

    Jussila, Maria; Ciruna, Brian

    2017-05-01

    Planar cell polarity (PCP) coordinates the uniform orientation, structure and movement of cells within the plane of a tissue or organ system. It is beautifully illustrated in the polarized arrangement of bristles and hairs that project from specialized cell surfaces of the insect abdomen and wings, and pioneering genetic studies using the fruit fly, Drosophila melanogaster, have defined a core signalling network underlying PCP. This core PCP/non-canonical Wnt signalling pathway is evolutionarily conserved, and studies in zebrafish have helped transform our understanding of PCP from a peculiarity of polarized epithelia to a more universal cellular property that orchestrates a diverse suite of polarized cell behaviors that are required for normal vertebrate development. Furthermore, application of powerful genetics, embryonic cell-transplantation, and live-imaging capabilities afforded by the zebrafish model have yielded novel insights into the establishment and maintenance of vertebrate PCP, over the course of complex and dynamic morphogenetic events like gastrulation and neural tube morphogenesis. Although key questions regarding vertebrate PCP remain, with the emergence of new genome-editing technologies and the promise of endogenous labeling and Cre/LoxP conditional targeting strategies, zebrafish remains poised to deliver fundamental new insights into the function and molecular dynamic regulation of PCP signalling from embryonic development through to late-onset phenotypes and adult disease states. WIREs Dev Biol 2017, 6:e267. doi: 10.1002/wdev.267 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  12. Integration of canonical and noncanonical Wnt signaling pathways patterns the neuroectoderm along the anterior-posterior axis of sea urchin embryos.

    Directory of Open Access Journals (Sweden)

    Ryan C Range

    Full Text Available Patterning the neuroectoderm along the anterior-posterior (AP axis is a critical event in the early development of deuterostome embryos. However, the mechanisms that regulate the specification and patterning of the neuroectoderm are incompletely understood. Remarkably, the anterior neuroectoderm (ANE of the deuterostome sea urchin embryo expresses many of the same transcription factors and secreted modulators of Wnt signaling, as does the early vertebrate ANE (forebrain/eye field. Moreover, as is the case in vertebrate embryos, confining the ANE to the anterior end of the embryo requires a Wnt/β-catenin-dependent signaling mechanism. Here we use morpholino- or dominant negative-mediated interference to demonstrate that the early sea urchin embryo integrates information not only from Wnt/β-catenin but also from Wnt/Fzl5/8-JNK and Fzl1/2/7-PKC pathways to provide precise spatiotemporal control of neuroectoderm patterning along its AP axis. Together, through the Wnt1 and Wnt8 ligands, they orchestrate a progressive posterior-to-anterior wave of re-specification that restricts the initial, ubiquitous, maternally specified, ANE regulatory state to the most anterior blastomeres. There, the Wnt receptor antagonist, Dkk1, protects this state through a negative feedback mechanism. Because these different Wnt pathways converge on the same cell fate specification process, our data suggest they may function as integrated components of an interactive Wnt signaling network. Our findings provide strong support for the idea that the sea urchin ANE regulatory state and the mechanisms that position and define its borders represent an ancient regulatory patterning system that was present in the common echinoderm/vertebrate ancestor.

  13. Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities

    Science.gov (United States)

    Edelbrock, Michael A.; Kaliyaperumal, Saravanan; Williams, Kandace J.

    2013-01-01

    The field of DNA mismatch repair (MMR) has rapidly expanded after the discovery of the MutHLS repair system in bacteria. By the mid 1990s yeast and human homologues to bacterial MutL and MutS had been identified and their contribution to hereditary non-polyposis colorectal cancer (HNPCC; Lynch Syndrome) was under intense investigation. The human MutS homologue 6 protein (hMSH6), was first reported in 1995 as a G:T binding partner (GTBP) of hMSH2, forming the hMutSα mismatch-binding complex. Signal transduction from each DNA-bound hMutSα complex is accomplished by the hMutLα heterodimer (hMLH1 and hPMS2). Molecular mechanisms and cellular regulation of individual MMR proteins are now areas of intensive research. This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell. MSH6 is unstable in the absence of MSH2, however it is the DNA lesion-binding partner of this heterodimer. MSH6, but not MSH2, has a conserved Phe-X-Glu motif that recognizes and binds several different DNA structural distortions, initiating different cellular responses. hMSH6 also contains the nuclear localization sequences required to shuttle hMutSα into the nucleus. For example, upon binding to O6meG:T, MSH6 triggers a DNA damage response that involves altered phosphorylation within the N-terminal disordered domain of this unique protein. While many investigations have focused on MMR as a post-replication DNA repair mechanism, MMR proteins are expressed and active in all phases of the cell cycle. There is much more to be discovered about regulatory cellular roles that require the presence of MutSα and, in particular, MSH6. PMID:23391514

  14. Inhibitory Effect of 1,8-Cineol on ?-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC

    OpenAIRE

    Roettger, Anna; Bruchhage, Karl-Ludwig; Drenckhan, Maren; Ploetze-Martin, Kirsten; Pries, Ralph; Wollenberg, Barbara

    2017-01-01

    Objectives Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumors worldwide. The high mortality rates have not changed during the last three decades, and thus there is an enormous need for innovative therapy approaches. Several recent studies suggest an important role of the Wnt/β-catenin signaling pathway in the tumorigenesis of HNSCC. We analyzed the effect of the monoterpene oxide 1,8-cineol on the regulation of the Wnt/β-catenin signaling pathway and the cellula...

  15. Relations between canonical and non-canonical inflation

    Energy Technology Data Exchange (ETDEWEB)

    Gwyn, Rhiannon [Max-Planck-Institut fuer Gravitationsphysik (Albert-Einstein-Institut), Potsdam (Germany); Rummel, Markus [Hamburg Univ. (Germany). 2. Inst. fuer Theoretische Physik; Westphal, Alexander [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group

    2012-12-15

    We look for potential observational degeneracies between canonical and non-canonical models of inflation of a single field {phi}. Non-canonical inflationary models are characterized by higher than linear powers of the standard kinetic term X in the effective Lagrangian p(X,{phi}) 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.

  16. Macrophages mediate a switch between canonical and non-canonical Wnt pathways in canine mammary tumors.

    Science.gov (United States)

    Król, Magdalena; Mucha, Joanna; Majchrzak, Kinga; Homa, Agata; Bulkowska, Małgorzata; Majewska, Alicja; Gajewska, Małgorzata; Pietrzak, Marta; Perszko, Mikołaj; Romanowska, Karolina; Pawłowski, Karol; Manuali, Elisabetta; Hellmen, Eva; Motyl, Tomasz

    2014-01-01

    According to the current hypothesis, tumor-associated macrophages (TAMs) are "corrupted" by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell-TAM interactions are complicated and controversial we aimed to better define this phenomenon. Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial-mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n = 50) and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs. We demonstrated that TAMs mediate a "switch" between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being "corrupted" by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM-cancer cell interactions.

  17. Macrophages mediate a switch between canonical and non-canonical Wnt pathways in canine mammary tumors.

    Directory of Open Access Journals (Sweden)

    Magdalena Król

    Full Text Available OBJECTIVE: According to the current hypothesis, tumor-associated macrophages (TAMs are "corrupted" by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell-TAM interactions are complicated and controversial we aimed to better define this phenomenon. METHODS AND RESULTS: Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial-mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n = 50 and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs. CONCLUSIONS: We demonstrated that TAMs mediate a "switch" between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being "corrupted" by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM-cancer cell interactions.

  18. PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer.

    Science.gov (United States)

    Vela, I; Morrissey, C; Zhang, X; Chen, S; Corey, E; Strutton, G M; Nelson, C C; Nicol, D L; Clements, J A; Gardiner, E M

    2014-02-01

    The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis.

  19. Adaptive Neural Network Based Control of Noncanonical Nonlinear Systems.

    Science.gov (United States)

    Zhang, Yanjun; Tao, Gang; Chen, Mou

    2016-09-01

    This paper presents a new study on the adaptive neural network-based control of a class of noncanonical nonlinear systems with large parametric uncertainties. Unlike commonly studied canonical form nonlinear systems whose neural network approximation system models have explicit relative degree structures, which can directly be used to derive parameterized controllers for adaptation, noncanonical form nonlinear systems usually do not have explicit relative degrees, and thus their approximation system models are also in noncanonical forms. It is well-known that the adaptive control of noncanonical form nonlinear systems involves the parameterization of system dynamics. As demonstrated in this paper, it is also the case for noncanonical neural network approximation system models. Effective control of such systems is an open research problem, especially in the presence of uncertain parameters. This paper shows that it is necessary to reparameterize such neural network system models for adaptive control design, and that such reparameterization can be realized using a relative degree formulation, a concept yet to be studied for general neural network system models. This paper then derives the parameterized controllers that guarantee closed-loop stability and asymptotic output tracking for noncanonical form neural network system models. An illustrative example is presented with the simulation results to demonstrate the control design procedure, and to verify the effectiveness of such a new design method.

  20. Non-canonical inflation in supergravity

    International Nuclear Information System (INIS)

    Gwyn, Rhiannon; Lehners, Jean-Luc

    2014-01-01

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

  1. Not all DDRs are created equal: Non-canonical DNA damage responses

    Science.gov (United States)

    Burgess, Rebecca C.; Misteli, Tom

    2015-01-01

    Summary It is commonly assumed that there is a single canonical DNA damage response (DDR) that protects cells from various types of double-strand breaks and that its activation occurs via recognition of DNA damage by the DDR machinery. Recent work suggests that both assumptions may be oversimplifications. Here, we discuss several variations of the DDR in which the pathway is activated by diverse cellular events or generates distinct signaling outcomes. The existence of multiple non-canonical DDRs provides insights into how DNA damage is sensed and suggests a highly modular organization of the DDR. PMID:26317463

  2. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a

    Science.gov (United States)

    Wang, Shuxia; Song, Kangxing; Srivastava, Roshni; Dong, Chao; Go, Gwang-Woong; Li, Na; Iwakiri, Yasuko; Mani, Arya

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6R611C mutation and phenotypically characterized their liver. Homozygote LRP6R611C (LRP6mut/mut) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-α/-μ pathways. Accordingly, there was increased TGF-β1 activity, coupled with enhanced expression of smooth muscle α-actin and vimentin that colocalized with albumin in LRP6mut/mut mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6mut/mut mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH.—Wang, S., Song, K., Srivastava, R., Dong, C., Go, G.-W., Li, N., Iwakiri, Y., Mani, A. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. PMID:25917329

  3. Modeling Small Noncanonical RNA Motifs with the Rosetta FARFAR Server.

    Science.gov (United States)

    Yesselman, Joseph D; Das, Rhiju

    2016-01-01

    Noncanonical RNA motifs help define the vast complexity of RNA structure and function, and in many cases, these loops and junctions are on the order of only ten nucleotides in size. Unfortunately, despite their small size, there is no reliable method to determine the ensemble of lowest energy structures of junctions and loops at atomic accuracy. This chapter outlines straightforward protocols using a webserver for Rosetta Fragment Assembly of RNA with Full Atom Refinement (FARFAR) ( http://rosie.rosettacommons.org/rna_denovo/submit ) to model the 3D structure of small noncanonical RNA motifs for use in visualizing motifs and for further refinement or filtering with experimental data such as NMR chemical shifts.

  4. Slow roll in simple non-canonical inflation

    Science.gov (United States)

    Barenboim, Gabriela; Kinney, William H.

    2007-03-01

    We consider inflation using a class of non-canonical Lagrangians for which the modification to the kinetic term depends on the field, but not its derivatives. We generalize the standard Hubble slow roll expansion to the non-canonical case and derive expressions for observables in terms of the generalized slow roll parameters. We apply the general results to the illustrative case of 'slinky' inflation, which has a simple, exactly solvable, non-canonical representation. However, when transformed into a canonical basis, slinky inflation consists of a field oscillating on a multi-valued potential. We calculate the power spectrum of curvature perturbations for slinky inflation directly in the non-canonical basis, and show that the spectrum is approximately a power law on large scales, with a 'blue' power spectrum. On small scales, the power spectrum exhibits strong oscillatory behaviour. This is an example of a model in which the widely used solution of Garriga and Mukhanov gives the wrong answer for the power spectrum.

  5. Adding diverse noncanonical backbones to rosetta: enabling peptidomimetic design.

    Directory of Open Access Journals (Sweden)

    Kevin Drew

    Full Text Available Peptidomimetics are classes of molecules that mimic structural and functional attributes of polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic oligomers are finding broad applications for molecular recognition and for inhibiting protein-protein interactions. One critical limitation is the limited set of design tools for identifying oligomer sequences that can adopt desired conformations. Here, we present expansions to the ROSETTA platform that enable structure prediction and design of five non-peptidic oligomer scaffolds (noncanonical backbones, oligooxopiperazines, oligo-peptoids, [Formula: see text]-peptides, hydrogen bond surrogate helices and oligosaccharides. This work is complementary to prior additions to model noncanonical protein side chains in ROSETTA. The main purpose of our manuscript is to give a detailed description to current and future developers of how each of these noncanonical backbones was implemented. Furthermore, we provide a general outline for implementation of new backbone types not discussed here. To illustrate the utility of this approach, we describe the first tests of the ROSETTA molecular mechanics energy function in the context of oligooxopiperazines, using quantum mechanical calculations as comparison points, scanning through backbone and side chain torsion angles for a model peptidomimetic. Finally, as an example of a novel design application, we describe the automated design of an oligooxopiperazine that inhibits the p53-MDM2 protein-protein interaction. For the general biological and bioengineering community, several noncanonical backbones have been incorporated into web applications that allow users to freely and rapidly test the presented protocols (http://rosie.rosettacommons.org. This work helps address the peptidomimetic community's need for an automated and expandable

  6. Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Hang Pong Ng

    2017-06-01

    Full Text Available Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR signaling in the absence of glucocorticoids (GCs and upregulated glucocorticoid-induced leucine zipper (gilz, a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs, was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR–GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response.

  7. Canonical and Noncanonical Mechanisms of Glucocorticoid Stress Hormones Action.

    Science.gov (United States)

    2016-01-01

    Hormones of stress, glucocorticoids, regulate numerous physiological processes and functions. These hormonal effects involve diverse mechanisms of action. Glucocorticoid receptors (GRs) are transcription factors which regulate gene expression by canonical mechanism of the hormone action through interaction with specific nucleotide sequence (GRE) in the regulatory region of the gene. The effects of the canonical mechanism develop for several hours. Non-genomic rapid effects of the hormone emerged in seconds- minuets and supposed to be associated with yet not identified receptor in the plasma membrane. In addition to these slow and rapid hormonal actions, one more slow non-canonical mechanism of glucocorticoid action become increasingly evident. This mechanism is based on protein-protein interactions of GRs with other transcription factors. The main modern concepts of canonical, non-canonical and membrane mechanisms of hormone action are discussed in the review.

  8. Noncanonical Hamiltonian density formulation of hydrodynamics and ideal MHD

    International Nuclear Information System (INIS)

    Morrison, P.J.; Greene, J.M.

    1980-04-01

    A new Hamiltonian density formulation of a perfect fluid with or without a magnetic field is presented. Contrary to previous work the dynamical variables are the physical variables, rho, v, B, and s, which form a noncanonical set. A Poisson bracket which satisfies the Jacobi identity is defined. This formulation is transformed to a Hamiltonian system where the dynamical variables are the spatial Fourier coefficients of the fluid variables

  9. Intermediate inflation from a non-canonical scalar field

    Energy Technology Data Exchange (ETDEWEB)

    Rezazadeh, K.; Karami, K. [Department of Physics, University of Kurdistan, Pasdaran St., Sanandaj (Iran, Islamic Republic of); Karimi, P., E-mail: rezazadeh86@gmail.com, E-mail: KKarami@uok.ac.ir, E-mail: parvin.karimi67@yahoo.com [Center for Excellence in Astronomy and Astrophysics (CEAA-RIAAM), P.O. Box 55134-441, Maragha (Iran, Islamic Republic of)

    2015-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Kristen M Grinstead

    Full Text Available 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Verhelst, Kelly, E-mail: Kelly.Verhelst@irc.VIB-UGent.be [Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent (Belgium); Department of Biomedical Molecular Biology, Ghent University, Ghent (Belgium); Gardam, Sandra, E-mail: s.gardam@garvan.org.au [Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent (Belgium); Department of Biomedical Molecular Biology, Ghent University, Ghent (Belgium); Borghi, Alice, E-mail: Alice.Borghi@irc.VIB-UGent.be [Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent (Belgium); Department of Biomedical Molecular Biology, Ghent University, Ghent (Belgium); Kreike, Marja, E-mail: Marja.Kreike@irc.VIB-UGent.be [Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent (Belgium); Department of Biomedical Molecular Biology, Ghent University, Ghent (Belgium); Carpentier, Isabelle, E-mail: Isabelle.Carpentier@irc.VIB-UGent.be [Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent (Belgium); Department of Biomedical Molecular Biology, Ghent University, Ghent (Belgium); Beyaert, Rudi, E-mail: Rudi.Beyaert@irc.VIB-UGent.be [Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent (Belgium); Department of Biomedical Molecular Biology, Ghent University, Ghent (Belgium)

    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.

  12. Stability of a Noncanonical Scalar Field Model during Cosmological Date

    International Nuclear Information System (INIS)

    Golanbari, T.; Sheikhahmadi, H.; Saaidi, Kh.; Ossoulian, Z.

    2016-01-01

    Using the noncanonical model of scalar field, the cosmological consequences of a pervasive, self-interacting, homogeneous, and rolling scalar field are studied. In this model, the scalar field potential is “nonlinear” and decreases in magnitude with increasing the value of the scalar field. A special solution of the nonlinear field equations of ϕ that has time dependency as fixed point is obtained. The fixed point relies on the noncanonical term of action and γ-parameter; this parameter appeared in energy density of scalar field redshift. By means of such fixed point the different eigenvalues of the equation of motion will be obtained. In different epochs in the evolution of the Universe for different values of q and n, the potentials as a function of scalar field are attained. The behavior of baryonic perturbations in linear perturbation scenario as a considerable amount of energy density of scalar field at low redshifts prevents the growth of perturbations in the ordinary matter fluid. The energy density in the scalar field is not appreciably perturbed by nonrelativistic gravitational fields, in either the radiation or matter dominant or scalar field dominated epoch.

  13. [Progress on Hedgehog signaling transduction].

    Science.gov (United States)

    Tang, Ying; Cheng, Steven

    2014-08-25

    Hedgehog (Hh) signaling pathway plays an important role during embryonic development and pattern formation. Disruption of Hh pathway results in various developmental disorders and increasing cancer incidence. Here we provide a comprehensive review of the pathway members, focusing on how mammalian Hh regulates the Gli family of transcription factors through its downstream members, the so-called "canonical signaling pathway". Hh signaling pathway is highly conserved among species, and primary cilia plays an important role as a "signaling center" during vertebrate signal transduction. Further, in the past few years, numerous studies have shown that Hh signal can also be transduced through Gli-independent ways collectively referred to as "non-canonical signaling pathways", which can be subdivided into two modules: (i) those not requiring Smo and (ii) those downstream of Smo that do not require Gli transcription factors. Thus, we review the rapid progress on canonical and non-canonical Hh pathways.

  14. Phase singularities and energy fluxes of a noncanonical vortex dipole Airy beam in the far field

    Science.gov (United States)

    Cheng, Ke; You, Yunqi; Zhong, Xianqiong

    2015-10-01

    Based on the vector angular spectrum representation and stationary phase method, analytical far-field vectorial expressions of a noncanonical vortex dipole Airy beam, namely, a pair of noncanonical vortices with opposite charges embedded in an Airy beam are derived and used to investigate the phase singularities and energy flux distributions of the corresponding beam in the far-field regime, where the noncanonical characteristic of vortex is stressed. It is shown that the noncanonical strength, off-axis distance, and aperture coefficient affect the position and number of phase singularities, and the motion, creation, and annihilation of phase singularities are found by adjusting these parameters. For a low aperture coefficient, the energy flux distributions exhibit different numbers and orientations of lobes by varying the noncanonical strength. With increasing aperture coefficient, the symmetries of lobes are broken, and the energy flux distributions gradually become ellipses and the directions of their major axes vary with different noncanonical strengths. Finally, the energy flux distributions of an Airy beam carrying a single noncanonical vortex are discussed and compared.

  15. The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human STING

    Directory of Open Access Journals (Sweden)

    Elie J. Diner

    2013-05-01

    Full Text Available The presence of foreign DNA in the cytosol of mammalian cells elicits a potent antiviral interferon response. Recently, cytosolic DNA was proposed to induce the synthesis of cyclic GMP-AMP (cGAMP upon binding to an enzyme called cGAMP synthase (cGAS. cGAMP activates an interferon response by binding to a downstream receptor called STING. Here, we identify natural variants of human STING (hSTING that are poorly responsive to cGAMP yet, unexpectedly, are normally responsive to DNA and cGAS signaling. We explain this paradox by demonstrating that the cGAS product is actually a noncanonical cyclic dinucleotide, cyclic [G(2′-5′pA(3′-5′p], which contains a single 2′-5′ phosphodiester bond. Cyclic [G(2′-5′pA(3′-5′p] potently activates diverse hSTING receptors and, therefore, may be a useful adjuvant or immunotherapeutic. Our results indicate that hSTING variants have evolved to distinguish conventional (3′-5′ cyclic dinucleotides, known to be produced mainly by bacteria, from the noncanonical cyclic dinucleotide produced by mammalian cGAS.

  16. Wnt signaling in triple-negative breast cancer

    Science.gov (United States)

    Pohl, SÖ-G; Brook, N; Agostino, M; Arfuso, F; Kumar, A P; Dharmarajan, A

    2017-01-01

    Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease. PMID:28368389

  17. Glia initiate brain assembly through non-canonical Chimaerin/Furin axon guidance in C. elegans

    Science.gov (United States)

    Rapti, Georgia; Li, Chang; Shan, Alan; Lu, Yun; Shaham, Shai

    2017-01-01

    Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet pioneer-neuron identities, their guidance substrates, and their interactions, are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans glia are key for assembly initiation, guiding pioneer and follower axons using distinct signals. Pioneer sublateral neurons, with unique growth properties, anatomy, and innervation, cooperate with glia to mediate follower-axon guidance. We further identify a CHIN-1/Chimaerin-KPC-1/Furin double mutant that severely disrupts assembly. CHIN-1/Chimaerin and KPC-1/Furin function non-canonically in glia and pioneer neurons for guidance-cue trafficking. We exploit this bottleneck to define roles for glial Netrin and Semaphorin in pioneer- and follower-axon guidance, respectively, and for glial and pioneer-neuron Flamingo/CELSR in follower-axon navigation. Altogether, our studies reveal previously-unknown glial roles in pioneer-axon guidance, suggesting conserved brain-assembly principles. PMID:28846083

  18. Wnt Signaling in Skeletal Muscle Development and Regeneration.

    Science.gov (United States)

    Girardi, Francesco; Le Grand, Fabien

    2018-01-01

    Wnt is a family of signaling molecules involved in embryogenesis, adult tissue repair, and cancer. They activate canonical and noncanonical Wnt signaling cascades in target cells. Several studies, within the last decades, showed that several Wnt ligands are involved in myogenesis and both canonical and noncanonical Wnt pathways regulate muscle formation and the maintenance of adult tissue homeostasis. In this review, we provide a comprehensive overview of the roles of Wnt signaling during muscle development and an updated description of Wnt functions during muscle repair. Lastly, we discuss the crosstalk between Wnt and TGFβ signaling pathways in skeletal muscle. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Wnt signaling in limb organogenesis

    OpenAIRE

    Geetha-Loganathan, Poongodi; Nimmagadda, Suresh; Scaal, Martin

    2008-01-01

    Secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development of a wide range of taxa from Hydra to humans. The most extensively studied Wnt signaling pathway is the canonical Wnt pathway, which controls gene expression by stabilizing β-catenin, and regulates a multitude of developmental processes. More recently, noncanonical Wnt pathways, which are β-catenin-independent, have been found to be important developmental regulators. Und...

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

    Directory of Open Access Journals (Sweden)

    Keeling Patrick J

    2010-10-01

    Full Text Available Abstract 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

  1. Base pair probability estimates improve the prediction accuracy of RNA non-canonical base pairs.

    Directory of Open Access Journals (Sweden)

    Michael F Sloma

    2017-11-01

    Full Text Available Prediction of RNA tertiary structure from sequence is an important problem, but generating accurate structure models for even short sequences remains difficult. Predictions of RNA tertiary structure tend to be least accurate in loop regions, where non-canonical pairs are important for determining the details of structure. Non-canonical pairs can be predicted using a knowledge-based model of structure that scores nucleotide cyclic motifs, or NCMs. In this work, a partition function algorithm is introduced that allows the estimation of base pairing probabilities for both canonical and non-canonical interactions. Pairs that are predicted to be probable are more likely to be found in the true structure than pairs of lower probability. Pair probability estimates can be further improved by predicting the structure conserved across multiple homologous sequences using the TurboFold algorithm. These pairing probabilities, used in concert with prior knowledge of the canonical secondary structure, allow accurate inference of non-canonical pairs, an important step towards accurate prediction of the full tertiary structure. Software to predict non-canonical base pairs and pairing probabilities is now provided as part of the RNAstructure software package.

  2. Base pair probability estimates improve the prediction accuracy of RNA non-canonical base pairs.

    Science.gov (United States)

    Sloma, Michael F; Mathews, David H

    2017-11-01

    Prediction of RNA tertiary structure from sequence is an important problem, but generating accurate structure models for even short sequences remains difficult. Predictions of RNA tertiary structure tend to be least accurate in loop regions, where non-canonical pairs are important for determining the details of structure. Non-canonical pairs can be predicted using a knowledge-based model of structure that scores nucleotide cyclic motifs, or NCMs. In this work, a partition function algorithm is introduced that allows the estimation of base pairing probabilities for both canonical and non-canonical interactions. Pairs that are predicted to be probable are more likely to be found in the true structure than pairs of lower probability. Pair probability estimates can be further improved by predicting the structure conserved across multiple homologous sequences using the TurboFold algorithm. These pairing probabilities, used in concert with prior knowledge of the canonical secondary structure, allow accurate inference of non-canonical pairs, an important step towards accurate prediction of the full tertiary structure. Software to predict non-canonical base pairs and pairing probabilities is now provided as part of the RNAstructure software package.

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

    Science.gov (United States)

    Hinz, FI; Dieterich, DC; Schuman, EM

    2016-01-01

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

  4. Noncanonical microRNAs and endogenous siRNAs in normal and psoriatic human skin.

    Science.gov (United States)

    Xia, Jing; Joyce, Cailin E; Bowcock, Anne M; Zhang, Weixiong

    2013-02-15

    Noncanonical microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs) are key gene regulators in eukaryotes. Noncanonical miRNAs, which bypass part of the canonical miRNA biogenesis pathway, can originate from a variety of genomic loci, which include small nucleolar RNAs (snoRNAs), transfer RNAs (tRNAs) and introns, whereas endo-siRNAs can arise from repetitive elements, some of which are transposable. The roles of noncanonical miRNAs and endo-siRNAs in complex diseases have yet to be characterized. To investigate their potential expression and function in psoriasis, we carried out a comprehensive, genome-wide search for noncanonical miRNAs and endo-siRNAs in small RNA deep-sequencing data sets from normal and psoriatic human skin. By analyzing more than 670 million qualified reads from 67 small RNA libraries, we identified 21 novel, noncanonical miRNAs (3 snoRNA-derived and 2 tRNA-derived miRNAs and 16 miRtrons) and 39 novel endo-siRNAs that were expressed in skin. The expression of four novel small RNAs was validated by qRT-PCR in human skin, and their Argonaute association was confirmed by co-immunoprecipitation of ectopic small RNAs in HEK293 cells. Fifteen noncanonical miRNAs or endo-siRNAs were significantly differentially expressed in psoriatic-involved versus normal skin, including an Alu-short interspersed element-derived siRNA which was 17-fold up-regulated in psoriatic-involved skin. These and other differentially expressed small noncoding RNAs may function as regulators of gene expression in skin and potentially play a role in psoriasis pathogenesis.

  5. Non-canonical programmed cell death mechanisms triggered by natural compounds.

    Science.gov (United States)

    Diederich, Marc; Cerella, Claudia

    2016-10-01

    Natural compounds are the fundament of pharmacological treatments and more than 50% of all anticancer drugs are of natural origins or at least derived from scaffolds present in Nature. Over the last 25 years, molecular mechanisms triggered by natural anticancer compounds were investigated. Emerging research showed that molecules of natural origins are useful for both preventive and therapeutic purposes by targeting essential hallmarks and enabling characteristics described by Hanahan and Weinberg. Moreover, natural compounds were able to change the differentiation status of selected cell types. One of the earliest response of cells treated by pharmacologically active compounds is the change of its morphology leading to ultra-structural perturbations: changes in membrane composition, cytoskeleton integrity, alterations of the endoplasmic reticulum, mitochondria and of the nucleus lead to formation of morphological alterations that are a characteristic of both compound and cancer type preceding cell death. Apoptosis and autophagy were traditionally considered as the most prominent cell death or cell death-related mechanisms. By now multiple other cell death modalities were described and most likely involved in response to chemotherapeutic treatment. It can be hypothesized that especially necrosis-related phenotypes triggered by various treatments or evolving from apoptotic or autophagic mechanisms, provide a more efficient therapeutic outcome depending on cancer type and genetic phenotype of the patient. In fact, the recent discovery of multiple regulated forms of necrosis and the initial elucidation of the corresponding cell signaling pathways appear nowadays as important tools to clarify the immunogenic potential of non-canonical forms of cell death induction. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

    De Bruck, Carsten van; Robinson, Mathew

    2014-01-01

    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

  7. Unifying Dark Matter and Dark Energy with non-Canonical Scalars

    OpenAIRE

    Mishra, Swagat S.; Sahni, Varun

    2018-01-01

    Non-canonical scalar fields with the Lagrangian ${\\cal L} = X^\\alpha - V(\\phi)$, possess the attractive property that the speed of sound, $c_s^{2} = (2\\,\\alpha - 1)^{-1}$, can be exceedingly small for large values of $\\alpha$. This allows a non-canonical field to cluster and behave like warm/cold dark matter on small scales. We demonstrate that simple potentials such as $V = V_0\\coth^2{\\phi}$ and the Starobinsky-type potential $V(\\phi) = V_0 \\left ( 1 - e^{-{\\phi}}\\right )^{2}$ can unify dark...

  8. The Role of the Noncanonical NF-KappaB Pathway in Colon Cancer

    Science.gov (United States)

    2016-08-01

    AWARD NUMBER: W81XWH-13-1-0321 TITLE: The Role of the Noncanonical NF-KappaB Pathway in Colon Cancer PRINCIPAL INVESTIGATOR: Yatrik Shah...2013 - 29 May 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0321 The Role of the Noncanonical NF-KappaB Pathway in Colon Cancer 5b...Inflammation is an essential mechanism leading to progression of colon cancer . We have found that in mouse models of colonic intestinal inflammation and in

  9. Non-canonical CRL4A/4B(CDT2 interacts with RAD18 to modulate post replication repair and cell survival.

    Directory of Open Access Journals (Sweden)

    Sarah Sertic

    Full Text Available The Cullin-4(CDT2 E3 ubiquitin ligase plays an essential role in DNA replication origin licensing directing degradation of several licensing factors at the G1/S transition in order to prevent DNA re-replication. Recently a RAD18-independent role of Cullin-4(CDT2 in PCNA monoubiquitylation has been proposed. In an effort to better understand the function of Cullin-4(CDT2 E3 ubiquitin ligase in mammalian Post-Replication Repair during an unperturbed S-phase, we show that down-regulation of Cullin-4(CDT2 leads to two distinguishable independent phenotypes in human cells that unveil at least two independent roles of Cullin-4(CDT2 in S-phase. Apart from the re-replication preventing activity, we identified a non-canonical Cullin-4(CDT2 complex, containing both CUL4A and CUL4B, associated to the COP9 signalosome, that controls a RAD18-dependent damage avoidance pathway essential during an unperturbed S-phase. Indeed, we show that the non-canonical Cullin-4A/4B(CDT2 complex binds to RAD18 and it is required to modulate RAD18 protein levels onto chromatin and the consequent dynamics of PCNA monoubiquitylation during a normal S-phase. This function prevents replication stress, ATR hyper-signaling and, ultimately, apoptosis. A very similar PRR regulatory mechanism has been recently described for Spartan. Our findings uncover a finely regulated process in mammalian cells involving Post-Replication Repair factors, COP9 signalosome and a non-canonical Cullin4-based E3 ligase which is essential to tolerate spontaneous damage and for cell survival during physiological DNA replication.

  10. Noncanonical microRNAs and endogenous siRNAs in lytic infection of murine gammaherpesvirus.

    Directory of Open Access Journals (Sweden)

    Jing Xia

    Full Text Available MicroRNA (miRNA and endogenous small interfering RNA (endo-siRNA are two essential classes of small noncoding RNAs (sncRNAs in eukaryotes. The class of miRNA is diverse and there exist noncanonical miRNAs that bypass the canonical miRNA biogenesis pathway. In order to identify noncanonical miRNAs and endo-siRNAs responding to virus infection and study their potential function, we sequenced small-RNA species from cells lytically infected with murine gammaherpesvirus 68 (MHV68. In addition to three novel canonical miRNAs in mouse, two antisense miRNAs in virus and 25 novel noncanonical miRNAs, including miRNAs derived from transfer RNAs, small nucleolar RNAs and introns, in the host were identified. These noncanonical miRNAs exhibited features distinct from that of canonical miRNAs in lengths of hairpins, base pairings and first nucleotide preference. Many of the novel miRNAs are conserved in mammals. Besides several known murine endo-siRNAs detected by the sequencing profiling, a novel locus in the mouse genome was identified to produce endo-siRNAs. This novel endo-siRNA locus is comprised of two tandem inverted B4 short interspersed nuclear elements (SINEs. Unexpectedly, the SINE-derived endo-siRNAs were found in a variety of sequencing data and virus-infected cells. Moreover, a murine miRNA was up-regulated more than 35 fold in infected than in mock-treated cells. The putative targets of the viral and the up-regulated murine miRNAs were potentially involved in processes of gene transcription and protein phosphorylation, and localized to membranes, suggesting their potential role in manipulating the host basal immune system during lytic infection. Our results extended the number of noncanonical miRNAs in mammals and shed new light on their potential functions of lytic infection of MHV68.

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

    Directory of Open Access Journals (Sweden)

    Annette Kaiser

    Full Text Available 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

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

    Directory of Open Access Journals (Sweden)

    Zakia A. Abdelhamed

    2015-06-01

    Full Text Available 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

  13. Non-canonical Wnt signaling via the Ryk and Ror receptors in the drosophila nervous system

    NARCIS (Netherlands)

    Petrova, Iveta Miroslavova

    2014-01-01

    Wnt genes encode highly conserved glycoproteins that play a variety of roles at different stages of development. Their functions include the regulation of cell proliferation, cell fate specification, cell polarity, apoptosis, stem cell self-renewal, cell migration and tissue homeostasis. In the

  14. Nitrilase-Activatable Noncanonical Amino Acid Precursors for Cell-Selective Metabolic Labeling of Proteomes.

    Science.gov (United States)

    Li, Zefan; Zhu, Yuntao; Sun, Yuting; Qin, Ke; Liu, Weibing; Zhou, Wen; Chen, Xing

    2016-12-16

    Cell-selective protein metabolic labeling is of great interest for studying cell-cell communications and tissue homeostasis. We herein describe a nitrilase-activatable noncanonical amino acid tagging (NANCAT) strategy that exploits an exogenous nitrilase to enzymatically convert the nitrile-substituted precursors to their corresponding noncanonical amino acids (ncAAs), l-azidohomoalanine (Aha) or homopropargylglycine (Hpg), in living cells. Only cells expressing the nitrilase can generate Aha or Hpg in cellulo and metabolically incorporate them into the nascent proteins. Subsequent click-labeling of the azide- or alkyne-incorporated proteins with fluorescent probes or with affinity tags enables visualization and proteomic profiling of nascent proteomes, respectively. We have demonstrated that NANCAT can serve as a versatile strategy for cell-selective labeling of proteomes in both bacterial and mammalian cells.

  15. A Non-canonical Reticular-Limbic Central Auditory Pathway via Medial Septum Contributes to Fear Conditioning.

    Science.gov (United States)

    Zhang, Guang-Wei; Sun, Wen-Jian; Zingg, Brian; Shen, Li; He, Jufang; Xiong, Ying; Tao, Huizhong W; Zhang, Li I

    2018-01-17

    In the mammalian brain, auditory information is known to be processed along a central ascending pathway leading to auditory cortex (AC). Whether there exist any major pathways beyond this canonical auditory neuraxis remains unclear. In awake mice, we found that auditory responses in entorhinal cortex (EC) cannot be explained by a previously proposed relay from AC based on response properties. By combining anatomical tracing and optogenetic/pharmacological manipulations, we discovered that EC received auditory input primarily from the medial septum (MS), rather than AC. A previously uncharacterized auditory pathway was then revealed: it branched from the cochlear nucleus, and via caudal pontine reticular nucleus, pontine central gray, and MS, reached EC. Neurons along this non-canonical auditory pathway responded selectively to high-intensity broadband noise, but not pure tones. Disruption of the pathway resulted in an impairment of specifically noise-cued fear conditioning. This reticular-limbic pathway may thus function in processing aversive acoustic signals. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Search for the non-canonical Ising spin glass on rewired square lattices

    Science.gov (United States)

    Surungan, Tasrief

    2018-03-01

    A spin glass (SG) of non-canonical type is a purely antiferromagnetic (AF) system, exemplified by the AF Ising model on a scale free network (SFN), studied by Bartolozzi et al. [ Phys. Rev. B73, 224419 (2006)]. Frustration in this new type of SG is rendered by topological factor and its randomness is caused by random connectivity. As an SFN corresponds to a large dimensional lattice, finding non-canonical SG in lattice with physical dimension is desireable. However, a regular lattice can not have random connectivity. In order to obtain lattices with random connection and preserving the notion of finite dimension, we costructed rewired lattices. We added some extra bonds randomly connecting each site of a regular lattice to its next-nearest neighbors. Very recently, Surungan et al., studied AF Heisenberg system on rewired square lattice and found no SG behavior [AIP Conf. Proc. 1719, 030006 (2016)]. Due to the importance of discrete symmetry for phase transition, here we study similar structure for the Ising model (Z 2 symmetry). We used Monte Carlo simulation with Replica Exchange algorithm. Two types of structures were studied, firstly, the rewired square lattices with one extra bonds added to each site, and secondly, two bonds added to each site. We calculated the Edwards-Anderson paremeter, the commonly used parameter in searching for SG phase. The non-canonical SG is clearly observed in the rewired square lattice with two extra bonds added.

  17. The Role of Canonical and Noncanonical Pre-mRNA Splicing in Plant Stress Responses

    Directory of Open Access Journals (Sweden)

    A. S. Dubrovina

    2013-01-01

    Full Text Available Plants are sessile organisms capable of adapting to various environmental constraints, such as high or low temperatures, drought, soil salinity, or pathogen attack. To survive the unfavorable conditions, plants actively employ pre-mRNA splicing as a mechanism to regulate expression of stress-responsive genes and reprogram intracellular regulatory networks. There is a growing evidence that various stresses strongly affect the frequency and diversity of alternative splicing events in the stress-responsive genes and lead to an increased accumulation of mRNAs containing premature stop codons, which in turn have an impact on plant stress response. A number of studies revealed that some mRNAs involved in plant stress response are spliced counter to the traditional conception of alternative splicing. Such noncanonical mRNA splicing events include trans-splicing, intraexonic deletions, or variations affecting multiple exons and often require short direct repeats to occur. The noncanonical alternative splicing, along with common splicing events, targets the spliced transcripts to degradation through nonsense-mediated mRNA decay or leads to translation of truncated proteins. Investigation of the diversity, biological consequences, and mechanisms of the canonical and noncanonical alternative splicing events will help one to identify those transcripts which are promising for using in genetic engineering and selection of stress-tolerant plants.

  18. A non-canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis.

    Directory of Open Access Journals (Sweden)

    Shintaro Imamura

    Full Text Available Although it is clear that telomerase expression is crucial for the maintenance of telomere homeostasis, there is increasing evidence that the TERT protein can have physiological roles that are independent of this central function. To further examine the role of telomerase during vertebrate development, the zebrafish telomerase reverse transcriptase (zTERT was functionally characterized. Upon zTERT knockdown, zebrafish embryos show reduced telomerase activity and are viable, but develop pancytopenia resulting from aberrant hematopoiesis. The blood cell counts in TERT-depleted zebrafish embryos are markedly decreased and hematopoietic cell differentiation is impaired, whereas other somatic lineages remain morphologically unaffected. Although both primitive and definitive hematopoiesis is disrupted by zTERT knockdown, the telomere lengths are not significantly altered throughout early development. Induced p53 deficiency, as well as overexpression of the anti-apoptotic proteins Bcl-2 and E1B-19K, significantly relieves the decreased blood cells numbers caused by zTERT knockdown, but not the impaired blood cell differentiation. Surprisingly, only the reverse transcriptase motifs of zTERT are crucial, but the telomerase RNA-binding domain of zTERT is not required, for rescuing complete hematopoiesis. This is therefore the first demonstration of a non-canonical catalytic activity of TERT, which is different from "authentic" telomerase activity, is required for during vertebrate hematopoiesis. On the other hand, zTERT deficiency induced a defect in hematopoiesis through a potent and specific effect on the gene expression of key regulators in the absence of telomere dysfunction. These results suggest that TERT non-canonically functions in hematopoietic cell differentiation and survival in vertebrates, independently of its role in telomere homeostasis. The data also provide insights into a non-canonical pathway by which TERT functions to modulate

  19. Noncanonical DNA motifs as transactivation targets by wild type and mutant p53.

    Directory of Open Access Journals (Sweden)

    Jennifer J Jordan

    2008-06-01

    Full Text Available Sequence-specific binding by the human p53 master regulator is critical to its tumor suppressor activity in response to environmental stresses. p53 binds as a tetramer to two decameric half-sites separated by 0-13 nucleotides (nt, originally defined by the consensus RRRCWWGYYY (n = 0-13 RRRCWWGYYY. To better understand the role of sequence, organization, and level of p53 on transactivation at target response elements (REs by wild type (WT and mutant p53, we deconstructed the functional p53 canonical consensus sequence using budding yeast and human cell systems. Contrary to early reports on binding in vitro, small increases in distance between decamer half-sites greatly reduces p53 transactivation, as demonstrated for the natural TIGER RE. This was confirmed with human cell extracts using a newly developed, semi-in vitro microsphere binding assay. These results contrast with the synergistic increase in transactivation from a pair of weak, full-site REs in the MDM2 promoter that are separated by an evolutionary conserved 17 bp spacer. Surprisingly, there can be substantial transactivation at noncanonical (1/2-(a single decamer and (3/4-sites, some of which were originally classified as biologically relevant canonical consensus sequences including PIDD and Apaf-1. p53 family members p63 and p73 yielded similar results. Efficient transactivation from noncanonical elements requires tetrameric p53, and the presence of the carboxy terminal, non-specific DNA binding domain enhanced transactivation from noncanonical sequences. Our findings demonstrate that RE sequence, organization, and level of p53 can strongly impact p53-mediated transactivation, thereby changing the view of what constitutes a functional p53 target. Importantly, inclusion of (1/2- and (3/4-site REs greatly expands the p53 master regulatory network.

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

    Czech Academy of Sciences Publication Activity Database

    Barvík, I.; Rejman, Dominik; Panova, Natalya; Šanderová, Hana; Krásný, Libor

    2017-01-01

    Roč. 41, č. 2 (2017), s. 131-138 ISSN 0168-6445 R&D Projects: GA ČR GA15-05228S; GA ČR GA15-11711S Institutional support: RVO:61388963 ; RVO:61388971 Keywords : RNA polymerase * non-canonical transcription initiation * transcription initiating substrate * nicotinamide adenine dinucleotide (NAD(+)) * coenzymes * RNA stability Subject RIV: EB - Genetics ; Molecular Biology; EE - Microbiology, Virology (MBU-M) OBOR OECD: Biochemistry and molecular biology; Microbiology (MBU-M) Impact factor: 12.198, year: 2016

  1. A Chern-Simons gauge-fixed Lagrangian in a 'non-canonical' BRST approach

    International Nuclear Information System (INIS)

    Constantinescu, R; Ionescu, C

    2009-01-01

    This paper presents a possible path which starts from the extended BRST Hamiltonian formalism and ends with a covariant Lagrangian action, using the equivalence between the two formalisms. The approach allows a simple account of the form of the master equation and offers a natural identification of some 'non-canonical' operators and variables. These are the main items which solve the major difficulty of the extended BRST Lagrangian formalism, i.e., the gauge-fixing problem. The algorithm we propose applies to a non-Abelian Chern-Simons model coupled with Dirac fields

  2. Generalizing a unified model of dark matter, dark energy, and inflation with a noncanonical kinetic term

    International Nuclear Information System (INIS)

    De-Santiago, Josue; Cervantes-Cota, Jorge L.

    2011-01-01

    We study a unification model for dark energy, dark matter, and inflation with a single scalar field with noncanonical kinetic term. In this model, the kinetic term of the Lagrangian accounts for the dark matter and dark energy, and at early epochs, a quadratic potential accounts for slow roll inflation. The present work is an extension to the work by Bose and Majumdar [Phys. Rev. D 79, 103517 (2009).] with a more general kinetic term that was proposed by Chimento in Phys. Rev. D 69, 123517 (2004). We demonstrate that the model is viable at the background and linear perturbation levels.

  3. Non-Smad pathways in TGF-β signaling

    OpenAIRE

    Zhang, Ying E

    2009-01-01

    Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focu...

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

    Science.gov (United States)

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

    2016-08-30

    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.

  5. Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia.

    Science.gov (United States)

    de Lorenzo, Laura; Sorenson, Reed; Bailey-Serres, Julia; Hunt, Arthur G

    2017-06-01

    Stresses from various environmental challenges continually confront plants, and their responses are important for growth and survival. One molecular response to such challenges involves the alternative polyadenylation of mRNA. In plants, it is unclear how stress affects the production and fate of alternative mRNA isoforms. Using a genome-scale approach, we show that in Arabidopsis thaliana , hypoxia leads to increases in the number of mRNA isoforms with polyadenylated 3' ends that map to 5'-untranslated regions (UTRs), introns, and protein-coding regions. RNAs with 3' ends within protein-coding regions and introns were less stable than mRNAs that end at 3'-UTR poly(A) sites. Additionally, these RNA isoforms were underrepresented in polysomes isolated from control and hypoxic plants. By contrast, mRNA isoforms with 3' ends that lie within annotated 5'-UTRs were overrepresented in polysomes and were as stable as canonical mRNA isoforms. These results indicate that the generation of noncanonical mRNA isoforms is an important feature of the abiotic stress response. The finding that several noncanonical mRNA isoforms are relatively unstable suggests that the production of non-stop and intronic mRNA isoforms may represent a form of negative regulation in plants, providing a conceptual link with mechanisms that generate these isoforms (such as alternative polyadenylation) and RNA surveillance. © 2017 American Society of Plant Biologists. All rights reserved.

  6. Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia[OPEN

    Science.gov (United States)

    2017-01-01

    Stresses from various environmental challenges continually confront plants, and their responses are important for growth and survival. One molecular response to such challenges involves the alternative polyadenylation of mRNA. In plants, it is unclear how stress affects the production and fate of alternative mRNA isoforms. Using a genome-scale approach, we show that in Arabidopsis thaliana, hypoxia leads to increases in the number of mRNA isoforms with polyadenylated 3′ ends that map to 5′-untranslated regions (UTRs), introns, and protein-coding regions. RNAs with 3′ ends within protein-coding regions and introns were less stable than mRNAs that end at 3′-UTR poly(A) sites. Additionally, these RNA isoforms were underrepresented in polysomes isolated from control and hypoxic plants. By contrast, mRNA isoforms with 3′ ends that lie within annotated 5′-UTRs were overrepresented in polysomes and were as stable as canonical mRNA isoforms. These results indicate that the generation of noncanonical mRNA isoforms is an important feature of the abiotic stress response. The finding that several noncanonical mRNA isoforms are relatively unstable suggests that the production of non-stop and intronic mRNA isoforms may represent a form of negative regulation in plants, providing a conceptual link with mechanisms that generate these isoforms (such as alternative polyadenylation) and RNA surveillance. PMID:28559476

  7. Prospects of In vivo Incorporation of non-canonical amino acids for the chemical diversification of antimicrobial peptides

    NARCIS (Netherlands)

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

    2017-01-01

    The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of

  8. Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas.

    Directory of Open Access Journals (Sweden)

    Yuwei Zhang

    Full Text Available Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT and telomerase RNA component (TERC in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability.Sequencing analysis revealed one deletion involving TERC (TERC del 341-360, and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous; A1062T (4 heterozygous]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01. Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-β-catenin complex, markedly depleted β-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs following Zeocin

  9. Far-red fluorescent probes for canonical and non-canonical nucleic acid structures: current progress and future implications.

    Science.gov (United States)

    Suseela, Y V; Narayanaswamy, Nagarjun; Pratihar, Sumon; Govindaraju, Thimmaiah

    2018-02-05

    The structural diversity and functional relevance of nucleic acids (NAs), mainly deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), are indispensable for almost all living organisms, with minute aberrations in their structure and function becoming causative factors in numerous human diseases. The standard structures of NAs, termed canonical structures, are supported by Watson-Crick hydrogen bonding. Under special physiological conditions, NAs adopt distinct spatial organisations, giving rise to non-canonical conformations supported by hydrogen bonding other than the Watson-Crick type; such non-canonical structures have a definite function in controlling gene expression and are considered as novel diagnostic and therapeutic targets. Development of molecular probes for these canonical and non-canonical DNA/RNA structures has been an active field of research. Among the numerous probes studied, probes with turn-on fluorescence in the far-red (600-750 nm) region are highly sought-after due to minimal autofluorescence and cellular damage. Far-red fluorescent probes are vital for real-time imaging of NAs in live cells as they provide good resolution and minimal perturbation of the cell under investigation. In this review, we present recent advances in the area of far-red fluorescent probes of DNA/RNA and non-canonical G-quadruplex structures. For the sake of continuity and completeness, we provide a brief overview of visible fluorescent probes. Utmost importance is given to design criteria, characteristic properties and biological applications, including in cellulo imaging, apart from critical discussion on limitations of the far-red fluorescent probes. Finally, we offer current and future prospects in targeting canonical and non-canonical NAs specific to cellular organelles, through sequence- and conformation-specific far-red fluorescent probes. We also cover their implications in chemical and molecular biology, with particular focus on decoding various disease

  10. Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages

    Directory of Open Access Journals (Sweden)

    Hirokazu Nakatsumi

    2017-11-01

    Full Text Available C-C chemokine ligand 2 (CCL2 plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF-κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1 as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB and that CCL2 produced by this pathway contributes to tumor progression.

  11. Spontaneous symmetry breaking and neutral stability in the noncanonical Hamiltonian formalism

    International Nuclear Information System (INIS)

    Morrison, P.J.; Eliezer, S.

    1985-10-01

    The noncanonical Hamiltonian formalism is based upon a generalization of the Poisson bracket, a particular form of which is possessed by continuous media fields. Associated with this generalization are special constants of motion called Casimirs. These are constants that can be viewed as being built into the phase space, for they are invariant for all Hamiltonians. Casimirs are important because when added to the Hamiltonian they yield an effective Hamiltonian that produces equilibrium states upon variation. The stability of these states can be ascertained by a second variation. Goldstone's theorem, in its usual context, determines zero eigenvalues of the mass matrix for a given vacuum state, the equilibrium with minimum energy. Here, since for fluids and plasmas the vacuum state is uninteresting, we examine symmetry breaking for general equilibria. Broken symmetries imply directions of neutral stability. Two examples are presented: the nonlinear Alfven wave of plasma physics and the Korteweg-de Vries soliton. 46 refs

  12. Complement factor H family proteins in their non-canonical role as modulators of cellular functions.

    Science.gov (United States)

    Józsi, Mihály; Schneider, Andrea E; Kárpáti, Éva; Sándor, Noémi

    2018-01-04

    Complement factor H is a major regulator of the alternative pathway of the complement system. The factor H-related proteins are less characterized, but recent data indicate that they rather promote complement activation. These proteins have some common ligands with factor H and have both overlapping and distinct functions depending on domain composition and the degree of conservation of amino acid sequence. Factor H and some of the factor H-related proteins also appear in a non-canonical function that is beyond their role in the modulation of complement activation. This review covers our current understanding on this emerging role of factor H family proteins in modulating the activation and function of various cells by binding to receptors or receptor ligands. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Light-Activated Proteomic Labeling via Photocaged Bioorthogonal Non-Canonical Amino Acids.

    Science.gov (United States)

    Adelmund, Steven M; Ruskowitz, Emily R; Farahani, Payam E; Wolfe, Julie V; DeForest, Cole A

    2018-03-16

    This work introduces light-activated bioorthogonal noncanonical amino acid tagging (laBONCAT) as a method to selectively label, isolate, and identify proteins newly synthesized at user-defined regions in tissue culture. By photocaging l-azidohomoalanine (Aha), metabolic incorporation into proteins is prevented. The caged compound remains stable for many hours in culture, but can be photochemically liberated rapidly and on demand with spatial control. Upon directed light exposure, the uncaged amino acid is available for local translation, enabling downstream proteomic interrogation via bioorthogonal conjugation. Exploiting the reactive azide moiety present on Aha's amino acid side chain, we demonstrate that newly synthesized proteins can be purified for quantitative proteomics or visualized in synthetic tissues with a new level of spatiotemporal control. Shedding light on when and where proteins are translated within living samples, we anticipate that laBONCAT will aid in understanding the progression of complex protein-related disorders.

  14. Intracrine angiotensin II functions originate from noncanonical pathways in the human heart.

    Science.gov (United States)

    Ferrario, Carlos M; Ahmad, Sarfaraz; Varagic, Jasmina; Cheng, Che Ping; Groban, Leanne; Wang, Hao; Collawn, James F; Dell Italia, Louis J

    2016-08-01

    Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

  15. A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad

    Science.gov (United States)

    2018-01-01

    One group of enzymes that confer resistance to aminoglycoside antibiotics through covalent modification belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily. We show how a unique GNAT subfamily member uses a previously unidentified noncanonical catalytic triad, consisting of a glutamic acid, a histidine, and the antibiotic substrate itself, which acts as a nucleophile and attacks the acetyl donor molecule. Neutron diffraction studies allow for unambiguous identification of a low-barrier hydrogen bond, predicted in canonical catalytic triads to increase basicity of the histidine. This work highlights the role of this unique catalytic triad in mediating antibiotic resistance while providing new insights into the design of the next generation of aminoglycosides. PMID:29632894

  16. Machine learning reveals a non-canonical mode of peptide binding to MHC class II molecules.

    Science.gov (United States)

    Andreatta, Massimo; Jurtz, Vanessa I; Kaever, Thomas; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

    2017-10-01

    MHC class II molecules play a fundamental role in the cellular immune system: they load short peptide fragments derived from extracellular proteins and present them on the cell surface. It is currently thought that the peptide binds lying more or less flat in the MHC groove, with a fixed distance of nine amino acids between the first and last residue in contact with the MHCII. While confirming that the great majority of peptides bind to the MHC using this canonical mode, we report evidence for an alternative, less common mode of interaction. A fraction of observed ligands were shown to have an unconventional spacing of the anchor residues that directly interact with the MHC, which could only be accommodated to the canonical MHC motif either by imposing a more stretched out peptide backbone (an 8mer core) or by the peptide bulging out of the MHC groove (a 10mer core). We estimated that on average 2% of peptides bind with a core deletion, and 0·45% with a core insertion, but the frequency of such non-canonical cores was as high as 10% for certain MHCII molecules. A mutational analysis and experimental validation of a number of these anomalous ligands demonstrated that they could only fit to their MHC binding motif with a non-canonical binding core of length different from nine. This previously undescribed mode of peptide binding to MHCII molecules gives a more complete picture of peptide presentation by MHCII and allows us to model more accurately this event. © 2017 John Wiley & Sons Ltd.

  17. Summary goodness-of-fit statistics for binary generalized linear models with noncanonical link functions.

    Science.gov (United States)

    Canary, Jana D; Blizzard, Leigh; Barry, Ronald P; Hosmer, David W; Quinn, Stephen J

    2016-05-01

    Generalized linear models (GLM) with a canonical logit link function are the primary modeling technique used to relate a binary outcome to predictor variables. However, noncanonical links can offer more flexibility, producing convenient analytical quantities (e.g., probit GLMs in toxicology) and desired measures of effect (e.g., relative risk from log GLMs). Many summary goodness-of-fit (GOF) statistics exist for logistic GLM. Their properties make the development of GOF statistics relatively straightforward, but it can be more difficult under noncanonical links. Although GOF tests for logistic GLM with continuous covariates (GLMCC) have been applied to GLMCCs with log links, we know of no GOF tests in the literature specifically developed for GLMCCs that can be applied regardless of link function chosen. We generalize the Tsiatis GOF statistic originally developed for logistic GLMCCs, (TG), so that it can be applied under any link function. Further, we show that the algebraically related Hosmer-Lemeshow (HL) and Pigeon-Heyse (J(2) ) statistics can be applied directly. In a simulation study, TG, HL, and J(2) were used to evaluate the fit of probit, log-log, complementary log-log, and log models, all calculated with a common grouping method. The TG statistic consistently maintained Type I error rates, while those of HL and J(2) were often lower than expected if terms with little influence were included. Generally, the statistics had similar power to detect an incorrect model. An exception occurred when a log GLMCC was incorrectly fit to data generated from a logistic GLMCC. In this case, TG had more power than HL or J(2) . © 2015 John Wiley & Sons Ltd/London School of Economics.

  18. Non-canonical functions of hunchback in segment patterning of the intermediate germ cricket Gryllus bimaculatus.

    Science.gov (United States)

    Mito, Taro; Sarashina, Isao; Zhang, Hongjie; Iwahashi, Akihiro; Okamoto, Haruko; Miyawaki, Katsuyuki; Shinmyo, Yohei; Ohuchi, Hideyo; Noji, Sumihare

    2005-05-01

    In short and intermediate germ insects, only the anterior segments are specified during the blastoderm stage, leaving the posterior segments to be specified later, during embryogenesis, which differs from the segmentation process in Drosophila, a long germ insect. To elucidate the segmentation mechanisms of short and intermediate germ insects, we have investigated the orthologs of the Drosophila segmentation genes in a phylogenetically basal, intermediate germ insect, Gryllus bimaculatus (Gb). Here, we have focused on its hunchback ortholog (Gb'hb), because Drosophila hb functions as a gap gene during anterior segmentation, referred as a canonical function. Gb'hb is expressed in a gap pattern during the early stages of embryogenesis, and later in the posterior growth zone. By means of embryonic and parental RNA interference for Gb'hb, we found the following: (1) Gb'hb regulates Hox gene expression to specify regional identity in the anterior region, as observed in Drosophila and Oncopeltus; (2) Gb'hb controls germband morphogenesis and segmentation of the anterior region, probably through the pair-rule gene, even-skipped at least; (3) Gb'hb may act as a gap gene in a limited region between the posterior of the prothoracic segment and the anterior of the mesothoracic segment; and (4) Gb'hb is involved in the formation of at least seven abdominal segments, probably through its expression in the posterior growth zone, which is not conserved in Drosophila. These findings suggest that Gb'hb functions in a non-canonical manner in segment patterning. A comparison of our results with the results for other derived species revealed that the canonical hb function may have evolved from the non-canonical hb functions during evolution.

  19. Cyperenoic acid suppresses osteoclast differentiation and delays bone loss in a senile osteoporosis mouse model by inhibiting non-canonical NF-κB pathway.

    Science.gov (United States)

    Chawalitpong, Supatta; Chokchaisiri, Ratchanaporn; Suksamrarn, Apichart; Katayama, Shigeru; Mitani, Takakazu; Nakamura, Soichiro; Athamneh, Ahmad Ai; Ritprajak, Patcharee; Leelahavanichkul, Asada; Aeimlapa, Ratchaneevan; Charoenphandhu, Narattaphol; Palaga, Tanapat

    2018-04-04

    Cyperenoic acid is a terpenoid isolated from the root of a medicinal plant Croton crassifolius with a wide range of biological activities. In this study, the effects of cyperenoic acid on osteoclast differentiation were investigated both in vitro and in vivo using receptor activator of nuclear factor-κB ligand (RANKL)-induced bone marrow-derived osteoclasts and senescence-accelerated mouse prone 6 (SAMP6). Cyperenoic acid significantly suppressed RANKL-induced osteoclast differentiation at the concentrations with no apparent cytotoxicity. The half maximum inhibitory concentration (IC 50 ) for osteoclast differentiation was 36.69 μM ± 1.02. Cyperenoic acid treatment evidently reduced the expression of two key transcription factors in osteoclast differentiation, NFATc1 and c-Fos. Detailed signaling analysis revealed that cyperenoic acid did not affect MAPK pathways and canonical NF-κB pathway but impaired activation of p100/p52 in the non-canonical NF-κB pathway upon RANKL stimulation. Moreover, the expression of osteoclast-related genes, nfatc1, ctsk, irf8, acp5 and cfos were disrupted by cyperenoic acid treatment. The bone resorption activity by cyperenoic acid-treated osteoclasts were impaired. In a senile osteoporosis mouse model SAMP6, mice fed on diet supplemented with cyperenoic acid showed delay in bone loss, compared to the control. Taken together, plant-derived cyperenoic acid shows great potential as therapeutic agent for osteoporosis.

  20. Neferine augments therapeutic efficacy of cisplatin through ROS- mediated non-canonical autophagy in human lung adenocarcinoma (A549 cells).

    Science.gov (United States)

    Kalai Selvi, Sivalingam; Vinoth, Amirthalingam; Varadharajan, Thiyagarajan; Weng, Ching Feng; Vijaya Padma, Viswanadha

    2017-05-01

    Combination of dietary components with chemotherapy drugs is an emerging new strategy for cancer therapy to increase antitumor responses. Neferine, major bisbenzylisoquinoline alkaloid isolated from the seed embryo of Nelumbo nucifera (Lotus). In the present study, we investigated the efficacy of the combinatorial regimen of neferine and cisplatin compared to cisplatin high dose in human lung adenocarcinoma (A549) cells. Co-treatment with neferine enhanced cisplatin-induced autophagy in A549 cells was accompanied by Acidic vesicular accumulation (AVO), enhanced generation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH), down regulation of PI3K/AKT/mTOR pathway, conversion of LC3B-I to LC3B-II. This enhanced autophagy developed via a non-canonical mechanism that did not require Beclin-1, PI3KCIII. In conclusion, these results suggest that neferine enhances cisplatin -induced autophagic cancer cell death through downregulation of PI3K/Akt/mTOR signaling pro-survival pathway and ROS- mediated Beclin-1 and PI3K CIII independent autophagy in human lung adenocarcinoma (A549 cells). Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Novel bioinformatics method for identification of genome-wide non-canonical spliced regions using RNA-Seq data.

    Directory of Open Access Journals (Sweden)

    Yongsheng Bai

    Full Text Available 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.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.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.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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Jianyuan [School of Nuclear Science and Technology and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China; Key Laboratory of Geospace Environment, CAS, Hefei, Anhui 230026, China; Qin, Hong [School of Nuclear Science and Technology and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China; Plasma Physics Laboratory, Princeton University, Princeton, New Jersey 08543, USA; Liu, Jian [School of Nuclear Science and Technology and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China; Key Laboratory of Geospace Environment, CAS, Hefei, Anhui 230026, China; He, Yang [School of Nuclear Science and Technology and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China; Key Laboratory of Geospace Environment, CAS, Hefei, Anhui 230026, China; Zhang, Ruili [School of Nuclear Science and Technology and Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China; Key Laboratory of Geospace Environment, CAS, Hefei, Anhui 230026, China; Sun, Yajuan [LSEC, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, P.O. Box 2719, Beijing 100190, China

    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.

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

    International Nuclear Information System (INIS)

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

    2015-01-01

    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 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

  4. Effects of Heterologous tRNA Modifications on the Production of Proteins Containing Noncanonical Amino Acids.

    Science.gov (United States)

    Crnković, Ana; Vargas-Rodriguez, Oscar; Merkuryev, Anna; Söll, Dieter

    2018-02-02

    Synthesis of proteins with noncanonical amino acids (ncAAs) enables the creation of protein-based biomaterials with diverse new chemical properties that may be attractive for material science. Current methods for large-scale production of ncAA-containing proteins, frequently carried out in Escherichia coli , involve the use of orthogonal aminoacyl-tRNA synthetases (o-aaRSs) and tRNAs (o-tRNAs). Although o-tRNAs are designed to be orthogonal to endogenous aaRSs, their orthogonality to the components of the E. coli metabolism remains largely unexplored. We systematically investigated how the E. coli tRNA modification machinery affects the efficiency and orthogonality of o-tRNA Sep used for production of proteins with the ncAA O- phosphoserine (Sep). The incorporation of Sep into a green fluorescent protein (GFP) in 42 E. coli strains carrying deletions of single tRNA modification genes identified several genes that affect the o-tRNA activity. Deletion of cysteine desulfurase ( iscS ) increased the yield of Sep-containing GFP more than eightfold, while overexpression of dimethylallyltransferase MiaA and pseudouridine synthase TruB improved the specificity of Sep incorporation. These results highlight the importance of tRNA modifications for the biosynthesis of proteins containing ncAAs, and provide a novel framework for optimization of o-tRNAs.

  5. Interactions of U24 from Roseolovirus with WW domains: canonical vs noncanonical.

    Science.gov (United States)

    Sang, Yurou; Zhang, Rui; Creagh, A Louise; Haynes, Charles A; Straus, Suzana K

    2017-06-01

    U24 is a C-terminal membrane-anchored protein found in both human herpes virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminal segment that is rich in prolines (PPxY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that U24 interacts strongly with Nedd4 WW domains, in particular, hNedd4L-WW3*. It was also shown that this interaction depends strongly on the nature of the amino acids that are upstream from the PY motif in U24. In this contribution, data was obtained from pull-downs, isothermal titration calorimetry, and NMR to further determine what modulates U24:WW domain interactions. Specifically, 3 non-canonical WW domains from human Smad ubiquitination regulatory factor (Smurf), namely hSmurf2-WW2, hSmurf2-WW3, and a tandem construct hSmurf2-WW2 + 3, were studied. Overall, the interactions between U24 and these Smurf WW domains were found to be weaker than those in U24:Nedd4 WW domain pairs, suggesting that U24 function is tightly linked to specific E3 ubiqitin ligases.

  6. Toward a generalized equation for the Reynolds stress: Turbulence momentum balance in non-canonical flows

    Science.gov (United States)

    Lee, T.-W.

    2017-11-01

    Recently, we developed a theoretical basis for determination of the Reynolds stress in canonical flows. Writing momentum balance for a control volume moving at the local mean velocity, along with a differential transform ∂/∂x =C1 U∂/∂y , a turbulence momentum balance is discovered which includes the Reynolds stress as a function of root turbulence parameters: ∂(u'v')/∂y = -C1 U∂u'2/∂y +νm∂2urms'/∂y2 . Then, the Reynolds stress can simply be computed by integrating in the y-direction using the right-hand side (RHS). This is obviously a far simplification of complex modeling of the Reynolds stress, but contains the correct physics, as borne out by comparisons with experimental and DNS data in canonical flows in our earlier works (e.g. in APS 2016). The RHS contains only two parameters, U and u'. In this work, we seek extensions of this solution to non-canonical flows such as wakes, flow over a step, and mixing layers. Comparisons with experimental and DNS data will be presented.

  7. Effects of Heterologous tRNA Modifications on the Production of Proteins Containing Noncanonical Amino Acids

    Directory of Open Access Journals (Sweden)

    Ana Crnković

    2018-02-01

    Full Text Available Synthesis of proteins with noncanonical amino acids (ncAAs enables the creation of protein-based biomaterials with diverse new chemical properties that may be attractive for material science. Current methods for large-scale production of ncAA-containing proteins, frequently carried out in Escherichia coli, involve the use of orthogonal aminoacyl-tRNA synthetases (o-aaRSs and tRNAs (o-tRNAs. Although o-tRNAs are designed to be orthogonal to endogenous aaRSs, their orthogonality to the components of the E. coli metabolism remains largely unexplored. We systematically investigated how the E. coli tRNA modification machinery affects the efficiency and orthogonality of o-tRNASep used for production of proteins with the ncAA O-phosphoserine (Sep. The incorporation of Sep into a green fluorescent protein (GFP in 42 E. coli strains carrying deletions of single tRNA modification genes identified several genes that affect the o-tRNA activity. Deletion of cysteine desulfurase (iscS increased the yield of Sep-containing GFP more than eightfold, while overexpression of dimethylallyltransferase MiaA and pseudouridine synthase TruB improved the specificity of Sep incorporation. These results highlight the importance of tRNA modifications for the biosynthesis of proteins containing ncAAs, and provide a novel framework for optimization of o-tRNAs.

  8. Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase.

    Science.gov (United States)

    Zhao, Yu; Majid, Mona C; Soll, Jennifer M; Brickner, Joshua R; Dango, Sebastian; Mosammaparast, Nima

    2015-06-12

    Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors. © 2015 The Authors.

  9. Endoplasmic Reticulum Thiol Oxidase Deficiency Leads to Ascorbic Acid Depletion and Noncanonical Scurvy in Mice

    Science.gov (United States)

    Zito, Ester; Hansen, Henning Gram; Yeo, Giles S.H.; Fujii, Junichi; Ron, David

    2012-01-01

    Summary Endoplasmic reticulum (ER) thiol oxidases initiate a disulfide relay to oxidatively fold secreted proteins. We found that combined loss-of-function mutations in genes encoding the ER thiol oxidases ERO1α, ERO1β, and PRDX4 compromised the extracellular matrix in mice and interfered with the intracellular maturation of procollagen. These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower procollagen 4-hydroxyproline content and enhanced cysteinyl sulfenic acid modification of ER proteins. Tissue ascorbic acid content was lower in mutant mice, and ascorbic acid supplementation improved procollagen maturation and lowered sulfenic acid content in vivo. In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H2O2-generating system. Compromised ER disulfide relay thus exposes protein thiols to competing oxidation to sulfenic acid, resulting in depletion of ascorbic acid, impaired procollagen proline 4-hydroxylation, and a noncanonical form of scurvy. PMID:22981861

  10. Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle.

    Science.gov (United States)

    Leymarie, Olivier; Lepont, Leslie; Berlioz-Torrent, Clarisse

    2017-09-23

    Autophagy is a lysosomal-dependent degradative process essential for maintaining cellular homeostasis, and is a key player in innate and adaptive immune responses to intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). In HIV-1 target cells, autophagy mechanisms can (i) selectively direct viral proteins and viruses for degradation; (ii) participate in the processing and presentation of viral-derived antigens through major histocompatibility complexes; and (iii) contribute to interferon production in response to HIV-1 infection. As a consequence, HIV-1 has evolved different strategies to finely regulate the autophagy pathway to favor its replication and dissemination. HIV-1 notably encodes accessory genes encoding Tat, Nef and Vpu proteins, which are able to perturb and hijack canonical and non-canonical autophagy mechanisms. This review outlines the current knowledge on the complex interplay between autophagy and HIV-1 replication cycle, providing an overview of the autophagy-mediated molecular processes deployed both by infected cells to combat the virus and by HIV-1 to evade antiviral response.

  11. Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications.

    Science.gov (United States)

    Zhu, Guizhi; Hu, Rong; Zhao, Zilong; Chen, Zhuo; Zhang, Xiaobing; Tan, Weihong

    2013-11-06

    DNA nanotechnology has been extensively explored to assemble various functional nanostructures for versatile applications. Mediated by Watson-Crick base-pairing, these DNA nanostructures have been conventionally assembled through hybridization of many short DNA building blocks. Here we report the noncanonical self-assembly of multifunctional DNA nanostructures, termed as nanoflowers (NFs), and the versatile biomedical applications. These NFs were assembled from long DNA building blocks generated via rolling circle replication (RCR) of a designer template. NF assembly was driven by liquid crystallization and dense packaging of building blocks, without relying on Watson-Crick base-pairing between DNA strands, thereby avoiding the otherwise conventional complicated DNA sequence design. NF sizes were readily tunable in a wide range, by simply adjusting such parameters as assembly time and template sequences. NFs were exceptionally resistant to nuclease degradation, denaturation, or dissociation at extremely low concentration, presumably resulting from the dense DNA packaging in NFs. The exceptional biostability is critical for biomedical applications. By rational design, NFs can be readily incorporated with myriad functional moieties. All these properties make NFs promising for versatile applications. As a proof-of-principle demonstration, in this study, NFs were integrated with aptamers, bioimaging agents, and drug loading sites, and the resultant multifunctional NFs were demonstrated for selective cancer cell recognition, bioimaging, and targeted anticancer drug delivery.

  12. Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification

    Science.gov (United States)

    Kugel, Susann; Baunach, Martin; Baer, Philipp; Ishida-Ito, Mie; Sundaram, Srividhya; Xu, Zhongli; Groll, Michael; Hertweck, Christian

    2017-06-01

    Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.

  13. Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

    Science.gov (United States)

    Ho, Hsin-Yi Henry; Susman, Michael W.; Bikoff, Jay B.; Ryu, Yun Kyoung; Jonas, Andrea M.; Hu, Linda; Kuruvilla, Rejji; Greenberg, Michael Eldon

    2012-01-01

    Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor β-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a–Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a–Ror–Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development. PMID:22343533

  14. Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis.

    Science.gov (United States)

    Ho, Hsin-Yi Henry; Susman, Michael W; Bikoff, Jay B; Ryu, Yun Kyoung; Jonas, Andrea M; Hu, Linda; Kuruvilla, Rejji; Greenberg, Michael Eldon

    2012-03-13

    Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor β-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a-Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a-Ror-Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development.

  15. Role of the Wnt signaling molecules in the tooth

    Directory of Open Access Journals (Sweden)

    Masato Tamura, PhD, DDS

    2016-11-01

    Full Text Available Wnt signaling plays a central role in many processes during embryonic development and adult homeostasis. At least 19 types of Wnt ligands, receptors, transducers, transcription factors, and antagonists have been identified in mammals. Two distinct Wnt signaling pathways, the canonical signaling pathway and the noncanonical signaling pathway, have been described. Some Wnt signaling pathway components are expressed in the dental epithelium and mesenchyme during tooth development in humans and mice. Functional studies and experimental analysis of relevant animal models confirm the effects of Wnt signaling pathway on the regulation of developing tooth formation and adult tooth homeostasis. Mutations in some Wnt signaling pathway components have been identified in syndromic and non-syndromic tooth agenesis. This review provides an overview of progress in elucidating the role of Wnt signaling pathway components in the tooth and the resulting possibilities for therapeutic development.

  16. Beta-Arrestin and casein kinase 1/2 define distinct branches of non-canonical WNT signalling pathways

    Czech Academy of Sciences Publication Activity Database

    Bryja, Vítězslav; Schambony, A.; Čajánek, L.; Dominguez, I.; Arenas, E.; Schulte, G.

    2008-01-01

    Roč. 9, č. 12 (2008), s. 1244-1250 ISSN 1469-221X Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : convergent extension movements * RAC-1 * RHO-like GTPases Subject RIV: BO - Biophysics Impact factor: 7.099, year: 2008

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

    NARCIS (Netherlands)

    Zappia, C.D.; Granja-Galeano, G.; Fernández, N.; Shayo, C.; Davio, C.; Fitzsimons, C.P.; Monczor, F.

    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

  18. Translation system engineering in Escherichia coli enhances non-canonical amino acid incorporation into proteins.

    Science.gov (United States)

    Gan, Rui; Perez, Jessica G; Carlson, Erik D; Ntai, Ioanna; Isaacs, Farren J; Kelleher, Neil L; Jewett, Michael C

    2017-05-01

    The ability to site-specifically incorporate non-canonical amino acids (ncAAs) into proteins has made possible the study of protein structure and function in fundamentally new ways, as well as the bio synthesis of unnatural polymers. However, the task of site-specifically incorporating multiple ncAAs into proteins with high purity and yield continues to present a challenge. At the heart of this challenge lies the lower efficiency of engineered orthogonal translation system components compared to their natural counterparts (e.g., translation elements that specifically use a ncAA and do not interact with the cell's natural translation apparatus). Here, we show that evolving and tuning expression levels of multiple components of an engineered translation system together as a whole enhances ncAA incorporation efficiency. Specifically, we increase protein yield when incorporating multiple p-azido-phenylalanine(pAzF) residues into proteins by (i) evolving the Methanocaldococcus jannaschii p-azido-phenylalanyl-tRNA synthetase anti-codon binding domain, (ii) evolving the elongation factor Tu amino acid-binding pocket, and (iii) tuning the expression of evolved translation machinery components in a single vector. Use of the evolved translation machinery in a genomically recoded organism lacking release factor one enabled enhanced multi-site ncAA incorporation into proteins. We anticipate that our approach to orthogonal translation system development will accelerate and expand our ability to site-specifically incorporate multiple ncAAs into proteins and biopolymers, advancing new horizons for synthetic and chemical biotechnology. Biotechnol. Bioeng. 2017;114: 1074-1086. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Rationally evolving tRNAPyl for efficient incorporation of noncanonical amino acids.

    Science.gov (United States)

    Fan, Chenguang; Xiong, Hai; Reynolds, Noah M; Söll, Dieter

    2015-12-15

    Genetic encoding of noncanonical amino acids (ncAAs) into proteins is a powerful approach to study protein functions. Pyrrolysyl-tRNA synthetase (PylRS), a polyspecific aminoacyl-tRNA synthetase in wide use, has facilitated incorporation of a large number of different ncAAs into proteins to date. To make this process more efficient, we rationally evolved tRNA(Pyl) to create tRNA(Pyl-opt) with six nucleotide changes. This improved tRNA was tested as substrate for wild-type PylRS as well as three characterized PylRS variants (N(ϵ)-acetyllysyl-tRNA synthetase [AcKRS], 3-iodo-phenylalanyl-tRNA synthetase [IFRS], a broad specific PylRS variant [PylRS-AA]) to incorporate ncAAs at UAG codons in super-folder green fluorescence protein (sfGFP). tRNA(Pyl-opt) facilitated a 5-fold increase in AcK incorporation into two positions of sfGFP simultaneously. In addition, AcK incorporation into two target proteins (Escherichia coli malate dehydrogenase and human histone H3) caused homogenous acetylation at multiple lysine residues in high yield. Using tRNA(Pyl-opt) with PylRS and various PylRS variants facilitated efficient incorporation of six other ncAAs into sfGFP. Kinetic analyses revealed that the mutations in tRNA(Pyl-opt) had no significant effect on the catalytic efficiency and substrate binding of PylRS enzymes. Thus tRNA(Pyl-opt) should be an excellent replacement of wild-type tRNA(Pyl) for future ncAA incorporation by PylRS enzymes. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. Increasing the fidelity of noncanonical amino acid incorporation in cell-free protein synthesis.

    Science.gov (United States)

    Gan, Qinglei; Fan, Chenguang

    2017-11-01

    Cell-free protein synthesis provides a robust platform for co-translational incorporation of noncanonical amino acid (ncAA) into proteins to facilitate biological studies and biotechnological applications. Recently, eliminating the activity of release factor 1 has been shown to increase ncAA incorporation in response to amber codons. However, this approach could promote mis-incorporation of canonical amino acids by near cognate suppression. We performed a facile protocol to remove near cognate tRNA isoacceptors of the amber codon from total tRNAs, and used the phosphoserine (Sep) incorporation system as validation. By manipulating codon usage of target genes and tRNA species introduced into the cell-free protein synthesis system, we increased the fidelity of Sep incorporation at a specific position. By removing three near cognate tRNA isoacceptors of the amber stop codon [tRNA Lys , tRNA Tyr , and tRNA Gln (CUG)] from the total tRNA, the near cognate suppression decreased by 5-fold without impairing normal protein synthesis in the cell-free protein synthesis system. Mass spectrometry analyses indicated that the fidelity of ncAA incorporation was improved. Removal of near cognate tRNA isoacceptors of the amber codon could increase ncAA incorporation fidelity towards the amber stop codon in release factor deficiency systems. We provide a general strategy to improve fidelity of ncAA incorporation towards stop, quadruplet and sense codons in cell-free protein synthesis systems. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.

    Science.gov (United States)

    Martinez, Jennifer; Cunha, Larissa D; Park, Sunmin; Yang, Mao; Lu, Qun; Orchard, Robert; Li, Quan-Zhen; Yan, Mei; Janke, Laura; Guy, Cliff; Linkermann, Andreas; Virgin, Herbert W; Green, Douglas R

    2016-05-05

    Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.

  2. Towards Reassignment of the Methionine Codon AUG to Two Different Noncanonical Amino Acids in Bacterial Translation

    Directory of Open Access Journals (Sweden)

    Alessandro De Simone

    2016-06-01

    Full Text Available Genetic encoding of noncanonical amino acids (ncAAs through sense codon reassignment is an efficient tool for expanding the chemical functionality of proteins. Incorporation of multiple ncAAs, however, is particularly challenging. This work describes the first attempts to reassign the sense methionine (Met codon AUG to two different ncAAs in bacterial protein translation. Escherichia coli methionyl-tRNA synthetase (MetRS charges two tRNAs with Met: tRNAfMet initiates protein synthesis (starting AUG codon, whereas elongator tRNAMet participates in protein elongation (internal AUG codon(s. Preliminary in vitro experiments show that these tRNAs can be charged with the Met analogues azidohomoalanine (Aha and ethionine (Eth by exploiting the different substrate specificities of EcMetRS and the heterologous MetRS / tRNAMet pair from the archaeon Sulfolobus acidocaldarius, respectively. Here, we explored whether this configuration would allow a differential decoding during in vivo protein initiation and elongation. First, we eliminated the elongator tRNAMet from a methionine auxotrophic E. coli strain, which was then equipped with a rescue plasmid harboring the heterologous pair. Although the imported pair was not fully orthogonal, it was possible to incorporate preferentially Eth at internal AUG codons in a model protein, suggesting that in vivo AUG codon reassignment is possible. To achieve full orthogonality during elongation, we imported the known orthogonal pair of Methanosarcina mazei pyrrolysyl-tRNA synthetase (PylRS / tRNAPyl and devised a genetic selection system based on the suppression of an amber stop codon in an important glycolytic gene, pfkA, which restores enzyme functionality and normal cellular growth. Using an evolved PylRS able to accept Met analogues, it should be possible to reassign the AUG codon to two different ncAAs by using directed evolution. This work is licensed under a Creative Commons Attribution 4.0 International

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

    Directory of Open Access Journals (Sweden)

    Hisae Tateishi-Karimata

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

  4. Gastrulation signalling makes the round go long

    NARCIS (Netherlands)

    Jopling, C.

    2006-01-01

    We sought to determine how the Src Family Kinases, Fyn and Yes, are involved in early vertebrate development. Using morpholinos we knocked down Fyn and Yes and found that the resultant phenotype bore striking similarities to Wnt11 and Wnt5 mutant zebrafish. Further analysis proved that Fyn/Yes

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

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Byeong-Moo [Department of Medicine/GI Unit, Massachusetts General Hospital, Boston, MA 02114 (United States); Department of Medicine, Harvard Medical School, Boston, MA 02115 (United States); Choi, Michael Y., E-mail: mchoi@partners.org [Department of Medicine/GI Unit, Massachusetts General Hospital, Boston, MA 02114 (United States); Department of Medicine, Harvard Medical School, Boston, MA 02115 (United States); Harvard Stem Cell Institute, Boston, MA 02114 (United States)

    2012-09-21

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

  6. Inhibition of adipocytogenesis by canonical WNT signaling in human mesenchymal stem cells

    International Nuclear Information System (INIS)

    Shen, Longxiang; Glowacki, Julie; Zhou, Shuanhu

    2011-01-01

    The WNT signaling pathway plays important roles in the self-renewal and differentiation of mesenchymal stem cells (MSCs). Little is known about WNT signaling in adipocyte differentiation of human MSCs. In this study, we tested the hypothesis that canonical and non-canonical WNTs differentially regulate in vitro adipocytogenesis in human MSCs. The expression of adipocyte gene PPARγ2, lipoprotein lipase, and adipsin increased during adipocytogenesis of hMSCs. Simultaneously, the expression of canonical WNT2, 10B, 13, and 14 decreased, whereas non-canonical WNT4 and 11 increased, and WNT5A was unchanged. A small molecule WNT mimetic, SB-216763, increased accumulation of β-catenin protein, inhibited induction of WNT4 and 11 and inhibited adipocytogenesis. In contrast, knockdown of β-catenin with siRNA resulted in spontaneous adipocytogenesis. These findings support the view that canonical WNT signaling inhibits and non-canonical WNT signaling promotes adipocytogenesis in adult human marrow-derived mesenchymal stem cells.

  7. Effects of protein-ligand interactions on hydrogen/deuterium exchange kinetics: canonical and noncanonical scenarios.

    Science.gov (United States)

    Sowole, Modupeola A; Konermann, Lars

    2014-07-01

    considered to be a hallmark of protein-ligand interactions, this work establishes that an overall deuteration increase also represents a viable outcome. HDX-based ligand screening assays, therefore, have to allow for canonical as well as noncanonical effects.

  8. Stepping towards new parameterizations for non-canonical atmospheric surface-layer conditions

    Science.gov (United States)

    Calaf, M.; Margairaz, F.; Pardyjak, E.

    2017-12-01

    -dynamics parameter is introduced to differentiate dispersive fluxes driven by surface thermal heterogeneities from those induced by surface shear. We believe that results from this research are a first step in developing new parameterizations appropriate for non-canonical ASL conditions.

  9. Study of non-canonical scalar field model using various parametrizations of dark energy equation of state

    International Nuclear Information System (INIS)

    Al Mamon, Abdulla; Das, Sudipta

    2015-01-01

    In this present work, we try to build up a cosmological model using a non-canonical scalar field within the framework of a spatially flat FRW space-time. In this context, we have considered four different parametrizations of the equation of state parameter of the non-canonical scalar field. Under this scenario, analytical solutions for various cosmological parameters have been found out. It has been found that the deceleration parameter shows a smooth transition from a positive value to some negative value which indicates that the universe was undergoing an early deceleration followed by late time acceleration which is essential for the structure formation of the universe. With these four parametrizations, the future evolution of the models are also discussed. It has been found that one of the models (Generalized Chaplygin gas model, GCG) mimics the concordance ΛCDM in the near future, whereas two other models (CPL and JBP) diverge due to future singularity. Finally, we have studied these theoretical models with the latest datasets from SN Ia + H(z) + BAO/CMB. (orig.)

  10. GPCR Signaling and Trafficking: The Long and Short of It.

    Science.gov (United States)

    Pavlos, Nathan J; Friedman, Peter A

    2017-03-01

    Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling, that is restricted to cell membranes, as well as newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor (PTHR) as a prototype, and on the actin-sorting nexin 27 (SNX27)-retromer tubule (ASRT) complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral ion metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Wnts and wing: Wnt signaling in vertebrate limb development and musculoskeletal morphogenesis.

    Science.gov (United States)

    Yang, Yingzi

    2003-11-01

    In the past twenty years, secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development from hydra to human. In the developing vertebrate limb, Wnt signaling is required for limb bud initiation, early limb patterning (which is governed by several well-characterized signaling centers), and, finally, late limb morphogenesis events. Wnt ligands are unique, in that they can activate several different receptor-mediated signal transduction pathways. The most extensively studied Wnt pathway is the canonical Wnt pathway, which controls gene expression by stabilizing beta-catenin in regulating a diverse array of biological processes. Recently, more attention has been given to the noncanonical Wnt pathway, which is beta-catenin-independent. The noncanonical Wnt pathway signals through activating Ca(2+) flux, JNK activation, and both small and heterotrimeric G proteins, to induce changes in gene expression, cell adhesion, migration, and polarity. Abnormal Wnt signaling leads to developmental defects and human diseases affecting either tissue development or homeostasis. Further understanding of the biological function and signaling mechanism of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. This review provides a critical perspective on how Wnt signaling regulates different developmental processes. As Wnt signaling in tumor formation has been reviewed extensively elsewhere, this part is not included in the review of the clinical significance of Wnt signaling.

  12. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1 beta via a noncanonical caspase-8 inflammasome

    NARCIS (Netherlands)

    Gringhuis, Sonja I.; Kaptein, Tanja M.; Wevers, Brigitte A.; Theelen, Bart; van der Vlist, Michiel; Boekhout, Teun; Geijtenbeek, Teunis B. H.

    2012-01-01

    Production of the proinflammatory cytokine interleukin 1 beta (IL-1 beta) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the

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

    Science.gov (United States)

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

    2017-02-07

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

  14. The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome.

    Science.gov (United States)

    Zwolanek, Florian; Riedelberger, Michael; Stolz, Valentina; Jenull, Sabrina; Istel, Fabian; Köprülü, Afitap Derya; Ellmeier, Wilfried; Kuchler, Karl

    2014-12-01

    Tec family kinases are intracellular non-receptor tyrosine kinases implicated in numerous functions, including T cell and B cell regulation. However, a role in microbial pathogenesis has not been described. Here, we identified Tec kinase as a novel key mediator of the inflammatory immune response in macrophages invaded by the human fungal pathogen C. albicans. Tec is required for both activation and assembly of the noncanonical caspase-8, but not of the caspase-1 inflammasome, during infections with fungal but not bacterial pathogens, triggering the antifungal response through IL-1β. Furthermore, we identify dectin-1 as the pathogen recognition receptor being required for Syk-dependent Tec activation. Hence, Tec is a novel innate-specific inflammatory kinase, whose genetic ablation or inhibition by small molecule drugs strongly protects mice from fungal sepsis. These data demonstrate a therapeutic potential for Tec kinase inhibition to combat invasive microbial infections by attenuating the host inflammatory response.

  15. Wet-dry cycles enable the parallel origin of canonical and non-canonical nucleosides by continuous synthesis.

    Science.gov (United States)

    Becker, Sidney; Schneider, Christina; Okamura, Hidenori; Crisp, Antony; Amatov, Tynchtyk; Dejmek, Milan; Carell, Thomas

    2018-01-11

    The molecules of life were created by a continuous physicochemical process on an early Earth. In this hadean environment, chemical transformations were driven by fluctuations of the naturally given physical parameters established for example by wet-dry cycles. These conditions might have allowed for the formation of (self)-replicating RNA as the fundamental biopolymer during chemical evolution. The question of how a complex multistep chemical synthesis of RNA building blocks was possible in such an environment remains unanswered. Here we report that geothermal fields could provide the right setup for establishing wet-dry cycles that allow for the synthesis of RNA nucleosides by continuous synthesis. Our model provides both the canonical and many ubiquitous non-canonical purine nucleosides in parallel by simple changes of physical parameters such as temperature, pH and concentration. The data show that modified nucleosides were potentially formed as competitor molecules. They could in this sense be considered as molecular fossils.

  16. Theoretical study of gas and solvent phase stability and molecular adsorption of noncanonical guanine bases on graphene.

    Science.gov (United States)

    Saikia, Nabanita; Karna, Shashi P; Pandey, Ravindra

    2017-06-28

    The gas and solvent phase stability of noncanonical (Gua) n nucleobases is investigated in the framework of dispersion-corrected density functional theory (DFT). The calculated results strongly support the high tendency for the dimerization of (Gua) n bases in both gas and solvent phases. An interplay between intermolecular and bifurcated H-bonds is suggested to govern the stability of (Gua) n bases which bears a correlation with the description of dispersion correction terms employed in the DFT calculations. For example, a higher polarity is predicted for (Gua) n bases by the dispersion-corrected DFT in contrast to the non-polar nature of (Gua) 3 and (Gua) 4 predicted by the hybrid meta-GGA calculations. This distinct variation becomes significant under physiological conditions as polar (Gua) n is likely to exhibit greater stabilization in the gas phase compared to solvated (Gua) n . Graphene acting as a substrate induces modification in base configurations via maximization of π-orbital overlap between the base and substrate. In solvent, the substrate-induced effects are further heightened with lowering of the dipole moments of (Gua) n as also displayed by the corresponding isosurface of the electrostatic potential. The graphene-induced stability in both gas and solvent phases appears to fulfill one of the prerequisite criteria for molecular self-assembly. The DFT results therefore provide atomistic insights into the stability and molecular assembly of free-standing noncanonical (Gua) n nucleobases which can be extended to understanding the self-assembly process of functional biomolecules on 2D materials for potential biosensing applications.

  17. Wnt Signaling in Kidney Development and Disease.

    Science.gov (United States)

    Wang, Yongping; Zhou, Chengji J; Liu, Youhua

    2018-01-01

    Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Wnt Signaling Cascades and the Roles of Syndecan Proteoglycans

    DEFF Research Database (Denmark)

    Pataki, Csilla A; Couchman, John R; Brábek, Jan

    2015-01-01

    Wnt signaling comprises a group of pathways emanating from the extracellular environment through cell-surface receptors into the intracellular milieu. Wnt signaling cascades can be divided into two main branches, the canonical/β-catenin pathway and the non-canonical pathways containing the Wnt....../planar cell polarity and Wnt/calcium signaling. Syndecans are type I transmembrane proteoglycans with a long evolutionary history, being expressed in all Bilateria and in almost all cell types. Both Wnt pathways have been extensively studied over the past 30 years and shown to have roles during development...... and in a multitude of diseases. Although the first evidence for interactions between syndecans and Wnts dates back to 1997, the number of studies connecting these pathways is low, and many open questions remained unanswered. In this review, syndecan's involvement in Wnt signaling pathways as well as some...

  19. A noncanonical auxin-sensing mechanism is required for organ morphogenesis in arabidopsis

    NARCIS (Netherlands)

    Simonini, Sara; Deb, Joyita; Moubayidin, Laila; Stephenson, Pauline; Valluru, Manoj; Freire-Rios, Alejandra; Sorefan, Karim; Weijers, Dolf; Friml, Jiří; Østergaard, Lars

    2016-01-01

    Tissue patterning in multicellular organisms is the output of precise spatio–temporal regulation of gene expression coupled with changes in hormone dynamics. In plants, the hormone auxin regulates growth and development at every stage of a plant’s life cycle. Auxin signaling occurs through

  20. The relevance of the non-canonical PTS1 of peroxisomal catalase

    NARCIS (Netherlands)

    Williams, Chris; Aksam, Eda Bener; Gunkel, Katja; Veenhuis, Marten; van der Klei, Ida J.

    Catalase is sorted to peroxisomes via a C-terminal peroxisomal targeting signal 1 (PTS1), which binds to the receptor protein Pex5. Analysis of the C-terminal sequences of peroxisomal catalases from various species indicated that catalase never contains the typical C-terminal PTS1 tripeptide-SKL,

  1. Pre-steady state kinetic analysis of HIV-1 reverse transcriptase for non-canonical ribonucleoside triphosphate incorporation and DNA synthesis from ribonucleoside-containing DNA template.

    Science.gov (United States)

    Nguyen, Laura A; Domaoal, Robert A; Kennedy, Edward M; Kim, Dong-Hyun; Schinazi, Raymond F; Kim, Baek

    2015-03-01

    Non-dividing macrophages maintain extremely low cellular deoxyribonucleotide triphosphate (dNTP) levels, but high ribonucleotide triphosphate (rNTP) concentrations. The disparate nucleotide pools kinetically forces Human Immunodeficiency Virus 1 (HIV-1) reverse transcriptase (RT) to incorporate non-canonical rNTPs during reverse transcription. HIV-1 RT pauses near ribonucleoside monophosphates (rNMPs) embedded in the template DNA, which has previously been shown to enhance mismatch extension. Here, pre-steady state kinetic analysis shows rNTP binding affinity (Kd) of HIV-1 RT for non-canonical rNTPs was 1.4- to 43-fold lower, and the rNTP rate of incorporation (kpol) was 15- to 1551-fold slower than for dNTPs. This suggests that RT is more selective for incorporation of dNTPs rather than rNTPs. HIV-1 RT selectivity for dNTP versus rNTP is the lowest for ATP, implying that HIV-1 RT preferentially incorporates ATP when dATP concentration is limited. We observed that incorporation of a dNTP occurring one nucleotide before an embedded rNMP in the template had a 29-fold greater Kd and a 20-fold slower kpol as compared to the same template containing dNMP. This reduced the overall dNTP incorporation efficiency of HIV-1 RT by 581-fold. Finally, the RT mutant Y115F displayed lower discrimination against rNTPs due to its increase in binding affinity for non-canonical rNTPs. Overall, these kinetic results demonstrate that HIV-1 RT utilizes both substrate binding and a conformational change during: (1) enzymatic discrimination of non-canonical rNTPs from dNTPs and (2) during dNTP primer extension with DNA templates containing embedded rNMP. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Activation-induced tumor necrosis factor receptor-associated factor 3 (Traf3) alternative splicing controls the noncanonical nuclear factor κB pathway and chemokine expression in human T cells.

    Science.gov (United States)

    Michel, Monika; Wilhelmi, Ilka; Schultz, Astrid-Solveig; Preussner, Marco; Heyd, Florian

    2014-05-09

    The noncanonical nuclear factor κB (ncNFκB) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. Whereas ncNFκB signaling has been well described in stromal cells and B cells, its role and regulation in T cells remain largely unexplored. ncNFκB activity critically depends on the upstream NFκB-inducing kinase (NIK). NIK expression is negatively regulated by the full-length isoform of TNF receptor-associated factor 3 (Traf3) as formation of a NIK-Traf3-Traf2 complex targets NIK for degradation. Here we show that T cell-specific and activation-dependent alternative splicing generates a Traf3 isoform lacking exon 8 (Traf3DE8) that, in contrast to the full-length protein, activates ncNFκB signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNFκB signaling in activated T cells. ncNFκB activity results in expression of several chemokines, among them B cell chemoattractant (CxCL13), both in a model T cell line and in primary human CD4(+) T cells. Because CxCL13 plays an important role in B cell migration and activation, our data suggest an involvement and provide a mechanistic basis for Traf3 alternative splicing and ncNFκB activation in contributing to T cell-dependent adaptive immunity.

  3. TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.

    Directory of Open Access Journals (Sweden)

    Ana B Sanz

    2010-01-01

    Full Text Available TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-lasting NFkappaB activation suggestive of engagement of the non-canonical NFkappaB pathway. We now explore TWEAK-induced activation of NFkappaB2 and RelB, as well as expression of CCL21, a T-cell chemotactic factor, in cultured murine tubular epithelial cells and in healthy kidneys in vivo. In cultured tubular cells, TWEAK and TNFalpha activated different DNA-binding NFkappaB complexes. TWEAK-induced sustained NFkappaB activation was associated with NFkappaB2 p100 processing to p52 via proteasome and nuclear translocation and DNA-binding of p52 and RelB. TWEAK, but not TNFalpha used as control, induced a delayed increase in CCL21a mRNA (3.5+/-1.22-fold over control and CCL21 protein (2.5+/-0.8-fold over control, which was prevented by inhibition of the proteasome, or siRNA targeting of NIK or RelB, but not by RelA inhibition with parthenolide. A second NFkappaB2-dependent chemokine, CCL19, was upregulates by TWEAK, but not by TNFalpha. However, both cytokines promoted chemokine RANTES expression (3-fold mRNA at 24 h. In vivo, TWEAK induced nuclear NFkappaB2 and RelB translocation and CCL21a mRNA (1.5+/-0.3-fold over control and CCL21 protein (1.6+/-0.5-fold over control expression in normal kidney. Increased tubular nuclear RelB and tubular CCL21 expression in acute kidney injury were decreased by neutralization (2+/-0.9 vs 1.3+/-0.6-fold over healthy control or deficiency of TWEAK (2+/-0.9 vs 0.8+/-0.6-fold over healthy control. Moreover, anti-TWEAK treatment prevented the recruitment of T cells to the kidney in this model (4.1+/-1.4 vs 1.8+/-1-fold over healthy control. Our results thus identify TWEAK as a regulator of non-canonical NFkappa

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

    Science.gov (United States)

    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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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

    Science.gov (United States)

    Mutschler, Hannes; Holliger, Philipp

    2014-04-09

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

  6. Noncanonical structures and their thermodynamics of DNA and RNA under molecular crowding: beyond the Watson-Crick double helix.

    Science.gov (United States)

    Sugimoto, Naoki

    2014-01-01

    How does molecular crowding affect the stability of nucleic acid structures inside cells? Water is the major solvent component in living cells, and the properties of water in the highly crowded media inside cells differ from that in buffered solution. As it is difficult to measure the thermodynamic behavior of nucleic acids in cells directly and quantitatively, we recently developed a cell-mimicking system using cosolutes as crowding reagents. The influences of molecular crowding on the structures and thermodynamics of various nucleic acid sequences have been reported. In this chapter, we discuss how the structures and thermodynamic properties of nucleic acids differ under various conditions such as highly crowded environments, compartment environments, and in the presence of ionic liquids, and the major determinants of the crowding effects on nucleic acids are discussed. The effects of molecular crowding on the activities of ribozymes and riboswitches on noncanonical structures of DNA- and RNA-like quadruplexes that play important roles in transcription and translation are also described. © 2014 Elsevier Inc. All rights reserved.

  7. From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

    Directory of Open Access Journals (Sweden)

    Izabella Bajusz

    2018-02-01

    Full Text Available Originally two types of Polycomb Repressive Complexes (PRCs were described, canonical PRC1 (cPRC1 and PRC2. Recently, a versatile set of complexes were identified and brought up several dilemmas in PRC mediated repression. These new class of complexes were named as non-canonical PRC1s (ncPRC1s. Both cPRC1s and ncPRC1s contain Ring finger protein (RING1, RNF2 and Polycomb group ring finger catalytic (PCGF core, but in ncPRCs, RING and YY1 binding protein (RYBP, or YY1 associated factor 2 (YAF2, replaces the Chromobox (CBX and Polyhomeotic (PHC subunits found in cPRC1s. Additionally, ncPRC1 subunits can associate with versatile accessory proteins, which determine their functional specificity. Homozygous null mutations of the ncPRC members in mice are often lethal or cause infertility, which underlines their essential functions in mammalian development. In this review, we summarize the mouse knockout phenotypes of subunits of the six major ncPRCs. We highlight several aspects of their discovery from fly to mice and emerging role in target recognition, embryogenesis and cell-fate decision making. We gathered data from stem cell mediated in vitro differentiation assays and genetically engineered mouse models. Accumulating evidence suggests that ncPRC1s play profound role in mammalian embryogenesis by regulating gene expression during lineage specification of pluripotent stem cells.

  8. Identification and characterization of multiple conserved nuclear localization signals within adenovirus E1A

    Energy Technology Data Exchange (ETDEWEB)

    Marshall, Kris S.; Cohen, Michael J.; Fonseca, Greg J.; Todorovic, Biljana; King, Cason R. [Department of Microbiology and Immunology, Western University, London Regional Cancer Program, London, ON, Canada N6A 4L6 (Canada); Yousef, Ahmed F. [Department of Chemical and Environmental Engineering, Masdar Institute, Abu Dhabi (United Arab Emirates); Zhang, Zhiying [College of Animal Science and Technologies, Northwest A and F University, Yangling, Shaanxi 712100 (China); Mymryk, Joe S., E-mail: jmymryk@uwo.ca [Department of Microbiology and Immunology, Western University, London Regional Cancer Program, London, ON, Canada N6A 4L6 (Canada); Department of Oncology, Western University, London Regional Cancer Program, London, ON, Canada N6A 4L6 (Canada)

    2014-04-15

    The human adenovirus 5 (HAdV-5) E1A protein has a well defined canonical nuclear localization signal (NLS) located at its C-terminus. We used a genetic assay in the yeast Saccharomyces cerevisiae to demonstrate that the canonical NLS is present and functional in the E1A proteins of each of the six HAdV species. This assay also detects a previously described non-canonical NLS within conserved region 3 and a novel active NLS within the N-terminal/conserved region 1 portion of HAdV-5 E1A. These activities were also present in the E1A proteins of each of the other five HAdV species. These results demonstrate that, despite substantial differences in primary sequence, HAdV E1A proteins are remarkably consistent in that they contain one canonical and two non-canonical NLSs. By utilizing independent mechanisms, these multiple NLSs ensure nuclear localization of E1A in the infected cell. - Highlights: • HAdV E1A uses multiple mechanisms for nuclear import. • We identified an additional non-canonical NLS in the N-terminal/CR1 portion of E1A. • The new NLS does not contact importin-alpha directly. • All NLSs are functionally conserved in the E1A proteins of all 6 HAdV species.

  9. Wnt and the Wnt signaling pathway in bone development and disease

    Science.gov (United States)

    Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

    2014-01-01

    Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

  10. Defying the stereotype: non-canonical roles of the peptide hormones guanylin and uroguanylin

    Directory of Open Access Journals (Sweden)

    Nirmalya eBasu

    2011-06-01

    Full Text Available The peptide hormones uroguanylin and guanylin have been traditionally thought to be mediators of fluid-ion homeostasis in the vertebrate intestine. They serve as ligands for receptor guanylyl cyclase C (GC-C, and both receptor and ligands are expressed predominantly in the intestine. Ligand binding to GC-C results in increased cGMP production in the cell which governs downstream signaling. In the last decade, a significant amount of research has unraveled novel functions for this class of peptide hormones, in addition to their action as intestinal secretagogues. An additional receptor for uroguanylin, receptor guanylyl cyclase D, has also been identified. Thus, unconventional roles of these peptides in regulating renal filtration, olfaction, reproduction and cell proliferation have begun to be elucidated in detail. These varied effects suggest that these peptide hormones act in an autocrine, paracrine as well as endocrine manner to regulate diverse cellular processes.

  11. MnTBAP Inhibits Bleomycin-Induced Pulmonary Fibrosis by Regulating VEGF and Wnt Signaling

    Science.gov (United States)

    Venkatadri, Rajkumar; Krishnan V. Iyer, Anand; Ramesh, Vani; Wright, Clayton; Castro, Carlos A.; Yakisich, Juan S.; Azad, Neelam

    2017-01-01

    Cellular oxidative stress is implicated not only in lung injury but also in contributing to the development of pulmonary fibrosis. We demonstrate that a cell-permeable superoxide dismutase (SOD) mimetic and peroxynitrite scavenger, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly inhibited bleomycin-induced fibrogenic effects both in vitro and in vivo. Further investigation into the underlying mechanisms revealed that MnTBAP targets canonical Wnt and non-canonical Wnt/Ca2+ signaling pathways, both of which were upregulated by bleomycin treatment. The effect of MnTBAP on canonical Wnt signaling was significant in vivo but inconclusive in vitro and the non-canonical Wnt/Ca2+ signaling pathway was observed to be the predominant pathway regulated by MnTBAP in bleomycin-induced pulmonary fibrosis. Furthermore, we show that the inhibitory effects of MnTBAP involve regulation of VEGF which is upstream of the Wnt signaling pathway. Overall, the data show that the superoxide scavenger MnTBAP attenuates bleomycin-induced pulmonary fibrosis by targeting VEGF and Wnt signaling pathways. PMID:27649046

  12. A novel non-canonical mechanism of regulation of MST3 (mammalian Sterile20-related kinase 3).

    Science.gov (United States)

    Fuller, Stephen J; McGuffin, Liam J; Marshall, Andrew K; Giraldo, Alejandro; Pikkarainen, Sampsa; Clerk, Angela; Sugden, Peter H

    2012-03-15

    The canonical pathway of regulation of the GCK (germinal centre kinase) III subgroup member, MST3 (mammalian Sterile20-related kinase 3), involves a caspase-mediated cleavage between N-terminal catalytic and C-terminal regulatory domains with possible concurrent autophosphorylation of the activation loop MST3(Thr(178)), induction of serine/threonine protein kinase activity and nuclear localization. We identified an alternative 'non-canonical' pathway of MST3 activation (regulated primarily through dephosphorylation) which may also be applicable to other GCKIII (and GCKVI) subgroup members. In the basal state, inactive MST3 co-immunoprecipitated with the Golgi protein GOLGA2/gm130 (golgin A2/Golgi matrix protein 130). Activation of MST3 by calyculin A (a protein serine/threonine phosphatase 1/2A inhibitor) stimulated (auto)phosphorylation of MST3(Thr(178)) in the catalytic domain with essentially simultaneous cis-autophosphorylation of MST3(Thr(328)) in the regulatory domain, an event also requiring the MST3(341-376) sequence which acts as a putative docking domain. MST3(Thr(178)) phosphorylation increased MST3 kinase activity, but this activity was independent of MST3(Thr(328)) phosphorylation. Interestingly, MST3(Thr(328)) lies immediately C-terminal to a STRAD (Sterile20-related adaptor) pseudokinase-like site identified recently as being involved in binding of GCKIII/GCKVI members to MO25 scaffolding proteins. MST3(Thr(178)/Thr(328)) phosphorylation was concurrent with dissociation of MST3 from GOLGA2/gm130 and association of MST3 with MO25, and MST3(Thr(328)) phosphorylation was necessary for formation of the activated MST3-MO25 holocomplex.

  13. Identification of genome-wide non-canonical spliced regions and analysis of biological functions for spliced sequences using Read-Split-Fly.

    Science.gov (United States)

    Bai, Yongsheng; Kinne, Jeff; Ding, Lizhong; Rath, Ethan C; Cox, Aaron; Naidu, Siva Dharman

    2017-10-03

    It is generally thought that most canonical or non-canonical splicing events involving U2- and U12 spliceosomes occur within nuclear pre-mRNAs. However, the question of whether at least some U12-type splicing occurs in the cytoplasm is still unclear. In recent years next-generation sequencing technologies have revolutionized the field. The "Read-Split-Walk" (RSW) and "Read-Split-Run" (RSR) methods were developed to identify genome-wide non-canonical spliced regions including special events occurring in cytoplasm. As the significant amount of genome/transcriptome data such as, Encyclopedia of DNA Elements (ENCODE) project, have been generated, we have advanced a newer more memory-efficient version of the algorithm, "Read-Split-Fly" (RSF), which can detect non-canonical spliced regions with higher sensitivity and improved speed. The RSF algorithm also outputs the spliced sequences for further downstream biological function analysis. We used open access ENCODE project RNA-Seq data to search spliced intron sequences against the U12-type spliced intron sequence database to examine whether some events could occur as potential signatures of U12-type splicing. The check was performed by searching spliced sequences against 5'ss and 3'ss sequences from the well-known orthologous U12-type spliceosomal intron database U12DB. Preliminary results of searching 70 ENCODE samples indicated that the presence of 5'ss with U12-type signature is more frequent than U2-type and prevalent in non-canonical junctions reported by RSF. The selected spliced sequences have also been further studied using miRBase to elucidate their functionality. Preliminary results from 70 samples of ENCODE datasets show that several miRNAs are prevalent in studied ENCODE samples. Two of these are associated with many diseases as suggested in the literature. Specifically, hsa-miR-1273 and hsa-miR-548 are associated with many diseases and cancers. Our RSF pipeline is able to detect many possible junctions

  14. Wnt signaling in planarians: new answers to old questions.

    Science.gov (United States)

    Almuedo-Castillo, Maria; Sureda-Gómez, Miquel; Adell, Teresa

    2012-01-01

    Wnts are secreted glycoproteins involved in a broad range of essential cell functions, including proliferation, migration and cell-fate determination. Recent years have seen substantial research effort invested in elucidating the role of the Wnt signaling pathway in planarians, flatworms with incredible regenerative capacities. In this review, we summarize current knowledge on the role of canonical (β-catenin-dependent) and non-canonical (β-catenin-independent) Wnt signaling in planarians, not only during regeneration, but also during normal homeostasis. We also describe some of the preliminary data that has been obtained regarding the role of these pathways during embryogenesis. Models are proposed to integrate the different results which have been obtained to date and highlight those questions that still remain to be answered.

  15. Deep sequencing of small RNAs identifies canonical and non-canonical miRNA and endogenous siRNAs in mammalian somatic tissues.

    Science.gov (United States)

    Castellano, Leandro; Stebbing, Justin

    2013-03-01

    MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. They are characterized by specific maturation processes defined by canonical and non-canonical biogenic pathways. Analysis of ∼0.5 billion sequences from mouse data sets derived from different tissues, developmental stages and cell types, partly characterized by either ablation or mutation of the main proteins belonging to miRNA processor complexes, reveals 66 high-confidence new genomic loci coding for miRNAs that could be processed in a canonical or non-canonical manner. A proportion of the newly discovered miRNAs comprises mirtrons, for which we define a new sub-class. Notably, some of these newly discovered miRNAs are generated from untranslated and open reading frames of coding genes, and we experimentally validate these. We also show that many annotated miRNAs do not present miRNA-like features, as they are neither processed by known processing complexes nor loaded on AGO2; this indicates that the current miRNA miRBase database list should be refined and re-defined. Accordingly, a group of them map on ribosomal RNA molecules, whereas others cannot undergo genuine miRNA biogenesis. Notably, a group of annotated miRNAs are Dgcr8 independent and DICER dependent endogenous small interfering RNAs that derive from a unique hairpin formed from a short interspersed nuclear element.

  16. Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity

    Directory of Open Access Journals (Sweden)

    Joshua R. Kane

    2015-05-01

    Full Text Available HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL complex as well as the non-canonical cofactor CBFβ, to antagonize APOBEC3 antiviral proteins. Non-canonical cofactor recruitment to CRL complexes by viral factors, to date, has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical, structural, and virological techniques to investigate Vif complexes across the lentivirus genus, including primate (HIV-1 and simian immunodeficiency virus macaque [SIVmac] and non-primate (FIV, BIV, and MVV viruses. We find that CBFβ is completely dispensable for the activity of non-primate lentiviral Vif proteins. Furthermore, we find that BIV Vif requires no cofactor and that MVV Vif requires a novel cofactor, cyclophilin A (CYPA, for stable CRL complex formation and anti-APOBEC3 activity. We propose modular conservation of Vif complexes allows for potential exaptation of functions through the acquisition of non-CRL-associated host cofactors while preserving anti-APOBEC3 activity.

  17. Retrograde signaling

    DEFF Research Database (Denmark)

    Kleine, Tatjana; Leister, Dario Michael

    2016-01-01

    The term retrograde signaling refers to the fact that chloroplasts and mitochondria utilize specific signaling molecules to convey information on their developmental and physiological states to the nucleus and modulate the expression of nuclear genes accordingly. Signals emanating from plastids...... of retrograde signaling has since been extended and revised. Elements of several 'operational' signaling circuits have come to light, including metabolites, signaling cascades in the cytosol and transcription factors. Here, we review recent advances in the identification and characterization of retrograde...

  18. Translational Control of the SigR-Directed Oxidative Stress Response in Streptomyces via IF3-Mediated Repression of a Noncanonical GTC Start Codon.

    Science.gov (United States)

    Feeney, Morgan A; Chandra, Govind; Findlay, Kim C; Paget, Mark S B; Buttner, Mark J

    2017-06-13

    The major oxidative stress response in Streptomyces is controlled by the sigma factor SigR and its cognate antisigma factor RsrA, and SigR activity is tightly controlled through multiple mechanisms at both the transcriptional and posttranslational levels. Here we show that sigR has a highly unusual GTC start codon and that this leads to another level of SigR regulation, in which SigR translation is repressed by translation initiation factor 3 (IF3). Changing the GTC to a canonical start codon causes SigR to be overproduced relative to RsrA, resulting in unregulated and constitutive expression of the SigR regulon. Similarly, introducing IF3* mutations that impair its ability to repress SigR translation has the same effect. Thus, the noncanonical GTC sigR start codon and its repression by IF3 are critical for the correct and proper functioning of the oxidative stress regulatory system. sigR and rsrA are cotranscribed and translationally coupled, and it had therefore been assumed that SigR and RsrA are produced in stoichiometric amounts. Here we show that RsrA can be transcribed and translated independently of SigR, present evidence that RsrA is normally produced in excess of SigR, and describe the factors that determine SigR-RsrA stoichiometry. IMPORTANCE In all sigma factor-antisigma factor regulatory switches, the relative abundance of the two proteins is critical to the proper functioning of the system. Many sigma-antisigma operons are cotranscribed and translationally coupled, leading to a generic assumption that the sigma and antisigma factors are produced in a fixed 1:1 ratio. In the case of sigR - rsrA , we show instead that the antisigma factor is produced in excess over the sigma factor, providing a buffer to prevent spurious release of sigma activity. This excess arises in part because sigR has an extremely rare noncanonical GTC start codon, and as a result, SigR translation initiation is repressed by IF3. This finding highlights the potential significance

  19. Wnt signaling through the Ror receptor in the nervous system.

    Science.gov (United States)

    Petrova, Iveta M; Malessy, Martijn J; Verhaagen, Joost; Fradkin, Lee G; Noordermeer, Jasprina N

    2014-02-01

    The receptor tyrosine kinase-like orphan receptor (Ror) proteins are conserved tyrosine kinase receptors that play roles in a variety of cellular processes that pattern tissues and organs during vertebrate and invertebrate development. Ror signaling is required for skeleton and neuronal development and modulates cell migration, cell polarity, and convergent extension. Ror has also been implicated in two human skeletal disorders, brachydactyly type B and Robinow syndrome. Rors are widely expressed during metazoan development including domains in the nervous system. Here, we review recent progress in understanding the roles of the Ror receptors in neuronal migration, axonal pruning, axon guidance, and synaptic plasticity. The processes by which Ror signaling execute these diverse roles are still largely unknown, but they likely converge on cytoskeletal remodeling. In multiple species, Rors have been shown to act as Wnt receptors signaling via novel non-canonical Wnt pathways mediated in some tissues by the adapter protein disheveled and the non-receptor tyrosine kinase Src. Rors can either activate or repress Wnt target expression depending on the cellular context and can also modulate signal transduction by sequestering Wnt ligands away from their signaling receptors. Future challenges include the identification of signaling components of the Ror pathways and bettering our understanding of the roles of these pleiotropic receptors in patterning the nervous system.

  20. Read-Split-Run: an improved bioinformatics pipeline for identification of genome-wide non-canonical spliced regions using RNA-Seq data.

    Science.gov (United States)

    Bai, Yongsheng; Kinne, Jeff; Donham, Brandon; Jiang, Feng; Ding, Lizhong; Hassler, Justin R; Kaufman, Randal J

    2016-08-22

    Most existing tools for detecting next-generation sequencing-based splicing events focus on generic splicing events. Consequently, special types of non-canonical splicing events of short mRNA regions (IRE1α targeted) have not yet been thoroughly addressed at a genome-wide level using bioinformatics approaches in conjunction with next-generation technologies. During endoplasmic reticulum (ER) stress, the gene encoding the RNase Ire1α is known to splice out a short 26 nt region from the mRNA of the transcription factor Xbp1 non-canonically within the cytosol. This causes an open reading frame-shift that induces expression of many downstream genes in reaction to ER stress as part of the unfolded protein response (UPR). We previously published an algorithm termed "Read-Split-Walk" (RSW) to identify non-canonical splicing regions using RNA-Seq data and applied it to ER stress-induced Ire1α heterozygote and knockout mouse embryonic fibroblast cell lines. In this study, we have developed an improved algorithm "Read-Split-Run" (RSR) for detecting genome-wide Ire1α-targeted genes with non-canonical spliced regions at a faster speed. We applied the RSR algorithm using different combinations of several parameters to the previously RSW tested mouse embryonic fibroblast cells (MEF) and the human Encyclopedia of DNA Elements (ENCODE) RNA-Seq data. We also compared the performance of RSR with two other alternative splicing events identification tools (TopHat (Trapnell et al., Bioinformatics 25:1105-1111, 2009) and Alt Event Finder (Zhou et al., BMC Genomics 13:S10, 2012)) utilizing the context of the spliced Xbp1 mRNA as a positive control in the data sets we identified it to be the top cleavage target present in Ire1α (+/-) but absent in Ire1α (-/-) MEF samples and this comparison was also extended to human ENCODE RNA-Seq data. Proof of principle came in our results by the fact that the 26 nt non-conventional splice site in Xbp1 was detected as the top hit by our new RSR

  1. The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer.

    Science.gov (United States)

    Hafstrand, Ida; Doorduijn, Elien M; Duru, Adil Doganay; Buratto, Jeremie; Oliveira, Claudia Cunha; Sandalova, Tatyana; van Hall, Thorbald; Achour, Adnane

    2016-03-01

    MHC class I downregulation represents a significant challenge for successful T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing-deficient cells. The TEIPP neoepitopes are CD8 T cell targets, derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study, the crystal structure of H-2D(b) in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2.25 Å resolution. In contrast to prototypic H-2D(b) peptides, Trh4 takes a noncanonical peptide-binding pattern with extensive sulfur-π interactions that contribute to the overall complex stability. Importantly, the noncanonical methionine at peptide position 5 acts as a main anchor, altering only the conformation of the H-2D(b) residues Y156 and H155 and thereby forming a unique MHC/peptide conformer that is essential for recognition by TEIPP-specific T cells. Substitution of peptide residues p2C and p5M to the conservative α-aminobutyric acid and norleucine, respectively, significantly reduced complex stability, without altering peptide conformation or T cell recognition. In contrast, substitution of p5M to a conventional asparagine abolished recognition by the H-2D(b)/Trh4-specific T cell clone LnB5. We anticipate that the H-2D(b)/Trh4 complex represents the first example, to our knowledge, of a broader repertoire of alternative MHC class I binders. Copyright © 2016 by The American Association of Immunologists, Inc.

  2. Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis.

    Science.gov (United States)

    Ackers, Ian; Szymanski, Candice; Duckett, K Jordan; Consitt, Leslie A; Silver, Mitchell J; Malgor, Ramiro

    2018-02-20

    Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells. Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining. Wnt5a (Pfoam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (Pfoam cells. Copyright © 2018. Published by Elsevier Inc.

  3. Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.

    Directory of Open Access Journals (Sweden)

    Daniel P S Osborn

    Full Text Available Common intronic variants in the Human fat mass and obesity-associated gene (FTO are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo (zebrafish and in vitro (Fto(-/- MEFs and HEK293T. Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca(2+ pathway is activated via its key signal mediators CaMKII and PKCδ. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.

  4. WNT regulation of embryonic development likely involves pathways independent of nuclear CTNNB1.

    Science.gov (United States)

    Tribulo, Paula; Moss, James I; Ozawa, Manabu; Jiang, Zongliang; Tian, Xiuchun Cindy; Hansen, Peter J

    2017-04-01

    The bovine was used to examine the potential for WNT signaling to affect the preimplantation embryo. Expression of seven key genes involved in canonical WNT signaling declined to a nadir at the morula or blastocyst stage. Expression of 80 genes associated with WNT signaling in the morula and inner cell mass (ICM) and trophectoderm (TE) of the blastocyst was also evaluated. Many genes associated with WNT signaling were characterized by low transcript abundance. Seven genes were different between ICM and TE, and all of them were overexpressed in TE as compared to ICM, including WNT6, FZD1, FZD7, LRP6, PORCN, APC and SFRP1 Immunoreactive CTNNB1 was localized primarily to the plasma membrane at all stages examined from the 2-cell to blastocyst stages of development. Strikingly, neither CTNNB1 nor non-phospho (i.e., active) CTNNB1 was observed in the nucleus of blastomeres at any stage of development even after the addition of WNT activators to culture. In contrast, CTNNB1 associated with the plasma membrane was increased by activators of WNT signaling. The planar cell polarity pathway (PCP) could be activated in the embryo as indicated by an experiment demonstrating an increase in phospho-JNK in the nucleus of blastocysts treated with the non-canonical WNT11. Furthermore, WNT11 improved development to the blastocyst stage. In conclusion, canonical WNT signaling is attenuated in the preimplantation bovine embryo but WNT can activate the PCP component JNK. Thus, regulation of embryonic development by WNT is likely to involve activation of pathways independent of nuclear actions of CTNNB1. © 2017 Society for Reproduction and Fertility.

  5. A Pathway Switch Directs BAFF Signaling to Distinct NFκB Transcription Factors in Maturing and Proliferating B Cells

    OpenAIRE

    Jonathan V. Almaden; Rachel Tsui; Yi C. Liu; Harry Birnbaum; Maxim N. Shokhirev; Kim A. Ngo; Jeremy C. Davis-Turak; Dennis Otero; Soumen Basak; Robert C. Rickert; Alexander Hoffmann

    2014-01-01

    SUMMARY BAFF, an activator of the noncanonical NF?B pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NF?B family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, wh...

  6. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    Energy Technology Data Exchange (ETDEWEB)

    Cannonier, Shellese A.; Sterling, Julie A., E-mail: Julie.sterling@vanderbilt.edu [Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37235 (United States); Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology Vanderbilt University, Nashville, TN 372335 (United States); Department of Cancer Biology, Vanderbilt University, Nashville, TN 37235 (United States)

    2015-08-26

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  7. Regulation of Wnt signaling by nociceptive input in animal models

    Directory of Open Access Journals (Sweden)

    Shi Yuqiang

    2012-06-01

    Full Text Available Abstract Background Central sensitization-associated synaptic plasticity in the spinal cord dorsal horn (SCDH critically contributes to the development of chronic pain, but understanding of the underlying molecular pathways is still incomplete. Emerging evidence suggests that Wnt signaling plays a crucial role in regulation of synaptic plasticity. Little is known about the potential function of the Wnt signaling cascades in chronic pain development. Results Fluorescent immunostaining results indicate that β-catenin, an essential protein in the canonical Wnt signaling pathway, is expressed in the superficial layers of the mouse SCDH with enrichment at synapses in lamina II. In addition, Wnt3a, a prototypic Wnt ligand that activates the canonical pathway, is also enriched in the superficial layers. Immunoblotting analysis indicates that both Wnt3a a β-catenin are up-regulated in the SCDH of various mouse pain models created by hind-paw injection of capsaicin, intrathecal (i.t. injection of HIV-gp120 protein or spinal nerve ligation (SNL. Furthermore, Wnt5a, a prototypic Wnt ligand for non-canonical pathways, and its receptor Ror2 are also up-regulated in the SCDH of these models. Conclusion Our results suggest that Wnt signaling pathways are regulated by nociceptive input. The activation of Wnt signaling may regulate the expression of spinal central sensitization during the development of acute and chronic pain.

  8. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    Directory of Open Access Journals (Sweden)

    Shellese A. Cannonier

    2015-08-01

    Full Text Available Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung, directly invade into bone (head and neck or originate from the bone (melanoma, chondrosarcoma where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  9. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    International Nuclear Information System (INIS)

    Cannonier, Shellese A.; Sterling, Julie A.

    2015-01-01

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors

  10. Wnt5a signaling is a substantial constituent in bone morphogenetic protein-2-mediated osteoblastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Nemoto, Eiji, E-mail: e-nemoto@dent.tohoku.ac.jp [Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575 (Japan); Ebe, Yukari; Kanaya, Sousuke [Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575 (Japan); Tsuchiya, Masahiro [Department of Aging and Geriatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai 980-8575 (Japan); Nakamura, Takashi [Department of Pediatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai 980-8575 (Japan); Tamura, Masato [Department of Biochemistry and Molecular Biology, Hokkaido University Graduate School of Dentistry, Sapporo 060-8586 (Japan); Shimauchi, Hidetoshi [Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai 980-8575 (Japan)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Wnt5a is identified in osteoblasts in tibial growth plate and bone marrow. Black-Right-Pointing-Pointer Osteoblastic differentiation is associated with increased expression of Wnt5a/Ror2. Black-Right-Pointing-Pointer Wnt5a/Ror2 signaling is important for BMP-2-mediated osteoblastic differentiation. Black-Right-Pointing-Pointer Wnt5a/Ror2 operates independently of BMP-Smad pathway. -- Abstract: Wnts are secreted glycoproteins that mediate developmental and post-developmental physiology by regulating cellular processes including proliferation, differentiation, and apoptosis through {beta}-catenin-dependent canonical and {beta}-catenin-independent noncanonical pathway. It has been reported that Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2). Although it appears that Wnt5a/Ror2 signaling supports normal bone physiology, the biological significance of noncanonical Wnts in osteogenesis is essentially unknown. In this study, we identified expression of Wnt5a in osteoblasts in the ossification zone of the tibial growth plate as well as bone marrow of the rat tibia as assessed by immunohistochemistry. In addition, we show that osteoblastic differentiation mediated by BMP-2 is associated with increased expression of Wnt5a and Ror2 using cultured pre-osteoblasts, MC3T3-E1 cells. Silencing gene expression of Wnt5a and Ror2 in MC3T3-E1 cells results in suppression of BMP-2-mediated osteoblastic differentiation, suggesting that Wnt5a and Ror2 signaling are of substantial importance for BMP-2-mediated osteoblastic differentiation. BMP-2 stimulation induced phosphorylation of Smad1/5/8 in a similar fashion in both siWnt5a-treated cells and control cells, suggesting that Wnt5a was dispensable for the phosphorylation of Smads by BMP-2. Taken together, our results suggest that Wnt5a/Ror2 signaling appears to be involved in BMP-2-mediated osteoblast differentiation in a Smad independent

  11. Wnt5a signaling is a substantial constituent in bone morphogenetic protein-2-mediated osteoblastogenesis

    International Nuclear Information System (INIS)

    Nemoto, Eiji; Ebe, Yukari; Kanaya, Sousuke; Tsuchiya, Masahiro; Nakamura, Takashi; Tamura, Masato; Shimauchi, Hidetoshi

    2012-01-01

    Highlights: ► Wnt5a is identified in osteoblasts in tibial growth plate and bone marrow. ► Osteoblastic differentiation is associated with increased expression of Wnt5a/Ror2. ► Wnt5a/Ror2 signaling is important for BMP-2-mediated osteoblastic differentiation. ► Wnt5a/Ror2 operates independently of BMP-Smad pathway. -- Abstract: Wnts are secreted glycoproteins that mediate developmental and post-developmental physiology by regulating cellular processes including proliferation, differentiation, and apoptosis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathway. It has been reported that Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2). Although it appears that Wnt5a/Ror2 signaling supports normal bone physiology, the biological significance of noncanonical Wnts in osteogenesis is essentially unknown. In this study, we identified expression of Wnt5a in osteoblasts in the ossification zone of the tibial growth plate as well as bone marrow of the rat tibia as assessed by immunohistochemistry. In addition, we show that osteoblastic differentiation mediated by BMP-2 is associated with increased expression of Wnt5a and Ror2 using cultured pre-osteoblasts, MC3T3-E1 cells. Silencing gene expression of Wnt5a and Ror2 in MC3T3-E1 cells results in suppression of BMP-2-mediated osteoblastic differentiation, suggesting that Wnt5a and Ror2 signaling are of substantial importance for BMP-2-mediated osteoblastic differentiation. BMP-2 stimulation induced phosphorylation of Smad1/5/8 in a similar fashion in both siWnt5a-treated cells and control cells, suggesting that Wnt5a was dispensable for the phosphorylation of Smads by BMP-2. Taken together, our results suggest that Wnt5a/Ror2 signaling appears to be involved in BMP-2-mediated osteoblast differentiation in a Smad independent pathway.

  12. Signal detection

    International Nuclear Information System (INIS)

    Tholomier, M.

    1985-01-01

    In a scanning electron microscope, whatever is the measured signal, the same set is found: incident beam, sample, signal detection, signal amplification. The resulting signal is used to control the spot luminosity with the observer cathodoscope. This is synchronized with the beam scanning on the sample; on the cathodoscope, the image in secondary electrons, backscattered electrons,... of the sample surface is reconstituted. The best compromise must be found between a register time low enough to remove eventual variations (under the incident beam) of the nature of the observed phenomenon, and a good spatial resolution of the image and a signal-to-noise ratio high enough. The noise is one of the basic limitations of the scanning electron microscope performance. The whose measurement line must be optimized to reduce it [fr

  13. Decoupled visually-guided reaching in optic ataxia: differences in motor control between canonical and non-canonical orientations in space.

    Directory of Open Access Journals (Sweden)

    Joshua A Granek

    Full Text Available Guiding a limb often involves situations in which the spatial location of the target for gaze and limb movement are not congruent (i.e. have been decoupled. Such decoupled situations involve both the implementation of a cognitive rule (i.e. strategic control and the online monitoring of the limb position relative to gaze and target (i.e. sensorimotor recalibration. To further understand the neural mechanisms underlying these different types of visuomotor control, we tested patient IG who has bilateral caudal superior parietal lobule (SPL damage resulting in optic ataxia (OA, and compared her performance with six age-matched controls on a series of center-out reaching tasks. The tasks comprised 1 directing a cursor that had been rotated (180° or 90° within the same spatial plane as the visual display, or 2 moving the hand along a different spatial plane than the visual display (horizontal or para-sagittal. Importantly, all conditions were performed towards visual targets located along either the horizontal axis (left and right; which can be guided from strategic control or the diagonal axes (top-left and top-right; which require on-line trajectory elaboration and updating by sensorimotor recalibration. The bilateral OA patient performed much better in decoupled visuomotor control towards the horizontal targets, a canonical situation in which well-categorized allocentric cues could be utilized (i.e. guiding cursor direction perpendicular to computer monitor border. Relative to neurologically intact adults, IG's performance suffered towards diagonal targets, a non-canonical situation in which only less-categorized allocentric cues were available (i.e. guiding cursor direction at an off-axis angle to computer monitor border, and she was therefore required to rely on sensorimotor recalibration of her decoupled limb. We propose that an intact caudal SPL is crucial for any decoupled visuomotor control, particularly when relying on the realignment

  14. Identification of Noncanonical Wnt Receptors Required for Wnt-3a-Induced Early Differentiation of Human Neural Stem Cells.

    Science.gov (United States)

    Bengoa-Vergniory, Nora; Gorroño-Etxebarria, Irantzu; López-Sánchez, Inmaculada; Marra, Michele; Di Chiaro, Pierluigi; Kypta, Robert

    2017-10-01

    Wnt proteins preferentially activate either β-catenin-dependent or β-catenin-independent signals, but the activity of a particular Wnt also depends on cellular context and receptor availability. We previously reported that Wnt-3a induces neural differentiation of human embryonic stem cell-derived neural stem cells (NSCs) in a β-catenin-independent manner by activating a signal involving JNK and the AP-1 family member ATF-2. Here, we report the results of a gene silencing approach to identify the Wnt receptors that mediate this response to Wnt-3a. Silencing of ROR2 increased neuronal differentiation, as measured by expression of the genes DCX, NEUROD1, and NGN1, suggesting ROR2 signals normally prevent differentiation. Silencing of the other Wnt receptors singly did not affect Wnt-3a-induced neuronal differentiation. However, pairwise silencing of ROR1 and FZD4 or FZD5 and of LRP6 and FZD4 or FZD5 inhibited neuronal differentiation, as detected by reductions in the expression of neuronal genes and immunocytochemical detection of DCX, NEUROD1 and DCX. Ectopic expression of these receptors in HEK 293 cells increased ATF2-dependent transcription. In addition, ROR1 coimmunoprecipitated with FZD4 and LRP6 in transfected HEK 293 cells and colocalized with FZD4 and with LRP6 at the cell surface of transfected L cells. Wnt-3a did not appear to affect these interactions but did alter the interactions between LRP6 and FZD4/5. Together, these observations highlight roles for ROR1, LRP6, FZD4, and FZD5 in neural stem cell differentiation and provide support for a model in which dynamic interactions among these receptors mediate Wnt-3a activation of ATF2 signaling.

  15. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis.

    Science.gov (United States)

    Cadwell, Ken

    2016-11-01

    Autophagy has broad functions in immunity, ranging from cell-autonomous defence to coordination of complex multicellular immune responses. The successful resolution of infection and avoidance of autoimmunity necessitates efficient and timely communication between autophagy and pathways that sense the immune environment. The recent literature indicates that a variety of immune mediators induce or repress autophagy. It is also becoming increasingly clear that immune signalling cascades are subject to regulation by autophagy, and that a return to homeostasis following a robust immune response is critically dependent on this pathway. Importantly, examples of non-canonical forms of autophagy in mediating immunity are pervasive. In this article, the progress in elucidating mechanisms of crosstalk between autophagy and inflammatory signalling cascades is reviewed. Improved mechanistic understanding of the autophagy machinery offers hope for treating infectious and inflammatory diseases.

  16. Phosphoinositide signaling.

    Science.gov (United States)

    Boss, Wendy F; Im, Yang Ju

    2012-01-01

    "All things flow and change…even in the stillest matter there is unseen flux and movement." Attributed to Heraclitus (530-470 BC), from The Story of Philosophy by Will Durant. Heraclitus, a Greek philosopher, was thinking on a much larger scale than molecular signaling; however, his visionary comments are an important reminder for those studying signaling today. Even in unstimulated cells, signaling pathways are in constant metabolic flux and provide basal signals that travel throughout the organism. In addition, negatively charged phospholipids, such as the polyphosphorylated inositol phospholipids, provide a circuit board of on/off switches for attracting or repelling proteins that define the membranes of the cell. This template of charged phospholipids is sensitive to discrete changes and metabolic fluxes-e.g., in pH and cations-which contribute to the oscillating signals in the cell. The inherent complexities of a constantly fluctuating system make understanding how plants integrate and process signals challenging. In this review we discuss one aspect of lipid signaling: the inositol family of negatively charged phospholipids and their functions as molecular sensors and regulators of metabolic flux in plants.

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

    Directory of Open Access Journals (Sweden)

    Vincent van den Boom

    2016-01-01

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

  18. The non-canonical Wnt/PKC pathway regulates mitochondrial dynamics through degradation of the arm-like domain-containing protein Alex3.

    Directory of Open Access Journals (Sweden)

    Román Serrat

    Full Text Available The regulation of mitochondrial dynamics is vital in complex cell types, such as neurons, that transport and localize mitochondria in high energy-demanding cell domains. The Armcx3 gene encodes a mitochondrial-targeted protein (Alex3 that contains several arm-like domains. In a previous study we showed that Alex3 protein regulates mitochondrial aggregation and trafficking. Here we studied the contribution of Wnt proteins to the mitochondrial aggregation and dynamics regulated by Alex3. Overexpression of Alex3 in HEK293 cells caused a marked aggregation of mitochondria, which was attenuated by treatment with several Wnts. We also found that this decrease was caused by Alex3 degradation induced by Wnts. While the Wnt canonical pathway did not alter the pattern of mitochondrial aggregation induced by Alex3, we observed that the Wnt/PKC non-canonical pathway regulated both mitochondrial aggregation and Alex3 protein levels, thereby rendering a mitochondrial phenotype and distribution similar to control patterns. Our data suggest that the Wnt pathway regulates mitochondrial distribution and dynamics through Alex3 protein degradation.

  19. Noncanonical substrate preference of lambda exonuclease for 5′-nonphosphate-ended dsDNA and a mismatch-induced acceleration effect on the enzymatic reaction

    Science.gov (United States)

    Yang, Yufei; Chen, Wei; Wang, Jiayu; Yang, Ziyu; Wang, Shenlin; Xiao, Xianjin; Li, Mengyuan

    2018-01-01

    Abstract Lambda exonuclease (λ exo) plays an important role in the resection of DNA ends for DNA repair. Currently, it is also a widely used enzymatic tool in genetic engineering, DNA-binding protein mapping, nanopore sequencing and biosensing. Herein, we disclose two noncanonical properties of this enzyme and suggest a previously undescribed hydrophobic interaction model between λ exo and DNA substrates. We demonstrate that the length of the free portion of the substrate strand in the dsDNA plays an essential role in the initiation of digestion reactions by λ exo. A dsDNA with a 5′ non-phosphorylated, two-nucleotide-protruding end can be digested by λ exo with very high efficiency. Moreover, we show that when a conjugated structure is covalently attached to an internal base of the dsDNA, the presence of a single mismatched base pair at the 5′ side of the modified base may significantly accelerate the process of digestion by λ exo. A detailed comparison study revealed additional π–π stacking interactions between the attached label and the amino acid residues of the enzyme. These new findings not only broaden our knowledge of the enzyme but will also be very useful for research on DNA repair and in vitro processing of nucleic acids. PMID:29490081

  20. The Non-Canonical Wnt/PKC Pathway Regulates Mitochondrial Dynamics through Degradation of the Arm-Like Domain-Containing Protein Alex3

    Science.gov (United States)

    Mirra, Serena; Quevedo, Martí; Garcia-Fernàndez, Jordi; Ulloa, Fausto; Burgaya, Ferrán; Soriano, Eduardo

    2013-01-01

    The regulation of mitochondrial dynamics is vital in complex cell types, such as neurons, that transport and localize mitochondria in high energy-demanding cell domains. The Armcx3 gene encodes a mitochondrial-targeted protein (Alex3) that contains several arm-like domains. In a previous study we showed that Alex3 protein regulates mitochondrial aggregation and trafficking. Here we studied the contribution of Wnt proteins to the mitochondrial aggregation and dynamics regulated by Alex3. Overexpression of Alex3 in HEK293 cells caused a marked aggregation of mitochondria, which was attenuated by treatment with several Wnts. We also found that this decrease was caused by Alex3 degradation induced by Wnts. While the Wnt canonical pathway did not alter the pattern of mitochondrial aggregation induced by Alex3, we observed that the Wnt/PKC non-canonical pathway regulated both mitochondrial aggregation and Alex3 protein levels, thereby rendering a mitochondrial phenotype and distribution similar to control patterns. Our data suggest that the Wnt pathway regulates mitochondrial distribution and dynamics through Alex3 protein degradation. PMID:23844091

  1. SGTA Recognizes a Noncanonical Ubiquitin-like Domain in the Bag6-Ubl4A-Trc35 Complex to Promote Endoplasmic Reticulum-Associated Degradation

    Directory of Open Access Journals (Sweden)

    Yue Xu

    2012-12-01

    Full Text Available Elimination of aberrantly folded polypeptides from the endoplasmic reticulum (ER by the ER-associated degradation (ERAD system promotes cell survival under stress conditions. This quality control mechanism requires movement of misfolded proteins across the ER membrane for targeting to the cytosolic proteasome, a process facilitated by a “holdase” complex, consisting of Bag6 and the cofactors Ubl4A and Trc35. This multiprotein complex also participates in several other protein quality control processes. Here, we report SGTA as a component of the Bag6 system, which cooperates with Bag6 to channel dislocated ERAD substrates that are prone to aggregation. Using nuclear magnetic resonance spectroscopy and biochemical assays, we demonstrate that SGTA contains a noncanonical ubiquitin-like-binding domain that interacts specifically with an unconventional ubiquitin-like protein/domain in Ubl4A at least in part via electrostatics. This interaction helps recruit SGTA to Bag6, enhances substrate loading to Bag6, and thus prevents the formation of nondegradable protein aggregates in ERAD.

  2. Non-canonical 3′-5′ Extension of RNA with Prebiotically Plausible Ribonucleoside 2′,3′-Cyclic Phosphates

    Science.gov (United States)

    2014-01-01

    Ribonucleoside 2′,3′-cyclic phosphates (N>p’s) are generated by multiple prebiotically plausible processes and are credible building blocks for the assembly of early RNA oligomers. While N>p’s can be polymerized into short RNAs by non-enzymatic processes with variable efficiency and regioselectivity, no enzymatic route for RNA synthesis had been described. Here we report such a non-canonical 3′-5′ nucleotidyl transferase activity. We engineered a variant of the hairpin ribozyme to catalyze addition of all four N>p’s (2′,3′-cyclic A-, G-, U-, and CMP) to the 5′-hydroxyl termini of RNA strands with 5′ nucleotide addition enhanced in all cases by eutectic ice phase formation at −7 °C. We also observed 5′ addition of 2′,3′-cyclic phosphate-activated β-nicotinamide adenine dinucleotide (NAD>p) and ACA>p RNA trinucleotide, and multiple additions of GUCCA>p RNA pentamers. Our results establish a new mode of RNA 3′-5′ extension with implications for RNA oligomer synthesis from prebiotic nucleotide pools. PMID:24660752

  3. Dengue Virus Uses a Non-Canonical Function of the Host GBF1-Arf-COPI System for Capsid Protein Accumulation on Lipid Droplets.

    Science.gov (United States)

    Iglesias, Nestor G; Mondotte, Juan A; Byk, Laura A; De Maio, Federico A; Samsa, Marcelo M; Alvarez, Cecilia; Gamarnik, Andrea V

    2015-09-01

    Dengue viruses cause the most important human viral disease transmitted by mosquitoes. In recent years, a great deal has been learned about molecular details of dengue virus genome replication; however, little is known about genome encapsidation and the functions of the viral capsid protein. During infection, dengue virus capsid progressively accumulates around lipid droplets (LDs) by an unknown mechanism. Here, we examined the process by which the viral capsid is transported from the endoplasmic reticulum (ER) membrane, where the protein is synthesized, to LDs. Using different methods of intervention, we found that the GBF1-Arf1/Arf4-COPI pathway is necessary for capsid transport to LDs, while the process is independent of both COPII components and Golgi integrity. The transport was sensitive to Brefeldin A, while a drug resistant form of GBF1 was sufficient to restore capsid subcellular distribution in infected cells. The mechanism by which LDs gain or lose proteins is still an open question. Our results support a model in which the virus uses a non-canonical function of the COPI system for capsid accumulation on LDs, providing new ideas for antiviral strategies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Non-canonical regulation of glutathione and trehalose biosynthesis characterizes non-Saccharomyces wine yeasts with poor performance in active dry yeast production

    Directory of Open Access Journals (Sweden)

    Esther Gamero-Sandemetrio

    2018-01-01

    Full Text Available Several yeast species, belonging to Saccharomyces and non-Saccharomyces genera, play fundamental roles during spontaneous must grape fermentation, and recent studies have shown that mixed fermentations, co-inoculated with S. cerevisiae and non-Saccharomyces strains, can improve wine organoleptic properties. During active dry yeast (ADY production, antioxidant systems play an essential role in yeast survival and vitality as both biomass propagation and dehydration cause cellular oxidative stress and negatively affect technological performance. Mechanisms for adaptation and resistance to desiccation have been described for S. cerevisiae, but no data are available on the physiology and oxidative stress response of non-Saccharomyces wine yeasts and their potential impact on ADY production. In this study we analyzed the oxidative stress response in several non-Saccharomyces yeast species by measuring the activity of reactive oxygen species (ROS scavenging enzymes, e.g., catalase and glutathione reductase, accumulation of protective metabolites, e.g., trehalose and reduced glutathione (GSH, and lipid and protein oxidation levels. Our data suggest that non-canonical regulation of glutathione and trehalose biosynthesis could cause poor fermentative performance after ADY production, as it corroborates the corrective effect of antioxidant treatments, during biomass propagation, with both pure chemicals and food-grade argan oil.

  5. Gleaning unexpected fruits from hard-won synthetases: probing principles of permissivity in non-canonical amino acid-tRNA synthetases.

    Science.gov (United States)

    Cooley, Richard B; Karplus, P Andrew; Mehl, Ryan A

    2014-08-18

    The site-specific incorporation of non-canonical amino acids (ncAAs) into proteins is an important tool for understanding biological function. Traditionally, each new ncAA targeted for incorporation requires a resource-consuming process of generating new ncAA aminoacyl tRNA synthetase/tRNACUA pairs. However, the discovery that some tRNA synthetases are "permissive", in that they can incorporate multiple ncAAs, means that it is no longer always necessary to develop a new synthetase for each newly desired ncAA. Developing a better understanding of what factors make ncAA synthetases more permissive would increase the utility of this new approach. Here, we characterized two synthetases selected for the same ncAA that have markedly different "permissivity profiles." Remarkably, the more permissive synthetase incorporated an ncAA for which we had not been able to generate a synthetase through de novo selection methods. Crystal structures revealed that the two synthetases recognize their parent ncAA through a conserved core of interactions, with the more permissive synthetase displaying a greater degree of flexibility in its interaction geometries. We also observed that intraprotein interactions not directly involved in ncAA binding can play a crucial role in synthetase permissivity and suggest that optimization of such interactions might provide an avenue to engineering synthetases with enhanced permissivity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Signal Processing

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    Signal processing techniques, extensively used nowadays to maximize the performance of audio and video equipment, have been a key part in the design of hardware and software for high energy physics detectors since pioneering applications in the UA1 experiment at CERN in 1979

  7. Expression and evolution of the non-canonically translated yeast mitochondrial acetyl-CoA carboxylase Hfa1p.

    Directory of Open Access Journals (Sweden)

    Fumi Suomi

    Full Text Available 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.

  8. Structure and specificity of a new class of Ca2+-independent housekeeping sortase fromStreptomyces avermitilisprovide insights into its non-canonical substrate preference.

    Science.gov (United States)

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

    2017-04-28

    Surface proteins in Gram-positive bacteria are incorporated into the cell wall through a peptide ligation reaction catalyzed by transpeptidase sortase. Six main classes (A-F) of sortase have been identified of which class A sortase is meant for housekeeping functions. The prototypic housekeeping sortase A (SaSrtA) from Staphylococcus aureus cleaves LP X TG-containing proteins at the scissile T-G peptide bond and ligates protein-LP X T to the terminal Gly residue of the nascent cross-bridge of peptidoglycan lipid II precursor. Sortase-mediated ligation ("sortagging") of LP X TG-containing substrates and Gly-terminated nucleophiles occurs in vitro as well as in cellulo in the presence of Ca 2+ and has been applied extensively for protein conjugations. Although the majority of applications emanate from SaSrtA, low catalytic efficiency, LP X TG specificity restriction, and Ca 2+ requirement (particularly for in cellulo applications) remain a drawback. Given that Gram-positive bacteria genomes encode a variety of sortases, natural sortase mining can be a viable complementary approach akin to engineering of wild-type SaSrtA. Here, we describe the structure and specificity of a new class E sortase (SavSrtE) annotated to perform housekeeping roles in Streptomyces avermitilis Biochemical experiments define the attributes of an optimum peptide substrate, demonstrate Ca 2+ -independent activity, and provide insights about contrasting functional characteristics of SavSrtE and SaSrtA. Crystal structure, substrate docking, and mutagenesis experiments have identified a critical residue that dictates the preference for a non-canonical LA X TG recognition motif over LP X TG. These results have implications for rational tailoring of substrate tolerance in sortases. Besides, Ca 2+ -independent orthogonal specificity of SavSrtE is likely to expand the sortagging toolkit. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Structural and Functional Characterization of a Short-Chain Flavodoxin Associated with a Noncanonical 1,2-Propanediol Utilization Bacterial Microcompartment

    Energy Technology Data Exchange (ETDEWEB)

    Plegaria, Jefferson S. [MSU-DOE; Sutter, Markus [MSU-DOE; Molecular; Ferlez, Bryan [MSU-DOE; Aussignargues, Clément [MSU-DOE; Niklas, Jens [Solar; Poluektov, Oleg G. [Solar; Fromwiller, Ciara [MSU-DOE; TerAvest, Michaela [Department; amp, Molecular Biology, Michigan State University, East; Utschig, Lisa M. [Solar; Tiede, David M. [Solar; Kerfeld, Cheryl A. [MSU-DOE; Molecular; Department; amp, Molecular Biology, Michigan State University, East; Berkeley Synthetic Biology Institute, Berkeley, California 94720, United States

    2017-09-21

    Bacterial microcompartments (BMCs) are proteinaceous organelles that encapsulate enzymes involved in CO2 fixation (carboxysomes). or carbon catabolism (metabolosomes). Metabolosomes share a common core of enzymes and a distinct signature enzyme for substrate degradation that defines the function of the BMC (e,g., propanediol or ethanolamine utilization BMCs, or glycyl-radical enzyme microcompartments). Loci encoding metabolosomes also typically contain genes for proteins that support organelle function, such as regulation, transport of substrate, and cofactor (e.g., vitamin B-12) synthesis and recycling. Flavoproteins are frequently among these ancillary gene products, suggesting that these redox active proteins play an undetermined function in many metabolosomes. Here, we report the first characterization of a BMC-associated flavodoxin (Fld1C), a small flavoprotein, derived from the noncanonical 1,2-propanediol utilization BMC locus (PDU1C) of Lactobacillus reuteri. The 2.0 angstrom X-ray structure of Fld1C displays the alpha/beta flavodoxin fold, which noncovalently binds a single flavin mononucleotide molecule. Fld1C is a short-chain flavodoxin with redox potentials of -240 +/- 3 mV oxidized/semiquinone and -344 +/- 1 mV semiquinone/hydroquinone versus the standard hydrogen electrode at pH 7.5. It can participate in an electron transfer reaction with a photoreductant to form a stable semiquinone species. Collectively, our structural and functional results suggest that PDU1C BMCs encapsulate Fld1C to store and transfer electrons for the reactivation and/or recycling of the B-12 cofactor utilized by the signature enzyme.

  10. β-agonists selectively modulate proinflammatory gene expression in skeletal muscle cells via non-canonical nuclear crosstalk mechanisms.

    Directory of Open Access Journals (Sweden)

    Krzysztof Kolmus

    Full Text Available The proinflammatory cytokine Tumour Necrosis Factor (TNF-α is implicated in a variety of skeletal muscle pathologies. Here, we have investigated how in vitro cotreatment of skeletal muscle C2C12 cells with β-agonists modulates the TNF-α-induced inflammatory program. We observed that C2C12 myotubes express functional TNF receptor 1 (TNF-R1 and β2-adrenoreceptors (β2-ARs. TNF-α activated the canonical Nuclear Factor-κB (NF-κB pathway and Mitogen-Activated Protein Kinases (MAPKs, culminating in potent induction of NF-κB-dependent proinflammatory genes. Cotreatment with the β-agonist isoproterenol potentiated the expression of inflammatory mediators, including Interleukin-6 (IL-6 and several chemokines. The enhanced production of chemotactic factors upon TNF-α/isoproterenol cotreatment was also suggested by the results from migrational analysis. Whereas we could not explain our observations by cytoplasmic crosstalk, we found that TNF-R1-and β2-AR-induced signalling cascades cooperate in the nucleus. Using the IL-6 promoter as a model, we demonstrated that TNF-α/isoproterenol cotreatment provoked phosphorylation of histone H3 at serine 10, concomitant with enhanced promoter accessibility and recruitment of the NF-κB p65 subunit, cAMP-response element-binding protein (CREB, CREB-binding protein (CBP and RNA polymerase II. In summary, we show that β-agonists potentiate TNF-α action, via nuclear crosstalk, that promotes chromatin relaxation at selected gene promoters. Our data warrant further study into the mode of action of β-agonists and urge for caution in their use as therapeutic agents for muscular disorders.

  11. Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Michael Boitard

    2015-03-01

    Full Text Available The precise timing of pyramidal cell migration from the ventricular germinal zone to the cortical plate is essential for establishing cortical layers, and migration errors can lead to neurodevelopmental disorders underlying psychiatric and neurological diseases. Here, we report that Wnt canonical as well as non-canonical signaling is active in pyramidal precursors during radial migration. We demonstrate using constitutive and conditional genetic strategies that transient downregulation of canonical Wnt/β-catenin signaling during the multipolar stage plays a critical role in polarizing and orienting cells for radial migration. In addition, we show that reduced canonical Wnt signaling is triggered cell autonomously by time-dependent expression of Wnt5A and activation of non-canonical signaling. We identify ephrin-B1 as a canonical Wnt-signaling-regulated target in control of the multipolar-to-bipolar switch. These findings highlight the critical role of Wnt signaling activity in neuronal positioning during cortical development.

  12. ‘WNT-er is coming’: WNT signalling in chronic lung diseases

    Science.gov (United States)

    Baarsma, H A

    2017-01-01

    Chronic lung diseases represent a major public health problem with only limited therapeutic options. An important unmet need is to identify compounds and drugs that target key molecular pathways involved in the pathogenesis of chronic lung diseases. Over the last decade, there has been extensive interest in investigating Wingless/integrase-1 (WNT) signalling pathways; and WNT signal alterations have been linked to pulmonary disease pathogenesis and progression. Here, we comprehensively review the cumulative evidence for WNT pathway alterations in chronic lung pathologies, including idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma and COPD. While many studies have focused on the canonical WNT/β-catenin signalling pathway, recent reports highlight that non-canonical WNT signalling may also significantly contribute to chronic lung pathologies; these studies will be particularly featured in this review. We further discuss recent advances uncovering the role of WNT signalling early in life, the potential of pharmaceutically modulating WNT signalling pathways and highlight (pre)clinical studies describing promising new therapies for chronic lung diseases. PMID:28416592

  13. Convergent Evolution of Sodium Ion Selectivity in Metazoan Neuronal Signaling

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    Maya Gur Barzilai

    2012-08-01

    Full Text Available Ion selectivity of metazoan voltage-gated Na+ channels is critical for neuronal signaling and has long been attributed to a ring of four conserved amino acids that constitute the ion selectivity filter (SF at the channel pore. Yet, in addition to channels with a preference for Ca2+ ions, the expression and characterization of Na+ channel homologs from the sea anemone Nematostella vectensis, a member of the early-branching metazoan phylum Cnidaria, revealed a sodium-selective channel bearing a noncanonical SF. Mutagenesis and physiological assays suggest that pore elements additional to the SF determine the preference for Na+ in this channel. Phylogenetic analysis assigns the Nematostella Na+-selective channel to a channel group unique to Cnidaria, which diverged >540 million years ago from Ca2+-conducting Na+ channel homologs. The identification of Cnidarian Na+-selective ion channels distinct from the channels of bilaterian animals indicates that selectivity for Na+ in neuronal signaling emerged independently in these two animal lineages.

  14. A complex relationship between TRAF3 and non-canonical NF-κB2 activation in B lymphocytes

    Directory of Open Access Journals (Sweden)

    Wai Wai Lin

    2013-12-01

    Full Text Available The adaptor protein TRAF3 restrains BAFF receptor (BAFFR and CD40-mediated activation of the NF-κB2 pathway in B cells. Mice lacking TRAF3 specifically in B cells revealed the critical role of TRAF3 in restraining homeostatic B cell survival. Furthermore, loss- of-function mutations of the traf3 gene have been associated with human B cell malignancies, especially multiple myeloma (MM. It has been proposed that receptor-induced TRAF3 degradation leads to stabilization of the NF-B inducing kinase NIK, and subsequent NF-κB2 activation. However, it is unclear how receptor-mediated TRAF3 degradation or loss of function contributes to B cell-specific NF-κB2 activation. In the current study, we employed two complementary models to address this question. One utilized a mutant traf3 gene found in a human MM-derived cell line called LP1. The LP1 mutant TRAF3 protein lacks the TRAF-N and TRAF-C domains. Consistent with the paradigm described, expression of LP1 TRAF3 in B cells promoted higher basal levels of NF-κB2 activation compared to Wt TRAF3. However, LP1 did not associate with TRAF2, CD40, or BAFFR, and no LP1 degradation was observed following receptor engagement. Interestingly, LP1 showed enhanced NIK association. Thus, TRAF3 degradation becomes dispensable to activate NF-κB2 when it is unable to associate with TRAF2. In a second model, we examined several mutant forms of BAFFR that are unable to induce NF-κB2 activation in B cells. Signaling to B cells by each of these BAFFR mutants, however, induced levels of TRAF3 degradation similar to those induced by Wt BAFFR. Thus, in B cells, receptor-mediated TRAF3 degradation is not sufficient to promote NF-B2 activation. We thus conclude that there is not a simple linear relationship in B lymphocytes between relative levels of cellular TRAF3, induced TRAF3 degradation, NIK activation and NF-B2 activation.

  15. TGF-β/Smad signaling in renal fibrosis

    Directory of Open Access Journals (Sweden)

    Xiao-Ming eMeng

    2015-03-01

    Full Text Available TGF-β (transforming growth factor-β is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF- signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix, and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases. Taken together, TGF-/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for chronic kidney diseases associated with renal fibrosis.

  16. Feedback Activation of Basic Fibroblast Growth Factor Signaling via the Wnt/β-Catenin Pathway in Skin Fibroblasts.

    Science.gov (United States)

    Wang, Xu; Zhu, Yuting; Sun, Congcong; Wang, Tao; Shen, Yingjie; Cai, Wanhui; Sun, Jia; Chi, Lisha; Wang, Haijun; Song, Na; Niu, Chao; Shen, Jiayi; Cong, Weitao; Zhu, Zhongxin; Xuan, Yuanhu; Li, Xiaokun; Jin, Litai

    2017-01-01

    Skin wound healing is a complex process requiring the coordinated behavior of many cell types, especially in the proliferation and migration of fibroblasts. Basic fibroblast growth factor (bFGF) is a member of the FGF family that promotes fibroblast migration, but the underlying molecular mechanism remains elusive. The present RNA sequencing study showed that the expression levels of several canonical Wnt pathway genes, including Wnt2b , Wnt3 , Wnt11 , T-cell factor 7 (TCF7) , and Frizzled 8 ( FZD8 ) were modified by bFGF stimulation in fibroblasts. Enzyme-linked immunosorbent assay (ELISA) analysis also showed that Wnt pathway was activated under bFGF treatment. Furthermore, treatment of fibroblasts with lithium chloride or IWR-1, an inducer and inhibitor of the Wnt signaling pathway, respectively, promoted and inhibited cell migration. Also, levels of cytosolic glycogen synthase kinase 3 beta phosphorylated at serine 9 (pGSK3β Ser 9 ) and nuclear β-catenin were increased upon exposure to bFGF. Molecular and biochemical assays indicated that phosphoinositide 3-kinase (PI3K) signaling activated the GSK3β/β-catenin/Wnt signaling pathway via activation of c-Jun N-terminal kinase (JNK), suggesting that PI3K and JNK act at the upstream of β-catenin. In contrast, knock-down of β -catenin delayed fibroblast cell migration even under bFGF stimulation. RNA sequencing analysis of β -catenin knock-down fibroblasts demonstrated that β-catenin positively regulated the transcription of bFGF and FGF21. Moreover, FGF21 treatment activated AKT and JNK, and accelerated fibroblast migration to a similar extent as bFGF does. In addition, ELISA analysis demonstrated that both of bFGF and FGF21 were auto secretion factor and be regulated by Wnt pathway stimulators. Taken together, our analyses define a feedback regulatory loop between bFGF (FGF21) and Wnt signaling acting through β-catenin in skin fibroblasts.

  17. Prosocial Signalling

    DEFF Research Database (Denmark)

    Kahsay, Goytom Abraha

    signalling can cause reverse price reactions resembling the crowding-out of pre-existing motives for prosocial behavior seen in situations of volunteering and charitable giving. Using a unique combination of questionnaire and purchase panel data, it presents evidence of such reputation-driven reverse price...... reactions in the Danish market for organic milk. The second paper proposes a self-image model to account consumers’ behaviour under PWYW. It finds that when a good’s fixed price is lower than an exogenously given threshold fair value, PWYW can lead to a lower utility, which may lead to lower purchase rate...

  18. Insulin Signaling in the Aging of Healthy and Proteotoxically Stressed Mechanosensory Neurons

    Directory of Open Access Journals (Sweden)

    Courtney eScerbak

    2014-07-01

    Full Text Available Insulin signaling is central to cellular metabolism and organismal aging. However, the role of insulin signaling in natural and proteotoxically stressed aging neurons has yet to be fully described. We studied aging of Caenorbaditis elegans mechanosensory neurons expressing a neurotoxic expanded polyglutamine transgene (polyQ128, or lacking this proteotoxicity stressor (polyQ0, under conditions in which the insulin signaling pathway was disrupted by RNA interference (RNAi. We describe specific changes in lifespan, mechanosensory neuronal morphologies, and mechansensory function following RNAi treatment targeting the insulin signaling pathway. Overall, we confirmed that transcription factor DAF-16 is neuroprotective in the proteotoxically stressed model, though not strikingly in the naturally aging model. Decreased insulin signaling through daf-2 RNAi improved mechanosensory function in both models and decreased protein aggregation load in polyQ128, yet showed opposing effects on accumulation of neuronal aberrations in both strains. Decreased daf-2 signaling slightly enhanced mechanosensation while greatly enhancing branching of the mechanosensory neuron axons and dendrites in polyQ0 animals, suggesting that branching is an adaptive response in natural aging. These effects in polyQ0 did not appear to involve DAF-16, suggesting the existence of a non-canonical DAF-2 pathway for the modulation of morphological adaptation. However, in polyQ128 animals, decreased daf-2 signaling significantly enhanced mechanosensation while decreasing neuronal aberrations. Unlike other interventions that reduce the strength of insulin signaling, daf-2 RNAi dramatically redistributed large polyQ128 aggregates to the cell body, away from neuronal processes. Our results suggest that insulin signaling strength can differentially affect specific neurons aging naturally or under proteotoxic stress.

  19. Sensing and Transmitting Intracellular Amino Acid Signals through Reversible Lysine Aminoacylations.

    Science.gov (United States)

    He, Xia-Di; Gong, Wei; Zhang, Jia-Nong; Nie, Ji; Yao, Cui-Fang; Guo, Fu-Shen; Lin, Yan; Wu, Xiao-Hui; Li, Feng; Li, Jie; Sun, Wei-Cheng; Wang, En-Duo; An, Yan-Peng; Tang, Hui-Ru; Yan, Guo-Quan; Yang, Peng-Yuan; Wei, Yun; Mao, Yun-Zi; Lin, Peng-Cheng; Zhao, Jian-Yuan; Xu, Yanhui; Xu, Wei; Zhao, Shi-Min

    2018-01-09

    Amino acids are known regulators of cellular signaling and physiology, but how they are sensed intracellularly is not fully understood. Herein, we report that each aminoacyl-tRNA synthetase (ARS) senses its cognate amino acid sufficiency through catalyzing the formation of lysine aminoacylation (K-AA) on its specific substrate proteins. At physiologic levels, amino acids promote ARSs bound to their substrates and form K-AAs on the ɛ-amine of lysines in their substrates by producing reactive aminoacyl adenylates. The K-AA marks can be removed by deacetylases, such as SIRT1 and SIRT3, employing the same mechanism as that involved in deacetylation. These dynamically regulated K-AAs transduce signals of their respective amino acids. Reversible leucylation on ras-related GTP-binding protein A/B regulates activity of the mammalian target of rapamycin complex 1. Glutaminylation on apoptosis signal-regulating kinase 1 suppresses apoptosis. We discovered non-canonical functions of ARSs and revealed systematic and functional amino acid sensing and signal transduction networks. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-κB activation.

    Directory of Open Access Journals (Sweden)

    Yukana Nakaima

    Full Text Available CD137 is a member of the tumor necrosis factor receptor family that is expressed on activated T cells. This molecule provides a co-stimulatory signal that enhances the survival, and differentiation of cells, and has a crucial role in the development of CD8 cytotoxic T cells and anti-tumor immunity. Here we report that CD137 expression is also induced on normal or malignant human B cells by CD40 ligation by its ligand CD154. This CD137 induction was more prominent in chronic lymphocytic leukemia (CLL cells than in other types of B cells. CD137 stimulation on B cells by its ligand induced the nuclear translocation of p52 (a non-canonical NF-κB factor. In agreement with this finding, expression of the survival factor BCL-XL was upregulated. Consequently, the CD137 signal augmented the survival of CD154-stimulated CLL B cells in vitro. This unexpected induction of CD137 on B cells by CD40 signal may influence the clinical course of CLL.

  1. PGE2/EP4Signaling Controls the Transfer of the Mammary Stem Cell State by Lipid Rafts in Extracellular Vesicles.

    Science.gov (United States)

    Lin, Meng-Chieh; Chen, Shih-Yin; Tsai, Ho-Min; He, Pei-Lin; Lin, Yen-Chun; Herschman, Harvey; Li, Hua-Jung

    2017-02-01

    Prostaglandin E 2 (PGE 2 )-initiated signaling contributes to stem cell homeostasis and regeneration. However, it is unclear how PGE 2 signaling controls cell stemness. This study identifies a previously unknown mechanism by which PGE 2 /prostaglandin E receptor 4 (EP 4 ) signaling regulates multiple signaling pathways (e.g., PI3K/Akt signaling, TGFβ signaling, Wnt signaling, EGFR signaling) which maintain the basal mammary stem cell phenotype. A shift of basal mammary epithelial stem cells (MaSCs) from a mesenchymal/stem cell state to a non-basal-MaSC state occurs in response to prostaglandin E receptor 4 (EP 4 ) antagonism. EP 4 antagonists elicit release of signaling components, by controlling their trafficking into extracellular vesicles/exosomes in a lipid raft/caveolae-dependent manner. Consequently, EP 4 antagonism indirectly inactivates, through induced extracellular vesicle/exosome release, pathways required for mammary epithelial stem cell homeostasis, e.g. canonical/noncanonical Wnt, TGFβ and PI3K/Akt pathways. EP 4 antagonism causes signaling receptors and signaling components to shift from non-lipid raft fractions to lipid raft fractions, and to then be released in EP 4 antagonist-induced extracellular vesicles/exosomes, resulting in the loss of the stem cell state by mammary epithelial stem cells. In contrast, luminal mammary epithelial cells can acquire basal stem cell properties following ingestion of EP 4 antagonist-induced stem cell extracellular vesicles/exosomes, and can then form mammary glands. These findings demonstrate that PGE 2 /EP 4 signaling controls homeostasis of mammary epithelial stem cells through regulating extracellular vesicle/exosome release. Reprogramming of mammary epithelial cells can result from EP 4 -mediated stem cell property transfer by extracellular vesicles/exosomes containing caveolae-associated proteins, between mammary basal and luminal epithelial cells. Stem Cells 2017;35:425-444. © 2016 The Authors STEM CELLS

  2. The Toll-like receptor 1/2 agonists Pam(3) CSK(4) and human β-defensin-3 differentially induce interleukin-10 and nuclear factor-κB signalling patterns in human monocytes.

    Science.gov (United States)

    Funderburg, Nicholas T; Jadlowsky, Julie K; Lederman, Michael M; Feng, Zhimin; Weinberg, Aaron; Sieg, Scott F

    2011-10-01

    Human β-defensin 3 (hBD-3) activates antigen-presenting cells through Toll-like receptors (TLRs) 1/2. Several TLR1/2 agonists have been identified but little is known about how they might differentially affect cellular activation. We compared the effects of hBD-3 with those of another TLR1/2 agonist, Pam(3) CSK(4) , in human monocytes. Monocytes incubated with hBD-3 or Pam(3) CSK(4) produced interleukin-6 (IL-6), IL-8 and IL-1β, but only Pam(3) CSK(4) induced IL-10. The IL-10 induction by Pam(3) CSK(4) caused down-modulation of the co-stimulatory molecule, CD86, whereas CD86 expression was increased in monocytes exposed to hBD-3. Assessment of signalling pathways linked to IL-10 induction indicated that mitogen-activated protein kinases were activated similarly by hBD-3 or Pam(3) CSK(4) , whereas the non-canonical nuclear factor-κB pathway was only induced by Pam(3) CSK(4) . Our data suggest that the lack of non-canonical nuclear factor-κB signalling by hBD-3 could contribute to the failure of this TLR agonist to induce production of the anti-inflammatory cytokine, IL-10, in human monocytes. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

  3. Activation of non-canonical Wnt/JNK pathway by Wnt3a is associated with differentiation fate determination of human bone marrow stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Qiu, Weimin; Chen, Li; Kassem, Moustapha

    2011-01-01

    patterns induced by Wnt3a treatment in two hMSC lines: hMSC-LRP5(T253) and hMSC-LRP5(T244) cells carrying known mutations of Wnt co-receptor LRP5 (T253I or T244M) that either enhances or represses canonical Wnt signaling, respectively. Wnt3a treatment of hMSC activated not only canonical Wnt signaling...

  4. Notching on cancer’s door: Notch signaling in brain tumors

    Directory of Open Access Journals (Sweden)

    Marcin eTeodorczyk

    2015-01-01

    Full Text Available Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1-4, which are activated by three Delta-like (Dll1/3/4 and two Serrate-like (Jagged1/2 ligands. Further, non-canonical Notch ligands such as EGFL7 have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differentiation in the central nervous system by driving neural stem cell maintenance and commitment of neural progenitor cells into the glial lineage. Notch is therefore often implicated in the development of brain tumors, as tumor cells share various characteristics with neural stem and progenitor cells. Notch receptors are overexpressed in gliomas and their oncogenicity has been confirmed by gain- and loss-of-function studies in vitro and in vivo. To this end, special attention is paid to the impact of Notch signaling on stem-like brain tumor-propagating cells as these cells contribute to growth, survival, invasion and recurrence of brain tumors. Based on the outcome of ongoing studies in vivo, Notch-directed therapies such as γ secretase inhibitors and blocking antibodies have entered and completed various clinical trials. This review summarizes the current knowledge on Notch signaling in brain tumor formation and therapy.

  5. NF-kappaB signaling: a tale of two pathways in skeletal myogenesis.

    Science.gov (United States)

    Bakkar, Nadine; Guttridge, Denis C

    2010-04-01

    NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

  6. The evolution of regulators of G protein signalling proteins as drug targets - 20 years in the making: IUPHAR Review 21.

    Science.gov (United States)

    Sjögren, B

    2017-03-01

    Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets. © 2017 The British Pharmacological Society.

  7. Basic digital signal processing

    CERN Document Server

    Lockhart, Gordon B

    1985-01-01

    Basic Digital Signal Processing describes the principles of digital signal processing and experiments with BASIC programs involving the fast Fourier theorem (FFT). The book reviews the fundamentals of the BASIC program, continuous and discrete time signals including analog signals, Fourier analysis, discrete Fourier transform, signal energy, power. The text also explains digital signal processing involving digital filters, linear time-variant systems, discrete time unit impulse, discrete-time convolution, and the alternative structure for second order infinite impulse response (IIR) sections.

  8. Inhibition of Wnt Signaling Pathways Impairs Chlamydia trachomatis Infection in Endometrial Epithelial Cells.

    Science.gov (United States)

    Kintner, Jennifer; Moore, Cheryl G; Whittimore, Judy D; Butler, Megan; Hall, Jennifer V

    2017-01-01

    Chlamydia trachomatis infections represent the predominant cause of bacterial sexually transmitted infections. As an obligate intracellular bacterium, C. trachomatis is dependent on the host cell for survival, propagation, and transmission. Thus, factors that affect the host cell, including nutrition, cell cycle, and environmental signals, have the potential to impact chlamydial development. Previous studies have demonstrated that activation of Wnt/β-catenin signaling benefits C. trachomatis infections in fallopian tube epithelia. In cervical epithelial cells chlamydiae sequester β-catenin within the inclusion. These data indicate that chlamydiae interact with the Wnt signaling pathway in both the upper and lower female genital tract (FGT). However, hormonal activation of canonical and non-canonical Wnt signaling pathways is an essential component of cyclic remodeling in another prominent area of the FGT, the endometrium. Given this information, we hypothesized that Wnt signaling would impact chlamydial infection in endometrial epithelial cells. To investigate this hypothesis, we analyzed the effect of Wnt inhibition on chlamydial inclusion development and elementary body (EB) production in two endometrial cell lines, Ishikawa (IK) and Hec-1B, in nonpolarized cell culture and in a polarized endometrial epithelial (IK)/stromal (SHT-290) cell co-culture model. Inhibition of Wnt by the small molecule inhibitor (IWP2) significantly decreased inclusion size in IK and IK/SHT-290 cultures ( p Wnt inhibition caused chlamydiae to become aberrant in morphology. EB formation was also impaired in IK, Hec-1B and IK/SHT-290 cultures regardless of whether Wnt inhibition occurred throughout, in the middle (24 hpi) or late (36 hpi) during the development cycle. Overall, these data lead us to conclude that Wnt signaling in the endometrium is a key host pathway for the proper development of C. trachomatis .

  9. A role for the non-canonical Wnt-ß-Catenin and TGF-ß signaling pathways in the induction of tolerance during the establishment of a Salmonella enterica serovar Enteritidis persistent cecal infection in chickens

    Science.gov (United States)

    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 infecti...

  10. Signal Processing and Restoration

    NARCIS (Netherlands)

    Biemond, J.; Slump, C.H.; Lagendijk, R.L.; Tolhuizen, L.M.G.M.; de With, P.H.N.

    2004-01-01

    Digital Signal Processing (DSP) concerns the theoretical and practical aspects of representing information-bearing signals in digital form and the use of processors or special purpose hardware to extract that information or to transform the signals in useful ways. Areas where digital signal

  11. Retroactive signaling in short signaling pathways.

    Directory of Open Access Journals (Sweden)

    Jacques-Alexandre Sepulchre

    Full Text Available In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles.

  12. Signal verification can promote reliable signalling.

    Science.gov (United States)

    Broom, Mark; Ruxton, Graeme D; Schaefer, H Martin

    2013-11-22

    The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer-resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism.

  13. Wnt3a Promotes the Vasculogenic Mimicry Formation of Colon Cancer via Wnt/β-Catenin Signaling.

    Science.gov (United States)

    Qi, Lisha; Song, Wangzhao; Liu, Zhiyong; Zhao, Xiulan; Cao, Wenfeng; Sun, Baocun

    2015-08-10

    Our previous study provided evidence that non-canonical Wnt signaling is involved in regulating vasculogenic mimicry (VM) formation. However, the functions of canonical Wnt signaling in VM formation have not yet been explored. In this study, we found the presence of VM was related to colon cancer histological differentiation (p colon cancer samples showed increased Wnt3a expression (p colon cancer cells promoted the capacity to form tube-like structures in the three-dimensional (3-D) culture together with increased expression of endothelial phenotype-associated proteins such as VEGFR2 and VE-cadherin. The mouse xenograft model showed that Wnt3a-overexpressing cells grew into larger tumor masses and formed more VM than the control cells. In addition, the Wnt/β-catenin signaling antagonist Dickkopf-1(Dkk1) can reverse the capacity to form tube-like structures and can decrease the expressions of VEGFR2 and VE-cadherin in Wnt3a-overexpressing cells. Taken together, our results suggest that Wnt/β-catenin signaling is involved in VM formation in colon cancer and might contribute to the development of more accurate treatment modalities aimed at VM.

  14. Biventricular differences in β-adrenergic receptor signaling following burn injury.

    Directory of Open Access Journals (Sweden)

    Ashley N Guillory

    Full Text Available Burn injury detrimentally affects the myocardium, primarily due to over-activation of β-adrenergic receptors (β-AR. Autopsy reports from our institution reveal that patients often suffer from right ventricle (RV failure. Since burn injury affects β-AR signaling in the left ventricle (LV, we proposed that β-AR signaling may also be altered in the RV. A rodent model with a scald burn of 60% of the total body surface area was used to test this hypothesis. Ventricles were isolated 7 days post-burn. We examined the expression of β-ARs via Western blotting and the mRNA expression of downstream signaling proteins via qRT-PCR. Cyclic adenosine monophosphate (cAMP production and protein kinase A (PKA activity were measured in membrane and cytosolic fractions, respectively, using enzyme immunoassay kits. β1-AR protein expression was significantly increased in the RV following burn injury compared to non-burned RV but not in the LV (p = 0.0022. In contrast, β2-AR expression was unaltered among the groups while Gαi expression was significantly higher in the LV post-burn (p = 0.023. B-arrestin-1 and G-protein coupled receptor kinase-2 mRNA expression were significantly increased in the left ventricle post-burn (p = 0.001, p<0.0001, respectively. cAMP production and PKA activity were significantly lower in the LV post-burn (p = 0.0063, 0.0042, respectively. These data indicate that burn injury affects the β-AR signaling pathway in the RV independently of the LV. Additionally, non-canonical β-AR signaling may be activated in the RV as cAMP production and PKA activity were unchanged despite changes in β1-AR protein expression.

  15. Stiffness-dependent cellular internalization of matrix-bound BMP-2 and its relation to Smad and non-Smad signaling.

    Science.gov (United States)

    Gilde, Flora; Fourel, Laure; Guillot, Raphael; Pignot-Paintrand, Isabelle; Okada, Takaharu; Fitzpatrick, Vincent; Boudou, Thomas; Albiges-Rizo, Corinne; Picart, Catherine

    2016-12-01

    Surface coatings delivering BMP are a promising approach to render biomaterials osteoinductive. In contrast to soluble BMPs which can interact with their receptors at the dorsal side of the cell, BMPs presented as an insoluble cue physically bound to a biomimetic matrix, called here matrix-bound (bBMP-2), are presented to cells by their ventral side. To date, BMP-2 internalization and signaling studies in cell biology have always been performed by adding soluble (sBMP-2) to cells adhered on cell culture plates or glass slides, which will be considered here as a "reference" condition. However, whether and how matrix-bound BMP-2 can be internalized by cells and its relation to canonical (SMAD) and non-canonical signaling (ALP) remain open questions. In this study, we investigated the uptake and processing of BMP-2 by C2C12 myoblasts. This BMP-2 was presented either embedded in polyelectrolyte multilayer films (matrix-bound presentation) or as soluble form. Using fluorescently labeled BMP-2, we showed that the amount of matrix-bound BMP-2 internalized is dependent on the level of crosslinking of the polyelectrolyte films. Cav-1-mediated internalization is related to both SMAD and ALP signaling, while clathrin-mediated is only related to ALP signaling. BMP-2 internalization was independent of the presentation mode (sBMP-2 versus bBMP-2) for low crosslinked films (soft, EDC10) in striking contrast with high crosslinked (stiff, EDC70) films where internalization was much lower and slower for bBMP-2. As anticipated, internalization of sBMP-2 barely depended on the underlying matrix. Taken together, these results indicate that BMP-2 internalization can be tuned by the underlying matrix and activates downstream BMP-2 signaling, which is key for the effective formation of bone tissue. The presentation of growth factors from material surfaces currently presents significant challenges in academic research, clinics and industry. Being able to deliver efficiently these growth

  16. Signal sciences workshop. Proceedings

    International Nuclear Information System (INIS)

    Candy, J.V.

    1997-01-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing

  17. Traffic signal timing manual

    Science.gov (United States)

    2008-06-01

    This report serves as a comprehensive guide to traffic signal timing and documents the tasks completed in association with its development. The focus of this document is on traffic signal control principles, practices, and procedures. It describes th...

  18. Signal sciences workshop proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Candy, J.V.

    1997-05-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing.

  19. Biomedical signal processing

    CERN Document Server

    Akay, Metin

    1994-01-01

    Sophisticated techniques for signal processing are now available to the biomedical specialist! Written in an easy-to-read, straightforward style, Biomedical Signal Processing presents techniques to eliminate background noise, enhance signal detection, and analyze computer data, making results easy to comprehend and apply. In addition to examining techniques for electrical signal analysis, filtering, and transforms, the author supplies an extensive appendix with several computer programs that demonstrate techniques presented in the text.

  20. Identification of a noncanonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain.

    Directory of Open Access Journals (Sweden)

    Yu-Ting Chou

    2018-01-01

    Full Text Available Altered metabolism is one of the hallmarks of cancers. Deregulation of ribose-5-phosphate isomerase A (RPIA in the pentose phosphate pathway (PPP is known to promote tumorigenesis in liver, lung, and breast tissues. Yet, the molecular mechanism of RPIA-mediated colorectal cancer (CRC is unknown. Our study demonstrates a noncanonical function of RPIA in CRC. Data from the mRNAs of 80 patients' CRC tissues and paired nontumor tissues and protein levels, as well as a CRC tissue array, indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of β-catenin in colon cancer cell lines. Unlike its role in PPP in which RPIA functions within the cytosol, RPIA enters the nucleus to form a complex with the adenomatous polyposis coli (APC and β-catenin. This association protects β-catenin by preventing its phosphorylation, ubiquitination, and subsequent degradation. The C-terminus of RPIA (amino acids 290 to 311, a region distinct from its enzymatic domain, is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of β-catenin and its target genes, and induces tumorigenesis in gut-specific promotor-carrying RPIA transgenic zebrafish. Together, we demonstrate a novel function of RPIA in CRC formation in which RPIA enters the nucleus and stabilizes β-catenin activity and suggests that RPIA might be a biomarker for targeted therapy and prognosis.

  1. 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.

    Science.gov (United States)

    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 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.

  2. TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation.

    Directory of Open Access Journals (Sweden)

    Hannah Greenfeld

    2015-05-01

    Full Text Available The Epstein-Barr virus (EBV encoded oncoprotein Latent Membrane Protein 1 (LMP1 signals through two C-terminal tail domains to drive cell growth, survival and transformation. The LMP1 membrane-proximal TES1/CTAR1 domain recruits TRAFs to activate MAP kinase, non-canonical and canonical NF-kB pathways, and is critical for EBV-mediated B-cell transformation. TRAF1 is amongst the most highly TES1-induced target genes and is abundantly expressed in EBV-associated lymphoproliferative disorders. We found that TRAF1 expression enhanced LMP1 TES1 domain-mediated activation of the p38, JNK, ERK and canonical NF-kB pathways, but not non-canonical NF-kB pathway activity. To gain insights into how TRAF1 amplifies LMP1 TES1 MAP kinase and canonical NF-kB pathways, we performed proteomic analysis of TRAF1 complexes immuno-purified from cells uninduced or induced for LMP1 TES1 signaling. Unexpectedly, we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC, and stimulated linear (M1-linked polyubiquitin chain attachment to TRAF1 complexes. LMP1 or TRAF1 complexes isolated from EBV-transformed lymphoblastoid B cell lines (LCLs were highly modified by M1-linked polyubiqutin chains. The M1-ubiquitin binding proteins IKK-gamma/NEMO, A20 and ABIN1 each associate with TRAF1 in cells that express LMP1. TRAF2, but not the cIAP1 or cIAP2 ubiquitin ligases, plays a key role in LUBAC recruitment and M1-chain attachment to TRAF1 complexes, implicating the TRAF1:TRAF2 heterotrimer in LMP1 TES1-dependent LUBAC activation. Depletion of either TRAF1, or the LUBAC ubiquitin E3 ligase subunit HOIP, markedly impaired LCL growth. Likewise, LMP1 or TRAF1 complexes purified from LCLs were decorated by lysine 63 (K63-linked polyubiqutin chains. LMP1 TES1 signaling induced K63-polyubiquitin chain attachment to TRAF1 complexes, and TRAF2 was identified as K63-Ub chain target. Co-localization of M1- and K63

  3. Optimal Signal Quality Index for Photoplethysmogram Signals

    Directory of Open Access Journals (Sweden)

    Mohamed Elgendi

    2016-09-01

    Full Text Available A photoplethysmogram (PPG is a noninvasive circulatory signal related to the pulsatile volume of blood in tissue and is typically collected by pulse oximeters. PPG signals collected via mobile devices are prone to artifacts that negatively impact measurement accuracy, which can lead to a significant number of misleading diagnoses. Given the rapidly increased use of mobile devices to collect PPG signals, developing an optimal signal quality index (SQI is essential to classify the signal quality from these devices. Eight SQIs were developed and tested based on: perfusion, kurtosis, skewness, relative power, non-stationarity, zero crossing, entropy, and the matching of systolic wave detectors. Two independent annotators annotated all PPG data (106 recordings, 60 s each and a third expert conducted the adjudication of differences. The independent annotators labeled each PPG signal with one of the following labels: excellent, acceptable or unfit for diagnosis. All indices were compared using Mahalanobis distance, linear discriminant analysis, quadratic discriminant analysis, and support vector machine with leave-one-out cross-validation. The skewness index outperformed the other seven indices in differentiating between excellent PPG and acceptable, acceptable combined with unfit, and unfit recordings, with overall F 1 scores of 86.0%, 87.2%, and 79.1%, respectively.

  4. Optimal Signal Quality Index for Photoplethysmogram Signals.

    Science.gov (United States)

    Elgendi, Mohamed

    2016-09-22

    A photoplethysmogram (PPG) is a noninvasive circulatory signal related to the pulsatile volume of blood in tissue and is typically collected by pulse oximeters. PPG signals collected via mobile devices are prone to artifacts that negatively impact measurement accuracy, which can lead to a significant number of misleading diagnoses. Given the rapidly increased use of mobile devices to collect PPG signals, developing an optimal signal quality index (SQI) is essential to classify the signal quality from these devices. Eight SQIs were developed and tested based on: perfusion, kurtosis, skewness, relative power, non-stationarity, zero crossing, entropy, and the matching of systolic wave detectors. Two independent annotators annotated all PPG data (106 recordings, 60 s each) and a third expert conducted the adjudication of differences. The independent annotators labeled each PPG signal with one of the following labels: excellent, acceptable or unfit for diagnosis. All indices were compared using Mahalanobis distance, linear discriminant analysis, quadratic discriminant analysis, and support vector machine with leave-one-out cross-validation. The skewness index outperformed the other seven indices in differentiating between excellent PPG and acceptable, acceptable combined with unfit, and unfit recordings, with overall F 1 scores of 86.0%, 87.2%, and 79.1%, respectively.

  5. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

    Science.gov (United States)

    Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

    2017-04-01

    In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

  6. The Signal Distribution System

    CERN Document Server

    Belohrad, D; CERN. Geneva. AB Department

    2005-01-01

    For the purpose of LHC signal observation and high frequency signal distribution, the Signal Distribution System (SDS) was built. The SDS can contain up to 5 switching elements, where each element allows the user to switch between one of the maximum 8 bi-directional signals. The coaxial relays are used to switch the signals. Depending of the coaxial relay type used, the transfer bandwidth can go up to 18GHz. The SDS is controllable via TCP/IP, parallel port, or locally by rotary switch.

  7. Acoustic Signals and Systems

    DEFF Research Database (Denmark)

    2008-01-01

    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook...... will present topics on signal processing which are important in a specific area of acoustics. These will be of interest to specialists in these areas because they will be presented from their technical perspective, rather than a generic engineering approach to signal processing. Non-specialists, or specialists...

  8. Method of signal analysis

    International Nuclear Information System (INIS)

    Berthomier, Charles

    1975-01-01

    A method capable of handling the amplitude and the frequency time laws of a certain kind of geophysical signals is described here. This method is based upon the analytical signal idea of Gabor and Ville, which is constructed either in the time domain by adding an imaginary part to the real signal (in-quadrature signal), or in the frequency domain by suppressing negative frequency components. The instantaneous frequency of the initial signal is then defined as the time derivative of the phase of the analytical signal, and his amplitude, or envelope, as the modulus of this complex signal. The method is applied to three types of magnetospheric signals: chorus, whistlers and pearls. The results obtained by analog and numerical calculations are compared to results obtained by classical systems using filters, i.e. based upon a different definition of the concept of frequency. The precision with which the frequency-time laws are determined leads then to the examination of the principle of the method and to a definition of instantaneous power density spectrum attached to the signal, and to the first consequences of this definition. In this way, a two-dimensional representation of the signal is introduced which is less deformed by the analysis system properties than the usual representation, and which moreover has the advantage of being obtainable practically in real time [fr

  9. Wnt signaling in cancer

    Science.gov (United States)

    Zhan, T; Rindtorff, N; Boutros, M

    2017-01-01

    Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches. PMID:27617575

  10. Biomedical signals and systems

    CERN Document Server

    Tranquillo, Joseph V

    2013-01-01

    Biomedical Signals and Systems is meant to accompany a one-semester undergraduate signals and systems course. It may also serve as a quick-start for graduate students or faculty interested in how signals and systems techniques can be applied to living systems. The biological nature of the examples allows for systems thinking to be applied to electrical, mechanical, fluid, chemical, thermal and even optical systems. Each chapter focuses on a topic from classic signals and systems theory: System block diagrams, mathematical models, transforms, stability, feedback, system response, control, time

  11. Digital signal processing

    CERN Document Server

    O'Shea, Peter; Hussain, Zahir M

    2011-01-01

    In three parts, this book contributes to the advancement of engineering education and that serves as a general reference on digital signal processing. Part I presents the basics of analog and digital signals and systems in the time and frequency domain. It covers the core topics: convolution, transforms, filters, and random signal analysis. It also treats important applications including signal detection in noise, radar range estimation for airborne targets, binary communication systems, channel estimation, banking and financial applications, and audio effects production. Part II considers sel

  12. Geolocation of RF signals

    CERN Document Server

    Progri, Ilir

    2011-01-01

    ""Geolocation of RF Signals - Principles and Simulations"" offers an overview of the best practices and innovative techniques in the art and science of geolocation over the last twenty years. It covers all research and development aspects including theoretical analysis, RF signals, geolocation techniques, key block diagrams, and practical principle simulation examples in the frequency band from 100 MHz to 18 GHz or even 60 GHz. Starting with RF signals, the book progressively examines various signal bands - such as VLF, LF, MF, HF, VHF, UHF, L, S, C, X, Ku, and, K and the corresponding geoloca

  13. Biomolecular Cell-Signaling Mechanisms and Dental Implants: A Review on the Regulatory Molecular Biologic Patterns Under Functional and Immediate Loading.

    Science.gov (United States)

    Romanos, Georgios E

    2016-01-01

    Bone tissue adapts its structure and mass to the stresses of mechanical loading. The purpose of this review article was to summarize recent advances on cell signaling relating to the phenomenon of bone remodeling, focused on bone ossification and healing at the interface of dental implants and bone under loading conditions. When a dental implant is placed within an osteotomy, osteocytes, osteoblasts, and osteoclasts are all present. As functional loads are imposed, the remodeling processes adapt the peri-implant bony tissues to mechanical stimuli over time and reestablish a steady state. Based on the current literature, this article demonstrates fundamental information to these remodeling processes, such as the conversion of mechanical cues to electrical or biochemical signals. Multiple intracellular signals are involved in cellular mechanotransduction; the two Wnt signaling pathways (the canonical, β-catenin-dependent and the noncanonical, β-catenin-independent Wnt pathway) are particularly significant. Knowledge of how these molecular signaling pathways are translated into intracellular signals that regulate cell behavior may provide new therapeutic approaches to enhancing osteogenesis, especially around implants with immediate function or placed in areas of poor bone quality. New knowledge about the primary cilia as an organelle and bone cellular mechanosensor is critical for endochondral ossification and proper signal transduction. Other mechanisms, such as the expression of sclerostin as a negative regulator of bone formation (due to deactivation of the Wnt receptor) and downregulation of sclerostin under loading conditions, also present new understanding of the cellular and pericellular mechanics of bone. The complexity of the cell signaling pathways and the mechanisms involved in the mechanoregulation of the bone formation provide new technologies and perspectives for mechanically induced cellular response. Future novel therapeutic approaches based on the

  14. Loss of a conserved tRNA anticodon modification perturbs cellular signaling.

    Directory of Open Access Journals (Sweden)

    Boris Zinshteyn

    Full Text Available Transfer RNA (tRNA modifications enhance the efficiency, specificity and fidelity of translation in all organisms. The anticodon modification mcm(5s(2U(34 is required for normal growth and stress resistance in yeast; mutants lacking this modification have numerous phenotypes. Mutations in the homologous human genes are linked to neurological disease. The yeast phenotypes can be ameliorated by overexpression of specific tRNAs, suggesting that the modifications are necessary for efficient translation of specific codons. We determined the in vivo ribosome distributions at single codon resolution in yeast strains lacking mcm(5s(2U. We found accumulations at AAA, CAA, and GAA codons, suggesting that translation is slow when these codons are in the ribosomal A site, but these changes appeared too small to affect protein output. Instead, we observed activation of the GCN4-mediated stress response by a non-canonical pathway. Thus, loss of mcm(5s(2U causes global effects on gene expression due to perturbation of cellular signaling.

  15. In-frame amber stop codon replacement mutagenesis for the directed evolution of proteins containing non-canonical amino acids: identification of residues open to bio-orthogonal modification.

    Science.gov (United States)

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

    2015-01-01

    Expanded genetic code approaches are a powerful means to add new and useful chemistry to proteins at defined residues positions. One such use is the introduction of non-biological reactive chemical handles for site-specific biocompatible orthogonal conjugation of proteins. Due to our currently limited information on the impact of non-canonical amino acids (nAAs) on the protein structure-function relationship, rational protein engineering is a "hit and miss" approach to selecting suitable sites. Furthermore, dogma suggests surface exposed native residues should be the primary focus for introducing new conjugation chemistry. Here we describe a directed evolution approach to introduce and select for in-frame codon replacement to facilitate engineering proteins with nAAs. To demonstrate the approach, the commonly reprogrammed amber stop codon (TAG) was randomly introduced in-frame in two different proteins: the bionanotechnologically important cyt b(562) and therapeutic protein KGF. The target protein is linked at the gene level to sfGFP via a TEV protease site. In absence of a nAA, an in-frame TAG will terminate translation resulting in a non-fluorescent cell phenotype. In the presence of a nAA, TAG will encode for nAA incorporation so instilling a green fluorescence phenotype on E. coli. The presence of endogenously expressed TEV proteases separates in vivo target protein from its fusion to sfGFP if expressed as a soluble fusion product. Using this approach, we incorporated an azide reactive handle and identified residue positions amenable to conjugation with a fluorescence dye via strain-promoted azide-alkyne cycloaddition (SPAAC). Interestingly, best positions for efficient conjugation via SPAAC were residues whose native side chain were buried through analysis of their determined 3D structures and thus may not have been chosen through rational protein engineering. Molecular modeling suggests these buried native residues could become partially exposed on

  16. TNFα modulates Fibroblast Growth Factor Receptor 2 gene expression through the pRB/E2F1 pathway: identification of a non-canonical E2F binding motif.

    Directory of Open Access Journals (Sweden)

    Sirio D'Amici

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

  17. 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.

    Directory of Open Access Journals (Sweden)

    Timokratis Karamitros

    Full Text Available 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(G50 and N(G75 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.

  18. In-frame amber stop codon replacement mutagenesis for the directed evolution of proteins containing non-canonical amino acids: identification of residues open to bio-orthogonal modification.

    Directory of Open Access Journals (Sweden)

    James A J Arpino

    Full Text Available Expanded genetic code approaches are a powerful means to add new and useful chemistry to proteins at defined residues positions. One such use is the introduction of non-biological reactive chemical handles for site-specific biocompatible orthogonal conjugation of proteins. Due to our currently limited information on the impact of non-canonical amino acids (nAAs on the protein structure-function relationship, rational protein engineering is a "hit and miss" approach to selecting suitable sites. Furthermore, dogma suggests surface exposed native residues should be the primary focus for introducing new conjugation chemistry. Here we describe a directed evolution approach to introduce and select for in-frame codon replacement to facilitate engineering proteins with nAAs. To demonstrate the approach, the commonly reprogrammed amber stop codon (TAG was randomly introduced in-frame in two different proteins: the bionanotechnologically important cyt b(562 and therapeutic protein KGF. The target protein is linked at the gene level to sfGFP via a TEV protease site. In absence of a nAA, an in-frame TAG will terminate translation resulting in a non-fluorescent cell phenotype. In the presence of a nAA, TAG will encode for nAA incorporation so instilling a green fluorescence phenotype on E. coli. The presence of endogenously expressed TEV proteases separates in vivo target protein from its fusion to sfGFP if expressed as a soluble fusion product. Using this approach, we incorporated an azide reactive handle and identified residue positions amenable to conjugation with a fluorescence dye via strain-promoted azide-alkyne cycloaddition (SPAAC. Interestingly, best positions for efficient conjugation via SPAAC were residues whose native side chain were buried through analysis of their determined 3D structures and thus may not have been chosen through rational protein engineering. Molecular modeling suggests these buried native residues could become partially

  19. Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates.

    Science.gov (United States)

    Susman, Michael W; Karuna, Edith P; Kunz, Ryan C; Gujral, Taranjit S; Cantú, Andrea V; Choi, Shannon S; Jong, Brigette Y; Okada, Kyoko; Scales, Michael K; Hum, Jennie; Hu, Linda S; Kirschner, Marc W; Nishinakamura, Ryuichi; Yamada, Soichiro; Laird, Diana J; Jao, Li-En; Gygi, Steven P; Greenberg, Michael E; Ho, Hsin-Yi Henry

    2017-09-08

    Wnt5a-Ror signaling constitutes a developmental pathway crucial for embryonic tissue morphogenesis, reproduction and adult tissue regeneration, yet the molecular mechanisms by which the Wnt5a-Ror pathway mediates these processes are largely unknown. Using a proteomic screen, we identify the kinesin superfamily protein Kif26b as a downstream target of the Wnt5a-Ror pathway. Wnt5a-Ror, through a process independent of the canonical Wnt/β-catenin-dependent pathway, regulates the cellular stability of Kif26b by inducing its degradation via the ubiquitin-proteasome system. Through this mechanism, Kif26b modulates the migratory behavior of cultured mesenchymal cells in a Wnt5a-dependent manner. Genetic perturbation of Kif26b function in vivo caused embryonic axis malformations and depletion of primordial germ cells in the developing gonad, two phenotypes characteristic of disrupted Wnt5a-Ror signaling. These findings indicate that Kif26b links Wnt5a-Ror signaling to the control of morphogenetic cell and tissue behaviors in vertebrates and reveal a new role for regulated proteolysis in noncanonical Wnt5a-Ror signal transduction.

  20. Signaling in symbiosis

    NARCIS (Netherlands)

    Limpens, E.H.M.; Bisseling, T.

    2003-01-01

    In recent years, the major focus in nodulation research has been on the genetic dissection of Nod-factor signaling. Components of this pathway appear to be shared with signaling processes that are induced during the formation of mycorrhiza. With the cloning of orthologs of the NIN and DMI2 genes

  1. SignalR blueprints

    CERN Document Server

    Ingebrigtsen, Einar

    2015-01-01

    This book is designed for software developers, primarily those with knowledge of C#, .NET, and JavaScript. Good knowledge and understanding of SignalR is assumed to allow efficient programming of core elements and applications in SignalR.

  2. Digital Signal Processors

    Indian Academy of Sciences (India)

    A computer controlling the motion of a satellite should acquire signals from the satellite while it is in motion, compute corrections (if required) to the trajectory and send control signals back within a specified time for effective control. Delays may be fatal to ..... emulators and system evaluation tools have facilitated concurrent.

  3. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  4. Second-hand signals

    DEFF Research Database (Denmark)

    Bergenholtz, Carsten

    2014-01-01

    used by various agents in their search for and assessment of products and firms. I conclude by arguing how this second‐hand nature of signals goes beyond a simple dyadic focus on senders and receivers of signals, and thus elucidates the more complex interrelations of the various types of agents...

  5. Quantum cloning without signaling

    OpenAIRE

    Gisin, Nicolas

    1998-01-01

    Perfect Quantum Cloning Machines (QCM) would allow to use quantum nonlocality for arbitrary fast signaling. However perfect QCM cannot exist. We derive a bound on the fidelity of QCM compatible with the no-signaling constraint. This bound equals the fidelity of the Bu\\v{z}ek-Hillery QCM.

  6. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2011-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  7. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2010-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  8. Optimal fault signal estimation

    NARCIS (Netherlands)

    Stoorvogel, Antonie Arij; Niemann, H.H.; Saberi, A.; Sannuti, P.

    2002-01-01

    We consider here both fault identification and fault signal estimation. Regarding fault identification, we seek either exact or almost fault identification. On the other hand, regarding fault signal estimation, we seek either $H_2$ optimal, $H_2$ suboptimal or Hinfinity suboptimal estimation. By

  9. Primary cilia are not required for normal canonical Wnt signaling in the mouse embryo.

    Directory of Open Access Journals (Sweden)

    Polloneal Jymmiel R Ocbina

    2009-08-01

    Full Text Available Sonic hedgehog (Shh signaling in the mouse requires the microtubule-based organelle, the primary cilium. The primary cilium is assembled and maintained through the process of intraflagellar transport (IFT and the response to Shh is blocked in mouse mutants that lack proteins required for IFT. Although the phenotypes of mouse IFT mutants do not overlap with phenotypes of known Wnt pathway mutants, recent studies report data suggesting that the primary cilium modulates responses to Wnt signals.We therefore carried out a systematic analysis of canonical Wnt signaling in mutant embryos and cells that lack primary cilia because of loss of the anterograde IFT kinesin-II motor (Kif3a or IFT complex B proteins (Ift172 or Ift88. We also analyzed mutant embryos with abnormal primary cilia due to defects in retrograde IFT (Dync2h1. The mouse IFT mutants express the canonical Wnt target Axin2 and activate a transgenic canonical Wnt reporter, BAT-gal, in the normal spatial pattern and to the same quantitative level as wild type littermates. Similarly, mouse embryonic fibroblasts (MEFs derived from IFT mutants respond normally to added Wnt3a. The switch from canonical to non-canonical Wnt also appears normal in IFT mutant MEFs, as both wild-type and mutant cells do not activate the canonical Wnt reporter in the presence of both Wnt3a and Wnt5a.We conclude that loss of primary cilia or defects in retrograde IFT do not affect the response of the midgestation embryo or embryo-derived fibroblasts to Wnt ligands.

  10. Rac1 modulates mammalian lung branching morphogenesis in part through canonical Wnt signaling.

    Science.gov (United States)

    Danopoulos, Soula; Krainock, Michael; Toubat, Omar; Thornton, Matthew; Grubbs, Brendan; Al Alam, Denise

    2016-12-01

    Lung branching morphogenesis relies on a number of factors, including proper epithelial cell proliferation and differentiation, cell polarity, and migration. Rac1, a small Rho GTPase, orchestrates a number of these cellular processes, including cell proliferation and differentiation, cellular alignment, and polarization. Furthermore, Rac1 modulates both noncanonical and canonical Wnt signaling, important pathways in lung branching morphogenesis. Culture of embryonic mouse lung explants in the presence of the Rac1 inhibitor (NSC23766) resulted in a dose-dependent decrease in branching. Increased cell death and BrdU uptake were notably seen in the mesenchyme, while no direct effect on the epithelium was observed. Moreover, vasculogenesis was impaired following Rac1 inhibition as shown by decreased Vegfa expression and impaired LacZ staining in Flk1-Lacz reporter mice. Rac1 inhibition decreased Fgf10 expression in conjunction with many of its associated factors. Moreover, using the reporter lines TOPGAL and Axin2-LacZ, there was an evident decrease in canonical Wnt signaling in the explants treated with the Rac1 inhibitor. Activation of canonical Wnt pathway using WNT3a or WNT7b only partially rescued the branching inhibition. Moreover, these results were validated on human explants, where Rac1 inhibition resulted in impaired branching and decreased AXIN2 and FGFR2b expression. We therefore conclude that Rac1 regulates lung branching morphogenesis, in part through canonical Wnt signaling. However, the exact mechanisms by which Rac1 interacts with canonical Wnt in human and mouse lung requires further investigation. Copyright © 2016 the American Physiological Society.

  11. Bone morphogenetic protein-7: Review of signalling and efficacy in fracture healing

    Directory of Open Access Journals (Sweden)

    Steven Cecchi

    2016-01-01

    Full Text Available Bone morphogenetic proteins (BMPs are a group of signalling molecules that belong to the transforming growth factor-β superfamily of proteins. Initially identified for their ability to induce bone formation, recent advances in the understanding of cellular and molecular mechanisms regarding BMPs have led to the use of the growth factor to accelerate bone healing. Recent clinical trials have demonstrated that BMPs, BMP-7 in particular, may present an alternative line of treatment other than the gold standard, autogenous bone grafting, in the treatment of fracture nonunion. We performed a literature search in September 2014 of PubMed and Embase using search terms, including “bone morphogenetic proteins”, “BMP-7”, “non-union”, “fracture healing” and “cost-effectiveness”, reviewing the efficacy, safety, and cost of treatment of nonunions with BMP-7. The authors further canvassed the reference lists of selected articles and used online search tools, such as Google Scholar. BMP-7 uses both the canonical and noncanonical signalling pathways. The treatment of fracture nonunion with recombinant human BMP-7 (rhBMP-7 has a comparable efficacy with that of autogenous bone grafting with an average union rate of 87% compared with 93% for bone grafting. Furthermore, fewer complications have been described with the use of rhBMP-7 compared with traditional bone grafting. We describe the signalling pathways that BMP-7 uses to exert its effect on bone. In nonunions, rhBMP-7 has been shown to have a similar efficacy to bone grafting with fewer complications.

  12. Neutron signal transfer analysis

    CERN Document Server

    Pleinert, H; Lehmann, E

    1999-01-01

    A new method called neutron signal transfer analysis has been developed for quantitative determination of hydrogenous distributions from neutron radiographic measurements. The technique is based on a model which describes the detector signal obtained in the measurement as a result of the action of three different mechanisms expressed by signal transfer functions. The explicit forms of the signal transfer functions are determined by Monte Carlo computer simulations and contain only the distribution as a variable. Therefore an unknown distribution can be determined from the detector signal by recursive iteration. This technique provides a simple and efficient tool for analysis of this type while also taking into account complex effects due to the energy dependency of neutron interaction and single and multiple scattering. Therefore this method provides an efficient tool for precise quantitative analysis using neutron radiography, as for example quantitative determination of moisture distributions in porous buil...

  13. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin

    2005-01-01

    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  14. Adaptive signal processor

    Energy Technology Data Exchange (ETDEWEB)

    Walz, H.V.

    1980-07-01

    An experimental, general purpose adaptive signal processor system has been developed, utilizing a quantized (clipped) version of the Widrow-Hoff least-mean-square adaptive algorithm developed by Moschner. The system accommodates 64 adaptive weight channels with 8-bit resolution for each weight. Internal weight update arithmetic is performed with 16-bit resolution, and the system error signal is measured with 12-bit resolution. An adapt cycle of adjusting all 64 weight channels is accomplished in 8 ..mu..sec. Hardware of the signal processor utilizes primarily Schottky-TTL type integrated circuits. A prototype system with 24 weight channels has been constructed and tested. This report presents details of the system design and describes basic experiments performed with the prototype signal processor. Finally some system configurations and applications for this adaptive signal processor are discussed.

  15. Adaptive signal processor

    International Nuclear Information System (INIS)

    Walz, H.V.

    1980-07-01

    An experimental, general purpose adaptive signal processor system has been developed, utilizing a quantized (clipped) version of the Widrow-Hoff least-mean-square adaptive algorithm developed by Moschner. The system accommodates 64 adaptive weight channels with 8-bit resolution for each weight. Internal weight update arithmetic is performed with 16-bit resolution, and the system error signal is measured with 12-bit resolution. An adapt cycle of adjusting all 64 weight channels is accomplished in 8 μsec. Hardware of the signal processor utilizes primarily Schottky-TTL type integrated circuits. A prototype system with 24 weight channels has been constructed and tested. This report presents details of the system design and describes basic experiments performed with the prototype signal processor. Finally some system configurations and applications for this adaptive signal processor are discussed

  16. Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

    Directory of Open Access Journals (Sweden)

    Julia Jellusova

    2013-11-01

    Full Text Available BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K, and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff−/− animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.

  17. Context-specific BAFF-R signaling by the NF-κB and PI3K pathways

    Science.gov (United States)

    Jellusova, Julia; Miletic, Ana V.; Cato, Matthew H.; Lin, Wai-Wai; Hu, Yinling; Bishop, Gail A.; Shlomchik, Mark J.; Rickert, Robert C.

    2014-01-01

    Summary BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the non-canonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via PI3K, and that co-inactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff−/− animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner. PMID:24239354

  18. A positive role for patched-smoothened signaling in promoting cell proliferation during normal head development in Drosophila.

    Science.gov (United States)

    Shyamala, Baragur V; Bhat, Krishna Moorthi

    2002-04-01

    The transmembrane receptor Patched regulates several developmental processes in both invertebrates and vertebrates. In vertebrates, Patched also acts as a tumor suppressor. The Patched pathway normally operates by negatively regulating Smoothened, a G-protein-coupled receptor; binding of Hedgehog ligand to Patched relieves this negative interaction and allows signaling by Smoothened. We show that Ptc regulates Drosophila head development by promoting cell proliferation in the eye-antennal disc. During head morphogenesis, Patched positively interacts with Smoothened, which leads to the activation of Activin type I receptor Baboon and stimulation of cell proliferation in the eye-antennal disc. Thus, loss of Ptc or Smoothened activity affects cell proliferation in the eye-antennal disc and results in adult head capsule defects. Similarly, reducing the dose of smoothened in a patched background enhances the head defects. Consistent with these results, gain-of-function Hedgehog interferes with the activation of Baboon by Patched and Smoothened, leading to a similar head capsule defect. Expression of an activated form of Baboon in the patched domain in a patched mutant background completely rescues the head defects. These results provide insight into head morphogenesis, a process we know very little about, and reveal an unexpected non-canonical positive signaling pathway in which Patched and Smoothened function to promote cell proliferation as opposed to repressing it.

  19. CLAMP/Spef1 regulates planar cell polarity signaling and asymmetric microtubule accumulation in the Xenopus ciliated epithelia.

    Science.gov (United States)

    Kim, Sun K; Zhang, Siwei; Werner, Michael E; Brotslaw, Eva J; Mitchell, Jennifer W; Altabbaa, Mohamed M; Mitchell, Brian J

    2018-03-07

    Most epithelial cells polarize along the axis of the tissue, a feature known as planar cell polarity (PCP). The initiation of PCP requires cell-cell signaling via the noncanonical Wnt/PCP pathway. Additionally, changes in the cytoskeleton both facilitate and reflect this polarity. We have identified CLAMP/Spef1 as a novel regulator of PCP signaling. In addition to decorating microtubules (MTs) and the ciliary rootlet, a pool of CLAMP localizes at the apical cell cortex. Depletion of CLAMP leads to the loss of PCP protein asymmetry, defects in cilia polarity, and defects in the angle of cell division. Additionally, depletion of CLAMP leads to a loss of the atypical cadherin-like molecule Celrs2, suggesting that CLAMP facilitates the stabilization of junctional interactions responsible for proper PCP protein localization. Depletion of CLAMP also affects the polarized organization of MTs. We hypothesize that CLAMP facilitates the establishment of cell polarity and promotes the asymmetric accumulation of MTs downstream of the establishment of proper PCP. © 2018 Kim et al.

  20. Wnt5a mediated canonical Wnt signaling pathway activation in orthodontic tooth movement: possible role in the tension force-induced bone formation.

    Science.gov (United States)

    Fu, Hai-Di; Wang, Bei-Ke; Wan, Zi-Qiu; Lin, Heng; Chang, Mao-Lin; Han, Guang-Li

    2016-10-01

    Orthodontic tooth movement (OTM) is associated with bone remodeling mediated by orthodontic mechanical loading. Increasing studies reported that Wnt signaling played crucial roles in mechanical stimuli induced bone remodeling. However, little is known about the involvement of Wnt signaling in orthodontic force-induced bone formation during OTM. In virtue of the OTM mice model as we previously reported, where new bone formation was determined by micro-CT and immunoreactivity of osteocalcin and osterix, we explored the activation of Wnt signaling pathway during OTM. Our results proved the nuclei translocation of β-catenin, suggesting the activation of canonical Wnt signaling pathway in the periodontal ligament cells (PDLCs) near the alveolar bone at the tension site (TS). Moreover, the immunoreactivity of Wnt5a, but not Wnt3a in PDLCs indicated the activation of canonical Wnt pathway might be mediated by Wnt5a, but not Wnt3a as in most cases. The co-location of Wnt5a and β-catenin that was evidenced by double labeling immunofluorescence staining further supported the hypothesis. In addition, the high expression of FZD4 and LRP5 in PDLCs at TS of periodontium suggested that the activation of Wnt signaling pathway was mediated by these receptors. The negligible expression of ROR2 also indicated that canonical but not non-canonical Wnt signaling pathway was activated by Wnt5a, since previous studies demonstrated that the activation of canonical/non-canonical Wnt signaling pathway was largely dependent on the receptors. In summary, we here reported that Wnt5a mediated activation of canonical Wnt signaling pathway might contribute to the orthodontic force induced bone remodeling.

  1. Wnt and β-Catenin Signaling and Skeletal Muscle Myogenesis in Response to Muscle Damage and Resistance Exercise and Training

    Directory of Open Access Journals (Sweden)

    Dan Newmire

    2015-10-01

    Full Text Available The factors that regulate skeletal muscle hypertrophy in human adults in response to resistance training (RT has largely focused on endogenous endocrine responses. However, the endocrine response to RT as having an obligatory role in muscle hypertrophy has come under scrutiny, as other mechanisms and pathways seem to also be involved in up-regulating muscle protein synthesis (MPS. Skeletal muscle myogenesis is a multifactorial process of tissue growth and repair in response to resistance training is regulated by many factors.  As a result, satellite cell-fused myogenesis is a possible factor in skeletal muscle regeneration and hypertrophy in response to RT.  The Wnt family ligands interact with various receptors and activate different downstream signaling pathways and have been classified as either canonical (β-catenin dependent or non-canonical (β-catenin independent.  Wnt is secreted from numerous tissues in a paracrine fashion. The Wnt/β-catenin signaling pathway is a highly-regulated and intricate pathway that is essential to skeletal muscle myogenesis.  The canonical Wnt/β-catenin pathway may influence satellite cells to myogenic commitment, differentiation, and fusion into muscle fibers in response to injury or trauma, self-renewal, and normal basal turnover.  The current literature has shown that, in response mechanical overload from acute resistance exercise and chronic resistance training, that the Wnt/β-catenin signaling pathway is stimulated which may actuate the process of muscle repair and hypertrophy in response to exercise-induced muscle damage. The purpose of this review is to elaborate on the Wnt/β-catenin signaling  pathway, the current literature investigating the relationship of the Wnt/β-catenin pathway and its effects on myogenesis is response to muscle damage and resistance exercise and training.      Keywords: skeletal muscle, hypertrophy, myogenesis, cell signaling, protein synthesis, resistance

  2. The late endosomal HOPS complex anchors active G-protein signaling essential for pathogenesis in magnaporthe oryzae.

    Directory of Open Access Journals (Sweden)

    Ravikrishna Ramanujam

    Full Text Available In Magnaporthe oryzae, the causal ascomycete of the devastating rice blast disease, the conidial germ tube tip must sense and respond to a wide array of requisite cues from the host in order to switch from polarized to isotropic growth, ultimately forming the dome-shaped infection cell known as the appressorium. Although the role for G-protein mediated Cyclic AMP signaling in appressorium formation was first identified almost two decades ago, little is known about the spatio-temporal dynamics of the cascade and how the signal is transmitted through the intracellular network during cell growth and morphogenesis. In this study, we demonstrate that the late endosomal compartments, comprising of a PI3P-rich (Phosphatidylinositol 3-phosphate highly dynamic tubulo-vesicular network, scaffold active MagA/GαS, Rgs1 (a GAP for MagA, Adenylate cyclase and Pth11 (a non-canonical GPCR in the likely absence of AKAP-like anchors during early pathogenic development in M. oryzae. Loss of HOPS component Vps39 and consequently the late endosomal function caused a disruption of adenylate cyclase localization, cAMP signaling and appressorium formation. Remarkably, exogenous cAMP rescued the appressorium formation defects associated with VPS39 deletion in M. oryzae. We propose that sequestration of key G-protein signaling components on dynamic late endosomes and/or endolysosomes, provides an effective molecular means to compartmentalize and control the spatio-temporal activation and rapid downregulation (likely via vacuolar degradation of cAMP signaling amidst changing cellular geometry during pathogenic development in M. oryzae.

  3. Plasticity of Signaling by Spinal Estrogen Receptor α, κ-Opioid Receptor, and Metabotropic Glutamate Receptors over the Rat Reproductive Cycle Regulates Spinal Endomorphin 2 Antinociception: Relevance of Endogenous-Biased Agonism.

    Science.gov (United States)

    Liu, Nai-Jiang; Murugaiyan, Vijaya; Storman, Emiliya M; Schnell, Stephen A; Kumar, Arjun; Wessendorf, Martin W; Gintzler, Alan R

    2017-11-15

    We previously showed that intrathecal application of endomorphin 2 [EM2; the highly specific endogenous μ-opioid receptor (MOR) ligand] induces antinociception that varies with stage of the rat estrous cycle: minimal during diestrus and prominent during proestrus. Earlier studies, however, did not identify proestrus-activated signaling strategies that enable spinal EM2 antinociception. We now report that in female rats, increased spinal dynorphin release and κ-opioid receptor (KOR) signaling, as well as the emergence of glutamate-activated metabotropic glutamate receptor 1 (mGluR 1 ) signaling, are critical to the transition from an EM2 nonresponsive state (during diestrus) to an analgesically responsive state (during proestrus). Differential signaling by mGluR 1 , depending on its activation by membrane estrogen receptor α (mERα; during diestrus) versus glutamate (during proestrus), concomitant with the ebb and flow of spinal dynorphin/KOR signaling, functions as a switch, preventing or promoting, respectively, spinal EM2 antinociception. Importantly, EM2 and glutamate-containing varicosities appose spinal neurons that express MOR along with mGluRs and mERα, suggesting that signaling mechanisms regulating analgesic effectiveness of intrathecally applied EM2 also pertain to endogenous EM2. Regulation of spinal EM2 antinociception by both the nature of the endogenous mGluR 1 activator (i.e., endogenous biased agonism at mGluR 1 ) and changes in spinal dynorphin/KOR signaling represent a novel mechanism for modulating analgesic responsiveness to endogenous EM2 (and perhaps other opioids). This points the way for developing noncanonical pharmacological approaches to pain management by harnessing endogenous opioids for pain relief. SIGNIFICANCE STATEMENT The current prescription opioid abuse epidemic underscores the urgency to develop alternative pharmacotherapies for managing pain. We find that the magnitude of spinal endomorphin 2 (EM2) antinociception not only

  4. Orexin/Hypocretin Signaling.

    Science.gov (United States)

    Kukkonen, Jyrki P

    Orexin/hypocretin peptide (orexin-A and orexin-B) signaling is believed to take place via the two G-protein-coupled receptors (GPCRs), named OX 1 and OX 2 orexin receptors, as described in the previous chapters. Signaling of orexin peptides has been investigated in diverse endogenously orexin receptor-expressing cells - mainly neurons but also other types of cells - and in recombinant cells expressing the receptors in a heterologous manner. Findings in the different systems are partially convergent but also indicate cellular background-specific signaling. The general picture suggests an inherently high degree of diversity in orexin receptor signaling.In the current chapter, I present orexin signaling on the cellular and molecular levels. Discussion of the connection to (potential) physiological orexin responses is only brief since these are in focus of other chapters in this book. The same goes for the post-synaptic signaling mechanisms, which are dealt with in Burdakov: Postsynaptic actions of orexin. The current chapter is organized according to the tissue type, starting from the central nervous system. Finally, receptor signaling pathways are discussed across tissues, cell types, and even species.

  5. Novel Mutation of LRP6 Identified in Chinese Han Population Links Canonical WNT Signaling to Neural Tube Defects.

    Science.gov (United States)

    Shi, Zhiwen; Yang, Xueyan; Li, Bin-Bin; Chen, Shuxia; Yang, Luming; Cheng, Liangping; Zhang, Ting; Wang, Hongyan; Zheng, Yufang

    2018-01-15

    Neural tube defects (NTDs), the second most frequent cause of human congenital abnormalities, are debilitating birth defects due to failure of neural tube closure. It has been shown that noncanonical WNT/planar cell polarity (PCP) signaling is required for convergent extension (CE), the initiation step of neural tube closure (NTC). But the effect of canonical WNT//β-catenin signaling during NTC is still elusive. LRP6 (low density lipoprotein receptor related proteins 6) was identified as a co-receptor for WNT/β-catenin signaling, but recent studies showed that it also can mediate WNT/PCP signaling. In this study, we screened mutations in the LRP6 gene in 343 NTDs and 215 ethnically matched normal controls of Chinese Han population. Three rare missense mutations (c.1514A>G, p.Y505C); c.2984A>G, p.D995G; and c.4280C>A, p.P1427Q) of the LRP6 gene were identified in Chinese NTD patients. The Y505C mutation is a loss-of-function mutation on both WNT/β-catenin and PCP signaling. The D995G mutation only partially lost inhibition on PCP signaling without affecting WNT/β-catenin signaling. The P1427Q mutation dramatically increased WNT/β-catenin signaling but only mildly loss of inhibition on PCP signaling. All three mutations failed to rescue CE defects caused by lrp6 morpholino oligos knockdown in zebrafish. Of interest, when overexpressed, D995G did not induce any defects, but Y505C and P1427Q caused more severe CE defects in zebrafish. Our results suggested that over-active canonical WNT signaling induced by gain-of-function mutation in LRP6 could also contribute to human NTDs, and a balanced WNT/β-catenin and PCP signaling is probably required for proper neural tube development. Birth Defects Research 110:63-71, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. Signal flow analysis

    CERN Document Server

    Abrahams, J R; Hiller, N

    1965-01-01

    Signal Flow Analysis provides information pertinent to the fundamental aspects of signal flow analysis. This book discusses the basic theory of signal flow graphs and shows their relation to the usual algebraic equations.Organized into seven chapters, this book begins with an overview of properties of a flow graph. This text then demonstrates how flow graphs can be applied to a wide range of electrical circuits that do not involve amplification. Other chapters deal with the parameters as well as circuit applications of transistors. This book discusses as well the variety of circuits using ther

  7. Purinergic signalling and diabetes

    DEFF Research Database (Denmark)

    Burnstock, Geoffrey; Novak, Ivana

    2013-01-01

    The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes mellitus, the balance is broken-cells can be starving in the midst of plenty. There are indications that the incidence of diabetes...... molecules in purinergic signalling cascades. This signalling takes place at the level of the pancreas, where the close apposition of various cells-endocrine, exocrine, stromal and immune cells-contributes to the integrated function. Following an introduction to diabetes, the pancreas and purinergic...... signalling, we will focus on the role of purinergic signalling and its changes associated with diabetes in the pancreas and selected tissues/organ systems affected by hyperglycaemia and other stress molecules of diabetes. Since this is the first review of this kind, a comprehensive historical angle is taken...

  8. Topological signal processing

    CERN Document Server

    Robinson, Michael

    2014-01-01

    Signal processing is the discipline of extracting information from collections of measurements. To be effective, the measurements must be organized and then filtered, detected, or transformed to expose the desired information.  Distortions caused by uncertainty, noise, and clutter degrade the performance of practical signal processing systems. In aggressively uncertain situations, the full truth about an underlying signal cannot be known.  This book develops the theory and practice of signal processing systems for these situations that extract useful, qualitative information using the mathematics of topology -- the study of spaces under continuous transformations.  Since the collection of continuous transformations is large and varied, tools which are topologically-motivated are automatically insensitive to substantial distortion. The target audience comprises practitioners as well as researchers, but the book may also be beneficial for graduate students.

  9. Transmembrane Signalling: Membrane messengers

    Science.gov (United States)

    Cockroft, Scott L.

    2017-05-01

    Life has evolved elaborate means of communicating essential chemical information across cell membranes. Inspired by biology, two new artificial mechanisms have now been developed that use synthetic messenger molecules to relay chemical signals into or across lipid membranes.

  10. Ultrahigh bandwidth signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo

    2016-01-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, an hence useful for all types of data signals including coherent multi......-level modulation founats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signa In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral...... regeneratio These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platform like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described....

  11. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  12. Signals and systems

    CERN Document Server

    Rao, K Deergha

    2018-01-01

    This textbook covers the fundamental theories of signals and systems analysis, while incorporating recent developments from integrated circuits technology into its examples. Starting with basic definitions in signal theory, the text explains the properties of continuous-time and discrete-time systems and their representation by differential equations and state space. From those tools, explanations for the processes of Fourier analysis, the Laplace transform, and the z-Transform provide new ways of experimenting with different kinds of time systems. The text also covers the separate classes of analog filters and their uses in signal processing applications. Intended for undergraduate electrical engineering students, chapter sections include exercise for review and practice for the systems concepts of each chapter. Along with exercises, the text includes MATLAB-based examples to allow readers to experiment with signals and systems code on their own. An online repository of the MATLAB code from this textbook can...

  13. Signal Station Inspection Reports

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Handwritten reports resulting from detailed inspections of US Army Signal Service Stations, 1871-1889. Features reported included instrument exposure and condition,...

  14. Foundations of signal processing

    CERN Document Server

    Vetterli, Martin; Goyal, Vivek K

    2014-01-01

    This comprehensive and engaging textbook introduces the basic principles and techniques of signal processing, from the fundamental ideas of signals and systems theory to real-world applications. Students are introduced to the powerful foundations of modern signal processing, including the basic geometry of Hilbert space, the mathematics of Fourier transforms, and essentials of sampling, interpolation, approximation and compression. The authors discuss real-world issues and hurdles to using these tools, and ways of adapting them to overcome problems of finiteness and localisation, the limitations of uncertainty and computational costs. Standard engineering notation is used throughout, making mathematical examples easy for students to follow, understand and apply. It includes over 150 homework problems and over 180 worked examples, specifically designed to test and expand students' understanding of the fundamentals of signal processing, and is accompanied by extensive online materials designed to aid learning, ...

  15. Traffic Signal Cycle Lengths

    Data.gov (United States)

    Town of Chapel Hill, North Carolina — Traffic signal location list for the town of Chapel Hill. This data set includes light cycle information as well as as intersection information.The Town of Chapel...

  16. Redox signaling in plants.

    Science.gov (United States)

    Foyer, Christine H; Noctor, Graham

    2013-06-01

    Our aim is to deliver an authoritative and challenging perspective of current concepts in plant redox signaling, focusing particularly on the complex interface between the redox and hormone-signaling pathways that allow precise control of plant growth and defense in response to metabolic triggers and environmental constraints and cues. Plants produce significant amounts of singlet oxygen and other reactive oxygen species (ROS) as a result of photosynthetic electron transport and metabolism. Such pathways contribute to the compartment-specific redox-regulated signaling systems in plant cells that convey information to the nucleus to regulate gene expression. Like the chloroplasts and mitochondria, the apoplast-cell wall compartment makes a significant contribution to the redox signaling network, but unlike these organelles, the apoplast has a low antioxidant-buffering capacity. The respective roles of ROS, low-molecular antioxidants, redox-active proteins, and antioxidant enzymes are considered in relation to the functions of plant hormones such as salicylic acid, jasmonic acid, and auxin, in the composite control of plant growth and defense. Regulation of redox gradients between key compartments in plant cells such as those across the plasma membrane facilitates flexible and multiple faceted opportunities for redox signaling that spans the intracellular and extracellular environments. In conclusion, plants are recognized as masters of the art of redox regulation that use oxidants and antioxidants as flexible integrators of signals from metabolism and the environment.

  17. Digital Signal Processing applied to Physical Signals

    CERN Document Server

    Alberto, Diego; Musa, L

    2011-01-01

    It is well known that many of the scientific and technological discoveries of the XXI century will depend on the capability of processing and understanding a huge quantity of data. With the advent of the digital era, a fully digital and automated treatment can be designed and performed. From data mining to data compression, from signal elaboration to noise reduction, a processing is essential to manage and enhance features of interest after every data acquisition (DAQ) session. In the near future, science will go towards interdisciplinary research. In this work there will be given an example of the application of signal processing to different fields of Physics from nuclear particle detectors to biomedical examinations. In Chapter 1 a brief description of the collaborations that allowed this thesis is given, together with a list of the publications co-produced by the author in these three years. The most important notations, definitions and acronyms used in the work are also provided. In Chapter 2, the last r...

  18. Rad and Rem are non-canonical G-proteins with respect to the regulatory role of guanine nucleotide binding in Ca(V)1.2 channel regulation.

    Science.gov (United States)

    Chang, Donald D; Colecraft, Henry M

    2015-12-01

    Rad and Rem are Ras-like G-proteins linked to diverse cardiovascular functions and pathophysiology. Understanding how Rad and Rem are regulated is important for deepened insights into their pathophysiological roles. As in other Ras-like G-proteins, Rad and Rem contain a conserved guanine-nucleotide binding domain (G-domain). Canonically, G-domains are key control modules, functioning as nucleotide-regulated switches of G-protein activity. Whether Rad and Rem G-domains conform to this canonical paradigm is ambiguous. Here, we used multiple functional measurements in HEK293 cells and cardiomyocytes (Ca(V)1.2 currents, Ca(2+) transients, Ca(V)β binding) as biosensors to probe the role of the G-domain in regulation of Rad and Rem function. We utilized Rad(S105N) and Rem(T94N), which are the cognate mutants to Ras(S17N), a dominant-negative variant of Ras that displays decreased nucleotide binding affinity. In HEK293 cells, over-expression of either Rad(S105N) or Rem(T94N) strongly inhibited reconstituted Ca(V)1.2 currents to the same extent as their wild-type (wt) counterparts, contrasting with reports that Rad(S105N) is functionally inert in HEK293 cells. Adenovirus-mediated expression of either wt Rad or Rad(S105N) in cardiomyocytes dramatically blocked L-type calcium current (I(Ca,L)) and inhibited Ca(2+)-induced Ca(2+) release, contradicting reports that Rad(S105N) acts as a dominant negative in heart. By contrast, Rem(T94N) was significantly less effective than wt Rem at inhibiting I(Ca,L) and Ca(2+) transients in cardiomyocytes. FRET analyses in cardiomyocytes revealed that both Rad(S105N) and Rem(T94N) had moderately reduced binding affinity for Ca(V)βs relative to their wt counterparts. The results indicate Rad and Rem are non-canonical G-proteins with respect to the regulatory role of their G-domain in Ca(V)1.2 regulation. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  19. CTHRC1 Acts as a Prognostic Factor and Promotes Invasiveness of Gastrointestinal Stromal Tumors by Activating Wnt/PCP-Rho Signaling

    Directory of Open Access Journals (Sweden)

    Ming-Ze Ma

    2014-03-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1 in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.

  20. Cellular signalling properties in microcircuits

    DEFF Research Database (Denmark)

    Toledo-Rodriguez, Maria; El Manira, Abdeljabbar; Wallén, Peter

    2005-01-01

    Molecules and cells are the signalling elements in microcircuits. Recent studies have uncovered bewildering diversity in postsynaptic signalling properties in all areas of the vertebrate nervous system. Major effort is now being invested in establishing the specialized signalling properties...

  1. FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-β autoinduction.

    Science.gov (United States)

    Smith, Edward R; Holt, Stephen G; Hewitson, Tim D

    2017-11-01

    Bone-derived fibroblast growth factor 23 (FGF23) is an important endocrine regulator of mineral homeostasis with effects transduced by cognate FGF receptor (FGFR)1-α-Klotho complexes. Circulating FGF23 levels rise precipitously in patients with kidney disease and portend worse renal and cardiovascular outcomes. De novo expression of FGF23 has been found in the heart and kidney following injury but its significance remains unclear. Studies showing that exposure to chronically high FGF23 concentrations activates hypertrophic gene programs in the cardiomyocyte has spawned intense interest in other pathological off-target effects of FGF23 excess. In the kidney, observational evidence points to a concordance of ectopic renal FGF23 expression and the activation of local transforming growth factor (TGF)-β signalling. Although we have previously shown that FGF23 activates injury-primed renal fibroblasts in vitro, our understanding of the mechanism underpinning these effects was incomplete. Here we show that in the absence of α-Klotho, FGF23 augments pro-fibrotic signalling cascades in injury-primed renal fibroblasts via activation of FGFR4 and upregulation of the calcium transporter, transient receptor potential cation channel 6. The resultant rise in intracellular calcium and production of mitochondrial reactive oxygen species induced expression of NFAT responsive-genes and enhanced TGF-β1 autoinduction through non-canonical JNK-dependent pathways. Reconstitution with transmembrane α-Klotho, or its soluble ectodomain, restored classical Egr signalling and antagonised FGF23-driven myofibroblast differentiation. Thus, renal FGF23 may amplify local myofibroblast activation in injury and perpetuate pro-fibrotic signalling. These findings strengthen the rationale for exploring therapeutic inhibition of FGFR4 or restoration of α-Klotho as upstream regulators of off-target FGF23 effects. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  2. VLSI signal processing technology

    CERN Document Server

    Swartzlander, Earl

    1994-01-01

    This book is the first in a set of forthcoming books focussed on state-of-the-art development in the VLSI Signal Processing area. It is a response to the tremendous research activities taking place in that field. These activities have been driven by two factors: the dramatic increase in demand for high speed signal processing, especially in consumer elec­ tronics, and the evolving microelectronic technologies. The available technology has always been one of the main factors in determining al­ gorithms, architectures, and design strategies to be followed. With every new technology, signal processing systems go through many changes in concepts, design methods, and implementation. The goal of this book is to introduce the reader to the main features of VLSI Signal Processing and the ongoing developments in this area. The focus of this book is on: • Current developments in Digital Signal Processing (DSP) pro­ cessors and architectures - several examples and case studies of existing DSP chips are discussed in...

  3. Honest signalling with costly gambles.

    Science.gov (United States)

    Meacham, Frazer; Perlmutter, Aaron; Bergstrom, Carl T

    2013-10-06

    Costly signalling theory is commonly invoked as an explanation for how honest communication can be stable when interests conflict. However, the signal costs predicted by costly signalling models often turn out to be unrealistically high. These models generally assume that signal cost is determinate. Here, we consider the case where signal cost is instead stochastic. We examine both discrete and continuous signalling games and show that, under reasonable assumptions, stochasticity in signal costs can decrease the average cost at equilibrium for all individuals. This effect of stochasticity for decreasing signal costs is a fundamental mechanism that probably acts in a wide variety of circumstances.

  4. Quantum signaling game

    International Nuclear Information System (INIS)

    Frackiewicz, Piotr

    2014-01-01

    We present a quantum approach to a signaling game; a special kind of extensive game of incomplete information. Our model is based on quantum schemes for games in strategic form where players perform unitary operators on their own qubits of some fixed initial state and the payoff function is given by a measurement on the resulting final state. We show that the quantum game induced by our scheme coincides with a signaling game as a special case and outputs nonclassical results in general. As an example, we consider a quantum extension of the signaling game in which the chance move is a three-parameter unitary operator whereas the players' actions are equivalent to classical ones. In this case, we study the game in terms of Nash equilibria and refine the pure Nash equilibria adapting to the quantum game the notion of a weak perfect Bayesian equilibrium. (paper)

  5. Signal integrity characterization techniques

    CERN Document Server

    Bogatin, Eric

    2009-01-01

    "Signal Integrity Characterization Techniques" addresses the gap between traditional digital and microwave curricula all while focusing on a practical and intuitive understanding of signal integrity effects within the data transmission channel. High-speed interconnects such as connectors, PCBs, cables, IC packages, and backplanes are critical elements of differential channels that must be designed using today's most powerful analysis and characterization tools.Both measurements and simulation must be done on the device under test, and both activities must yield data that correlates with each other. Most of this book focuses on real-world applications of signal integrity measurements - from backplane for design challenges to error correction techniques to jitter measurement technologies. The authors' approach wisely addresses some of these new high-speed technologies, and it also provides valuable insight into its future direction and will teach the reader valuable lessons on the industry.

  6. PKD signaling and pancreatitis

    Science.gov (United States)

    Yuan, Jingzhen; Pandol, Stephen J.

    2016-01-01

    Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder. PMID:26879861

  7. Electronic signal conditioning

    CERN Document Server

    NEWBY, BRUCE

    1994-01-01

    At technician level, brief references to signal conditioning crop up in a fragmented way in various textbooks, but there has been no single textbook, until now!More advanced texts do exist but they are more mathematical and presuppose a higher level of understanding of electronics and statistics. Electronic Signal Conditioning is designed for HNC/D students and City & Guilds Electronics Servicing 2240 Parts 2 & 3. It will also be useful for BTEC National, Advanced GNVQ, A-level electronics and introductory courses at degree level.

  8. Purinergic Signalling: Therapeutic Developments

    OpenAIRE

    Burnstock, Geoffrey

    2017-01-01

    Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and ...

  9. Genomic signal processing

    CERN Document Server

    Shmulevich, Ilya

    2007-01-01

    Genomic signal processing (GSP) can be defined as the analysis, processing, and use of genomic signals to gain biological knowledge, and the translation of that knowledge into systems-based applications that can be used to diagnose and treat genetic diseases. Situated at the crossroads of engineering, biology, mathematics, statistics, and computer science, GSP requires the development of both nonlinear dynamical models that adequately represent genomic regulation, and diagnostic and therapeutic tools based on these models. This book facilitates these developments by providing rigorous mathema

  10. TOR signalling in plants.

    Science.gov (United States)

    Rexin, Daniel; Meyer, Christian; Robaglia, Christophe; Veit, Bruce

    2015-08-15

    Although the eukaryotic TOR (target of rapamycin) kinase signalling pathway has emerged as a key player for integrating nutrient-, energy- and stress-related cues with growth and metabolic outputs, relatively little is known of how this ancient regulatory mechanism has been adapted in higher plants. Drawing comparisons with the substantial knowledge base around TOR kinase signalling in fungal and animal systems, functional aspects of this pathway in plants are reviewed. Both conserved and divergent elements are discussed in relation to unique aspects associated with an autotrophic mode of nutrition and adaptive strategies for multicellular development exhibited by plants. © 2015 Authors; published by Portland Press Limited.

  11. Signaling and Accounting Information

    OpenAIRE

    Stewart C. Myers

    1989-01-01

    This paper develops a signaling model in which accounting information improves real investment decisions. Pure cash flow reporting is shown to lead to underinvestment when managers have superior information but are acting in shareholders' interests. Accounting by prespecified, "objective" rules alleviates the underinvestment problem.

  12. Analog signal isolation techniques

    Energy Technology Data Exchange (ETDEWEB)

    Beadle, E.R.

    1992-12-31

    This paper discusses several techniques for isolating analog signals in an accelerator environment. The techniques presented here encompass isolation amplifiers, voltage-to-frequency converters (VIFCs), transformers, optocouplers, discrete fiber optics, and commercial fiber optic links. Included within the presentation of each method are the design issues that must be considered when selecting the isolation method for a specific application.

  13. Analog signal isolation techniques

    Energy Technology Data Exchange (ETDEWEB)

    Beadle, E.R.

    1992-01-01

    This paper discusses several techniques for isolating analog signals in an accelerator environment. The techniques presented here encompass isolation amplifiers, voltage-to-frequency converters (VIFCs), transformers, optocouplers, discrete fiber optics, and commercial fiber optic links. Included within the presentation of each method are the design issues that must be considered when selecting the isolation method for a specific application.

  14. Calcium signaling in neurodegeneration

    Directory of Open Access Journals (Sweden)

    Dreses-Werringloer Ute

    2009-05-01

    Full Text Available Abstract Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed. In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival. Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer's disease, provides strong support for a role of calcium in neurodegeneration. These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer's, Parkinson's, and Huntington's diseases.

  15. Quantum cloning and signaling

    International Nuclear Information System (INIS)

    Simon, C.; Weihs, G.; Zeilinger, A.

    1999-01-01

    We discuss the close connections between cloning of quantum states and superluminal signaling. We present an optimal universal cloning machine based on stimulated emission recently proposed by the authors. As an instructive example, we show how a scheme for superluminal communication based on this cloning machine fails. (Authors)

  16. Intersection auxiliary signal system

    Science.gov (United States)

    Zhang, Jian

    1995-12-01

    Many intersection accidents are related to drivers' inappropriate responses to an amber signal light, due to their misjudgment on the traffic situation and/or their aggressive behavior. To reduce intersection accidents of this nature, this paper proposes the Intersection Auxiliary Signal System (IAS). IAS can be installed at selected intersections, where information regarding signal phasing, intersection geometry and speed limit is transmitted from an ultrasonic/infra-red transmitter. An on-vehicle device receivers and processes the information, the provides the driver with explicit suggestions on the correct action to take (continue to pass or decelerate to stop), or warnings against on-going incorrect actions. IAS is expected to be more effective in suburban intersections, which are usually characterized by greater dimension, longer amber phases, and higher vehicle speeds. Both the intersection transmitters and the on-vehicle processors are expected to have simple structures and low costs. Simulation results show that IAS has a significant effect on reducing red signal violation, especially when there is no significant dilemma zones.

  17. Signalling control strength.

    Science.gov (United States)

    Westerhoff, Hans V

    2008-06-07

    Metabolic control analysis (MCA) has become what it is, largely because the special organization of living cells led to rather specific questions. These questions focused on the role of enzymes, genes, and, in subsequent generalizations, on well-defined process activities. With an emphasis on the work by Heinrich and co-workers, the theory behind MCA is summarized in a way that leads naturally to its extensions to hierarchical systems, such as gene expression and signal transduction, and to control beyond the steady state. The analysis of the control properties of signal transduction cascades is reviewed with an emphasis on the relative importance of the protein kinases and the protein phosphatases. The two types of enzyme are both important for the amplitude of signal transduction, whereas phosphatases may be more important for the later phases of signal transduction and for its duration. Novel MCA of concentrations and fluxes that vary with time is explicated. It is concluded that the clarity and operationality of concepts such as control strength (now control coefficient) plus the clear theoretical frameworks provided by Heinrich and colleagues, should enable us greatly to reduce the Babylonian confusion that could otherwise occur in the data deluges of Systems Biology.

  18. Multimodal signalling in estrildid finches

    DEFF Research Database (Denmark)

    Gomes, A. C. R.; Funghi, C.; Soma, M.

    2017-01-01

    Sexual traits (e.g. visual ornaments, acoustic signals, courtship behaviour) are often displayed together as multimodal signals. Some hypotheses predict joint evolution of different sexual signals (e.g. to increase the efficiency of communication) or that different signals trade off with each oth...

  19. Sinusoidal Representation of Acoustic Signals

    Science.gov (United States)

    Honda, Masaaki

    Sinusoidal representation of acoustic signals has been an important tool in speech and music processing like signal analysis, synthesis and time scale or pitch modifications. It can be applicable to arbitrary signals, which is an important advantage over other signal representations like physical modeling of acoustic signals. In sinusoidal representation, acoustic signals are composed as sums of sinusoid (sine wave) with different amplitudes, frequencies and phases, which is based on the timedependent short-time Fourier transform (STFT). This article describes the principles of acoustic signal analysis/synthesis based on a sinusoid representation with focus on sine waves with rapidly varying frequency.

  20. A Pathway Switch Directs BAFF Signaling to Distinct NFκB Transcription Factors in Maturing and Proliferating B Cells

    Directory of Open Access Journals (Sweden)

    Jonathan V. Almaden

    2014-12-01

    Full Text Available BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.

  1. A pathway switch directs BAFF signaling to distinct NFκB transcription factors in maturing and proliferating B cells.

    Science.gov (United States)

    Almaden, Jonathan V; Tsui, Rachel; Liu, Yi C; Birnbaum, Harry; Shokhirev, Maxim N; Ngo, Kim A; Davis-Turak, Jeremy C; Otero, Dennis; Basak, Soumen; Rickert, Robert C; Hoffmann, Alexander

    2014-12-24

    BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  2. The newest digital signal processing

    International Nuclear Information System (INIS)

    Lee, Chae Uk

    2002-08-01

    This book deal with the newest digital signal processing, which contains introduction on conception of digital signal processing, constitution and purpose, signal and system such as signal, continuos signal, discrete signal and discrete system, I/O expression on impress response, convolution, mutual connection of system and frequency character,z transform of definition, range, application of z transform and relationship with laplace transform, Discrete fourier, Fast fourier transform on IDFT algorithm and FFT application, foundation of digital filter of notion, expression, types, frequency characteristic of digital filter and design order of filter, Design order of filter, Design of FIR digital filter, Design of IIR digital filter, Adaptive signal processing, Audio signal processing, video signal processing and application of digital signal processing.

  3. Variable reflectivity signal mirrors and signal response measurements

    International Nuclear Information System (INIS)

    Vine, Glenn de; Shaddock, Daniel A; McClelland, David E

    2002-01-01

    Future gravitational wave detectors will include some form of signal mirror in order to alter the signal response of the device. We introduce interferometer configurations which utilize a variable reflectivity signal mirror allowing a tunable peak frequency and variable signal bandwidth. A detector configured with a Fabry-Perot cavity as the signal mirror is compared theoretically with one using a Michelson interferometer for a signal mirror. A system for the measurement of the interferometer signal responses is introduced. This technique is applied to a power-recycled Michelson interferometer with resonant sideband extraction. We present broadband measurements of the benchtop prototype's signal response for a range of signal cavity detunings. This technique is also applicable to most other gravitational wave detector configurations

  4. Variable reflectivity signal mirrors and signal response measurements

    CERN Document Server

    Vine, G D; McClelland, D E

    2002-01-01

    Future gravitational wave detectors will include some form of signal mirror in order to alter the signal response of the device. We introduce interferometer configurations which utilize a variable reflectivity signal mirror allowing a tunable peak frequency and variable signal bandwidth. A detector configured with a Fabry-Perot cavity as the signal mirror is compared theoretically with one using a Michelson interferometer for a signal mirror. A system for the measurement of the interferometer signal responses is introduced. This technique is applied to a power-recycled Michelson interferometer with resonant sideband extraction. We present broadband measurements of the benchtop prototype's signal response for a range of signal cavity detunings. This technique is also applicable to most other gravitational wave detector configurations.

  5. Elevation of WNT5A expression in polyp formation in Lkb1+/- mice and Peutz-Jeghers syndrome.

    Science.gov (United States)

    Lai, Cecilia; Robinson, James; Clark, Sue; Stamp, Gordon; Poulsom, Richard; Silver, Andrew

    2011-04-01

    Peutz-Jeghers syndrome (PJS) is a rare, inherited disease caused by germline mutation of the LKB1 gene. Patients with PJS develop characteristic polyps in the digestive tract and carry an elevated risk of cancers in multiple organs, including the intestinal tract. While LKB1 is capable of phosphorylating AMPK and regulates the mTOR pathway, it is also known to be a multitasking protein that can influence other cellular processes, including cell polarity. We hypothesized that there may be other biological pathways directly or indirectly affected by the loss of LKB1 in PJS and aimed to investigate this possibility through transcriptional profiling of polyps harvested from an Lkb1(+/-) mouse model of PJS and from PJS patients. We identified alterations in the mRNA level of a wide range of genes, including some that are involved in Wnt signalling (Wnt5a, Wif1, Dixdc1, Wnt11, Ccnd1, and Ccnd2), although we did not observe nuclear localization of β-catenin in over 93 human PJS intestinal polyps or in 24 gastric polyps from Lkb1(+/-) mice. Among these genes, WNT5A, a non-canonical and non-transforming Wnt, is consistently up-regulated in both Lkb1(+/-) mice and human PJS polyps at a high level. We performed in situ hybridization to further define the spatial expression pattern of WNT5A and observed a strong signal in the stroma of mouse and human polyps compared to no or very low expression in the mucosa. Our findings indicate that WNT5A plays an important role in PJS polyposis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  6. Activation of Intracellular Calcium by Multiple Wnt Ligands and Translocation of β-Catenin into the Nucleus

    Science.gov (United States)

    Thrasivoulou, Christopher; Millar, Michael; Ahmed, Aamir

    2013-01-01

    Ca2+ and β-catenin, a 92-kDa negatively charged transcription factor, transduce Wnt signaling via the non-canonical, Wnt/Ca2+ and canonical, Wnt/β-catenin pathways independently. The nuclear envelope is a barrier to large protein entry, and this process is regulated by intracellular calcium [Ca2+]i and trans-nuclear potential. How β-catenin traverses the nuclear envelope is not well known. We hypothesized that Wnt/Ca2+ and Wnt/β-catenin pathways act in a coordinated manner and that [Ca2+]i release facilitates β-catenin entry into the nucleus in mammalian cells. In a live assay using calcium dyes in PC3 prostate cancer cells, six Wnt peptides (3A, 4, 5A, 7A, 9B, and 10B) mobilized [Ca2+]i but Wnt11 did not. Based upon dwell time (range = 15–30 s) of the calcium waveform, these Wnts could be classified into three classes: short, 3A and 5A; long, 7A and 10B; and very long, 4 and 9B. Wnt-activated [Ca2+]i release was followed by an increase in intranuclear calcium and the depolarization of both the cell and nuclear membranes, determined by using FM4-64. In cells treated with Wnts 5A, 9B, and 10B, paradigm substrates for each Wnt class, increased [Ca2+]i was followed by β-catenin translocation into the nucleus in PC3, MCF7, and 253J, prostate, breast, and bladder cancer cell lines; both the increase in Wnt 5A, 9B, and 10B induced [Ca2+]i release and β-catenin translocation are suppressed by thapsigargin in PC3 cell line. We propose a convergent model of Wnt signaling network where Ca2+ and β-catenin pathways may act in a coordinated, interdependent, rather than independent, manner. PMID:24158438

  7. Activation of intracellular calcium by multiple Wnt ligands and translocation of β-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/β-catenin pathways.

    Science.gov (United States)

    Thrasivoulou, Christopher; Millar, Michael; Ahmed, Aamir

    2013-12-13

    Ca(2+) and β-catenin, a 92-kDa negatively charged transcription factor, transduce Wnt signaling via the non-canonical, Wnt/Ca(2+) and canonical, Wnt/β-catenin pathways independently. The nuclear envelope is a barrier to large protein entry, and this process is regulated by intracellular calcium [Ca(2+)]i and trans-nuclear potential. How β-catenin traverses the nuclear envelope is not well known. We hypothesized that Wnt/Ca(2+) and Wnt/β-catenin pathways act in a coordinated manner and that [Ca(2+)]i release facilitates β-catenin entry into the nucleus in mammalian cells. In a live assay using calcium dyes in PC3 prostate cancer cells, six Wnt peptides (3A, 4, 5A, 7A, 9B, and 10B) mobilized [Ca(2+)]i but Wnt11 did not. Based upon dwell time (range = 15-30 s) of the calcium waveform, these Wnts could be classified into three classes: short, 3A and 5A; long, 7A and 10B; and very long, 4 and 9B. Wnt-activated [Ca(2+)]i release was followed by an increase in intranuclear calcium and the depolarization of both the cell and nuclear membranes, determined by using FM4-64. In cells treated with Wnts 5A, 9B, and 10B, paradigm substrates for each Wnt class, increased [Ca(2+)]i was followed by β-catenin translocation into the nucleus in PC3, MCF7, and 253J, prostate, breast, and bladder cancer cell lines; both the increase in Wnt 5A, 9B, and 10B induced [Ca(2+)]i release and β-catenin translocation are suppressed by thapsigargin in PC3 cell line. We propose a convergent model of Wnt signaling network where Ca(2+) and β-catenin pathways may act in a coordinated, interdependent, rather than independent, manner.

  8. The Adaptor Protein SAP Directly Associates with CD3ζ Chain and Regulates T Cell Receptor Signaling

    Science.gov (United States)

    Proust, Richard; Bertoglio, Jacques; Gesbert, Franck

    2012-01-01

    Mutations altering the gene encoding the SLAM associated protein (SAP) are responsible for the X-linked lymphoproliferative disease or XLP1. Its absence is correlated with a defective NKT cells development, a decrease in B cell functions and a reduced T cells and NK cells cytotoxic activities, thus leading to an immunodeficiency syndrome. SAP is a small 128 amino-acid long protein that is almost exclusively composed of an SH2 domain. It has been shown to interact with the CD150/SLAM family of receptors, and in a non-canonical manner with SH3 containing proteins such as Fyn, βPIX, PKCθ and Nck1. It would thus play the role of a minimal adaptor protein. It has been shown that SAP plays an important function in the activation of T cells through its interaction with the SLAM family of receptors. Therefore SAP defective T cells display a reduced activation of signaling events downstream of the TCR-CD3 complex triggering. In the present work, we evidence that SAP is a direct interactor of the CD3ζ chain. This direct interaction occurs through the first ITAM of CD3ζ, proximal to the membrane. Additionally, we show that, in the context of the TCR-CD3 signaling, an Sh-RNA mediated silencing of SAP is responsible for a decrease of several canonical T cell signaling pathways including Erk, Akt and PLCγ1 and to a reduced induction of IL-2 and IL-4 mRNA. Altogether, we show that SAP plays a central function in the T cell activation processes through a direct association with the CD3 complex. PMID:22912825

  9. Biomedical signal analysis

    CERN Document Server

    Rangayyan, Rangaraj M

    2015-01-01

    The book will help assist a reader in the development of techniques for analysis of biomedical signals and computer aided diagnoses with a pedagogical examination of basic and advanced topics accompanied by over 350 figures and illustrations. Wide range of filtering techniques presented to address various applications. 800 mathematical expressions and equations. Practical questions, problems and laboratory exercises. Includes fractals and chaos theory with biomedical applications.

  10. Plant peptide hormone signalling.

    Science.gov (United States)

    Motomitsu, Ayane; Sawa, Shinichiro; Ishida, Takashi

    2015-01-01

    The ligand-receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone-receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions. © 2015 Authors; published by Portland Press Limited.

  11. Membrane-associated proteomics of chickpea identifies Sad1/UNC-84 protein (CaSUN1), a novel component of dehydration signaling

    Science.gov (United States)

    Jaiswal, Dinesh Kumar; Mishra, Poonam; Subba, Pratigya; Rathi, Divya; Chakraborty, Subhra; Chakraborty, Niranjan

    2014-02-01

    Dehydration affects almost all the physiological processes including those that result in the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which in turn elicits a highly conserved signaling, the unfolded protein response (UPR). We investigated the dehydration-responsive membrane-associated proteome of a legume, chickpea, by 2-DE coupled with mass spectrometry. A total of 184 protein spots were significantly altered over a dehydration treatment of 120 h. Among the differentially expressed proteins, a non-canonical SUN domain protein, designated CaSUN1 (Cicer arietinum Sad1/UNC-84), was identified. CaSUN1 localized to the nuclear membrane and ER, besides small vacuolar vesicles. The transcripts were downregulated by both abiotic and biotic stresses, but not by abscisic acid treatment. Overexpression of CaSUN1 conferred stress tolerance in transgenic Arabidopsis. Furthermore, functional complementation of the yeast mutant, slp1, could rescue its growth defects. We propose that the function of CaSUN1 in stress response might be regulated via UPR signaling.

  12. TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1

    Science.gov (United States)

    Etemadi, Nima; Chopin, Michael; Anderton, Holly; Tanzer, Maria C; Rickard, James A; Abeysekera, Waruni; Hall, Cathrine; Spall, Sukhdeep K; Wang, Bing; Xiong, Yuquan; Hla, Timothy; Pitson, Stuart M; Bonder, Claudine S; Wong, Wendy Wei-Lynn; Ernst, Matthias; Smyth, Gordon K; Vaux, David L; Nutt, Stephen L; Nachbur, Ueli; Silke, John

    2015-01-01

    TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1. DOI: http://dx.doi.org/10.7554/eLife.10592.001 PMID:26701909

  13. Biomedical signal and image processing

    CERN Document Server

    Najarian, Kayvan

    2012-01-01

    INTRODUCTION TO DIGITAL SIGNAL AND IMAGE PROCESSINGSignals and Biomedical Signal ProcessingIntroduction and OverviewWhat is a ""Signal""?Analog, Discrete, and Digital SignalsProcessing and Transformation of SignalsSignal Processing for Feature ExtractionSome Characteristics of Digital ImagesSummaryProblemsFourier TransformIntroduction and OverviewOne-Dimensional Continuous Fourier TransformSampling and NYQUIST RateOne-Dimensional Discrete Fourier TransformTwo-Dimensional Discrete Fourier TransformFilter DesignSummaryProblemsImage Filtering, Enhancement, and RestorationIntroduction and Overview

  14. Purinergic Signalling: Therapeutic Developments.

    Science.gov (United States)

    Burnstock, Geoffrey

    2017-01-01

    Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990's when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A 2A receptor antagonists are promising for the treatment of Parkinson's disease. Clopidogrel, a P2Y 12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y 12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y 2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

  15. Purinergic Signalling: Therapeutic Developments

    Directory of Open Access Journals (Sweden)

    Geoffrey Burnstock

    2017-09-01

    Full Text Available Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

  16. Generation of earthquake signals

    International Nuclear Information System (INIS)

    Kjell, G.

    1994-01-01

    Seismic verification can be performed either as a full scale test on a shaker table or as numerical calculations. In both cases it is necessary to have an earthquake acceleration time history. This report describes generation of such time histories by filtering white noise. Analogue and digital filtering methods are compared. Different methods of predicting the response spectrum of a white noise signal filtered by a band-pass filter are discussed. Prediction of both the average response level and the statistical variation around this level are considered. Examples with both the IEEE 301 standard response spectrum and a ground spectrum suggested for Swedish nuclear power stations are included in the report

  17. Signal Processing for Communications

    CERN Document Server

    Prandoni, Paolo

    2008-01-01

    Taking a novel, less classical approach to the subject, the authors have written this book with the conviction that signal processing should be fun. Their treatment is less focused on the mathematics and more on the conceptual aspects, allowing students to think about the subject at a higher conceptual level, thus building the foundations for more advanced topics and helping students solve real-world problems. The last chapter pulls together the individual topics into an in-depth look at the development of an end-to-end communication system. Richly illustrated with examples and exercises in ea

  18. Phonocardiography Signal Processing

    CERN Document Server

    Abbas, Abbas K

    2009-01-01

    The auscultation method is an important diagnostic indicator for hemodynamic anomalies. Heart sound classification and analysis play an important role in the auscultative diagnosis. The term phonocardiography refers to the tracing technique of heart sounds and the recording of cardiac acoustics vibration by means of a microphone-transducer. Therefore, understanding the nature and source of this signal is important to give us a tendency for developing a competent tool for further analysis and processing, in order to enhance and optimize cardiac clinical diagnostic approach. This book gives the

  19. Transmembrane Signaling Proteoglycans

    DEFF Research Database (Denmark)

    Couchman, John R

    2010-01-01

    and their glycosaminoglycan chains is matched by diverse functions. However, all assume roles as coreceptors, often working alongside high-affinity growth factor receptors or adhesion receptors such as integrins. Other common themes are an ability to signal through their cytoplasmic domains, often to the actin cytoskeleton......, and linkage to PDZ protein networks. Many transmembrane proteoglycans associate on the cell surface with metzincin proteases and can be shed by them. Work with model systems in vivo and in vitro reveal roles in growth, adhesion, migration, and metabolism. Furthermore, a wide range of phenotypes for the core...

  20. Multiscale Signal Analysis and Modeling

    CERN Document Server

    Zayed, Ahmed

    2013-01-01

    Multiscale Signal Analysis and Modeling presents recent advances in multiscale analysis and modeling using wavelets and other systems. This book also presents applications in digital signal processing using sampling theory and techniques from various function spaces, filter design, feature extraction and classification, signal and image representation/transmission, coding, nonparametric statistical signal processing, and statistical learning theory. This book also: Discusses recently developed signal modeling techniques, such as the multiscale method for complex time series modeling, multiscale positive density estimations, Bayesian Shrinkage Strategies, and algorithms for data adaptive statistics Introduces new sampling algorithms for multidimensional signal processing Provides comprehensive coverage of wavelets with presentations on waveform design and modeling, wavelet analysis of ECG signals and wavelet filters Reviews features extraction and classification algorithms for multiscale signal and image proce...

  1. Hedgehog: an unusual signal transducer

    NARCIS (Netherlands)

    Bijlsma, Maarten F.; Spek, C. Arnold; Peppelenbosch, Maikel P.

    2004-01-01

    Hedgehog proteins are of pivotal importance for development and maintenance of tissue patterns in adult organisms. Despite the role of Hedgehogs in differentiation and tumorigenesis, signal transduction of Hedgehog remains a relatively uncharted area of signalling biochemistry. For proper Hedgehog

  2. Biological signals classification and analysis

    CERN Document Server

    Kiasaleh, Kamran

    2015-01-01

    This authored monograph presents key aspects of signal processing analysis in the biomedical arena. Unlike wireless communication systems, biological entities produce signals with underlying nonlinear, chaotic nature that elude classification using the standard signal processing techniques, which have been developed over the past several decades for dealing primarily with standard communication systems. This book separates what is random from that which appears to be random, and yet is truly deterministic with random appearance. At its core, this work gives the reader a perspective on biomedical signals and the means to classify and process such signals. In particular, a review of random processes along with means to assess the behavior of random signals is also provided. The book also includes a general discussion of biological signals in order to demonstrate the inefficacy of the well-known techniques to correctly extract meaningful information from such signals. Finally, a thorough discussion of recently ...

  3. Two-dimensional signal analysis

    CERN Document Server

    Garello, René

    2010-01-01

    This title sets out to show that 2-D signal analysis has its own role to play alongside signal processing and image processing.Concentrating its coverage on those 2-D signals coming from physical sensors (such as radars and sonars), the discussion explores a 2-D spectral approach but develops the modeling of 2-D signals and proposes several data-oriented analysis techniques for dealing with them. Coverage is also given to potential future developments in this area.

  4. Astrocytes in endocannabinoid signalling.

    Science.gov (United States)

    Navarrete, Marta; Díez, Adolfo; Araque, Alfonso

    2014-10-19

    Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  5. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...

  6. Detection of signals in noise

    CERN Document Server

    Whalen, Anthony D; Declaris, Nicholas

    1971-01-01

    Detection of Signals in Noise serves as an introduction to the principles and applications of the statistical theory of signal detection. The book discusses probability and random processes; narrowband signals, their complex representation, and their properties described with the aid of the Hilbert transform; and Gaussian-derived processes. The text also describes the application of hypothesis testing for the detection of signals and the fundamentals required for statistical detection of signals in noise. Problem exercises, references, and a supplementary bibliography are included after each c

  7. Signals and systems for dummies

    CERN Document Server

    Wickert, Mark

    2013-01-01

    Getting mixed signals in your signals and systems course? The concepts covered in a typical signals and systems course are often considered by engineering students to be some of the most difficult to master. Thankfully, Signals & Systems For Dummies is your intuitive guide to this tricky course, walking you step-by-step through some of the more complex theories and mathematical formulas in a way that is easy to understand. From Laplace Transforms to Fourier Analyses, Signals & Systems For Dummies explains in plain English the difficult concepts that can trip you up

  8. Machine intelligence and signal processing

    CERN Document Server

    Vatsa, Mayank; Majumdar, Angshul; Kumar, Ajay

    2016-01-01

    This book comprises chapters on key problems in machine learning and signal processing arenas. The contents of the book are a result of a 2014 Workshop on Machine Intelligence and Signal Processing held at the Indraprastha Institute of Information Technology. Traditionally, signal processing and machine learning were considered to be separate areas of research. However in recent times the two communities are getting closer. In a very abstract fashion, signal processing is the study of operator design. The contributions of signal processing had been to device operators for restoration, compression, etc. Applied Mathematicians were more interested in operator analysis. Nowadays signal processing research is gravitating towards operator learning – instead of designing operators based on heuristics (for example wavelets), the trend is to learn these operators (for example dictionary learning). And thus, the gap between signal processing and machine learning is fast converging. The 2014 Workshop on Machine Intel...

  9. Measuring signal generators theory & design

    CERN Document Server

    Rybin, Yuriy K

    2014-01-01

    The book brings together the following issues: Theory of deterministic, random and discrete signals reproducible in oscillatory systems of generators; Generation of periodic signals with a specified spectrum, harmonic distortion factor and random signals with specified probability density function and spectral density; Synthesis of oscillatory system structures; Analysis of oscillatory systems with non-linear elements and oscillation amplitude stabilization systems; It considers the conditions and criteria of steady-state modes in signal generators on active four-pole elements with unidirectional and bidirectional transmission of signals and on two-pole elements; analogues of Barkhausen criteria; Optimization of oscillatory system structures by harmonic distortion level, minimization of a frequency error and set-up time of the steady state mode; Theory of construction of random signal generators; Construction of discrete and digital signal generators; Practical design of main units of generators; Practical bl...

  10. [Signal Processing Suite Design

    Science.gov (United States)

    Sahr, John D.; Mir, Hasan; Morabito, Andrew; Grossman, Matthew

    2003-01-01

    Our role in this project was to participate in the design of the signal processing suite to analyze plasma density measurements on board a small constellation (3 or 4) satellites in Low Earth Orbit. As we are new to space craft experiments, one of the challenges was to simply gain understanding of the quantity of data which would flow from the satellites, and possibly to interact with the design teams in generating optimal sampling patterns. For example, as the fleet of satellites were intended to fly through the same volume of space (displaced slightly in time and space), the bulk plasma structure should be common among the spacecraft. Therefore, an optimal, limited bandwidth data downlink would take advantage of this commonality. Also, motivated by techniques in ionospheric radar, we hoped to investigate the possibility of employing aperiodic sampling in order to gain access to a wider spatial spectrum without suffering aliasing in k-space.

  11. The Pseudomonas aeruginosa lectin LecA triggers host cell signalling by glycosphingolipid-dependent phosphorylation of the adaptor protein CrkII.

    Science.gov (United States)

    Zheng, Shuangshuang; Eierhoff, Thorsten; Aigal, Sahaja; Brandel, Annette; Thuenauer, Roland; de Bentzmann, Sophie; Imberty, Anne; Römer, Winfried

    2017-07-01

    The human pathogen Pseudomonas aeruginosa induces phosphorylation of the adaptor protein CrkII by activating the non-receptor tyrosine kinase Abl to promote its uptake into host cells. So far, specific factors of P. aeruginosa, which induce Abl/CrkII signalling, are entirely unknown. In this research, we employed human lung epithelial cells H1299, Chinese hamster ovary cells and P. aeruginosa wild type strain PAO1 to study the invasion process of P. aeruginosa into host cells by using microbiological, biochemical and cell biological approaches such as Western Blot, immunofluorescence microscopy and flow cytometry. Here, we demonstrate that the host glycosphingolipid globotriaosylceramide, also termed Gb3, represents a signalling receptor for the P. aeruginosa lectin LecA to induce CrkII phosphorylation at tyrosine 221. Alterations in Gb3 expression and LecA function correlate with CrkII phosphorylation. Interestingly, phosphorylation of CrkII Y221 occurs independently of Abl kinase. We further show that Src family kinases transduce the signal induced by LecA binding to Gb3, leading to Crk Y221 phosphorylation. In summary, we identified LecA as a bacterial factor, which utilizes a so far unrecognized mechanism for phospho-CrkII Y221 induction by binding to the host glycosphingolipid receptor Gb3. The LecA/Gb3 interaction highlights the potential of glycolipids to mediate signalling processes across the plasma membrane and should be further elucidated to gain deeper insights into this non-canonical mechanism of activating host cell processes. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Ca2+/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation.

    Science.gov (United States)

    Kumar, Raju; Raman, Ratheesh; Kotapalli, Viswakalyan; Gowrishankar, Swarnalata; Pyne, Saumyadipta; Pollack, Jonathan R; Bashyam, Murali D

    2018-02-01

    Our previous extensive analysis revealed a significant proportion of early-onset colorectal tumors from India to be localized to the rectum in younger individuals and devoid of deregulated Wnt/β-catenin signaling. In the current study, we performed a comprehensive genome-wide analysis of clinically well-annotated microsatellite stable early-onset sporadic rectal cancer (EOSRC) samples. Results revealed extensive DNA copy number alterations in rectal tumors in the absence of deregulated Wnt/β-catenin signaling. More importantly, transcriptome profiling revealed a (non-Wnt/β-catenin, non-MSI) genetic signature that could efficiently and specifically identify Wnt- rectal cancer. The genetic signature included a significant representation of genes belonging to Ca 2+ /NFAT signaling pathways that were validated in additional samples. The validated NFAT target genes exhibited significantly higher expression levels than canonical Wnt/β-catenin targets in Wnt- samples, an observation confirmed in other CRC expression data sets as well. We confirmed the validated genes to be transcriptionally regulated by NFATc1 by (a) evaluating their respective transcript levels and (b) performing promoter-luciferase and chromatin immunoprecipitation assays following ectopic expression as well as knockdown of NFATc1 in CRC cells. NFATc1 and its targets RUNX2 and GSN could drive increased migration in CRC cells. Finally, the validated genes were associated with poor survival in the cancer genome atlas CRC expression data set. This study is the first comprehensive molecular characterization of EOSRC that appears to be driven by noncanonical tumorigenesis pathways. Early-onset sporadic rectal cancer exhibits DNA gain and loss without Wnt activation. Ca 2+ /NFAT signaling appears to be activated in the absence of Wnt activation. An eight-gene genetic signature distinguishes Wnt+ and Wnt- rectal tumors. NFAT and its target genes regulate tumorigenic properties in CRC cells.

  13. LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-β and BMP-associated proinflammatory and proangiogenic signals.

    Science.gov (United States)

    Flechsig, Paul; Dadrich, Monika; Bickelhaupt, Sebastian; Jenne, Jürgen; Hauser, Kai; Timke, Carmen; Peschke, Peter; Hahn, Eric W; Gröne, Hermann-Josef; Yingling, Jonathan; Lahn, Michael; Wirkner, Ute; Huber, Peter E

    2012-07-01

    Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-β signaling is considered to play an important role. We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-β receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Noninvasive lung imaging including volume computed tomography (VCT) and MRI was conducted 6, 16, and 20 weeks after irradiation and was correlated to histologic findings. Expression profiling analysis and protein analysis was conducted in human primary fibroblasts. Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced life span. VCT, MRI, and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically, we found that LY2109761 reduced p-SMAD2 and p-SMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and noncanonical TGF-β signaling and downstream signaling of bone morphogenetic proteins (BMP). LY2109761 also suppressed radiation-induced inflammatory [e.g., interleukin (IL)-6, IL-7R, IL-8] and proangiogenic genes (e.g., ID1) indicating that LY2109761 achieves its antifibrotic effect by suppressing radiation-induced proinflammatory, proangiogenic, and profibrotic signals. Small-molecule inhibitors of the TGF-β receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis. ©2012 AACR.

  14. Wavelet analysis for nonstationary signals

    International Nuclear Information System (INIS)

    Penha, Rosani Maria Libardi da

    1999-01-01

    Mechanical vibration signals play an important role in anomalies identification resulting of equipment malfunctioning. Traditionally, Fourier spectral analysis is used where the signals are assumed to be stationary. However, occasional transient impulses and start-up process are examples of nonstationary signals that can be found in mechanical vibrations. These signals can provide important information about the equipment condition, as early fault detection. The Fourier analysis can not adequately be applied to nonstationary signals because the results provide data about the frequency composition averaged over the duration of the signal. In this work, two methods for nonstationary signal analysis are used: Short Time Fourier Transform (STFT) and wavelet transform. The STFT is a method of adapting Fourier spectral analysis for nonstationary application to time-frequency domain. To have a unique resolution throughout the entire time-frequency domain is its main limitation. The wavelet transform is a new analysis technique suitable to nonstationary signals, which handles the STFT drawbacks, providing multi-resolution frequency analysis and time localization in a unique time-scale graphic. The multiple frequency resolutions are obtained by scaling (dilatation/compression) the wavelet function. A comparison of the conventional Fourier transform, STFT and wavelet transform is made applying these techniques to: simulated signals, arrangement rotor rig vibration signal and rotate machine vibration signal Hanning window was used to STFT analysis. Daubechies and harmonic wavelets were used to continuos, discrete and multi-resolution wavelet analysis. The results show the Fourier analysis was not able to detect changes in the signal frequencies or discontinuities. The STFT analysis detected the changes in the signal frequencies, but with time-frequency resolution problems. The wavelet continuos and discrete transform demonstrated to be a high efficient tool to detect

  15. Steganography in arrhythmic electrocardiogram signal.

    Science.gov (United States)

    Edward Jero, S; Ramu, Palaniappan; Ramakrishnan, S

    2015-08-01

    Security and privacy of patient data is a vital requirement during exchange/storage of medical information over communication network. Steganography method hides patient data into a cover signal to prevent unauthenticated accesses during data transfer. This study evaluates the performance of ECG steganography to ensure secured transmission of patient data where an abnormal ECG signal is used as cover signal. The novelty of this work is to hide patient data into two dimensional matrix of an abnormal ECG signal using Discrete Wavelet Transform and Singular Value Decomposition based steganography method. A 2D ECG is constructed according to Tompkins QRS detection algorithm. The missed R peaks are computed using RR interval during 2D conversion. The abnormal ECG signals are obtained from the MIT-BIH arrhythmia database. Metrics such as Peak Signal to Noise Ratio, Percentage Residual Difference, Kullback-Leibler distance and Bit Error Rate are used to evaluate the performance of the proposed approach.

  16. Unmixing binocular signals

    Directory of Open Access Journals (Sweden)

    Sidney R Lehky

    2011-08-01

    Full Text Available Incompatible images presented to the two eyes lead to perceptual oscillations in which one image at a time is visible. Early models portrayed this binocular rivalry as involving reciprocal inhibition between monocular representations of images, occurring at an early visual stage prior to binocular mixing. However, psychophysical experiments found conditions where rivalry could also occur at a higher, more abstract level of representation. In those cases, the rivalry was between image representations dissociated from eye-of-origin information, rather than between monocular representations from the two eyes. Moreover, neurophysiological recordings found the strongest rivalry correlate in inferotemporal cortex, a high-level, predominantly binocular visual area involved in object recognition, rather than early visual structures. An unresolved issue is how can the separate identities of the two images be maintained after binocular mixing in order for rivalry to be possible at higher levels? Here we demonstrate that after the two images are mixed, they can be unmixed at any subsequent stage using a physiologically plausible nonlinear signal-processing algorithm, non-negative matrix factorization, previously proposed for parsing object parts during object recognition. The possibility that unmixed left and right images can be regenerated at late stages within the visual system provides a mechanism for creating various binocular representations and interactions de novo in different cortical areas for different purposes, rather than inheriting then from early areas. This is a clear example how nonlinear algorithms can lead to highly non-intuitive behavior in neural information processing.

  17. Digitally programmable signal generator

    International Nuclear Information System (INIS)

    Priatko, G.J.; Kaskey, J.A.

    1988-01-01

    A digitally programmable signal generator (DPSG) includes a first memory from which data is written into a second memory formed of n banks. Each bank includes four memories and a multiplexer, the banks being read once during each time frame, the read-out bits being multiplexed and fed out serially in synchronism with a plurality of clock pulses occuring during a time frame. The resulting serial bit streams may be fed in parallel to a digital-to-analog converter. The DPSG can be used in applications such as Atomic Vapor Laser Isotope Separation (AVLIS) to create an optimal match between the process laser's spectral profile and that of the vaporized material, optical telecommunications, non-optical telecommunication in the microwave and radio spectrum, radar, electronic countermeasures, high speed computer interconnects, local area networks, high definition video transport and the multiplexing of large quantities of slow digital memory into high speed data streams. This invention extends the operation of DPSGs into the GHz range. (author)

  18. Volcanic signals in oceans

    KAUST Repository

    Stenchikov, Georgiy L.

    2009-08-22

    Sulfate aerosols resulting from strong volcanic explosions last for 2–3 years in the lower stratosphere. Therefore it was traditionally believed that volcanic impacts produce mainly short-term, transient climate perturbations. However, the ocean integrates volcanic radiative cooling and responds over a wide range of time scales. The associated processes, especially ocean heat uptake, play a key role in ongoing climate change. However, they are not well constrained by observations, and attempts to simulate them in current climate models used for climate predictions yield a range of uncertainty. Volcanic impacts on the ocean provide an independent means of assessing these processes. This study focuses on quantification of the seasonal to multidecadal time scale response of the ocean to explosive volcanism. It employs the coupled climate model CM2.1, developed recently at the National Oceanic and Atmospheric Administration\\'s Geophysical Fluid Dynamics Laboratory, to simulate the response to the 1991 Pinatubo and the 1815 Tambora eruptions, which were the largest in the 20th and 19th centuries, respectively. The simulated climate perturbations compare well with available observations for the Pinatubo period. The stronger Tambora forcing produces responses with higher signal-to-noise ratio. Volcanic cooling tends to strengthen the Atlantic meridional overturning circulation. Sea ice extent appears to be sensitive to volcanic forcing, especially during the warm season. Because of the extremely long relaxation time of ocean subsurface temperature and sea level, the perturbations caused by the Tambora eruption could have lasted well into the 20th century.

  19. Fundamentals of statistical signal processing

    CERN Document Server

    Kay, Steven M

    1993-01-01

    A unified presentation of parameter estimation for those involved in the design and implementation of statistical signal processing algorithms. Covers important approaches to obtaining an optimal estimator and analyzing its performance; and includes numerous examples as well as applications to real- world problems. MARKETS: For practicing engineers and scientists who design and analyze signal processing systems, i.e., to extract information from noisy signals — radar engineer, sonar engineer, geophysicist, oceanographer, biomedical engineer, communications engineer, economist, statistician, physicist, etc.

  20. Queen signaling in social wasps

    DEFF Research Database (Denmark)

    van Zweden, Jelle Stijn; Bonckaert, Wim; Wenseleers, Tom

    2014-01-01

    , thereby arguing against fast evolution of signals as a result of a queen-worker arms race ensuing from queen control. Lastly, levels of worker reproduction in these species correspond well with their average colony kin structures, as predicted by the queen signaling hypothesis but not the queen control...... hypothesis. Altogether, this correlative yet comprehensive analysis provides compelling evidence that honest signaling explains levels of reproductive division of labor in social wasps....

  1. Semi-classical signal analysis

    KAUST Repository

    Laleg-Kirati, Taous-Meriem

    2012-09-30

    This study introduces a new signal analysis method, based on a semi-classical approach. The main idea in this method is to interpret a pulse-shaped signal as a potential of a Schrödinger operator and then to use the discrete spectrum of this operator for the analysis of the signal. We present some numerical examples and the first results obtained with this method on the analysis of arterial blood pressure waveforms. © 2012 Springer-Verlag London Limited.

  2. Signal generation in gas detectors

    International Nuclear Information System (INIS)

    Stillman, A.

    1993-01-01

    This tutorial describes the generation of electrical signals in gas detectors. Ionization of the gas by the passage of charged particles generates these signals. Starting with the Bethe-Bloch equation, the treatment is a general introduction to the production of ion-pairs in gas devices. I continue with the characterization of the ionization as an electrical signal, and calculate the signal current in a simple example. Another example demonstrates the effect of space charge on the design of a detector. The AGS Booster ionization profile monitor is a model for this calculation

  3. Signal generation in gas detectors

    Energy Technology Data Exchange (ETDEWEB)

    Stillman, A.

    1993-11-01

    This tutorial describes the generation of electrical signals in gas detectors. Ionization of the gas by the passage of charged particles generates these signals. Starting with the Bethe-Bloch equation, the treatment is a general introduction to the production of ion-pairs in gas devices. I continue with the characterization of the ionization as an electrical signal, and calculate the signal current in a simple example. Another example demonstrates the effect of space charge on the design of a detector. The AGS Booster ionization profile monitor is a model for this calculation.

  4. Virtual Vertical Aircraft Signal Training

    National Research Council Canada - National Science Library

    Norling, William

    1998-01-01

    .... Advances in virtual environments may provide a cost effective solution to the current live helicopter operations method of training, provided technical issues associated with hand and wand signal...

  5. Signal anomaly detection and characterization

    International Nuclear Information System (INIS)

    Morgenstern, V.M.; Upadhyaya, B.R.; Gloeckler, O.

    1988-08-01

    As part of a comprehensive signal validation system, we have developed a signal anomaly detector, without specifically establishing the cause of the anomaly. A signal recorded from process instrumentation is said to have an anomaly, if during steady-state operation, the deviation in the level of the signal, its root-mean-square (RMS) value, or its statistical distribution changes by a preset value. This deviation could be an unacceptable increase or a decrease in the quantity being monitored. An anomaly in a signal may be characterized by wideband or single-frequency noise, bias error, pulse-type error, nonsymmetric behavior, or a change in the signal bandwidth. Various signatures can be easily computed from data samples and compared against specified threshold values. We want to point out that in real processes, pulses can appear with different time widths, and at different rates of change of the signal. Thus, in characterizing an anomaly as a pulse-type, the fastest pulse width is constrained by the signal sampling interval. For example, if a signal is sampled at 100 Hz, we will not be able to detect pulses occurring at kHz rates. Discussion with utility and Combustion Engineering personnel indicated that it is not practical to detect pulses having a narrow time width. 9 refs., 11 figs., 8 tabs

  6. Pragmatic circuits signals and filters

    CERN Document Server

    Eccles, William

    2006-01-01

    Pragmatic Circuits: Signals and Filters is built around the processing of signals. Topics include spectra, a short introduction to the Fourier series, design of filters, and the properties of the Fourier transform. The focus is on signals rather than power. But the treatment is still pragmatic. For example, the author accepts the work of Butterworth and uses his results to design filters in a fairly methodical fashion. This third of three volumes finishes with a look at spectra by showing how to get a spectrum even if a signal is not periodic. The Fourier transform provides a way of dealing wi

  7. Smoke Signal or Smoke Screen?

    DEFF Research Database (Denmark)

    Vergne, Jean-Philippe; Wernicke, Georg; Brenner, Steffen

    This paper explains the amount of disapproval faced by firms that overpay their CEO by integrating signaling and categorization theories. We argue that, in contexts characterized by intense scrutiny, ambivalent signals sent by firms suspend categorization by stakeholders, leading to further disap...

  8. Signals in Communication Engineering History

    Science.gov (United States)

    Consonni, Denise; Silva, Magno T. M.

    2010-01-01

    This paper is a study of various electric signals, which have been employed throughout the history of communication engineering in its two main landmarks: the telegraph and the telephone. The signals are presented in their time and frequency domain representations. The historical order has been followed in the presentation: wired systems, spark…

  9. Cellular semiotics and signal transduction

    DEFF Research Database (Denmark)

    Bruni, Luis Emilio

    2007-01-01

    (s)" in signal transduction; i.e.: how specificity is determined, how ubiquitous signals or messengers convey specific information, how undesired cross-talk is avoided, how redundancy integrates the system. This chapter proposes a basic conceptual toolbox for interpreting empirical data that deals...

  10. Hippo signalling directs intestinal fate

    DEFF Research Database (Denmark)

    le Bouteiller, Marie Catherine M; Jensen, Kim Bak

    2015-01-01

    Hippo signalling has been associated with many important tissue functions including the regulation of organ size. In the intestinal epithelium differing functions have been proposed for the effectors of Hippo signalling, YAP and TAZ1. These are now shown to have a dual role in the intestinal epit...

  11. Signals and systems with MATLAB

    CERN Document Server

    Yang, Won Young; Song, Ik H; Cho, Yong S

    2009-01-01

    Covers some of the theoretical foundations and mathematical derivations that can be used in higher-level related subjects such as signal processing, communication, and control, minimizing the mathematical difficulty and computational burden. This book illustrates the usage of MATLAB and Simulink for signal and system analysis and design.

  12. Signaling a Change of Heart

    DEFF Research Database (Denmark)

    Schumacher, Gijs

    2011-01-01

    introduced welfare state retrenchment measures. Social Democrats can win votes and join coalitions by shifting rightwards. In contrast, they can pursue policy objectives by shifting leftwards. To communicate these shifts, in other words, ‘changes of heart’, parties send signals to voters and other parties...... after having signalled ‘a change of heart’....

  13. Intracellular signal modulation by nanomaterials.

    Science.gov (United States)

    Hussain, Salik; Garantziotis, Stavros; Rodrigues-Lima, Fernando; Dupret, Jean-Marie; Baeza-Squiban, Armelle; Boland, Sonja

    2014-01-01

    A thorough understanding of the interactions of nanomaterials with biological systems and the resulting activation of signal transduction pathways is essential for the development of safe and consumer friendly nanotechnology. Here we present an overview of signaling pathways induced by nanomaterial exposures and describe the possible correlation of their physicochemical characteristics with biological outcomes. In addition to the hierarchical oxidative stress model and a review of the intrinsic and cell-mediated mechanisms of reactive oxygen species (ROS) generating capacities of nanomaterials, we also discuss other oxidative stress dependent and independent cellular signaling pathways. Induction of the inflammasome, calcium signaling, and endoplasmic reticulum stress are reviewed. Furthermore, the uptake mechanisms can be of crucial importance for the cytotoxicity of nanomaterials and membrane-dependent signaling pathways have also been shown to be responsible for cellular effects of nanomaterials. Epigenetic regulation by nanomaterials, effects of nanoparticle-protein interactions on cell signaling pathways, and the induction of various cell death modalities by nanomaterials are described. We describe the common trigger mechanisms shared by various nanomaterials to induce cell death pathways and describe the interplay of different modalities in orchestrating the final outcome after nanomaterial exposures. A better understanding of signal modulations induced by nanomaterials is not only essential for the synthesis and design of safer nanomaterials but will also help to discover potential nanomedical applications of these materials. Several biomedical applications based on the different signaling pathways induced by nanomaterials are already proposed and will certainly gain a great deal of attraction in the near future.

  14. A Serpentine Way to Signaling

    Indian Academy of Sciences (India)

    IAS Admin

    tude inside the cells, leading to activation of effectors molecules. Effectors are protein molecules that bind to DNA and cause. Figure 1. Simplified diagram of a signal transduction cas- cade. A signal transduction cascade represents the route of transfer of information from outside to inside the cell. There are many molecules.

  15. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome.

    Science.gov (United States)

    Cook, Jason R; Clayton, Nicholas P; Carta, Luca; Galatioto, Josephine; Chiu, Emily; Smaldone, Silvia; Nelson, Carol A; Cheng, Seng H; Wentworth, Bruce M; Ramirez, Francesco

    2015-04-01

    Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice). Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFβ-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA. By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFβ. © 2015 American Heart Association, Inc.

  16. Signal processing for radiation detectors

    CERN Document Server

    Nakhostin, Mohammad

    2018-01-01

    This book provides a clear understanding of the principles of signal processing of radiation detectors. It puts great emphasis on the characteristics of pulses from various types of detectors and offers a full overview on the basic concepts required to understand detector signal processing systems and pulse processing techniques. Signal Processing for Radiation Detectors covers all of the important aspects of signal processing, including energy spectroscopy, timing measurements, position-sensing, pulse-shape discrimination, and radiation intensity measurement. The book encompasses a wide range of applications so that readers from different disciplines can benefit from all of the information. In addition, this resource: * Describes both analog and digital techniques of signal processing * Presents a complete compilation of digital pulse processing algorithms * Extrapolates content from more than 700 references covering classic papers as well as those of today * Demonstrates concepts with more than 340 origin...

  17. Signal focusing through active transport

    Science.gov (United States)

    Godec, Aljaž; Metzler, Ralf

    2015-07-01

    The accuracy of molecular signaling in biological cells and novel diagnostic devices is ultimately limited by the counting noise floor imposed by the thermal diffusion. Motivated by the fact that messenger RNA and vesicle-engulfed signaling molecules transiently bind to molecular motors and are actively transported in biological cells, we show here that the random active delivery of signaling particles to within a typical diffusion distance to the receptor generically reduces the correlation time of the counting noise. Considering a variety of signaling particle sizes from mRNA to vesicles and cell sizes from prokaryotic to eukaryotic cells, we show that the conditions for active focusing—faster and more precise signaling—are indeed compatible with observations in living cells. Our results improve the understanding of molecular cellular signaling and novel diagnostic devices.

  18. Endocannabinoid signaling and synaptic function

    Science.gov (United States)

    Castillo, Pablo E.; Younts, Thomas J.; Chávez, Andrés E.; Hashimotodani, Yuki

    2012-01-01

    Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain. PMID:23040807

  19. Piezoelectric extraction of ECG signal

    Science.gov (United States)

    Ahmad, Mahmoud Al

    2016-11-01

    The monitoring and early detection of abnormalities or variations in the cardiac cycle functionality are very critical practices and have significant impact on the prevention of heart diseases and their associated complications. Currently, in the field of biomedical engineering, there is a growing need for devices capable of measuring and monitoring a wide range of cardiac cycle parameters continuously, effectively and on a real-time basis using easily accessible and reusable probes. In this paper, the revolutionary generation and extraction of the corresponding ECG signal using a piezoelectric transducer as alternative for the ECG will be discussed. The piezoelectric transducer pick up the vibrations from the heart beats and convert them into electrical output signals. To this end, piezoelectric and signal processing techniques were employed to extract the ECG corresponding signal from the piezoelectric output voltage signal. The measured electrode based and the extracted piezoelectric based ECG traces are well corroborated. Their peaks amplitudes and locations are well aligned with each other.

  20. Aberrant Signaling Pathways in Glioma

    International Nuclear Information System (INIS)

    Nakada, Mitsutoshi; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka; Teng, Lei; Pyko, Ilya V.; Hamada, Jun-Ichiro

    2011-01-01

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  1. Loss of Arabidopsis thaliana Dynamin-Related Protein 2B reveals separation of innate immune signaling pathways.

    Directory of Open Access Journals (Sweden)

    John M Smith

    2014-12-01

    Full Text Available Vesicular trafficking has emerged as an important means by which eukaryotes modulate responses to microbial pathogens, likely by contributing to the correct localization and levels of host components necessary for effective immunity. However, considering the complexity of membrane trafficking in plants, relatively few vesicular trafficking components with functions in plant immunity are known. Here we demonstrate that Arabidopsis thaliana Dynamin-Related Protein 2B (DRP2B, which has been previously implicated in constitutive clathrin-mediated endocytosis (CME, functions in responses to flg22 (the active peptide derivative of bacterial flagellin and immunity against flagellated bacteria Pseudomonas syringae pv. tomato (Pto DC3000. Consistent with a role of DRP2B in Pattern-Triggered Immunity (PTI, drp2b null mutant plants also showed increased susceptibility to Pto DC3000 hrcC-, which lacks a functional Type 3 Secretion System, thus is unable to deliver effectors into host cells to suppress PTI. Importantly, analysis of drp2b mutant plants revealed three distinct branches of the flg22-signaling network that differed in their requirement for RESPIRATORY BURST OXIDASE HOMOLOGUE D (RBOHD, the NADPH oxidase responsible for flg22-induced apoplastic reactive oxygen species production. Furthermore, in drp2b, normal MAPK signaling and increased immune responses via the RbohD/Ca2+-branch were not sufficient for promoting robust PR1 mRNA expression nor immunity against Pto DC3000 and Pto DC3000 hrcC-. Based on live-cell imaging studies, flg22-elicited internalization of the plant flagellin-receptor, FLAGELLIN SENSING 2 (FLS2, was found to be partially dependent on DRP2B, but not the closely related protein DRP2A, thus providing genetic evidence for a component, implicated in CME, in ligand-induced endocytosis of FLS2. Reduced trafficking of FLS2 in response to flg22 may contribute in part to the non-canonical combination of immune signaling defects

  2. Quorum Quenching Revisited—From Signal Decays to Signalling Confusion

    Directory of Open Access Journals (Sweden)

    Kok-Gan Chan

    2012-04-01

    Full Text Available In a polymicrobial community, while some bacteria are communicating with neighboring cells (quorum sensing, others are interrupting the communication (quorum quenching, thus creating a constant arms race between intercellular communication. In the past decade, numerous quorum quenching enzymes have been found and initially thought to inactivate the signalling molecules. Though this is widely accepted, the actual roles of these quorum quenching enzymes are now being uncovered. Recent evidence extends the role of quorum quenching to detoxification or metabolism of signalling molecules as food and energy source; this includes “signalling confusion”, a term coined in this paper to refer to the phenomenon of non-destructive modification of signalling molecules. While quorum quenching has been explored as a novel anti-infective therapy targeting, quorum sensing evidence begins to show the development of resistance against quorum quenching.

  3. Signal transduction by growth factor receptors: signaling in an instant

    DEFF Research Database (Denmark)

    Dengjel, Joern; Akimov, Vyacheslav; Blagoev, Blagoy

    2007-01-01

    -out by mass spectrometry-based proteomics has allowed exciting views on the very early events in signal transduction. Activation profiles of regulated phosphorylation sites on epidermal growth factor receptor and downstream signal transducers showed different kinetics within the first ten seconds......Phosphorylation-based signaling events happening within the first minute of receptor stimulation have so far only been analyzed by classical cell biological approaches like live-cell microscopy. The development of a quench flow system with a time resolution of one second coupled to a read...... of stimulation. This new technique opens the perspectives for accurate analysis of rapid cellular processes and will help to establish models describing signal initiation at the plasma membrane....

  4. MHC signaling during social communication

    Science.gov (United States)

    Ruff, James S.; Nelson, Adam C.; Kubinak, Jason L.; Potts, Wayne K.

    2016-01-01

    The major histocompatibility complex (MHC) has been known to play a critical role in immune recognition since the 1950s. It was a surprise, then, in the 1970s when the first report appeared indicating MHC might also function in social signaling and in mate choice. Since this seminal discovery, MHC signaling has been found throughout vertebrates and its known functions have expanded beyond mate choice to include a suite of behaviors from kin-biased cooperation, parent-progeny recognition to pregnancy block. The widespread occurrence of MHC in social signaling has revealed conserved behavioral-genetic mechanisms that span vertebrates and includes humans. The identity of the signal’s chemical constituents and the receptors responsible for the perception of the signal have remained elusive, but recent advances have enabled the identification of the key components of the behavioral circuit. In this chapter we organize recent findings from the literature and discuss them in relation to four non-mutually exclusive models wherein MHC functions as a signal of (i) individuality, (ii) relatedness, (iii) genetic compatibility and (iv) quality. We also synthesize current mechanistic studies, showing how knowledge about the molecular basis of MHC signaling can lead to elegant and informative experimental manipulations. Finally, we discuss current evidence relating to the primordial functions of the MHC, including the possibility that its role in social signaling may be ancestral to its central role in adaptive immunity. PMID:22399386

  5. Baird's beaked whale echolocation signals.

    Science.gov (United States)

    Baumann-Pickering, Simone; Yack, Tina M; Barlow, Jay; Wiggins, Sean M; Hildebrand, John A

    2013-06-01

    Echolocation signals from Baird's beaked whales were recorded during visual and acoustic shipboard surveys of cetaceans in the California Current ecosystem and with autonomous, long-term recorders in the Southern California Bight. The preliminary measurement of the visually validated Baird's beaked whale echolocation signals from towed array data were used as a basis for identifying Baird's signals in the autonomous recorder data. Two distinct signal types were found, one being a beaked whale-like frequency modulated (FM) pulse, the other being a dolphin-like broadband click. The median FM inter-pulse interval was 230 ms. Both signal types showed a consistent multi-peak structure in their spectra with peaks at ~9, 16, 25, and 40 kHz. Depending on signal type, as well as recording aspect and distance to the hydrophone, these peaks varied in relative amplitude. The description of Baird's echolocation signals will allow for studies of their distribution and abundance using towed array data without associated visual sightings and from autonomous seafloor hydrophones.

  6. Microsystem for signal processing applications

    Science.gov (United States)

    Frankenstein, B.; Froehlich, K.-J.; Hentschel, D.; Reppe, G.

    2005-05-01

    Acoustic monitoring of technological processes requires methods that eliminate noise as much as possible. Sensor-near signal evaluation can contribute substantially. Frequently, a further necessity exists to integrate the measuring technique in the monitored structure. The solution described contains components for analog preprocessing of acoustic signals, their digitization, algorithms for data reduction, and digital communication. The core component is a digital signal processor (DSP). Digital signal processors perform the algorithms necessary for filtering, down sampling, FFT computation and correlation of spectral components particularly effective. A compact, sensor-near signal processing structure was realized. It meets the Match-X standard, which as specified by the German Association for Mechanical and Plant Engineering (VDMA) for development of micro-technical modules, which can be combined to applicaiton specific systems. The solution is based on AL2O3 ceramic components including different signal processing modules as ADC, as well as memory and power supply. An arbitrary waveform generator has been developed and combined with a power amplifier for piezoelectric transducers in a special module. A further module interfaces to these transducers. It contains a multi-channel preamplifier, some high-pass filters for analog signal processing and an ADC-driver. A Bluetooth communication chip for wireless data transmission and a DiscOnChip module are under construction. As a first application, the combustion behavior of safety-relevant contacts is monitored. A special waveform up to 5MHz is produced and sent to the monitored object. The resulting signal form is evaluated with special algorithms, which extract significant parameters of the signal, and transmitted via CAN-bus.

  7. Advanced optical signal processing of broadband parallel data signals

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo; Hu, Hao; Kjøller, Niels-Kristian

    2016-01-01

    Optical signal processing may aid in reducing the number of active components in communication systems with many parallel channels, by e.g. using telescopic time lens arrangements to perform format conversion and allow for WDM regeneration.......Optical signal processing may aid in reducing the number of active components in communication systems with many parallel channels, by e.g. using telescopic time lens arrangements to perform format conversion and allow for WDM regeneration....

  8. Fast digitizing and digital signal processing of detector signals

    International Nuclear Information System (INIS)

    Hannaske, Roland

    2008-01-01

    A fast-digitizer data acquisition system recently installed at the neutron time-of-flight experiment nELBE, which is located at the superconducting electron accelerator ELBE of Forschungszentrum Dresden-Rossendorf, is tested with two different detector types. Preamplifier signals from a high-purity germanium detector are digitized, stored and finally processed. For a precise determination of the energy of the detected radiation, the moving-window deconvolution algorithm is used to compensate the ballistic deficit and different shaping algorithms are applied. The energy resolution is determined in an experiment with γ-rays from a 22 Na source and is compared to the energy resolution achieved with analogously processed signals. On the other hand, signals from the photomultipliers of barium fluoride and plastic scintillation detectors are digitized. These signals have risetimes of a few nanoseconds only. The moment of interaction of the radiation with the detector is determined by methods of digital signal processing. Therefore, different timing algorithms are implemented and tested with data from an experiment at nELBE. The time resolutions achieved with these algorithms are compared to each other as well as to reference values coming from analog signal processing. In addition to these experiments, some properties of the digitizing hardware are measured and a program for the analysis of stored, digitized data is developed. The analysis of the signals shows that the energy resolution achieved with the 10-bit digitizer system used here is not competitive to a 14-bit peak-sensing ADC, although the ballistic deficit can be fully corrected. However, digital methods give better result in sub-ns timing than analog signal processing. (orig.)

  9. ESR signals of irradiated insects

    International Nuclear Information System (INIS)

    Ukai, Mitsuko; Kameya, Hiromi; Imamura, Taro; Miyanoshita, Akihiro; Todoriki, Setsuko; Shimoyama, Yuhei

    2009-01-01

    Analysis of irradiated insects using Electron Spin Resonance (ESR) spectroscopy was reported. The insects were maize weevil, red flour beetle, Indian meal moth and cigarette beetle that are hazardous to crops. The ESR spectra were consisted of a singlet at g=2 and a sextet centered at the similar g-value. The singlet signal is due to an organic free radical. The sextet signal is attributable to the hyperfine interactions from Mn 2+ ions. Upon irradiation, new signals were not detected. The relaxation times, T 1 and T 2 , showed no variations before and after irradiation. (author)

  10. Ultrasound imaging using coded signals

    DEFF Research Database (Denmark)

    Misaridis, Athanasios

    coded excitation can be used for increasing the frame rate. The work includes both simulated results using Field II, and experimental results based on measurements on phantoms as well as clinical images. Initially a mathematical foundation of signal modulation is given. Pulse compression based...... is described. Application of coded excitation in array imaging is evaluated through simulations in Field II. The low degree of the orthogonality among coded signals for ultrasound systems is first discussed, and the effect of mismatched filtering in the cross-correlation properties of the signals is evaluated...... emissions. Finally, a novel coding technique which uses pulse train excitation is presented....

  11. Statistical theory of signal detection

    CERN Document Server

    Helstrom, Carl Wilhelm; Costrell, L; Kandiah, K

    1968-01-01

    Statistical Theory of Signal Detection, Second Edition provides an elementary introduction to the theory of statistical testing of hypotheses that is related to the detection of signals in radar and communications technology. This book presents a comprehensive survey of digital communication systems. Organized into 11 chapters, this edition begins with an overview of the theory of signal detection and the typical detection problem. This text then examines the goals of the detection system, which are defined through an analogy with the testing of statistical hypotheses. Other chapters consider

  12. Subjective Evaluation of Audiovisual Signals

    Directory of Open Access Journals (Sweden)

    F. Fikejz

    2010-01-01

    Full Text Available This paper deals with subjective evaluation of audiovisual signals, with emphasis on the interaction between acoustic and visual quality. The subjective test is realized by a simple rating method. The audiovisual signal used in this test is a combination of images compressed by JPEG compression codec and sound samples compressed by MPEG-1 Layer III. Images and sounds have various contents. It simulates a real situation when the subject listens to compressed music and watches compressed pictures without the access to original, i.e. uncompressed signals.

  13. EUROmediCAT signal detection

    DEFF Research Database (Denmark)

    Given, Joanne E; Loane, Maria; Luteijn, Johannes Michiel

    2016-01-01

    AIMS: To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation. METHODS: Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level...... persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity. RESULTS: Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis...

  14. On Generalized Fractional Differentiator Signals

    Directory of Open Access Journals (Sweden)

    Hamid A. Jalab

    2013-01-01

    Full Text Available By employing the generalized fractional differential operator, we introduce a system of fractional order derivative for a uniformly sampled polynomial signal. The calculation of the bring in signal depends on the additive combination of the weighted bring-in of N cascaded digital differentiators. The weights are imposed in a closed formula containing the Stirling numbers of the first kind. The approach taken in this work is to consider that signal function in terms of Newton series. The convergence of the system to a fractional time differentiator is discussed.

  15. Terminality implies non-signalling

    Directory of Open Access Journals (Sweden)

    Bob Coecke

    2014-12-01

    Full Text Available A 'process theory' is any theory of systems and processes which admits sequential and parallel composition. `Terminality' unifies normalisation of pure states, trace-preservation of CP-maps, and adding up to identity of positive operators in quantum theory, and generalises this to arbitrary process theories. We show that terminality and non-signalling coincide in any process theory, provided one makes causal structure explicit. In fact, making causal structure explicit is necessary to even make sense of non-signalling in process theories. We conclude that because of its much simpler mathematical form, terminality should be taken to be a more fundamental notion than non-signalling.

  16. NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling.

    Science.gov (United States)

    Lech, Maciej; Lorenz, Georg; Kulkarni, Onkar P; Grosser, Marian O O; Stigrot, Nora; Darisipudi, Murthy N; Günthner, Roman; Wintergerst, Maximilian W M; Anz, David; Susanti, Heni Eka; Anders, Hans-Joachim

    2015-12-01

    The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1β/IL-18, but its potential role in autoimmunity is speculative. We generated and phenotyped Nlrp3-deficient, Asc-deficient, Il-1r-deficient and Il-18-deficient C57BL/6-lpr/lpr mice, the latter being a mild model of spontaneous lupus-like autoimmunity. While lack of IL-1R or IL-18 did not affect the C57BL/6-lpr/lpr phenotype, lack of NLRP3 or ASC triggered massive lymphoproliferation, lung T cell infiltrates and severe proliferative lupus nephritis within 6 months, which were all absent in age-matched C57BL/6-lpr/lpr controls. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous proinflammatory mediators, lymphocyte necrosis and the expansion of most T cell and B cell subsets. In contrast, plasma cells and autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC may relate to their known role in SMAD2/3 phosphorylation during tumour growth factor (TGF)-β receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-β target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-β1-deficient mice. These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  17. Subcellular Organization of GPCR Signaling.

    Science.gov (United States)

    Eichel, Kelsie; von Zastrow, Mark

    2018-02-01

    G protein-coupled receptors (GPCRs) comprise a large and diverse class of signal-transducing receptors that undergo dynamic and isoform-specific membrane trafficking. GPCRs thus have an inherent potential to initiate or regulate signaling reactions from multiple membrane locations. This review discusses emerging insights into the subcellular organization of GPCR function in mammalian cells, focusing on signaling transduced by heterotrimeric G proteins and β-arrestins. We summarize recent evidence indicating that GPCR-mediated activation of G proteins occurs not only from the plasma membrane (PM) but also from endosomes and Golgi membranes and that β-arrestin-dependent signaling can be transduced from the PM by β-arrestin trafficking to clathrin-coated pits (CCPs) after dissociation from a ligand-activated GPCR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Automobile Crash Sensor Signal Processor

    Science.gov (United States)

    1973-11-01

    The crash sensor signal processor described interfaces between an automobile-installed doppler radar and an air bag activating solenoid or equivalent electromechanical device. The processor utilizes both digital and analog techniques to produce an ou...

  19. Endothelial signaling in leukocyte transmigration

    NARCIS (Netherlands)

    Hordijk, Peter

    2003-01-01

    Leukocyte transendothelial migration is a multistep process coordinated by chemokine receptors, integrins and cell adhesion molecules. The interaction between leukocytes and endothelial cells is accompanied by bidirectional signaling in both cell types, which is initiated following formation of

  20. Invariants of DNA genomic signals

    Science.gov (United States)

    Cristea, Paul Dan A.

    2005-02-01

    For large scale analysis purposes, the conversion of genomic sequences into digital signals opens the possibility to use powerful signal processing methods for handling genomic information. The study of complex genomic signals reveals large scale features, maintained over the scale of whole chromosomes, that would be difficult to find by using only the symbolic representation. Based on genomic signal methods and on statistical techniques, the paper defines parameters of DNA sequences which are invariant to transformations induced by SNPs, splicing or crossover. Re-orienting concatenated coding regions in the same direction, regularities shared by the genomic material in all exons are revealed, pointing towards the hypothesis of a regular ancestral structure from which the current chromosome structures have evolved. This property is not found in non-nuclear genomic material, e.g., plasmids.

  1. Dopamine signaling: target in glioblastoma

    Czech Academy of Sciences Publication Activity Database

    Bartek, Jiří; Hodný, Zdeněk

    2014-01-01

    Roč. 5, č. 5 (2014), 1116-1117 ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : Dopamine signaling * glioblastoma * MAPK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

  2. Digital storage of repeated signals

    International Nuclear Information System (INIS)

    Prozorov, S.P.

    1984-01-01

    An independent digital storage system designed for repeated signal discrimination from background noises is described. The signal averaging is performed off-line in the real time mode by means of multiple selection of the investigated signal and integration in each point. Digital values are added in a simple summator and the result is recorded the storage device with the volume of 1024X20 bit from where it can be output on an oscillograph, a plotter or transmitted to a compUter for subsequent processing. The described storage is reliable and simple device on one base of which the systems for the nuclear magnetic resonapce signal acquisition in different experiments are developed

  3. Signal transforms in dynamic measurements

    CERN Document Server

    Layer, Edward

    2015-01-01

    This book is devoted to the analysis of measurement signals which requires specific mathematical operations like Convolution, Deconvolution, Laplace, Fourier, Hilbert, Wavelet or Z transform which are all presented in the present book. The different problems refer to the modulation of signals, filtration of disturbance as well as to the orthogonal signals and their use in digital form for the measurement of current, voltage, power and frequency are also widely discussed. All the topics covered in this book are presented in detail and illustrated by means of examples in MathCad and LabVIEW. This book provides a useful source for researchers, scientists and engineers who in their daily work are required to deal with problems of measurement and signal processing and can also be helpful to undergraduate students of electrical engineering.    

  4. Nuclear Receptor Signaling Atlas (NURSA)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Nuclear Receptor Signaling Atlas (NURSA) is designed to foster the development of a comprehensive understanding of the structure, function, and role in disease...

  5. Cytonemes as specialized signaling filopodia

    OpenAIRE

    Kornberg, Thomas B.; Roy, Sougata

    2014-01-01

    Development creates a vast array of forms and patterns with elegant economy, using a small vocabulary of pattern-generating proteins such as BMPs, FGFs and Hh in similar ways in many different contexts. Despite much theoretical and experimental work, the signaling mechanisms that disperse these morphogen signaling proteins remain controversial. Here, we review the conceptual background and evidence that establishes a fundamental and essential role for cytonemes as specialized filopodia that t...

  6. RET Signaling in Prostate Cancer.

    Science.gov (United States)

    Ban, Kechen; Feng, Shu; Shao, Longjiang; Ittmann, Michael

    2017-08-15

    Purpose: Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its coreceptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Because both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. Experimental Design: Expression of RET, GDNF, and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion, and growth in vivo was determined. Cellular signaling downstream of RET was examined by Western blotting. Results: RET is expressed in all prostate cancer cell lines. GFRα1 is only expressed in 22Rv1 cells, which is the only line that responds to exogenous GDNF. In contrast, all cell lines respond to GDNF plus GFRα1. Conditioned medium from dorsal root ganglia contains secreted GFRα1 and promotes transformation-related phenotypes, which can be blocked by anti-GFRα1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFRα antibody and RET knockdown. In vivo , knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. Finally, RET is expressed in 18% of adenocarcinomas and all three small-cell carcinomas examined. Conclusions: RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFRα1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur. Clin Cancer Res; 23(16); 4885-96. ©2017 AACR . ©2017 American Association for Cancer Research.

  7. Neurotransmitter signaling in white matter.

    Science.gov (United States)

    Butt, Arthur M; Fern, Robert F; Matute, Carlos

    2014-11-01

    White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca(2+) signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. © 2014 Wiley Periodicals, Inc.

  8. Sentiment analysis for PTSD signals

    CERN Document Server

    Kagan, Vadim; Sapounas, Demetrios

    2013-01-01

    This book describes a computational framework for real-time detection of psychological signals related to Post-Traumatic Stress Disorder (PTSD) in online text-based posts, including blogs and web forums. Further, it explores how emerging computational techniques such as sentiment mining can be used in real-time to identify posts that contain PTSD-related signals, flag those posts, and bring them to the attention of psychologists, thus providing an automated flag and referral capability.

  9. Hedgehog signalling in foregut malignancy.

    Science.gov (United States)

    Watkins, D N; Peacock, C D

    2004-09-15

    Hedgehog (Hh) signalling mediates axial patterning and stem cell fate in development. This is mediated by Sonic, Desert and Indian Hedgehogs whose morphogen gradients determine the level of signalling in recipient tissues. Aberrant, cell autonomous, ligand-dependent Hh signalling has recently been demonstrated in small cell lung cancer (SCLC), as well as in upper gastrointestinal malignancies arising from pancreas, esophagus and stomach. These tumors lack mutations in the Hh receptor PATCHED, identifying a mechanism of pathway activation distinct from Gorlin's syndrome associated neural and skin tumors. We believe that this phenomenon represents a conserved mechanism for establishing niche-independent stem cell fates in cancer which is essential for malignant transformation and metastasis. Specific inhibition of Hh signalling by the naturally occurring plant alkaloid cyclopamine provides the opportunity for pharmacologic assessment of the role of Hh signalling in these tumors. Cyclopamine inhibits growth of SCLC and a wide range of foregut derived malignancies both in vitro and in vivo. This demonstrates an ongoing requirement for Hh signalling in these highly lethal and aggressive tumors. A novel therapeutic strategy is proposed using pharmacologic targeting of Hh dependent tumors with high potency pathway antagonists.

  10. Insulin Signaling and Heart Failure

    Science.gov (United States)

    Riehle, Christian; Abel, E. Dale

    2016-01-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin resistant states such as type 2 diabetes and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes alters the systemic and neurohumoral milieu leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead (FOXO) transcriptional signaling or glucose transport which may also impair cardiac metabolism, structure and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

  11. Metabolites in vertebrate Hedgehog signaling.

    Science.gov (United States)

    Roberg-Larsen, Hanne; Strand, Martin Frank; Krauss, Stefan; Wilson, Steven Ray

    2014-04-11

    The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. SignalPlant: an open signal processing software platform.

    Science.gov (United States)

    Plesinger, F; Jurco, J; Halamek, J; Jurak, P

    2016-07-01

    The growing technical standard of acquisition systems allows the acquisition of large records, often reaching gigabytes or more in size as is the case with whole-day electroencephalograph (EEG) recordings, for example. Although current 64-bit software for signal processing is able to process (e.g. filter, analyze, etc) such data, visual inspection and labeling will probably suffer from rather long latency during the rendering of large portions of recorded signals. For this reason, we have developed SignalPlant-a stand-alone application for signal inspection, labeling and processing. The main motivation was to supply investigators with a tool allowing fast and interactive work with large multichannel records produced by EEG, electrocardiograph and similar devices. The rendering latency was compared with EEGLAB and proves significantly faster when displaying an image from a large number of samples (e.g. 163-times faster for 75  ×  10(6) samples). The presented SignalPlant software is available free and does not depend on any other computation software. Furthermore, it can be extended with plugins by third parties ensuring its adaptability to future research tasks and new data formats.

  13. Bystander signaling via oxidative metabolism

    Directory of Open Access Journals (Sweden)

    Sawal HA

    2017-08-01

    Full Text Available Humaira Aziz Sawal,1 Kashif Asghar,2 Matthias Bureik,3 Nasir Jalal4 1Healthcare Biotechnology Department, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, 2Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; 3Health Science Platform, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China; 4Health Science Platform, Department of Molecular and Cellular Pharmacology, Tianjin University, Tianjin, China Abstract: The radiation-induced bystander effect (RIBE is the initiation of biological end points in cells (bystander cells that are not directly traversed by an incident-radiation track, but are in close proximity to cells that are receiving the radiation. RIBE has been indicted of causing DNA damage via oxidative stress, besides causing direct damage, inducing tumorigenesis, producing micronuclei, and causing apoptosis. RIBE is regulated by signaling proteins that are either endogenous or secreted by cells as a means of communication between cells, and can activate intracellular or intercellular oxidative metabolism that can further trigger signaling pathways of inflammation. Bystander signals can pass through gap junctions in attached cell lines, while the suspended cell lines transmit these signals via hormones and soluble proteins. This review provides the background information on how reactive oxygen species (ROS act as bystander signals. Although ROS have a very short half-life and have a nanometer-scale sphere of influence, the wide variety of ROS produced via various sources can exert a cumulative effect, not only in forming DNA adducts but also setting up signaling pathways of inflammation, apoptosis, cell-cycle arrest, aging, and even tumorigenesis. This review outlines the sources of the bystander effect linked to ROS in a cell, and provides methods of investigation for researchers who would like to

  14. Thyroid hormone-regulated Wnt5a/Ror2 signaling is essential for dedifferentiation of larval epithelial cells into adult stem cells in the Xenopus laevis intestine.

    Directory of Open Access Journals (Sweden)

    Atsuko Ishizuya-Oka

    Full Text Available Amphibian intestinal remodeling, where thyroid hormone (T3 induces some larval epithelial cells to become adult stem cells analogous to the mammalian intestinal ones, serves as a unique model for studying how the adult stem cells are formed. To clarify its molecular mechanisms, we here investigated roles of non-canonical Wnt signaling in the larval-to-adult intestinal remodeling during Xenopus laevis metamorphosis.Our quantitative RT-PCR (qRT-PCR and immunohistochemical analyses indicated that the expressions of Wnt5a and its receptors, frizzled 2 (Fzd2 and receptor tyrosine kinase-like orphan receptor 2 (Ror2 are up-regulated by T3 and are spatiotemporally correlated with adult epithelial development in the X. laevis intestine. Notably, changes in morphology of larval absorptive epithelial cells expressing Ror2 coincide well with formation of the adult stem cells during metamorphosis. In addition, by using organ cultures of the tadpole intestine, we have experimentally shown that addition of exogenous Wnt5a protein to the culture medium causes morphological changes in the larval epithelium expressing Ror2 even in the absence of T3. In contrast, in the presence of T3 where the adult stem cells are formed in vitro, inhibition of endogenous Wnt5a by an anti-Wnt5a antibody suppressed the epithelial morphological changes, leading to the failure of stem cell formation.Our findings strongly suggest that the adult stem cells originate from the larval absorptive cells expressing Ror2, which require Wnt5a/Ror2 signaling for their dedifferentiation accompanied by changes in cell morphology.

  15. Hepatitis B virus polymerase suppresses NF-κB signaling by inhibiting the activity of IKKs via interaction with Hsp90β.

    Directory of Open Access Journals (Sweden)

    Dan Liu

    Full Text Available Nuclear factor-κB (NF-κB plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host's antiviral immune defenses. In the case of hepatitis B virus (HBV, which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol inhibits interferon-β (IFN-β activity by disrupting the interaction between IKKε and the DDX3. In the current study, we found that HBV Pol suppressed NF-κB signaling, which can also contribute to IFN-β production. HBV Pol did not alter the level of NF-κB expression, but it prevented NF-κB subunits involved in both the canonical and non-canonical NF-κB pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the IκB kinase (IKK complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1. Furthermore, we found that HBV Pol inhibited the NF-κB-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-β activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.

  16. Liquid Argon TPC Signal Formation, Signal Processing and Hit Reconstruction

    Energy Technology Data Exchange (ETDEWEB)

    Baller, Bruce [Fermilab

    2017-03-11

    This document describes the early stage of the reconstruction chain that was developed for the ArgoNeuT and MicroBooNE experiments at Fermilab. These experiments study accelerator neutrino interactions that occur in a Liquid Argon Time Projection Chamber. Reconstructing the properties of particles produced in these interactions requires knowledge of the micro-physics processes that affect the creation and transport of ionization electrons to the readout system. A wire signal deconvolution technique was developed to convert wire signals to a standard form for hit reconstruction, to remove artifacts in the electronics chain and to remove coherent noise.

  17. Biomedical signal and image processing.

    Science.gov (United States)

    Cerutti, Sergio; Baselli, Giuseppe; Bianchi, Anna; Caiani, Enrico; Contini, Davide; Cubeddu, Rinaldo; Dercole, Fabio; Rienzo, Luca; Liberati, Diego; Mainardi, Luca; Ravazzani, Paolo; Rinaldi, Sergio; Signorini, Maria; Torricelli, Alessandro

    2011-01-01

    Generally, physiological modeling and biomedical signal processing constitute two important paradigms of biomedical engineering (BME): their fundamental concepts are taught starting from undergraduate studies and are more completely dealt with in the last years of graduate curricula, as well as in Ph.D. courses. Traditionally, these two cultural aspects were separated, with the first one more oriented to physiological issues and how to model them and the second one more dedicated to the development of processing tools or algorithms to enhance useful information from clinical data. A practical consequence was that those who did models did not do signal processing and vice versa. However, in recent years,the need for closer integration between signal processing and modeling of the relevant biological systems emerged very clearly [1], [2]. This is not only true for training purposes(i.e., to properly prepare the new professional members of BME) but also for the development of newly conceived research projects in which the integration between biomedical signal and image processing (BSIP) and modeling plays a crucial role. Just to give simple examples, topics such as brain–computer machine or interfaces,neuroengineering, nonlinear dynamical analysis of the cardiovascular (CV) system,integration of sensory-motor characteristics aimed at the building of advanced prostheses and rehabilitation tools, and wearable devices for vital sign monitoring and others do require an intelligent fusion of modeling and signal processing competences that are certainly peculiar of our discipline of BME.

  18. 300 Area signal cable study

    International Nuclear Information System (INIS)

    Whattam, J.W.

    1994-01-01

    This report was prepared to discuss the alternatives available for removing the 300 Area overhead signal cable system. This system, installed in 1969, has been used for various monitoring and communication signaling needs throughout the 300 Area. Over the years this cabling system has deteriorated, has been continually reconfigured, and has been poorly documented to the point of nonreliability. The first step was to look at the systems utilizing the overhead signal cable that are still required for operation. Of the ten systems that once operated via the signal cable, only five are still required; the civil defense evacuation alarms, the public address (PA) system, the criticality alarms, the Pacific Northwest Laboratory Facilities Management Control System (FMCS), and the 384 annunciator panel. Of these five, the criticality alarms and the FMCS have been dealt with under other proposals. Therefore, this study focused on the alternatives available for the remaining three systems (evacuation alarms, PA system, and 384 panel) plus the accountability aid phones. Once the systems to be discussed were determined, then three alternatives for providing the signaling pathway were examined for each system: (1) re-wire using underground communication ducts, (2) use the Integrated Voice/Data Telecommunications System (IVDTS) already installed and operated by US West, and (3) use radio control. Each alternative was developed with an estimated cost, advantages, and disadvantages. Finally, a recommendation was provided for the best alternative for each system

  19. EGFR Signaling in Liver Diseases

    Directory of Open Access Journals (Sweden)

    Karin Komposch

    2015-12-01

    Full Text Available The epidermal growth factor receptor (EGFR is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs.

  20. Dialkylresorcinols as bacterial signaling molecules.

    Science.gov (United States)

    Brameyer, Sophie; Kresovic, Darko; Bode, Helge B; Heermann, Ralf

    2015-01-13

    It is well recognized that bacteria communicate via small diffusible molecules, a process termed quorum sensing. The best understood quorum sensing systems are those that use acylated homoserine lactones (AHLs) for communication. The prototype of those systems consists of a LuxI-like AHL synthase and a cognate LuxR receptor that detects the signal. However, many proteobacteria possess LuxR receptors, yet lack any LuxI-type synthase, and thus these receptors are referred to as LuxR orphans or solos. In addition to the well-known AHLs, little is known about the signaling molecules that are sensed by LuxR solos. Here, we describe a novel cell-cell communication system in the insect and human pathogen Photorhabdus asymbiotica. We identified the LuxR homolog PauR to sense dialkylresorcinols (DARs) and cyclohexanediones (CHDs) instead of AHLs as signals. The DarABC synthesis pathway produces the molecules, and the entire system emerged as important for virulence. Moreover, we have analyzed more than 90 different Photorhabdus strains by HPLC/MS and showed that these DARs and CHDs are specific to the human pathogen P. asymbiotica. On the basis of genomic evidence, 116 other bacterial species are putative DAR producers, among them many human pathogens. Therefore, we discuss the possibility of DARs as novel and widespread bacterial signaling molecules and show that bacterial cell-cell communication goes far beyond AHL signaling in nature.

  1. Optical time-lens signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo; Galili, Michael; Mulvad, Hans Christian Hansen

    2014-01-01

    This paper describes the use of optical time lenses for optical signal processing of advanced optical data signals. Examples given include 1.28 Tbaud Nyquist channel serial-to-parallel conversion and spectral magnification of OFDM signals.......This paper describes the use of optical time lenses for optical signal processing of advanced optical data signals. Examples given include 1.28 Tbaud Nyquist channel serial-to-parallel conversion and spectral magnification of OFDM signals....

  2. Mathematical model for classification of EEG signals

    Science.gov (United States)

    Ortiz, Victor H.; Tapia, Juan J.

    2015-09-01

    A mathematical model to filter and classify brain signals from a brain machine interface is developed. The mathematical model classifies the signals from the different lobes of the brain to differentiate the signals: alpha, beta, gamma and theta, besides the signals from vision, speech, and orientation. The model to develop further eliminates noise signals that occur in the process of signal acquisition. This mathematical model can be used on different platforms interfaces for rehabilitation of physically handicapped persons.

  3. [Signaling network-based functional cell design].

    Science.gov (United States)

    Ju, Jianqi; Wei, Ping

    2017-03-25

    Cellular signaling networks act as the central processor to deal with environmental signals and regulate cell function, and determine cell fate. Using synthetic biology approach to engineer cell signaling networks is crucial for ultimately constructing man-made "cell machines". Cellular signaling networks can encode sophisticated cell information by processing quantitatively signaling dynamics, which enables multi-dimensional regulation of functional sub-circuits. Here, we first review the research progresses on the signaling coding mechanisms; and then elaborate the methodologies and applications of cells signaling engineering; finally, we envision that signaling-based cell engineering are important for the increasingly-complicated next generation synthetic biology.

  4. Cytokinin signaling during root development.

    Science.gov (United States)

    Bishopp, Anthony; Help, Hanna; Helariutta, Ykä

    2009-01-01

    The cytokinin class of phytohormones regulates division and differentiation of plant cells. They are perceived and signaled by a phosphorelay mechanism similar to those observed in prokaryotes. Research into the components of phosphorelay had previously been marred by genetic redundancy. However, recent studies have addressed this with the creation of high-order mutants. In addition, several new elements regulating cytokinin signaling have been identified. This has uncovered many roles in diverse developmental and physiological processes. In this review, we look at these processes specifically in the context of root development. We focus on the formation and maintenance of the root apical meristem, primary and secondary vascular development, lateral root emergence and development, and root nodulation. We believe that the root is an ideal organ with which to investigate cytokinin signaling in a wider context.

  5. Neural networks in signal processing

    International Nuclear Information System (INIS)

    Govil, R.

    2000-01-01

    Nuclear Engineering has matured during the last decade. In research and design, control, supervision, maintenance and production, mathematical models and theories are used extensively. In all such applications signal processing is embedded in the process. Artificial Neural Networks (ANN), because of their nonlinear, adaptive nature are well suited to such applications where the classical assumptions of linearity and second order Gaussian noise statistics cannot be made. ANN's can be treated as nonparametric techniques, which can model an underlying process from example data. They can also adopt their model parameters to statistical change with time. Algorithms in the framework of Neural Networks in Signal processing have found new applications potentials in the field of Nuclear Engineering. This paper reviews the fundamentals of Neural Networks in signal processing and their applications in tasks such as recognition/identification and control. The topics covered include dynamic modeling, model based ANN's, statistical learning, eigen structure based processing and generalization structures. (orig.)

  6. The Dynamics of Costly Signaling

    Directory of Open Access Journals (Sweden)

    Elliott O. Wagner

    2013-04-01

    Full Text Available Costly signaling is a mechanism through which the honesty of signals can be secured in equilibrium, even in interactions where communicators have conflicting interests. This paper explores the dynamics of one such signaling game: Spence’s model of education. It is found that separating equilibria are unlikely to emerge under either the replicator or best response dynamics, but that partially communicative mixed equilibria are quite important dynamically. These mixtures are Lyapunov stable in the replicator dynamic and asymptotically stable in the best response dynamic. Moreover, they have large basins of attraction, in fact larger than those of either pooling or separating equilibria. This suggests that these mixtures may play significant, and underappreciated, roles in the explanation of the emergence and stability of information transfer.

  7. Ocean circulation generated magnetic signals

    DEFF Research Database (Denmark)

    Manoj, C.; Kuvshinov, A.; Maus, S.

    2006-01-01

    Conducting ocean water, as it flows through the Earth's magnetic field, generates secondary electric and magnetic fields. An assessment of the ocean-generated magnetic fields and their detectability may be of importance for geomagnetism and oceanography. Motivated by the clear identification...... of ocean tidal signatures in the CHAMP magnetic field data we estimate the ocean magnetic signals of steady flow using a global 3-D EM numerical solution. The required velocity data are from the ECCO ocean circulation experiment and alternatively from the OCCAM model for higher resolution. We assume...... of the magnetic field, as compared to the ECCO simulation. Besides the expected signatures of the global circulation patterns, we find significant seasonal variability of ocean magnetic signals in the Indian and Western Pacific Oceans. Compared to seasonal variation, interannual variations produce weaker signals....

  8. Notch Signaling and Brain Tumors

    DEFF Research Database (Denmark)

    Stockhausen, Marie; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2011-01-01

    Human brain tumors are a heterogenous group of neoplasms occurring inside the cranium and the central spinal cord. In adults and children, astrocytic glioma and medulloblastoma are the most common subtypes of primary brain tumors. These tumor types are thought to arise from cells in which Notch...... signaling plays a fundamental role during development. Recent findings have shown that Notch signaling is dysregulated, and contributes to the malignant potential of these tumors. Growing evidence point towards an important role for cancer stem cells in the initiation and maintenance of glioma...... and medulloblastoma. In this chapter we will cover the present findings of Notch signaling in human glioma and medulloblastoma and try to create an overall picture of its relevance in the pathogenesis of these tumors....

  9. Wavelets and multiscale signal processing

    CERN Document Server

    Cohen, Albert

    1995-01-01

    Since their appearance in mid-1980s, wavelets and, more generally, multiscale methods have become powerful tools in mathematical analysis and in applications to numerical analysis and signal processing. This book is based on "Ondelettes et Traitement Numerique du Signal" by Albert Cohen. It has been translated from French by Robert D. Ryan and extensively updated by both Cohen and Ryan. It studies the existing relations between filter banks and wavelet decompositions and shows how these relations can be exploited in the context of digital signal processing. Throughout, the book concentrates on the fundamentals. It begins with a chapter on the concept of multiresolution analysis, which contains complete proofs of the basic results. The description of filter banks that are related to wavelet bases is elaborated in both the orthogonal case (Chapter 2), and in the biorthogonal case (Chapter 4). The regularity of wavelets, how this is related to the properties of the filters and the importance of regularity for t...

  10. Hedgehog signaling in the stomach.

    Science.gov (United States)

    Konstantinou, Daniel; Bertaux-Skeirik, Nina; Zavros, Yana

    2016-12-01

    The Hedgehog (Hh) signaling pathway not only plays a key part in controlling embryonic development, but in the adult stomach governs important cellular events such as epithelial cell differentiation, proliferation, gastric disease, and regeneration. In particular, Sonic Hedgehog (Shh) signaling has been well studied for its role in gastric physiology and pathophysiology. Shh is secreted from the gastric parietal cells and contributes to the regeneration of the epithelium in response to injury, or the development of gastritis during Helicobacter pylori infection. Dysregulation of the Shh signaling pathway leads to the disruption of gastric differentiation, loss of gastric acid secretion and the development of cancer. In this chapter, we will review the most recent findings that reveal the role of Shh as a regulator of gastric physiology, regeneration, and disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Multichannel Coding of Applause Signals

    Directory of Open Access Journals (Sweden)

    Jeroen Breebaart

    2007-08-01

    Full Text Available We develop a parametric multichannel audio codec dedicated to coding signals consisting of a dense series of transient-type events. These signals of which applause is a typical example are known to be problematic for such audio codecs. The codec design is based on preservation of both timbre and transient-type event density. It combines a very low complexity and a low parameter bit rate (0.2 kbps. In a formal listening test, we compared the proposed codec to the recently standardised MPEG Surround multichannel codec, with an associated parameter bit rate of 9 kbps. We found the new codec to have a significantly higher audio quality than the MPEG Surround codec for the two multichannel applause signals under test. Though this seems promising, the technique presented is not fully mature, for example, because issues related to integration of the proposed codec in the MPEG Surround codec were not addressed.

  12. Multichannel Coding of Applause Signals

    Science.gov (United States)

    Hotho, Gerard; van de Par, Steven; Breebaart, Jeroen

    2007-12-01

    We develop a parametric multichannel audio codec dedicated to coding signals consisting of a dense series of transient-type events. These signals of which applause is a typical example are known to be problematic for such audio codecs. The codec design is based on preservation of both timbre and transient-type event density. It combines a very low complexity and a low parameter bit rate (0.2 kbps). In a formal listening test, we compared the proposed codec to the recently standardised MPEG Surround multichannel codec, with an associated parameter bit rate of 9 kbps. We found the new codec to have a significantly higher audio quality than the MPEG Surround codec for the two multichannel applause signals under test. Though this seems promising, the technique presented is not fully mature, for example, because issues related to integration of the proposed codec in the MPEG Surround codec were not addressed.

  13. Humanin signal for Alzheimer's disease.

    Science.gov (United States)

    Matsuoka, Masaaki

    2011-01-01

    Despite a bulk of evidence supporting the idea that increased neurotoxic insults lead to Alzheimer's disease (AD), the possibility still remains that insufficiency of an endogenous defense system contributes to the disease progression. Humanin is a bioactive peptide that is likely to inhibit both neuronal death and dysfunction only related to AD by binding to a Humanin receptor on the cell-surface and by activating a STAT3-mediated signal, preventing the onset of dementia. A couple of recent studies presented evidence suggesting that the Humanin signal is decreased in neurons of AD patients. If this is the case, the restoration or activation of the Humanin signal in neurons may change the course of AD.

  14. Signals, systems, transforms, and digital signal processing with Matlab

    CERN Document Server

    Corinthios, Michael

    2009-01-01

    Continuous-Time and Discrete-Time Signals and SystemsIntroductionContinuous-Time SignalsPeriodic FunctionsUnit Step FunctionGraphical Representation of FunctionsEven and Odd Parts of a FunctionDirac-Delta ImpulseBasic Properties of the Dirac-Delta ImpulseOther Important Properties of the ImpulseContinuous-Time SystemsCausality, StabilityExamples of Electrical Continuous-Time SystemsMechanical SystemsTransfer Function and Frequency ResponseConvolution and CorrelationA Right-Sided and a Left-Sided FunctionConvolution with an Impulse and Its DerivativesAdditional Convolution PropertiesCorrelation FunctionProperties of the Correlation FunctionGraphical InterpretationCorrelation of Periodic FunctionsAverage, Energy and Power of Continuous-Time SignalsDiscrete-Time SignalsPeriodicityDifference EquationsEven/Odd DecompositionAverage Value, Energy and Power SequencesCausality, StabilityProblemsAnswers to Selected ProblemsFourier Series ExpansionTrigonometric Fourier SeriesExponential Fourier SeriesExponential versus ...

  15. DMPD: Signal integration between IFNgamma and TLR signalling pathways in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16920490 Signal integration between IFNgamma and TLR signalling pathways in macroph...tml) (.csml) Show Signal integration between IFNgamma and TLR signalling pathways in macrophages. PubmedID 1...6920490 Title Signal integration between IFNgamma and TLR signalling pathways in

  16. Signal processing for cognitive radios

    CERN Document Server

    Jayaweera, Sudharman K

    2014-01-01

    This book covers power electronics, in depth, by presenting the basic principles and application details, and it can be used both as a textbook and reference book.  Introduces the specific type of CR that has gained the most research attention in recent years: the CR for Dynamic Spectrum Access (DSA). Provides signal processing solutions to each task by relating the tasks to materials covered in Part II. Specialized chapters then discuss specific signal processing algorithms required for DSA and DSS cognitive radios  

  17. PSpice for digital signal processing

    CERN Document Server

    Tobin, Paul

    2007-01-01

    PSpice for Digital Signal Processing is the last in a series of five books using Cadence Orcad PSpice version 10.5 and introduces a very novel approach to learning digital signal processing (DSP). DSP is traditionally taught using Matlab/Simulink software but has some inherent weaknesses for students particularly at the introductory level. The 'plug in variables and play' nature of these software packages can lure the student into thinking they possess an understanding they don't actually have because these systems produce results quicklywithout revealing what is going on. However, it must be

  18. Genomic Signals of Reoriented ORFs

    Directory of Open Access Journals (Sweden)

    Paul Dan Cristea

    2004-01-01

    Full Text Available Complex representation of nucleotides is used to convert DNA sequences into complex digital genomic signals. The analysis of the cumulated phase and unwrapped phase of DNA genomic signals reveals large-scale features of eukaryote and prokaryote chromosomes that result from statistical regularities of base and base-pair distributions along DNA strands. By reorienting the chromosome coding regions, a “hidden” linear variation of the cumulated phase has been revealed, along with the conspicuous almost linear variation of the unwrapped phase. A model of chromosome longitudinal structure is inferred on these bases.

  19. Signal processing for remote sensing

    CERN Document Server

    Chen, CH

    2007-01-01

    Written by leaders in the field, Signal Processing for Remote Sensing explores the data acquisitions segment of remote sensing. Each chapter presents a major research result or the most up to date development of a topic. The book includes a chapter by Dr. Norden Huang, inventor of the Huang-Hilbert transform who, along with and Dr. Steven Long discusses the application of the transform to remote sensing problems. It also contains a chapter by Dr. Enders A. Robinson, who has made major contributions to seismic signal processing for over half a century, on the basic problem of constructing seism

  20. Digital signal processing for NDT

    International Nuclear Information System (INIS)

    Georgel, B.

    1994-01-01

    NDT begins to adapt and use the most recent developments of digital signal and image processing. We briefly sum up the main characteristics of NDT situations (particularly noise and inverse problem formulation) and comment on techniques already used or just emerging (SAFT, split spectrum, adaptive learning network, noise reference filtering, stochastic models, neural networks). This survey is focused on ultrasonics, eddy currents and X-ray radiography. The final objective of end users (availability of automatic diagnosis systems) cannot be achieved only by signal processing algorithms. A close cooperation with other techniques such as artificial intelligence has therefore to be implemented. (author). 20 refs

  1. Multichannel Coding of Applause Signals

    OpenAIRE

    Jeroen Breebaart; Steven van de Par; Gerard Hotho

    2007-01-01

    We develop a parametric multichannel audio codec dedicated to coding signals consisting of a dense series of transient-type events. These signals of which applause is a typical example are known to be problematic for such audio codecs. The codec design is based on preservation of both timbre and transient-type event density. It combines a very low complexity and a low parameter bit rate (0.2 kbps). In a formal listening test, we compared the proposed codec to the recently standardised MPEG Su...

  2. Notch Signaling and Brain Tumors

    DEFF Research Database (Denmark)

    Stockhausen, Marie; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2011-01-01

    Human brain tumors are a heterogenous group of neoplasms occurring inside the cranium and the central spinal cord. In adults and children, astrocytic glioma and medulloblastoma are the most common subtypes of primary brain tumors. These tumor types are thought to arise from cells in which Notch...... signaling plays a fundamental role during development. Recent findings have shown that Notch signaling is dysregulated, and contributes to the malignant potential of these tumors. Growing evidence point towards an important role for cancer stem cells in the initiation and maintenance of glioma...

  3. The Pseudomonas Quinolone Signal (PQS)

    DEFF Research Database (Denmark)

    Sams, Thomas; Baker, Ysobel; Hodgkinson, James

    2015-01-01

    Pseudomonas aeruginosa is an opportunistichuman pathogen that routinely appears near the top ofpublic health threat lists worldwide. P. aeruginosa causes in-fections by secreting a wealth of exceptionally active exo-products, leading to tissue damage. The synthesis of manyof these virulence factors...... is now known to be under the con-trol of the quorum sensing (QS) system. Over the last15 years, the Pseudomonas quinolone signal (PQS) has beenfound to play a crucial role in QS by linking the two seg-ments (las and rhl) of the P. aeruginosa N-acylhomoserinelactone-dependent QS signaling pathways. Herein...

  4. Chaotic signals in digital communications

    CERN Document Server

    Eisencraft, Marcio; Suyama, Ricardo

    2013-01-01

    Chaotic Signals in Digital Communications combines fundamental background knowledge with state-of-the-art methods for using chaotic signals and systems in digital communications. The book builds a bridge between theoretical works and practical implementation to help researchers attain consistent performance in realistic environments. It shows the possible shortcomings of the chaos-based communication systems proposed in the literature, particularly when they are subjected to non-ideal conditions. It also presents a toolbox of techniques for researchers working to actually implement such system

  5. Signal recovery in imaging photoplethysmography

    International Nuclear Information System (INIS)

    Holton, Benjamin D; Mannapperuma, Kavan; Lesniewski, Peter J; Thomas, John C

    2013-01-01

    Imaging photoplethysmography is an emerging technique for the extraction of biometric information from people using video recordings. The focus is on extracting the cardiac heart rate of the subject by analysing the luminance of the colour video signal and identifying periodic components. Advanced signal processing is needed to recover the information required. In this paper, independent component analysis (ICA), principal component analysis, auto- and cross-correlation are investigated and compared with respect to their effectiveness in extracting the relevant information from video recordings. Results obtained are compared with those recorded by a modern commercial finger pulse oximeter. It is found that ICA produces the most consistent results. (paper)

  6. Signal recovery in imaging photoplethysmography.

    Science.gov (United States)

    Holton, Benjamin D; Mannapperuma, Kavan; Lesniewski, Peter J; Thomas, John C

    2013-11-01

    Imaging photoplethysmography is an emerging technique for the extraction of biometric information from people using video recordings. The focus is on extracting the cardiac heart rate of the subject by analysing the luminance of the colour video signal and identifying periodic components. Advanced signal processing is needed to recover the information required. In this paper, independent component analysis (ICA), principal component analysis, auto- and cross-correlation are investigated and compared with respect to their effectiveness in extracting the relevant information from video recordings. Results obtained are compared with those recorded by a modern commercial finger pulse oximeter. It is found that ICA produces the most consistent results.

  7. Subgraph detection using graph signals

    KAUST Repository

    Chepuri, Sundeep Prabhakar

    2017-03-06

    In this paper we develop statistical detection theory for graph signals. In particular, given two graphs, namely, a background graph that represents an usual activity and an alternative graph that represents some unusual activity, we are interested in answering the following question: To which of the two graphs does the observed graph signal fit the best? To begin with, we assume both the graphs are known, and derive an optimal Neyman-Pearson detector. Next, we derive a suboptimal detector for the case when the alternative graph is not known. The developed theory is illustrated with numerical experiments.

  8. Signal processing systems for nuclear reactor

    International Nuclear Information System (INIS)

    Hirano, Kazuo.

    1981-01-01

    Purpose: To carry out the works signal processing, in a nuclear power plant, automatically. Constitution: Neutron flux signal from reactor instruments is inputted into a reactivity meter, and processes in accordance with reactor characteristic equations and, as the result, outputted as a reactivity signal rho. The signal rho, as well as the neutron flux signal and temperature signal are inputted together to a pen recorder and recorded on a record chart. While on the other hand, these signals are inputted into a signal processor, together with a range-switching signal from the reactivity meter and with a control-rod-position signal n from other instrument. In the signal processor, the differentiation and integration values such as Δrho/(n 1 -n 2 ) and ΣΔrho of the control element are conducted automatically. The results are indicated on a graphic display. (J.P.N.)

  9. Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD.

    Directory of Open Access Journals (Sweden)

    Lin Qu

    2011-09-01

    Full Text Available Toll-like receptor 3 (TLR3 and cytosolic RIG-I-like helicases (RIG-I and MDA5 sense viral RNAs and activate innate immune signaling pathways that induce expression of interferon (IFN through specific adaptor proteins, TIR domain-containing adaptor inducing interferon-β (TRIF, and mitochondrial antiviral signaling protein (MAVS, respectively. Previously, we demonstrated that hepatitis A virus (HAV, a unique hepatotropic human picornavirus, disrupts RIG-I/MDA5 signaling by targeting MAVS for cleavage by 3ABC, a precursor of the sole HAV protease, 3C(pro, that is derived by auto-processing of the P3 (3ABCD segment of the viral polyprotein. Here, we show that HAV also disrupts TLR3 signaling, inhibiting poly(I:C-stimulated dimerization of IFN regulatory factor 3 (IRF-3, IRF-3 translocation to the nucleus, and IFN-β promoter activation, by targeting TRIF for degradation by a distinct 3ABCD processing intermediate, the 3CD protease-polymerase precursor. TRIF is proteolytically cleaved by 3CD, but not by the mature 3C(pro protease or the 3ABC precursor that degrades MAVS. 3CD-mediated degradation of TRIF depends on both the cysteine protease activity of 3C(pro and downstream 3D(pol sequence, but not 3D(pol polymerase activity. Cleavage occurs at two non-canonical 3C(pro recognition sequences in TRIF, and involves a hierarchical process in which primary cleavage at Gln-554 is a prerequisite for scission at Gln-190. The results of mutational studies indicate that 3D(pol sequence modulates the substrate specificity of the upstream 3C(pro protease when fused to it in cis in 3CD, allowing 3CD to target cleavage sites not normally recognized by 3C(pro. HAV thus disrupts both RIG-I/MDA5 and TLR3 signaling pathways through cleavage of essential adaptor proteins by two distinct protease precursors derived from the common 3ABCD polyprotein processing intermediate.

  10. Error signals driving locomotor adaptation

    DEFF Research Database (Denmark)

    Choi, Julia T; Jensen, Peter; Nielsen, Jens Bo

    2016-01-01

    anaesthesia (n = 5) instead of repetitive nerve stimulation. Foot anaesthesia reduced ankle adaptation to external force perturbations during walking. Our results suggest that cutaneous input plays a role in force perception, and may contribute to the 'error' signal involved in driving walking adaptation when...

  11. Syndecans, signaling, and cell adhesion

    DEFF Research Database (Denmark)

    Couchman, J R; Woods, A

    1996-01-01

    structures within the heparan sulfate chains, leaving the roles of chondroitin sulfate chains and extracellular portion of the core proteins to be elucidated. Evidence that syndecans are a class of receptor involved in cell adhesion is mounting, and their small cytoplasmic domains may link...... transmembrane signaling from matrix to cytoskeleton, as proposed for other classes of adhesion receptors....

  12. VLSI mixed signal processing system

    Science.gov (United States)

    Alvarez, A.; Premkumar, A. B.

    1993-01-01

    An economical and efficient VLSI implementation of a mixed signal processing system (MSP) is presented in this paper. The MSP concept is investigated and the functional blocks of the proposed MSP are described. The requirements of each of the blocks are discussed in detail. A sample application using active acoustic cancellation technique is described to demonstrate the power of the MSP approach.

  13. Mathematical Modelling Plant Signalling Networks

    KAUST Repository

    Muraro, D.

    2013-01-01

    During the last two decades, molecular genetic studies and the completion of the sequencing of the Arabidopsis thaliana genome have increased knowledge of hormonal regulation in plants. These signal transduction pathways act in concert through gene regulatory and signalling networks whose main components have begun to be elucidated. Our understanding of the resulting cellular processes is hindered by the complex, and sometimes counter-intuitive, dynamics of the networks, which may be interconnected through feedback controls and cross-regulation. Mathematical modelling provides a valuable tool to investigate such dynamics and to perform in silico experiments that may not be easily carried out in a laboratory. In this article, we firstly review general methods for modelling gene and signalling networks and their application in plants. We then describe specific models of hormonal perception and cross-talk in plants. This mathematical analysis of sub-cellular molecular mechanisms paves the way for more comprehensive modelling studies of hormonal transport and signalling in a multi-scale setting. © EDP Sciences, 2013.

  14. Noisy signaling: theory and experiment

    NARCIS (Netherlands)

    de Haan, T.; Offerman, T.; Sloof, R.

    2009-01-01

    We investigate a noisy signaling game, in which nature adds random noise to the message chosen. Theoretically, with an unfavorable prior the separating equilibrium vanishes for low noise. It reappears for intermediate and high noise, where messages increase with noise. A pooling equilibrium always

  15. Syndecans, signaling, and cell adhesion

    DEFF Research Database (Denmark)

    Couchman, J R; Woods, A

    1996-01-01

    with the microfilament cytoskeleton, thereby mediating signaling events. The molecular details are unknown, but the conservation of regions of syndecan cytoplasmic domains, and a strong tendency for homotypic association, support the idea that the ligand-induced clustering may be a discrete source of specific...

  16. Text Signals Influence Team Artifacts

    Science.gov (United States)

    Clariana, Roy B.; Rysavy, Monica D.; Taricani, Ellen

    2015-01-01

    This exploratory quasi-experimental investigation describes the influence of text signals on team visual map artifacts. In two course sections, four-member teams were given one of two print-based text passage versions on the course-related topic "Social influence in groups" downloaded from Wikipedia; this text had two paragraphs, each…

  17. Maternal health Indicators Signal Optimism

    African Journals Online (AJOL)

    user

    Maternal health Indicators Signal Optimism. Abraham Haileamlak, MD, Professor of Pediatrics and Child Health. Maternal health is a major health priority for international agencies and the Ethiopian. Government. Many low income countries including. Ethiopia, made substantial improvements in maternal health achieving ...

  18. Biophysical Aspects of Transmembrane Signaling

    CERN Document Server

    Damjanovich, Sandor

    2005-01-01

    Transmembrane signaling is one of the most significant cell biological events in the life and death of cells in general and lymphocytes in particular. Until recently biochemists and biophysicists were not accustomed to thinking of these processes from the side of a high number of complex biochemical events and an equally high number of physical changes at molecular and cellular levels at the same time. Both types of researchers were convinced that their findings are the most decisive, having higher importance than the findings of the other scientist population. Both casts were wrong. Life, even at cellular level, has a number of interacting physical and biochemical mechanisms, which finally build up the creation of an "excited" cell that will respond to particular signals from the outer or inner world. This book handles both aspects of the signalling events, and in some cases tries to unify our concepts and help understand the signals that govern the life and death of our cells. Not only the understanding, bu...

  19. Handbook of signal processing systems

    CERN Document Server

    Bhattacharyya, Shuvra S; Leupers, Rainer; Takala, Jarmo

    2010-01-01

    The Handbook is organized in four parts. The first part motivates representative applications that drive and apply state-of-the art methods for design and implementation of signal processing systems; the second part discusses architectures for implementing these applications; the third part focuses on compilers and simulation tools; and the fourth part describes models of computation and their associated design tools and methodologies.

  20. On statistical significance of signal

    International Nuclear Information System (INIS)

    Zhu Yongsheng

    2006-01-01

    A definition for the statistical significance of a signal in an experiment is proposed by establishing a correlation between the observed p-value and the normal distribution integral probability, which is suitable for both counting experiment and continuous test statistics. The explicit expressions to calculate the statistical significance for both cases are given. (author)

  1. Insulin Signalling: The Inside Story.

    Science.gov (United States)

    Posner, Barry I

    2017-02-01

    Insulin signalling begins with binding to its cell surface insulin receptor (IR), which is a tyrosine kinase. The insulin receptor kinase (IRK) is subsequently autophosphorylated and activated to tyrosine phosphorylate key cellular substrates that are essential for entraining the insulin response. Although IRK activation begins at the cell surface, it is maintained and augmented following internalization into the endosomal system (ENS). The peroxovanadium compounds (pVs) were discovered to activate the IRK in the absence of insulin and lead to a full insulin response. Thus, IRK activation is both necessary and sufficient for insulin signalling. Furthermore, this could be shown to occur with activation of only the endosomal IRK. The mechanism of pV action was shown to be the inhibition of IRK-associated phosphotyrosine phosphatases (PTPs). Our studies showed that the duration and intensity of insulin signalling are modulated within ENS by the recruitment of cellular substrates to ENS; intra-endosomal acidification, which promotes dissociation of insulin from the IRK; an endosomal acidic insulinase, which degrades intra-endosomal insulin; and IRK-associated PTPs, which dephosphorylate and, hence, deactivate the IRK. Therefore, the internalization of IRKs is central to insulin signalling and its regulation. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  2. VEGF Signaling in Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Joon W. Shim

    2018-01-01

    Full Text Available Vascular endothelial growth factor (VEGF is a potent growth factor playing diverse roles in vasculogenesis and angiogenesis. In the brain, VEGF mediates angiogenesis, neural migration and neuroprotection. As a permeability factor, excessive VEGF disrupts intracellular barriers, increases leakage of the choroid plexus endothelia, evokes edema, and activates the inflammatory pathway. Recently, we discovered that a heparin binding epidermal growth factor like growth factor (HB-EGF—a class of EGF receptor (EGFR family ligands—contributes to the development of hydrocephalus with subarachnoid hemorrhage through activation of VEGF signaling. The objective of this review is to entail a recent update on causes of death due to neurological disorders involving cerebrovascular and age-related neurological conditions and to understand the mechanism by which angiogenesis-dependent pathological events can be treated with VEGF antagonisms. The Global Burden of Disease study indicates that cancer and cardiovascular disease including ischemic and hemorrhagic stroke are two leading causes of death worldwide. The literature suggests that VEGF signaling in ischemic brains highlights the importance of concentration, timing, and alternate route of modulating VEGF signaling pathway. Molecular targets distinguishing two distinct pathways of VEGF signaling may provide novel therapies for the treatment of neurological disorders and for maintaining lower mortality due to these conditions.

  3. Systems theory of Smad signalling.

    Science.gov (United States)

    Clarke, D C; Betterton, M D; Liu, X

    2006-11-01

    Transforming growth factor-beta (TGFbeta) signalling is an important regulator of cellular growth and differentiation. The principal intracellular mediators of TGFbeta signalling are the Smad proteins, which upon TGFbeta stimulation accumulate in the nucleus and regulate the transcription of target genes. To investigate the mechanisms of Smad nuclear accumulation, we developed a simple mathematical model of canonical Smad signalling. The model was built using both published data and our experimentally determined cellular Smad concentrations (isoforms 2, 3 and 4). We found in mink lung epithelial cells that Smad2 (8.5-12 x 10(4) molecules cell(-1)) was present in similar amounts to Smad4 (9.3-12 x 10(4) molecules cell(-1)), whereas both were in excess of Smad3 (1.1-2.0 x 10(4) molecules cell(-1)). Variation of the model parameters and statistical analysis showed that Smad nuclear accumulation is most sensitive to parameters affecting the rates of R-Smad phosphorylation and dephosphorylation and Smad complex formation/ dissociation in the nucleus. Deleting Smad4 from the model revealed that rate-limiting phospho-R-Smad dephosphorylation could be an important mechanism for Smad nuclear accumulation. Furthermore, we observed that binding factors constitutively localised to the nucleus do not efficiently mediate Smad nuclear accumulation, if dephosphorylation is rapid. We therefore conclude that an imbalance in the rates of R-Smad phosphorylation and dephosphorylation is likely an important mechanism of Smad nuclear accumulation during TGFbeta signalling.

  4. A Serpentine Way to Signaling

    Indian Academy of Sciences (India)

    IAS Admin

    coding genome. This article will take you through the years of discovery, experimentation and characterization of the structure and molecular mechanisms of GPCR signaling and how this discovery impacts a vast area of research in health and medicine. History: John Langley, Paul Ehrlich and the birth of the receptor theory.

  5. Robust power detector for wideband signals among many single tone signals

    Energy Technology Data Exchange (ETDEWEB)

    Musgrove, Cameron H.; Thompson, Douglas

    2018-03-06

    Various technologies for isolating a signal of interest from signals received contemporaneously by an antenna are described herein. A time period for which a signal of interest is present in a second signal can be identified based upon ratios of values of the second signal to the mean value of the second signal. When the ratio of the value of the second signal at a particular time to the mean of the second signal exceeds a threshold value, the signal of interest is considered to be present in the second signal.

  6. BPSK Demodulation Using Digital Signal Processing

    Science.gov (United States)

    Garcia, Thomas R.

    1996-01-01

    A digital communications signal is a sinusoidal waveform that is modified by a binary (digital) information signal. The sinusoidal waveform is called the carrier. The carrier may be modified in amplitude, frequency, phase, or a combination of these. In this project a binary phase shift keyed (BPSK) signal is the communication signal. In a BPSK signal the phase of the carrier is set to one of two states, 180 degrees apart, by a binary (i.e., 1 or 0) information signal. A digital signal is a sampled version of a "real world" time continuous signal. The digital signal is generated by sampling the continuous signal at discrete points in time. The rate at which the signal is sampled is called the sampling rate (f(s)). The device that performs this operation is called an analog-to-digital (A/D) converter or a digitizer. The digital signal is composed of the sequence of individual values of the sampled BPSK signal. Digital signal processing (DSP) is the modification of the digital signal by mathematical operations. A device that performs this processing is called a digital signal processor. After processing, the digital signal may then be converted back to an analog signal using a digital-to-analog (D/A) converter. The goal of this project is to develop a system that will recover the digital information from a BPSK signal using DSP techniques. The project is broken down into the following steps: (1) Development of the algorithms required to demodulate the BPSK signal; (2) Simulation of the system; and (3) Implementation a BPSK receiver using digital signal processing hardware.

  7. Signaling Molecules and Pulp Regeneration.

    Science.gov (United States)

    Schmalz, Gottfried; Widbiller, Matthias; Galler, Kerstin M

    2017-09-01

    Signaling molecules play an essential role in tissue engineering because they regulate regenerative processes. Evidence exists from animal studies that single molecules such as members of the transforming growth factor beta superfamily and factors that induce the growth of blood vessels (vascular endothelial growth factor), nerves (brain-derived neurotrophic factor), or fibroblasts (fibroblast growth factor) may induce reparative dentin formation. Mainly the formation of atubular dentin (osteodentin) has been described after the application of single molecules or combinations of recombinant growth factors on healthy exposed pulps or in pulp regeneration. Generally, such preparations have not received regulatory approval on the market so far. Only the use of granulocyte colony-stimulating factors together with cell transplantation is presently tested clinically. Besides approaches with only 1 or few combined molecules, the exploitation of tissue-derived growth factors depicts a third promising way in dental pulp tissue engineering. Preparations such as platelet-rich plasma or platelet-rich fibrin provide a multitude of endogenous signaling molecules, and special regulatory approval for the market does not seem necessary. Furthermore, dentin is a perfect reservoir of signaling molecules that can be mobilized by treatment with demineralizing agents such as EDTA. This conditions the dentin surface and allows for contact differentiation of pulp stem cells into odontoblastlike cells, protects dentin from resorption, and enhances cell growth as well as attachment to dentin. By ultrasonic activation, signaling molecules can be further released from EDTA pretreated dentin into saline, thus avoiding cytotoxic EDTA in the final preparation. The use of dentin-derived growth factors offers a number of advantages because they are locally available and presumably are most fit to induce signaling processes in dental pulp. However, better characterization and standardization of the

  8. 33 CFR 62.47 - Sound signals.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Sound signals. 62.47 Section 62... UNITED STATES AIDS TO NAVIGATION SYSTEM The U.S. Aids to Navigation System § 62.47 Sound signals. (a) Often sound signals are located on or adjacent to aids to navigation. When visual signals are obscured...

  9. Predicting Secretory Proteins with SignalP

    DEFF Research Database (Denmark)

    Nielsen, Henrik

    2017-01-01

    SignalP is the currently most widely used program for prediction of signal peptides from amino acid sequences. Proteins with signal peptides are targeted to the secretory pathway, but are not necessarily secreted. After a brief introduction to the biology of signal peptides and the history...

  10. Empirical mode decomposition for analyzing acoustical signals

    Science.gov (United States)

    Huang, Norden E. (Inventor)

    2005-01-01

    The present invention discloses a computer implemented signal analysis method through the Hilbert-Huang Transformation (HHT) for analyzing acoustical signals, which are assumed to be nonlinear and nonstationary. The Empirical Decomposition Method (EMD) and the Hilbert Spectral Analysis (HSA) are used to obtain the HHT. Essentially, the acoustical signal will be decomposed into the Intrinsic Mode Function Components (IMFs). Once the invention decomposes the acoustic signal into its constituting components, all operations such as analyzing, identifying, and removing unwanted signals can be performed on these components. Upon transforming the IMFs into Hilbert spectrum, the acoustical signal may be compared with other acoustical signals.

  11. Experiment and practice on signal processing

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2002-11-15

    The contents of this book contains basic practice of CEM Tool, discrete time signal and experiment and practice of system, experiment and practice of discrete time signal sampling, practice of frequency analysis, experiment of digital filter design, application of digital signal processing, project related voice, basic principle of signal processing, the technique of basic image signal processing, biology astronomy and Robot soccer with apply of image signal processing technique, control video signal and project related image. It also has an introduction of CEM Linker I. O in the end.

  12. Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5 (ERK5) nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex.

    Science.gov (United States)

    Erazo, Tatiana; Moreno, Ana; Ruiz-Babot, Gerard; Rodríguez-Asiain, Arantza; Morrice, Nicholas A; Espadamala, Josep; Bayascas, Jose R; Gómez, Nestor; Lizcano, Jose M

    2013-04-01

    The mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 5 (ERK5) plays a crucial role in cell proliferation, regulating gene transcription. ERK5 has a unique C-terminal tail which contains a transcriptional activation domain, and activates transcription by phosphorylating transcription factors and acting itself as a transcriptional coactivator. However, the molecular mechanisms that regulate its nucleocytoplasmatic traffic are unknown. We have used tandem affinity purification to identify proteins that interact with ERK5. We show that ERK5 interacts with the Hsp90-Cdc37 chaperone in resting cells, and that inhibition of Hsp90 or Cdc37 results in ERK5 ubiquitylation and proteasomal degradation. Interestingly, activation of cellular ERK5 induces Hsp90 dissociation from the ERK5-Cdc37 complex, leading to ERK5 nuclear translocation and activation of transcription, by a mechanism which requires the autophosphorylation at its C-terminal tail. Consequently, active ERK5 is no longer sensitive to Hsp90 or Cdc37 inhibitors. Cdc37 overexpression also induces Hsp90 dissociation and the nuclear translocation of a kinase-inactive form of ERK5 which retains transcriptional activity. This is the first example showing that ERK5 transcriptional activity does not require kinase activity. Since Cdc37 cooperates with ERK5 to promote cell proliferation, Cdc37 overexpression (as happens in some cancers) might represent a new, noncanonical mechanism by which ERK5 regulates tumor proliferation.

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

    Science.gov (United States)

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

    2017-09-20

    Phenylalanine ammonia lyase (PAL) from Arabidopsis thaliana (AtPAL2) was comparatively characterized to the well-studied enzyme from parsley (PcPAL1) and Rhodosporidium toruloides (RtPAL) with respect to kinetic parameters for the deamination and the amination reaction, pH- and temperature optima and the substrate range of the amination reaction. Whereas both plant enzymes are specific for phenylalanine, the bifunctional enzyme from Rhodosporidium toruloides shows K M -values for L-Phe and L-Tyr in the same order of magnitude and, compared to both plant enzymes, a 10-15-fold higher activity. At 30°C all enzymes were sufficiently stable with half-lives of 3.4days (PcPAL1), 4.6days (AtPAL2) and 9.7days (RtPAL/TAL). Very good results for the amination of various trans-cinnamic acid derivatives were obtained using E. coli cells as whole cell biocatalysts in ammonium carbonate buffer. Investigation of the substrate ranges gave interesting results for the newly tested enzymes from A. thaliana and R. toruloides. Only the latter accepts besides 4-hydroxy-CA also 3-methoxy-4-hydroxy-CA as a substrate, which is an interesting intermediate for the formation of pharmaceutically relevant L-Dopa. AtPAL2 is a very good catalyst for the formation of (S)-3-F-Phe, (S)-4-F-Phe and (S)-2-Cl-Phe. Such non-canonical amino acids are valuable building blocks for the formation of various drug molecules. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Alternatives to Pyrotechnic Distress Signals; Additional Signal Evaluation

    Science.gov (United States)

    2017-06-01

    stars ” include 3 LEDs pre-soldered to a small aluminum based circuit board/heat sink. For each color, RDC installed 2 stars , yielding six, series...connected LEDS. The Red-Orange color, with a lower maximum current rating required 4 LED stars to achieve the desired luminosity. Figure 5. Signal...Behavioral Sciences: New York, MCGraw- Hill . Young R., Dye D., Brunsman-Johnson C., Locklear C., Amerson T., Lewandowski M., Reubelt V., Rothblum A

  15. SignalPlant: an open signal processing software platform

    Czech Academy of Sciences Publication Activity Database

    Plešinger, Filip; Jurčo, Juraj; Halámek, Josef; Jurák, Pavel

    2016-01-01

    Roč. 37, č. 7 (2016), N38-N48 ISSN 0967-3334 R&D Projects: GA ČR GAP103/11/0933; GA MŠk(CZ) LO1212; GA ČR GAP102/12/2034 Institutional support: RVO:68081731 Keywords : data visualization * software * signal processing * ECG * EEG Subject RIV: FS - Medical Facilities ; Equipment Impact factor: 2.058, year: 2016

  16. Subversion of cell signaling by pathogens.

    Science.gov (United States)

    Alto, Neal M; Orth, Kim

    2012-09-01

    Pathogens exploit several eukaryotic signaling pathways during an infection. They have evolved specific effectors and toxins to hijack host cell machinery for their own benefit. Signaling molecules are preferentially targeted by pathogens because they globally regulate many cellular processes. Both viruses and bacteria manipulate and control pathways that regulate host cell survival and shape, including MAPK signaling, G-protein signaling, signals controlling cytoskeletal dynamics, and innate immune responses.

  17. Signal-to-Signal Ratio Independent Speaker Identification for Co-channel Speech Signals

    DEFF Research Database (Denmark)

    Saeidi, Rahim; Mowlaee, Pejman; Kinnunen, Tomi

    2010-01-01

    In this paper, we consider speaker identification for the co-channel scenario in which speech mixture from speakers is recorded by one microphone only. The goal is to identify both of the speakers from their mixed signal. High recognition accuracies have already been reported when an accurately...

  18. Signalling pathways in pemphigus vulgaris.

    Science.gov (United States)

    Li, Xiaoguang; Ishii, Norito; Ohata, Chika; Furumura, Minao; Hashimoto, Takashi

    2014-03-01

    Acantholysis in pemphigus vulgaris is induced by binding of autoantibodies to desmoglein 3 (Dsg3). The roles of signalling pathways on development of acantholysis have recently been extensively studied. In the study by Sayar et al., recently published in Exp Dermatol, epidermal growth factor receptor (EGFR) signalling was activated in both in vivo and in vitro pemphigus vulgaris experimental models. However, while EGFR inhibitors suppressed activity of p38 mitogen-activated protein kinase (p38MAPK) linearly, they suppressed activity of c-Myc and acantholysis in a non-linear, V-shaped relationship. These findings indicated complicated interactions among EGFR, p38MAPK and c-Myc in pemphigus vulgaris pathology. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Low power digital signal processing

    DEFF Research Database (Denmark)

    Paker, Ozgun

    2003-01-01

    This thesis introduces a novel approach to programmable and low power platform design for audio signal processing, in particular hearing aids. The proposed programmable platform is a heterogeneous multiprocessor architecture consisting of small and simple instruction set processors called mini......-cores as well as standard DSP/CPU-cores that communicate using message passing. The work has been based on a study of the algorithm suite covering the application domain. The observation of dominant tasks for certain algorithms (FIR, IIR, correlation, etc.) that require custom computational units and special...... data addressing capabilities lead to the design of low power mini-cores. The algorithm suite also consisted of less demanding and/or irregular algorithms (LMS, compression) that required subsample rate signal processing justifying the use of a DSP/CPU-core. The thesis also contributes to the recent...

  20. Cancer, signal transduction and nanotechnology.

    Science.gov (United States)

    Sengupta, Poulomi; Basu, Sudipta; Sengupta, Shiladitya

    2011-05-01

    Understanding the mechanisms underlying different cellular signaling pathways implicated in the pathogenesis of cancer are leading to the identification of novel drug targets as well as novel drug candidates. Multiple targeted therapeutics that modulate aberrant molecular pathways have already reached the clinic. However, targeted therapeutics can exert mechanism-driven side effects as a result of the implication of the molecular target in normal physiological functions besides tumorigenesis. We hypothesize that targeted therapeutics can be optimized by merging them with nanotechnology, which offers the potential for preferential targeting to the tumor, resulting in increased intratumoral concentrations of the active agent with reduced distribution to other parts of the body. This review will address some of the emerging concepts that integrate these two disciplines to engineer novel nanovectors that target different signaling pathways.

  1. Peroxynitrite: From interception to signaling.

    Science.gov (United States)

    Speckmann, Bodo; Steinbrenner, Holger; Grune, Tilman; Klotz, Lars-Oliver

    2016-04-01

    Peroxynitrite is a strong oxidant and nitrating species that mediates certain biological effects of superoxide and nitrogen monoxide. These biological effects include oxidative damage to proteins as well as the formation of 3-nitrotyrosyl moieties in proteins. As a consequence, such proteins may lose their activity, gain altered function, or become prone to proteolytic degradation - resulting in modulation of cellular protein turnover and in the modulation of signaling cascades. In analogy to hydrogen peroxide, peroxynitrite may be scavenged by selenoproteins like glutathione peroxidase-1 (GPx-1) or by selenocompounds with a GPx-like activity, such as ebselen; in further analogy to H2O2, peroxiredoxins have also been established as contributors to peroxynitrite reduction. This review covers three aspects of peroxynitrite biochemistry, (i) the interaction of selenocompounds/-proteins with peroxynitrite, (ii) peroxynitrite-induced modulation of cellular proteolysis, and (iii) peroxynitrite-induced modulation of cellular signaling. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. ROS signalling - specificity is required

    DEFF Research Database (Denmark)

    Møller, Ian M; Sweetlove, Lee J

    2010-01-01

    Reactive oxygen species (ROS) production increases in plants under stress. ROS can damage cellular components, but they can also act in signal transduction to help the cell counteract the oxidative damage in the stressed compartment. H2O2 might induce a general stress response, but it does not have...... the required specificity to selectively regulate nuclear genes required for dealing with localized stress, e.g. in chloroplasts or mitochondria. Here we argue that peptides deriving from proteolytic breakdown of oxidatively damaged proteins have the requisite specificity to act as secondary ROS messengers...... and regulate source-specific genes and in this way contribute to retrograde ROS signalling during oxidative stress. Likewise, unmodified peptides deriving from the breakdown of redundant proteins could help coordinate organellar and nuclear gene expression...

  3. Contextual predictability shapes signal autonomy.

    Science.gov (United States)

    Winters, James; Kirby, Simon; Smith, Kenny

    2018-03-10

    Aligning on a shared system of communication requires senders and receivers reach a balance between simplicity, where there is a pressure for compressed representations, and informativeness, where there is a pressure to be communicatively functional. We investigate the extent to which these two pressures are governed by contextual predictability: the amount of contextual information that a sender can estimate, and therefore exploit, in conveying their intended meaning. In particular, we test the claim that contextual predictability is causally related to signal autonomy: the degree to which a signal can be interpreted in isolation, without recourse to contextual information. Using an asymmetric communication game, where senders and receivers are assigned fixed roles, we manipulate two aspects of the referential context: (i) whether or not a sender shares access to the immediate contextual information used by the receiver in interpreting their utterance; (ii) the extent to which the relevant solution in the immediate referential context is generalisable to the aggregate set of contexts. Our results demonstrate that contextual predictability shapes the degree of signal autonomy: when the context is highly predictable (i.e., the sender has access to the context in which their utterances will be interpreted, and the semantic dimension which discriminates between meanings in context is consistent across communicative episodes), languages develop which rely heavily on the context to reduce uncertainty about the intended meaning. When the context is less predictable, senders favour systems composed of autonomous signals, where all potentially relevant semantic dimensions are explicitly encoded. Taken together, these results suggest that our pragmatic faculty, and how it integrates information from the context in reducing uncertainty, plays a central role in shaping language structure. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. The IRS-1 signaling system.

    Science.gov (United States)

    Myers, M G; Sun, X J; White, M F

    1994-07-01

    Insulin-receptor substrate 1 (IRS-1) is a principal substrate of the receptor tyrosine kinase for insulin and insulin-like growth factor 1, and a substrate for a tyrosine kinase activated by interleukin 4. IRS-1 undergoes multisite tyrosine phosphorylation and mediates downstream signals by 'docking' various proteins that contain Src homology 2 domains. IRS-1 appears to be a unique molecule; however, 4PS, a protein found mainly in hemopoietic cells, may represent another member of this family.

  5. Signals of Supersymmetric Dark Matter

    OpenAIRE

    Abbas, Afsar

    1999-01-01

    The Lightest Supersymmetric Particle predicted in most of the supersymmetric scenarios is an ideal candidate for the dark matter of cosmology. Their detection is of extreme significance today. Recently there have been intriguing signals of a 59 Gev neutralino dark matter at DAMA in Gran Sasso. We look at other possible signatures of dark matter in astrophysical and geological frameworks. The passage of the earth through dense clumps of dark matter would produce large quantities of heat in the...

  6. Cell signalling and phospholipid metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Boss, W.F.

    1990-01-01

    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  7. Detection of signals in noise

    CERN Document Server

    McDonough, Robert N

    1995-01-01

    The Second Edition is an updated revision to the authors highly successful and widely used introduction to the principles and application of the statistical theory of signal detection. This book emphasizes those theories that have been found to be particularly useful in practice including principles applied to detection problems encountered in digital communications, radar, and sonar.Detection processing based upon the fast Fourier transform

  8. Cytoskeleton in mast cell signaling

    Czech Academy of Sciences Publication Activity Database

    Dráber, Pavel; Sulimenko, Vadym; Dráberová, Eduarda

    2012-01-01

    Roč. 3, May (2012), s. 130 ISSN 1664-3224 R&D Projects: GA ČR GAP302/10/1701; GA ČR GPP302/11/P709; GA ČR GAP302/12/1673 Grant - others:ECST(XE) Action BM1007 Institutional research plan: CEZ:AV0Z50520514 Keywords : cytoskeleton * mast cell activation * signal transduction Subject RIV: EB - Genetics ; Molecular Biology

  9. Signal and image multiresolution analysis

    CERN Document Server

    Ouahabi, Abdelialil

    2012-01-01

    Multiresolution analysis using the wavelet transform has received considerable attention in recent years by researchers in various fields. It is a powerful tool for efficiently representing signals and images at multiple levels of detail with many inherent advantages, including compression, level-of-detail display, progressive transmission, level-of-detail editing, filtering, modeling, fractals and multifractals, etc.This book aims to provide a simple formalization and new clarity on multiresolution analysis, rendering accessible obscure techniques, and merging, unifying or completing

  10. Signalling properties of lysophosphatidic acid.

    Science.gov (United States)

    Durieux, M E; Lynch, K R

    1993-06-01

    Lysophosphatidic acid (LPA) is the simplest natural phospholipid, primarily known as a membrane component and metabolic intermediate. However, a remarkable variety of biological effects of this compound have come to light, seemingly pointing to an additional role for LPA as a signalling molecule. In this review, Marcel Durieux and Kevin Lynch integrate the recent information that indicates that LPA could be an intercellular messenger, possibly acting through a G protein-coupled receptor, and with a role in cell growth and motility.

  11. AR Signaling in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Bilal Rahim

    2017-02-01

    Full Text Available Androgen receptor (AR, a member of the steroid hormone receptor family status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2 amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC, which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

  12. Voting as a Signaling Device

    OpenAIRE

    R. Emre Aytimur; Aristotelis Boukouras; Robert Schwager

    2012-01-01

    In this paper, citizens vote in order to influence the election outcome and in order to signal their unobserved characteristics to others. The model is one of rational voting and generates the following predictions: (i) The paradox of not voting does not arise, because the benefit of voting does not vanish with population size. (ii) Turnout in elections is positively related to the size of the local community and the importance of social interactions. (iii) Voting may exhibit bandwagon effect...

  13. Intracellular calcium homeostasis and signaling.

    Science.gov (United States)

    Brini, Marisa; Calì, Tito; Ottolini, Denis; Carafoli, Ernesto

    2013-01-01

    Ca(2+) is a universal carrier of biological information: it controls cell life from its origin at fertilization to its end in the process of programmed cell death. Ca(2+) is a conventional diffusible second messenger released inside cells by the interaction of first messengers with plasma membrane receptors. However, it can also penetrate directly into cells to deliver information without the intermediation of first or second messengers. Even more distinctively, Ca(2+) can act as a first messenger, by interacting with a plasma membrane receptor to set in motion intracellular signaling pathways that involve Ca(2+) itself. Perhaps the most distinctive property of the Ca(2+) signal is its ambivalence: while essential to the correct functioning of cells, Ca(2+) becomes an agent that mediates cell distress, or even (toxic) cell death, if its concentration and movements inside cells are not carefully tuned. Ca(2+) is controlled by reversible complexation to specific proteins, which could be pure Ca(2+) buffers, or which, in addition to buffering Ca(2+), also decode its signal to pass it on to targets. The most important actors in the buffering of cell Ca(2+) are proteins that transport it across the plasma membrane and the membrane of the organelles: some have high Ca(2+) affinity and low transport capacity (e.g., Ca(2+) pumps), others have opposite properties (e.g., the Ca(2+) uptake system of mitochondria). Between the initial event of fertilization, and the terminal event of programmed cell death, the Ca(2+) signal regulates the most important activities of the cell, from the expression of genes, to heart and muscle contraction and other motility processes, to diverse metabolic pathways involved in the generation of cell fuels.

  14. Ketone bodies as signaling metabolites

    OpenAIRE

    Newman, John C.; Verdin, Eric

    2013-01-01

    Traditionally, the ketone body β-hydroxybutyrate (βOHB) has been looked upon as a carrier of energy from liver to peripheral tissues during fasting or exercise. However, βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs). These recent findings support a model in which βOHB functions to link the environment, in this case the diet, and gene expression via chromatin modifications. Here, we review the regulation and functions of keton...

  15. Terminality implies non-signalling

    OpenAIRE

    Coecke, Bob

    2014-01-01

    A 'process theory' is any theory of systems and processes which admits sequential and parallel composition. `Terminality' unifies normalisation of pure states, trace-preservation of CP-maps, and adding up to identity of positive operators in quantum theory, and generalises this to arbitrary process theories. We show that terminality and non-signalling coincide in any process theory, provided one makes causal structure explicit. In fact, making causal structure explicit is necessary to even ma...

  16. Calcium Signals from the Vacuole

    Directory of Open Access Journals (Sweden)

    Gerald Schönknecht

    2013-10-01

    Full Text Available The vacuole is by far the largest intracellular Ca2+ store in most plant cells. Here, the current knowledge about the molecular mechanisms of vacuolar Ca2+ release and Ca2+ uptake is summarized, and how different vacuolar Ca2+ channels and Ca2+ pumps may contribute to Ca2+ signaling in plant cells is discussed. To provide a phylogenetic perspective, the distribution of potential vacuolar Ca2+ transporters is compared for different clades of photosynthetic eukaryotes. There are several candidates for vacuolar Ca2+ channels that could elicit cytosolic [Ca2+] transients. Typical second messengers, such as InsP3 and cADPR, seem to trigger vacuolar Ca2+ release, but the molecular mechanism of this Ca2+ release still awaits elucidation. Some vacuolar Ca2+ channels have been identified on a molecular level, the voltage-dependent SV/TPC1 channel, and recently two cyclic-nucleotide-gated cation channels. However, their function in Ca2+ signaling still has to be demonstrated. Ca2+ pumps in addition to establishing long-term Ca2+ homeostasis can shape cytosolic [Ca2+] transients by limiting their amplitude and duration, and may thus affect Ca2+ signaling.

  17. Purinergic signaling in the airways.

    Science.gov (United States)

    Burnstock, Geoffrey; Brouns, Inge; Adriaensen, Dirk; Timmermans, Jean-Pierre

    2012-10-01

    Evidence for a significant role and impact of purinergic signaling in normal and diseased airways is now beyond dispute. The present review intends to provide the current state of knowledge of the involvement of purinergic pathways in the upper and lower airways and lungs, thereby differentiating the involvement of different tissues, such as the epithelial lining, immune cells, airway smooth muscle, vasculature, peripheral and central innervation, and neuroendocrine system. In addition to the vast number of well illustrated functions for purinergic signaling in the healthy respiratory tract, increasing data pointing to enhanced levels of ATP and/or adenosine in airway secretions of patients with airway damage and respiratory diseases corroborates the emerging view that purines act as clinically important mediators resulting in either proinflammatory or protective responses. Purinergic signaling has been implicated in lung injury and in the pathogenesis of a wide range of respiratory disorders and diseases, including asthma, chronic obstructive pulmonary disease, inflammation, cystic fibrosis, lung cancer, and pulmonary hypertension. These ostensibly enigmatic actions are based on widely different mechanisms, which are influenced by the cellular microenvironment, but especially the subtypes of purine receptors involved and the activity of distinct members of the ectonucleotidase family, the latter being potential protein targets for therapeutic implementation.

  18. Dynamics in atomic signaling games

    KAUST Repository

    Fox, Michael J.

    2015-04-08

    We study an atomic signaling game under stochastic evolutionary dynamics. There are a finite number of players who repeatedly update from a finite number of available languages/signaling strategies. Players imitate the most fit agents with high probability or mutate with low probability. We analyze the long-run distribution of states and show that, for sufficiently small mutation probability, its support is limited to efficient communication systems. We find that this behavior is insensitive to the particular choice of evolutionary dynamic, a property that is due to the game having a potential structure with a potential function corresponding to average fitness. Consequently, the model supports conclusions similar to those found in the literature on language competition. That is, we show that efficient languages eventually predominate the society while reproducing the empirical phenomenon of linguistic drift. The emergence of efficiency in the atomic case can be contrasted with results for non-atomic signaling games that establish the non-negligible possibility of convergence, under replicator dynamics, to states of unbounded efficiency loss.

  19. Method for acoustic signal detection

    International Nuclear Information System (INIS)

    Blalock, S.E.

    1980-01-01

    The disclosure relates to a method and apparatus for acoustic signal detection, adapted for use in acoustic velocity well logging to measure the difference in transit times of an acoustic signal between a transmitter and two or more receivers. In a preferred embodiment of the present invention two timing measurements of the signal arriving at each of two receivers may be made by activating zero crossing detectors at the arrival of the first negative and first positive half-cycles at each receiver. A transit time is calculated from the zero crossing times following the first negative half-cycle. This first transit time may be checked for accuracy by comparing the first transit time with a second transit time calculated from zero crossing times following the first positive half-cycles, by comparing the first transit time to a previously measured transit time and/or by detecting the order of arrival of the negative and positive half-cycles to determine whether the half-cycles have been detected out of sequence at either receiver. Should the first transit time be determined to be inaccurate, the previously measured transit time or the second transit time may be substituted therefor

  20. Regulation of TGF-β Signal Transduction.

    Science.gov (United States)

    Zhao, Bing; Chen, Ye-Guang

    2014-01-01

    Transforming growth factor-β (TGF-β) signaling regulates diverse cellular processes, including cell proliferation, differentiation, apoptosis, cell plasticity, and migration. TGF-β signaling can be mediated by Smad proteins or other signaling proteins such as MAP kinases and Akt. TGF-β signaling is tightly regulated at different levels along the pathways to ensure its proper physiological functions in different cells and tissues. Deregulation of TGF-β signaling has been associated with various kinds of diseases, such as cancer and tissue fibrosis. This paper focuses on our recent work on regulation of TGF-β signaling.