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Sample records for gain-of-function mechanism distinct

  1. Gain-of-function SOS1 mutations cause a distinctive form of noonansyndrome

    Tartaglia, Marco; Pennacchio, Len A.; Zhao, Chen; Yadav, KamleshK.; Fodale, Valentina; Sarkozy, Anna; Pandit, Bhaswati; Oishi, Kimihiko; Martinelli, Simone; Schackwitz, Wendy; Ustaszewska, Anna; Martin, Joes; Bristow, James; Carta, Claudio; Lepri, Francesca; Neri, Cinzia; Vasta,Isabella; Gibson, Kate; Curry, Cynthia J.; Lopez Siguero, Juan Pedro; Digilio, Maria Cristina; Zampino, Giuseppe; Dallapiccola, Bruno; Bar-Sagi, Dafna; Gelb, Brude D.

    2006-09-01

    Noonan syndrome (NS) is a developmental disordercharacterized by short stature, facial dysmorphia, congenital heartdefects and skeletal anomalies1. Increased RAS-mitogenactivated proteinkinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percentof NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 orKRAS mutation (17 percent) have missense mutations in SOS1, which encodesa RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutationscluster at residues implicated in the maintenance of SOS1 in itsautoinhibited form and ectopic expression of two NS-associated mutantsinduced enhanced RAS activation. The phenotype associated with SOS1defects is distinctive, although within NS spectrum, with a highprevalence of ectodermal abnormalities but generally normal developmentand linear growth. Our findings implicate for the first timegain-of-function mutations in a RAS GEF in inherited disease and define anew mechanism by which upregulation of the RAS pathway can profoundlychange human development.

  2. HD CAG-correlated gene expression changes support a simple dominant gain of function

    Jacobsen, Jessie C.; Gregory, Gillian C.; Woda, Juliana M.; Thompson, Morgan N.; Coser, Kathryn R.; Murthy, Vidya; Kohane, Isaac S.; Gusella, James F.; Seong, Ihn Sik; MacDonald, Marcy E.; Shioda, Toshi; Lee, Jong-Min

    2011-01-01

    Huntington's disease is initiated by the expression of a CAG repeat-encoded polyglutamine region in full-length huntingtin, with dominant effects that vary continuously with CAG size. The mechanism could involve a simple gain of function or a more complex gain of function coupled to a loss of function (e.g. dominant negative-graded loss of function). To distinguish these alternatives, we compared genome-wide gene expression changes correlated with CAG size across an allelic series of heterozygous CAG knock-in mouse embryonic stem (ES) cell lines (HdhQ20/7, HdhQ50/7, HdhQ91/7, HdhQ111/7), to genes differentially expressed between Hdhex4/5/ex4/5 huntingtin null and wild-type (HdhQ7/7) parental ES cells. The set of 73 genes whose expression varied continuously with CAG length had minimal overlap with the 754-member huntingtin-null gene set but the two were not completely unconnected. Rather, the 172 CAG length-correlated pathways and 238 huntingtin-null significant pathways clustered into 13 shared categories at the network level. A closer examination of the energy metabolism and the lipid/sterol/lipoprotein metabolism categories revealed that CAG length-correlated genes and huntingtin-null-altered genes either were different members of the same pathways or were in unique, but interconnected pathways. Thus, varying the polyglutamine size in full-length huntingtin produced gene expression changes that were distinct from, but related to, the effects of lack of huntingtin. These findings support a simple gain-of-function mechanism acting through a property of the full-length huntingtin protein and point to CAG-correlative approaches to discover its effects. Moreover, for therapeutic strategies based on huntingtin suppression, our data highlight processes that may be more sensitive to the disease trigger than to decreased huntingtin levels. PMID:21536587

  3. Gain-of-function HCN2 variants in genetic epilepsy.

    Li, Melody; Maljevic, Snezana; Phillips, A Marie; Petrovski, Slave; Hildebrand, Michael S; Burgess, Rosemary; Mount, Therese; Zara, Federico; Striano, Pasquale; Schubert, Julian; Thiele, Holger; Nürnberg, Peter; Wong, Michael; Weisenberg, Judith L; Thio, Liu Lin; Lerche, Holger; Scheffer, Ingrid E; Berkovic, Samuel F; Petrou, Steven; Reid, Christopher A

    2018-02-01

    Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism. © 2017 Wiley Periodicals, Inc.

  4. Two distinct neural mechanisms underlying indirect reciprocity.

    Watanabe, Takamitsu; Takezawa, Masanori; Nakawake, Yo; Kunimatsu, Akira; Yamasue, Hidenori; Nakamura, Mitsuhiro; Miyashita, Yasushi; Masuda, Naoki

    2014-03-18

    Cooperation is a hallmark of human society. Humans often cooperate with strangers even if they will not meet each other again. This so-called indirect reciprocity enables large-scale cooperation among nonkin and can occur based on a reputation mechanism or as a succession of pay-it-forward behavior. Here, we provide the functional and anatomical neural evidence for two distinct mechanisms governing the two types of indirect reciprocity. Cooperation occurring as reputation-based reciprocity specifically recruited the precuneus, a region associated with self-centered cognition. During such cooperative behavior, the precuneus was functionally connected with the caudate, a region linking rewards to behavior. Furthermore, the precuneus of a cooperative subject had a strong resting-state functional connectivity (rsFC) with the caudate and a large gray matter volume. In contrast, pay-it-forward reciprocity recruited the anterior insula (AI), a brain region associated with affective empathy. The AI was functionally connected with the caudate during cooperation occurring as pay-it-forward reciprocity, and its gray matter volume and rsFC with the caudate predicted the tendency of such cooperation. The revealed difference is consistent with the existing results of evolutionary game theory: although reputation-based indirect reciprocity robustly evolves as a self-interested behavior in theory, pay-it-forward indirect reciprocity does not on its own. The present study provides neural mechanisms underlying indirect reciprocity and suggests that pay-it-forward reciprocity may not occur as myopic profit maximization but elicit emotional rewards.

  5. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy

    Syrbe, Steffen; Hedrich, Ulrike B S; Riesch, Erik

    2015-01-01

    disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype....... They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing...

  6. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

    Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

    2016-02-04

    Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

  7. Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S

    Stewart, Andrew K.; Shmukler, Boris E.; Vandorpe, David H.; Rivera, Alicia; Heneghan, John F.; Li, Xiaojin; Hsu, Ann; Karpatkin, Margaret; O'Neill, Allison F.; Bauer, Daniel E.; Heeney, Matthew M.; John, Kathryn; Kuypers, Frans A.; Gallagher, Patrick G.; Lux, Samuel E.; Brugnara, Carlo; Westhoff, Connie M.

    2011-01-01

    Four patients with overhydrated cation leak stomatocytosis (OHSt) exhibited the heterozygous RhAG missense mutation F65S. OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity. Xenopus oocytes expressing wild-type RhAG and RhAG F65S exhibited increased ouabain and bumetanide-resistant uptake of Li+ and 86Rb+, with secondarily increased 86Rb+ influx sensitive to ouabain and to bumetanide. Increased RhAG-associated 14C-methylammonium (MA) influx was severely reduced in RhAG F65S-expressing oocytes. RhAG-associated influxes of Li+, 86Rb+, and 14C-MA were pharmacologically distinct, and Li+ uptakes associated with RhAG and RhAG F65S were differentially inhibited by NH4+ and Gd3+. RhAG-expressing oocytes were acidified and depolarized by 5 mM bath NH3/NH4+, but alkalinized and depolarized by subsequent bath exposure to 5 mM methylammonium chloride (MA/MA+). RhAG F65S-expressing oocytes exhibited near-wild-type responses to NH4Cl, but MA/MA+ elicited attenuated alkalinization and strong hyperpolarization. Expression of RhAG or RhAG F65S increased steady-state cation currents unaltered by bath Li+ substitution or bath addition of 5 mM NH4Cl or MA/MA+. These oocyte studies suggest that 1) RhAG expression increases oocyte transport of NH3/NH4+ and MA/MA+; 2) RhAG F65S exhibits gain-of-function phenotypes of increased cation conductance/permeability, and loss-of-function phenotypes of decreased and modified MA/MA+ transport, and decreased NH3/NH4+-associated depolarization; and 3) RhAG transports NH3/NH4+ and MA/MA+ by distinct mechanisms, and/or the substrates elicit distinct cellular responses. Thus, RhAG F65S is a loss-of-function mutation for amine transport. The altered oocyte intracellular pH, membrane potential, and currents associated with RhAG or RhAG F65S expression may reflect distinct transport mechanisms. PMID:21849667

  8. SIRT1 Gain of Function Does Not Mimic or Enhance the Adaptations to Intermittent Fasting

    Marie Boutant

    2016-03-01

    Full Text Available Caloric restriction (CR has been shown to prevent the onset of insulin resistance and to delay age-related physiological decline in mammalian organisms. SIRT1, a NAD+-dependent deacetylase enzyme, has been suggested to mediate the adaptive responses to CR, leading to the speculation that SIRT1 activation could be therapeutically used as a CR-mimetic strategy. Here, we used a mouse model of moderate SIRT1 overexpression to test whether SIRT1 gain of function could mimic or boost the metabolic benefits induced by every-other-day feeding (EODF. Our results indicate that SIRT1 transgenesis does not affect the ability of EODF to decrease adiposity and improve insulin sensitivity. Transcriptomic analyses revealed that SIRT1 transgenesis and EODF promote very distinct adaptations in individual tissues, some of which can be even be metabolically opposite, as in brown adipose tissue. Therefore, whereas SIRT1 overexpression and CR both improve glucose metabolism and insulin sensitivity, the etiologies of these benefits are largely different.

  9. SIRT1 Gain of Function Does Not Mimic or Enhance the Adaptations to Intermittent Fasting.

    Boutant, Marie; Kulkarni, Sameer S; Joffraud, Magali; Raymond, Frédéric; Métairon, Sylviane; Descombes, Patrick; Cantó, Carles

    2016-03-08

    Caloric restriction (CR) has been shown to prevent the onset of insulin resistance and to delay age-related physiological decline in mammalian organisms. SIRT1, a NAD(+)-dependent deacetylase enzyme, has been suggested to mediate the adaptive responses to CR, leading to the speculation that SIRT1 activation could be therapeutically used as a CR-mimetic strategy. Here, we used a mouse model of moderate SIRT1 overexpression to test whether SIRT1 gain of function could mimic or boost the metabolic benefits induced by every-other-day feeding (EODF). Our results indicate that SIRT1 transgenesis does not affect the ability of EODF to decrease adiposity and improve insulin sensitivity. Transcriptomic analyses revealed that SIRT1 transgenesis and EODF promote very distinct adaptations in individual tissues, some of which can be even be metabolically opposite, as in brown adipose tissue. Therefore, whereas SIRT1 overexpression and CR both improve glucose metabolism and insulin sensitivity, the etiologies of these benefits are largely different. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Organism versus mechanism: Losing our grip on the distinction

    Henk Reitsema

    2013-11-01

    Full Text Available The distinction between organism and mechanism is often subtle or unclear and yet can prove to be fundamental to our understanding of the world. It has been tempting for many thinkers to seek to ‘understand’ all of reality through the lens of either the one or the other of these concepts rather than by giving both a place. This article sets out to argue that there is a substantial loss of understanding when either of these metaphors is absolutised to explain all causal processes and patterns in reality. Clarifying the distinction between the two may provide one more tool to grasp what is reductionist in many of the perspectives that have come to dominate public life and science today. This contention is tested on the quest for the design of self-replicating systems (i.e. synthetic organisms in the nanotech industry. It is common that the concepts of organic functioning and mechanism are used imprecisely and in an overlapping way. This is also true of much scientific debate, especially in the fields of biology, micro-biology and nano-science. This imprecise use signals a reductionist tendency both in the way that the organic is perceived and in terms of the distinctive nature of mechanisms.

  11. Directed networks' different link formation mechanisms causing degree distribution distinction

    Behfar, Stefan Kambiz; Turkina, Ekaterina; Cohendet, Patrick; Burger-Helmchen, Thierry

    2016-11-01

    Within undirected networks, scientists have shown much interest in presenting power-law features. For instance, Barabási and Albert (1999) claimed that a common property of many large networks is that vertex connectivity follows scale-free power-law distribution, and in another study Barabási et al. (2002) showed power law evolution in the social network of scientific collaboration. At the same time, Jiang et al. (2011) discussed deviation from power-law distribution; others indicated that size effect (Bagrow et al., 2008), information filtering mechanism (Mossa et al., 2002), and birth and death process (Shi et al., 2005) could account for this deviation. Within directed networks, many authors have considered that outlinks follow a similar mechanism of creation as inlinks' (Faloutsos et al., 1999; Krapivsky et al., 2001; Tanimoto, 2009) with link creation rate being the linear function of node degree, resulting in a power-law shape for both indegree and outdegree distribution. Some other authors have made an assumption that directed networks, such as scientific collaboration or citation, behave as undirected, resulting in a power-law degree distribution accordingly (Barabási et al., 2002). At the same time, we claim (1) Outlinks feature different degree distributions than inlinks; where different link formation mechanisms cause the distribution distinctions, (2) in/outdegree distribution distinction holds for different levels of system decomposition; therefore this distribution distinction is a property of directed networks. First, we emphasize in/outlink formation mechanisms as causal factors for distinction between indegree and outdegree distributions (where this distinction has already been noticed in Barker et al. (2010) and Baxter et al. (2006)) within a sample network of OSS projects as well as Java software corpus as a network. Second, we analyze whether this distribution distinction holds for different levels of system decomposition: open

  12. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

    Toubiana, Julie; Okada, Satoshi; Hiller, Julia; Oleastro, Matias; Lagos Gomez, Macarena; Aldave Becerra, Juan Carlos; Ouachée-Chardin, Marie; Fouyssac, Fanny; Girisha, Katta Mohan; Etzioni, Amos; van Montfrans, Joris M.; Camcioglu, Yildiz; Kerns, Leigh Ann; Belohradsky, Bernd; Blanche, Stéphane; Bousfiha, Aziz; Rodriguez-Gallego, Carlos; Meyts, Isabelle; Kisand, Kai; Reichenbach, Janine; Renner, Ellen D; Rosenzweig, Sergio; Grimbacher, Bodo; van de Veerdonk, Frank L; Traidl-Hoffmann, Claudia; Picard, Capucine; Marodi, Laszlo; Morio, Tomohiro; Kobayashi, Masao; Lilic, Desa; Milner, Joshua D; Holland, Steven; Casanova, Jean-Laurent; Puel, Anne

    2016-01-01

    Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274

  13. Two Distinct Moral Mechanisms for Ascribing and Denying Intentionality.

    Ngo, Lawrence; Kelly, Meagan; Coutlee, Christopher G; Carter, R McKell; Sinnott-Armstrong, Walter; Huettel, Scott A

    2015-12-04

    Philosophers and legal scholars have long theorized about how intentionality serves as a critical input for morality and culpability, but the emerging field of experimental philosophy has revealed a puzzling asymmetry. People judge actions leading to negative consequences as being more intentional than those leading to positive ones. The implications of this asymmetry remain unclear because there is no consensus regarding the underlying mechanism. Based on converging behavioral and neural evidence, we demonstrate that there is no single underlying mechanism. Instead, two distinct mechanisms together generate the asymmetry. Emotion drives ascriptions of intentionality for negative consequences, while the consideration of statistical norms leads to the denial of intentionality for positive consequences. We employ this novel two-mechanism model to illustrate that morality can paradoxically shape judgments of intentionality. This is consequential for mens rea in legal practice and arguments in moral philosophy pertaining to terror bombing, abortion, and euthanasia among others.

  14. Two Distinct Moral Mechanisms for Ascribing and Denying Intentionality

    Ngo, Lawrence; Kelly, Meagan; Coutlee, Christopher G.; Carter, R. McKell; Sinnott-Armstrong, Walter; Huettel, Scott A.

    2015-01-01

    Philosophers and legal scholars have long theorized about how intentionality serves as a critical input for morality and culpability, but the emerging field of experimental philosophy has revealed a puzzling asymmetry. People judge actions leading to negative consequences as being more intentional than those leading to positive ones. The implications of this asymmetry remain unclear because there is no consensus regarding the underlying mechanism. Based on converging behavioral and neural evidence, we demonstrate that there is no single underlying mechanism. Instead, two distinct mechanisms together generate the asymmetry. Emotion drives ascriptions of intentionality for negative consequences, while the consideration of statistical norms leads to the denial of intentionality for positive consequences. We employ this novel two-mechanism model to illustrate that morality can paradoxically shape judgments of intentionality. This is consequential for mens rea in legal practice and arguments in moral philosophy pertaining to terror bombing, abortion, and euthanasia among others. PMID:26634909

  15. Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

    Parmeggiani, Francesco; Barbaro, Vanessa; De Nadai, Katia; Lavezzo, Enrico; Toppo, Stefano; Chizzolini, Marzio; Palù, Giorgio; Parolin, Cristina; Di Iorio, Enzo

    2016-01-01

    The aim of this study was to describe a new pathogenic variant in the mutational hot spot exon ORF15 of retinitis pigmentosa GTPase regulator (RPGR) gene within an Italian family with X-linked retinitis pigmentosa (RP), detailing its distinctive genotype-phenotype correlation with pathologic myopia (PM). All members of this RP-PM family underwent a complete ophthalmic examination. The entire open reading frames of RPGR and retinitis pigmentosa 2 genes were analyzed by Sanger sequencing. A novel frame-shift mutation in exon ORF15 of RPGR gene (c.2091_2092insA; p.A697fs) was identified as hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibited symmetrical PM in both eyes. The c.2091_2092insA mutation coherently co-segregated with the observed phenotypes. These findings expand the spectrum of X-linked RP variants. Interestingly, focusing on Caucasian ethnicity, just three RPGR mutations are hitherto reported in RP-PM families: one of these is located in exon ORF15, but none appears to be characterized by a high penetrance of PM trait as observed in the present, relatively small, pedigree. The geno-phenotypic attributes of this heterozygosity suggest that gain-of-function mechanism could give rise to PM via a degenerative cell-cell remodeling of the retinal structures. PMID:27995965

  16. The mechanism of the emergence of distinct overstretched DNA states

    Zhu, You-Liang; Sun, Zhao-Yan, E-mail: zysun@ciac.ac.cn [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Lu, Zhong-Yuan [State Key Laboratory of Supramolecular Structure and Materials, Institute of Theoretical Chemistry, Jilin University, Changchun 130023 (China)

    2016-01-14

    Although multiple overstretched DNA states were identified in experiments, the mechanism of the emergence of distinct states is still unclear. Molecular dynamics simulation is an ideal tool to clarify the mechanism, but the force loading rates in stretching achieved by conventional all-atom DNA models are much faster, which essentially affect overstretching states. We employed a modified coarse-grained DNA model with an unprecedented low loading rate in simulations to study the overstretching transitions of end-opened double-stranded DNA. We observed two-strand peeling off for DNA with low stability and the S-DNA with high stability under tension. By introducing a melting-forbidden model which prevents base-pair breaking, we still observed the overstretching transition induced by the formation of S-DNA due to the change of dihedral angle. Hence, we confirmed that the competition between the two strain-softening manners, i.e., base-pair breaking and dihedral angle variation, results in the emergence of distinct overstretched DNA states.

  17. Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models.

    Carmen Blanco-Aparicio

    Full Text Available Elevated expression of AKT has been noted in a significant percentage of primary human breast cancers, mainly as a consequence of the PTEN/PI3K pathway deregulation. To investigate the mechanistic basis of the AKT gain of function-dependent mechanisms of breast tumorigenesis, we explored the phenotype induced by activated AKT transgenes in a quantitative manner. We generated several transgenic mice lines expressing different levels of constitutively active AKT in the mammary gland. We thoroughly analyzed the preneoplastic and neoplastic mammary lesions of these mice and correlated the process of tumorigenesis to AKT levels. Finally, we analyzed the impact that a possible senescent checkpoint might have in the tumor promotion inhibition observed, crossing these lines to mammary specific p53(R172H mutant expression, and to p27 knock-out mice. We analyzed the benign, premalignant and malignant lesions extensively by pathology and at molecular level analysing the expression of proteins involved in the PI3K/AKT pathway and in cellular senescence. Our findings revealed an increased preneoplastic phenotype depending upon AKT signaling which was not altered by p27 or p53 loss. However, p53 inactivation by R172H point mutation combined with myrAKT transgenic expression significantly increased the percentage and size of mammary carcinoma observed, but was not sufficient to promote full penetrance of the tumorigenic phenotype. Molecular analysis suggest that tumors from double myrAKT;p53(R172H mice result from acceleration of initiated p53(R172H tumors and not from bypass of AKT-induced oncogenic senescence. Our work suggests that tumors are not the consequence of the bypass of senescence in MIN. We also show that AKT-induced oncogenic senescence is dependent of pRb but not of p53. Finally, our work also suggests that the cooperation observed between mutant p53 and activated AKT is due to AKT-induced acceleration of mutant p53-induced tumors. Finally, our

  18. Distinct timing mechanisms produce discrete and continuous movements.

    Raoul Huys

    2008-04-01

    Full Text Available The differentiation of discrete and continuous movement is one of the pillars of motor behavior classification. Discrete movements have a definite beginning and end, whereas continuous movements do not have such discriminable end points. In the past decade there has been vigorous debate whether this classification implies different control processes. This debate up until the present has been empirically based. Here, we present an unambiguous non-empirical classification based on theorems in dynamical system theory that sets discrete and continuous movements apart. Through computational simulations of representative modes of each class and topological analysis of the flow in state space, we show that distinct control mechanisms underwrite discrete and fast rhythmic movements. In particular, we demonstrate that discrete movements require a time keeper while fast rhythmic movements do not. We validate our computational findings experimentally using a behavioral paradigm in which human participants performed finger flexion-extension movements at various movement paces and under different instructions. Our results demonstrate that the human motor system employs different timing control mechanisms (presumably via differential recruitment of neural subsystems to accomplish varying behavioral functions such as speed constraints.

  19. Astragalus polysaccharides lowers plasma cholesterol through mechanisms distinct from statins.

    Yunjiu Cheng

    Full Text Available To determine the efficacy and underlying mechanism of Astragalus polysaccharides (APS on plasma lipids in hypercholesterolemia hamsters. The effect of APS (0.25 g/kg/d on plasma and liver lipids, fecal bile acids and neutral sterol, cholesterol absorption and synthesis, HMG-CoA reductase activity, and gene and protein expressions in the liver and small intestine was investigated in twenty-four hypercholesterolemia hamsters. Treatment periods lasted for three months. APS significantly lowered plasma total cholesterol by 45.8%, triglycerides by 30%, and low-density lipoprotein-cholesterol by 47.4%, comparable to simvastatin. Further examinations revealed that APS reduced total cholesterol and triglycerides in the liver, increased fecal bile acid and neutral sterol excretion, inhibited cholesterol absorption, and by contrast, increased hepatic cholesterol synthesis and HMG-CoA reductase activity. Plasma total cholesterol or low-density lipoprotein-cholesterol levels were significantly correlated with cholesterol absorption rates. APS up-regulated cholesterol-7α-hydroxylase and LDL-receptor gene expressions. These new findings identify APS as a potential natural cholesterol lowering agent, working through mechanisms distinct from statins.

  20. Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression.

    Yue, Xuetian; Zhang, Cen; Zhao, Yuhan; Liu, Juan; Lin, Alan W; Tan, Victor M; Drake, Justin M; Liu, Lianxin; Boateng, Michael N; Li, Jun; Feng, Zhaohui; Hu, Wenwei

    2017-08-15

    Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53. © 2017 Yue et al.; Published by Cold Spring Harbor Laboratory Press.

  1. Perceptual learning shapes multisensory causal inference via two distinct mechanisms.

    McGovern, David P; Roudaia, Eugenie; Newell, Fiona N; Roach, Neil W

    2016-04-19

    To accurately represent the environment, our brains must integrate sensory signals from a common source while segregating those from independent sources. A reasonable strategy for performing this task is to restrict integration to cues that coincide in space and time. However, because multisensory signals are subject to differential transmission and processing delays, the brain must retain a degree of tolerance for temporal discrepancies. Recent research suggests that the width of this 'temporal binding window' can be reduced through perceptual learning, however, little is known about the mechanisms underlying these experience-dependent effects. Here, in separate experiments, we measure the temporal and spatial binding windows of human participants before and after training on an audiovisual temporal discrimination task. We show that training leads to two distinct effects on multisensory integration in the form of (i) a specific narrowing of the temporal binding window that does not transfer to spatial binding and (ii) a general reduction in the magnitude of crossmodal interactions across all spatiotemporal disparities. These effects arise naturally from a Bayesian model of causal inference in which learning improves the precision of audiovisual timing estimation, whilst concomitantly decreasing the prior expectation that stimuli emanate from a common source.

  2. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation

    Xia, Min; Jin, Qingfeng; Bendahhou, Saïd

    2005-01-01

    that KCNJ2 was associated with familial AF. Thirty Chinese AF kindreds were evaluated for mutations in KCNJ2 gene. A valine-to-isoleucine mutation at position 93 (V93I) of Kir2.1 was found in all affected members in one kindred. This valine and its flanking sequence is highly conserved in Kir2.1 proteins...... among different species. Functional analysis of the V93I mutant demonstrated a gain-of-function consequence on the Kir2.1 current. This effect is opposed to the loss-of-function effect of previously reported mutations in Andersen's syndrome. Kir2.1 V93I mutation may play a role in initiating and...

  3. Comparison of effects of p53 null and gain-of-function mutations on salivary tumors in MMTV-Hras transgenic mice.

    Dadi Jiang

    Full Text Available p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53(+/+, MMTV-Hras/p53(-/-, and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53(-/- and MMTV-Hras/p53R172H/R172H mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV-Hras/p53(+/+ mice by these measurements. In addition, the gene expression profiles of the MMTV-Hras/p53(-/- and MMTV-Hras/p53(R172H/R172H tumors were tightly clustered, and clearly distinct from the profiles of the MMTV-Hras/p53(+/+ tumors. Only a small group of genes showing differential expression between the MMTV-Hras/p53(-/- and MMTV-Hras/p53(R172H/R172H tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV-Hras-driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of-function mutant of p53.

  4. Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis.

    Marchesi, Vincent T

    2016-02-01

    Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes. © FASEB.

  5. EPO Receptor Gain-of-Function Causes Hereditary Polycythemia, Alters CD34+ Cell Differentiation and Increases Circulating Endothelial Precursors

    Perrotta, Silverio; Cucciolla, Valeria; Ferraro, Marcella; Ronzoni, Luisa; Tramontano, Annunziata; Rossi, Francesca; Scudieri, Anna Chiara; Borriello, Adriana; Roberti, Domenico; Nobili, Bruno; Cappellini, Maria Domenica; Oliva, Adriana; Amendola, Giovanni; Migliaccio, Anna Rita; Mancuso, Patrizia; Martin-Padura, Ines; Bertolini, Francesco; Yoon, Donghoon; Prchal, Josef T.; Della Ragione, Fulvio

    2010-01-01

    Background Gain-of-function of erythropoietin receptor (EPOR) mutations represent the major cause of primary hereditary polycythemia. EPOR is also found in non-erythroid tissues, although its physiological role is still undefined. Methodology/Principal Findings We describe a family with polycythemia due to a heterozygous mutation of the EPOR gene that causes a G→T change at nucleotide 1251 of exon 8. The novel EPOR G1251T mutation results in the replacement of a glutamate residue by a stop codon at amino acid 393. Differently from polycythemia vera, EPOR G1251T CD34+ cells proliferate and differentiate towards the erythroid phenotype in the presence of minimal amounts of EPO. Moreover, the affected individuals show a 20-fold increase of circulating endothelial precursors. The analysis of erythroid precursor membranes demonstrates a heretofore undescribed accumulation of the truncated EPOR, probably due to the absence of residues involved in the EPO-dependent receptor internalization and degradation. Mutated receptor expression in EPOR-negative cells results in EPOR and Stat5 phosphorylation. Moreover, patient erythroid precursors present an increased activation of EPOR and its effectors, including Stat5 and Erk1/2 pathway. Conclusions/Significance Our data provide an unanticipated mechanism for autosomal dominant inherited polycythemia due to a heterozygous EPOR mutation and suggest a regulatory role of EPO/EPOR pathway in human circulating endothelial precursors homeostasis. PMID:20700488

  6. Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner.

    Zheng, Hong; Yu, Wen-Mei; Waclaw, Ronald R; Kontaridis, Maria I; Neel, Benjamin G; Qu, Cheng-Kui

    2018-03-20

    Catalytically activating mutations in Ptpn11 , which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11 E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell-specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  7. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.

    Chang, Kai-Hsiung; Li, Rui; Kuri, Barbara; Lotan, Yair; Roehrborn, Claus G; Liu, Jiayan; Vessella, Robert; Nelson, Peter S; Kapur, Payal; Guo, Xiaofeng; Mirzaei, Hamid; Auchus, Richard J; Sharifi, Nima

    2013-08-29

    Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Gain-of-function mutagenesis approaches in rice for functional genomics and improvement of crop productivity.

    Moin, Mazahar; Bakshi, Achala; Saha, Anusree; Dutta, Mouboni; Kirti, P B

    2017-07-01

    The epitome of any genome research is to identify all the existing genes in a genome and investigate their roles. Various techniques have been applied to unveil the functions either by silencing or over-expressing the genes by targeted expression or random mutagenesis. Rice is the most appropriate model crop for generating a mutant resource for functional genomic studies because of the availability of high-quality genome sequence and relatively smaller genome size. Rice has syntenic relationships with members of other cereals. Hence, characterization of functionally unknown genes in rice will possibly provide key genetic insights and can lead to comparative genomics involving other cereals. The current review attempts to discuss the available gain-of-function mutagenesis techniques for functional genomics, emphasizing the contemporary approach, activation tagging and alterations to this method for the enhancement of yield and productivity of rice. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

    Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin-Ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi

    2013-07-11

    RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  10. Hepatic fibrosis and carcinogenesis in α1-antitrypsin deficiency: a prototype for chronic tissue damage in gain-of-function disorders.

    Perlmutter, David H; Silverman, Gary A

    2011-03-01

    In α1-antitrypsin (AT) deficiency, a point mutation renders a hepatic secretory glycoprotein prone to misfolding and polymerization. The mutant protein accumulates in the endoplasmic reticulum of liver cells and causes hepatic fibrosis and hepatocellular carcinoma by a gain-of-function mechanism. Genetic and/or environmental modifiers determine whether an affected homozygote is susceptible to hepatic fibrosis/carcinoma. Two types of proteostasis mechanisms for such modifiers have been postulated: variation in the function of intracellular degradative mechanisms and/or variation in the signal transduction pathways that are activated to protect the cell from protein mislocalization and/or aggregation. In recent studies we found that carbamazepine, a drug that has been used safely as an anticonvulsant and mood stabilizer, reduces the hepatic load of mutant AT and hepatic fibrosis in a mouse model by enhancing autophagic disposal of this mutant protein. These results provide evidence that pharmacological manipulation of endogenous proteostasis mechanisms is an appealing strategy for chemoprophylaxis in disorders involving gain-of-function mechanisms.

  11. Distinct mechanisms act in concert to mediate cell cycle arrest.

    Toettcher, Jared E; Loewer, Alexander; Ostheimer, Gerard J; Yaffe, Michael B; Tidor, Bruce; Lahav, Galit

    2009-01-20

    In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53-dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome.

  12. Characterization of phospholipase C gamma enzymes with gain-of-function mutations.

    Everett, Katy L; Bunney, Tom D; Yoon, Youngdae; Rodrigues-Lima, Fernando; Harris, Richard; Driscoll, Paul C; Abe, Koichiro; Fuchs, Helmut; de Angelis, Martin Hrabé; Yu, Philipp; Cho, Wohnwa; Katan, Matilda

    2009-08-21

    Phospholipase C gamma isozymes (PLC gamma 1 and PLC gamma 2) have a crucial role in the regulation of a variety of cellular functions. Both enzymes have also been implicated in signaling events underlying aberrant cellular responses. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we have recently identified single point mutations in murine PLC gamma 2 that lead to spontaneous inflammation and autoimmunity. Here we describe further, mechanistic characterization of two gain-of-function mutations, D993G and Y495C, designated as ALI5 and ALI14. The residue Asp-993, mutated in ALI5, is a conserved residue in the catalytic domain of PLC enzymes. Analysis of PLC gamma 1 and PLC gamma 2 with point mutations of this residue showed that removal of the negative charge enhanced PLC activity in response to EGF stimulation or activation by Rac. Measurements of PLC activity in vitro and analysis of membrane binding have suggested that ALI5-type mutations facilitate membrane interactions without compromising substrate binding and hydrolysis. The residue mutated in ALI14 (Tyr-495) is within the spPH domain. Replacement of this residue had no effect on folding of the domain and enhanced Rac activation of PLC gamma 2 without increasing Rac binding. Importantly, the activation of the ALI14-PLC gamma 2 and corresponding PLC gamma 1 variants was enhanced in response to EGF stimulation and bypassed the requirement for phosphorylation of critical tyrosine residues. ALI5- and ALI14-type mutations affected basal activity only slightly; however, their combination resulted in a constitutively active PLC. Based on these data, we suggest that each mutation could compromise auto-inhibition in the inactive PLC, facilitating the activation process; in addition, ALI5-type mutations could enhance membrane interaction in the activated state.

  13. Distinct Neural Mechanisms Mediate Olfactory Memory Formation at Different Timescales

    McNamara, Ann Marie; Magidson, Phillip D.; Linster, Christiane; Wilson, Donald A.; Cleland, Thomas A.

    2008-01-01

    Habituation is one of the oldest forms of learning, broadly expressed across sensory systems and taxa. Here, we demonstrate that olfactory habituation induced at different timescales (comprising different odor exposure and intertrial interval durations) is mediated by different neural mechanisms. First, the persistence of habituation memory is…

  14. Distinct mechanisms regulate Lck spatial organization in activated T cells

    Natasha eKapoor-Kaushik

    2016-03-01

    Full Text Available Phosphorylation of the T cell receptor (TCR by the kinase Lck is the first detectable signaling event upon antigen engagement. The distribution of Lck within the plasma membrane, its conformational state, kinase activity and protein interactions all contribute to determine how efficiently Lck phosphorylates the engaged TCR. Here we used cross-correlation raster image spectroscopy (ccRICS and photoactivated localization microscopy (PALM to identify two mechanisms of Lck clustering: an intrinsic mechanism of Lck clustering induced by locking Lck in its open conformation, and an extrinsic mechanism of clustering controlled by the phosphorylation of tyrosine 192, which regulates the affinity of Lck SH2 domain. Both mechanisms of clustering were differently affected by the absence of the kinase Zap70 or the adaptor Lat. We further observed that the adaptor TSAd bound to and promoted the diffusion of Lck when it is phosphorylated on tyrosine 192. Our data suggest that while Lck open conformation drives aggregation and clustering, the spatial organization of Lck is further controlled by signaling events downstream of TCR phosphorylation.

  15. Distinct neural mechanisms for body form and body motion discriminations

    Vangeneugden, Joris; Peelen, Marius V; Tadin, Duje; Battelli, Lorella

    2014-01-01

    Actions can be understood based on form cues (e.g., static body posture) as well as motion cues (e.g., gait patterns). A fundamental debate centers on the question of whether the functional and neural mechanisms processing these two types of cues are dissociable. Here, using fMRI, psychophysics, and

  16. Understanding and imitating unfamiliar actions: distinct underlying mechanisms.

    Joana C Carmo

    Full Text Available The human "mirror neuron system" has been proposed to be the neural substrate that underlies understanding and, possibly, imitating actions. However, since the brain activity with mirror properties seems insufficient to provide a good description for imitation of actions outside one's own repertoire, the existence of supplementary processes has been proposed. Moreover, it is unclear whether action observation requires the same neural mechanisms as the explicit access to their meaning. The aim of this study was two-fold as we investigated whether action observation requires different processes depending on 1 whether the ultimate goal is to imitate or understand the presented actions and 2 whether the to-be-imitated actions are familiar or unfamiliar to the subject. Participants were presented with both meaningful familiar actions and meaningless unfamiliar actions that they had to either imitate or discriminate later. Event-related Potentials were used as differences in brain activity could have been masked by the use of other techniques with lower temporal resolution. In the imitation task, a sustained left frontal negativity was more pronounced for meaningless actions than for meaningful ones, starting from an early time-window. Conversely, observing unfamiliar versus familiar actions with the intention of discriminating them led to marked differences over right centro-posterior scalp regions, in both middle and latest time-windows. These findings suggest that action imitation and action understanding may be sustained by dissociable mechanisms: while imitation of unfamiliar actions activates left frontal processes, that are likely to be related to learning mechanisms, action understanding involves dedicated operations which probably require right posterior regions, consistent with their involvement in social interactions.

  17. Exploiting orthologue diversity for systematic detection of gain-of-function phenotypes

    Cantarella Daniela

    2008-05-01

    Full Text Available Abstract Background Systematic search for genes whose gain-of-function by exogenous expression confers an advantage in cell-based selective screenings is a powerful method for unbiased functional exploration of the genome, and has the potential to disclose new targets for cancer therapy. A major limit of this approach resides in the labor-intensive cloning of resistant cells, identification of the integrated genes and validation of their ability to confer a selective advantage. Moreover, the selection has to be drastic and genes conferring a limited advantage are typically missed. Results We developed a new functional screening strategy based on transduction of mammalian cells of a given species with an expression library from another species, followed by one-shot quantitative tracing with DNA microarrays of all library-derived transcripts before and after selection. In this way, exogenous transcripts enriched after selection, and therefore likely to confer resistance, are readily detected. We transduced a retroviral cDNA expression library from mouse testis into human and canine cells, and optimized the use of commercial murine gene expression arrays for species-specific detection of library-derived transcripts. We then conducted a functional screening by growing library-transduced canine MDCK cells in suspension, to enrich for cDNAs conferring anchorage independence. Notably, these cells show partial resistance to loss of anchorage, and the selection can be of limited stringency, compromising approaches based on clonal selection or anyway requiring high stringency. Microarray analysis revealed reproducible enrichment after three weeks of growth on polyhema for seven genes, among which the Hras proto-oncogene and Sox5. When individually transduced into MDCK cells, Sox5 specifically promoted anchorage-independent growth, thereby confirming the validity and specificity of the approach. Conclusion The procedure described here brings substantial

  18. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H

    Mulkey, Sarah B; Ben-Zeev, Bruria; Nicolai, Joost

    2017-01-01

    OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide...... patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG...... respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H...

  19. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation

    Yang, Yiqing; Xia, Min; Jin, Qingfeng

    2004-01-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an alpha subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF...

  20. Gain-of-function assays in the axolotl (Ambystoma mexicanum) to identify signaling pathways that induce and regulate limb regeneration.

    Lee, Jangwoo; Aguilar, Cristian; Gardiner, David

    2013-01-01

    The adult salamander has been studied as a model for regeneration of complex tissues for many decades. Only recently with the development of gain-of-function assays for regeneration, has it been possible to screen for and assay the function of the multitude of signaling factors that have been identified in studies of embryonic development and tumorigenesis. Given the conservation of function of these regulatory pathways controlling growth and pattern formation, it is now possible to use the functional assays in the salamander to test the ability of endogenous as well as small-molecule signaling factors to induce a regenerative response.

  1. Gain-of-function mutant p53 but not p53 deletion promotes head and neck cancer progression in response to oncogenic K-ras

    Acin, Sergio; Li, Zhongyou; Mejia, Olga; Roop, Dennis R; El-Naggar, Adel K; Caulin, Carlos

    2015-01-01

    Mutations in p53 occur in over 50% of the human head and neck squamous cell carcinomas (SCCHN). The majority of these mutations result in the expression of mutant forms of p53, rather than deletions in the p53 gene. Some p53 mutants are associated with poor prognosis in SCCHN patients. However, the molecular mechanisms that determine the poor outcome of cancers carrying p53 mutations are unknown. Here, we generated a mouse model for SCCHN and found that activation of the endogenous p53 gain-of-function mutation p53R172H, but not deletion of p53, cooperates with oncogenic K-ras during SCCHN initiation, accelerates oral tumour growth, and promotes progression to carcinoma. Mechanistically, expression profiling of the tumours that developed in these mice and studies using cell lines derived from these tumours determined that mutant p53 induces the expression of genes involved in mitosis, including cyclin B1 and cyclin A, and accelerates entry in mitosis. Additionally, we discovered that this oncogenic function of mutant p53 was dependent on K-ras because the expression of cyclin B1 and cyclin A decreased, and entry in mitosis was delayed, after suppressing K-ras expression in oral tumour cells that express p53R172H. The presence of double-strand breaks in the tumours suggests that oncogene-dependent DNA damage resulting from K-ras activation promotes the oncogenic function of mutant p53. Accordingly, DNA damage induced by doxorubicin also induced increased expression of cyclin B1 and cyclin A in cells that express p53R172H. These findings represent strong in vivo evidence for an oncogenic function of endogenous p53 gain-of-function mutations in SCCHN and provide a mechanistic explanation for the genetic interaction between oncogenic K-ras and mutant p53. PMID:21952947

  2. The Meritocratic Ideal in Education Systems: The Mechanisms of Academic Distinction in the International Context

    Maria Luisa Quaresma

    2017-07-01

    Full Text Available The state school lives immersed in the tension between democratic purposes and the ideals of merit and selectivity. In this context, state schools establish instruments of public praise for students who stand out academically or in other dimensions. We propose to map the rituals of academic distinction in Portuguese state schools and to discuss the widespread adoption of these mechanisms by secondary schools. However, neither their configuration nor the selection criteria are homogeneous, which points to the existence of distinct conceptualisations of excellence and margins of freedom for each school to define their own criteria for success.

  3. PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

    Sherenian, M G; Cho, S H; Levin, A; Min, J-Y; Oh, S S; Hu, D; Galanter, J; Sen, S; Huntsman, S; Eng, C; Rodriguez-Santana, J R; Serebrisky, D; Avila, P C; Kalhan, R; Smith, L J; Borrell, L N; Seibold, M A; Keoki Williams, L; Burchard, E G; Kumar, R

    2017-09-01

    PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. There was an interaction between asthma status and the PAI-1 polymorphism on FEV 1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV 1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV 1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. The decrease in the FEV 1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation. © 2017

  4. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.

    Sousa, Sérgio B; Jenkins, Dagan; Chanudet, Estelle; Tasseva, Guergana; Ishida, Miho; Anderson, Glenn; Docker, James; Ryten, Mina; Sa, Joaquim; Saraiva, Jorge M; Barnicoat, Angela; Scott, Richard; Calder, Alistair; Wattanasirichaigoon, Duangrurdee; Chrzanowska, Krystyna; Simandlová, Martina; Van Maldergem, Lionel; Stanier, Philip; Beales, Philip L; Vance, Jean E; Moore, Gudrun E

    2014-01-01

    Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

  5. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

    Hopkins, Paul N.; Defesche, Joep; Fouchier, Sigrid W.; Bruckert, Eric; Luc, Gérald; Cariou, Bertrand; Sjouke, Barbara; Leren, Trond P.; Harada-Shiba, Mariko; Mabuchi, Hiroshi; Rabès, Jean-Pierre; Carrié, Alain; van Heyningen, Charles; Carreau, Valérie; Farnier, Michel; Teoh, Yee P.; Bourbon, Mafalda; Kawashiri, Masa-Aki; Nohara, Atsushi; Soran, Handrean; Marais, A. David; Tada, Hayato; Abifadel, Marianne; Boileau, Catherine; Chanu, Bernard; Katsuda, Shoji; Kishimoto, Ichiro; Lambert, Gilles; Makino, Hisashi; Miyamoto, Yoshihiro; Pichelin, Matthieu; Yagi, Kunimasa; Yamagishi, Masakazu; Zair, Yassine; Mellis, Scott; Yancopoulos, George D.; Stahl, Neil; Mendoza, Johanna; Du, Yunling; Hamon, Sara; Krempf, Michel; Swergold, Gary D.

    2015-01-01

    Background Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been

  6. Comparing and contrasting Escherichia coli and Mycobacterium tuberculosis mechanosensitive channels (MscL) - New gain of function mutations in the loop region

    Maurer, Joshua A.; Elmore, Donald E.; Lester, Henry A.; Dougherty, Dennis A.

    2000-01-01

    Sequence analysis of 35 putative MscL homologues was used to develop an optimal alignment for Escherichia coli and Mycobacterium tuberculosis MscL and to place these homologues into sequence subfamilies. By using this alignment, previously identified E. coli MscL mutants that displayed severe and very severe gain of function phenotypes were mapped onto the M. tuberculosis MscL sequence. Not all of the resulting M. tuberculosis mutants displayed a gain of function phenotype; for instance, norm...

  7. Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

    Farnaz Fekri

    Full Text Available Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR, and distinct mechanism(s that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may

  8. The Biology of Atherosclerosis: General Paradigms and Distinct Pathogenic Mechanisms Among HIV-Infected Patients

    Lo, Janet; Plutzky, Jorge

    2012-01-01

    Complications of atherosclerosis, including myocardial infarction and stroke, are the leading cause of death and disability worldwide. Recent data strongly implicate cardiovascular death as a contributor to mortality among patients with human immunodeficiency virus (HIV) infection, with evidence suggesting increased incidence of atherosclerosis among these patients. Therefore, greater understanding of atherosclerotic mechanisms and how these responses may be similar or distinct in HIV-infecte...

  9. Latent memory facilitates relearning through molecular signaling mechanisms that are distinct from original learning.

    Menges, Steven A; Riepe, Joshua R; Philips, Gary T

    2015-09-01

    A highly conserved feature of memory is that it can exist in a latent, non-expressed state which is revealed during subsequent learning by its ability to significantly facilitate (savings) or inhibit (latent inhibition) subsequent memory formation. Despite the ubiquitous nature of latent memory, the mechanistic nature of the latent memory trace and its ability to influence subsequent learning remains unclear. The model organism Aplysia californica provides the unique opportunity to make strong links between behavior and underlying cellular and molecular mechanisms. Using Aplysia, we have studied the mechanisms of savings due to latent memory for a prior, forgotten experience. We previously reported savings in the induction of three distinct temporal domains of memory: short-term (10min), intermediate-term (2h) and long-term (24h). Here we report that savings memory formation utilizes molecular signaling pathways that are distinct from original learning: whereas the induction of both original intermediate- and long-term memory in naïve animals requires mitogen activated protein kinase (MAPK) activation and ongoing protein synthesis, 2h savings memory is not disrupted by inhibitors of MAPK or protein synthesis, and 24h savings memory is not dependent on MAPK activation. Collectively, these findings reveal that during forgetting, latent memory for the original experience can facilitate relearning through molecular signaling mechanisms that are distinct from original learning. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Learning Similar Actions by Reinforcement or Sensory-Prediction Errors Rely on Distinct Physiological Mechanisms.

    Uehara, Shintaro; Mawase, Firas; Celnik, Pablo

    2017-09-14

    Humans can acquire knowledge of new motor behavior via different forms of learning. The two forms most commonly studied have been the development of internal models based on sensory-prediction errors (error-based learning) and success-based feedback (reinforcement learning). Human behavioral studies suggest these are distinct learning processes, though the neurophysiological mechanisms that are involved have not been characterized. Here, we evaluated physiological markers from the cerebellum and the primary motor cortex (M1) using noninvasive brain stimulations while healthy participants trained finger-reaching tasks. We manipulated the extent to which subjects rely on error-based or reinforcement by providing either vector or binary feedback about task performance. Our results demonstrated a double dissociation where learning the task mainly via error-based mechanisms leads to cerebellar plasticity modifications but not long-term potentiation (LTP)-like plasticity changes in M1; while learning a similar action via reinforcement mechanisms elicited M1 LTP-like plasticity but not cerebellar plasticity changes. Our findings indicate that learning complex motor behavior is mediated by the interplay of different forms of learning, weighing distinct neural mechanisms in M1 and the cerebellum. Our study provides insights for designing effective interventions to enhance human motor learning. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies

    Sanem Eren Akarcan

    2017-01-01

    Full Text Available Chronic Mucocutaneous Candidiasis (CMC is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF (c.1154 C>T, p.Thr385Met in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.

  12. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

    Scekic-Zahirovic, Jelena; Sendscheid, Oliver; El Oussini, Hajer; Jambeau, Mélanie; Sun, Ying; Mersmann, Sina; Wagner, Marina; Dieterlé, Stéphane; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Drenner, Kevin; Birling, Marie-Christine; Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong; Rouaux, Caroline; Shelkovnikova, Tatyana; Witting, Anke; Ludolph, Albert C; Kiefer, Friedemann; Storkebaum, Erik; Lagier-Tourenne, Clotilde; Dupuis, Luc

    2016-05-17

    FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  13. The biology of atherosclerosis: general paradigms and distinct pathogenic mechanisms among HIV-infected patients.

    Lo, Janet; Plutzky, Jorge

    2012-06-01

    Complications of atherosclerosis, including myocardial infarction and stroke, are the leading cause of death and disability worldwide. Recent data strongly implicate cardiovascular death as a contributor to mortality among patients with human immunodeficiency virus (HIV) infection, with evidence suggesting increased incidence of atherosclerosis among these patients. Therefore, greater understanding of atherosclerotic mechanisms and how these responses may be similar or distinct in HIV-infected patients is needed. Key concepts in atherosclerosis are reviewed, including the evidence that inflammation and abnormal metabolism are major drivers of atherosclerosis, and connected to the current literature regarding atherosclerosis in the context of HIV.

  14. Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

    Kristina Kirschner

    2015-03-01

    Full Text Available The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage and chronically activated (in senescent or pro-apoptotic conditions p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

  15. Excessive signal transduction of gain-of-function variants of the calcium-sensing receptor (CaSR are associated with increased ER to cytosol calcium gradient.

    Marianna Ranieri

    Full Text Available In humans, gain-of-function mutations of the calcium-sensing receptor (CASR gene are the cause of autosomal dominant hypocalcemia or type 5 Bartter syndrome characterized by an abnormality of calcium metabolism with low parathyroid hormone levels and excessive renal calcium excretion. Functional characterization of CaSR activating variants has been so far limited at demonstrating an increased sensitivity to external calcium leading to lower Ca-EC50. Here we combine high resolution fluorescence based techniques and provide evidence that for the efficiency of calcium signaling system, cells expressing gain-of-function variants of CaSR monitor cytosolic and ER calcium levels increasing the expression of the Sarco-Endoplasmic Reticulum Calcium-ATPase (SERCA and reducing expression of Plasma Membrane Calcium-ATPase (PMCA. Wild-type CaSR (hCaSR-wt and its gain-of-function (hCaSR-R990G; hCaSR-N124K variants were transiently transfected in HEK-293 cells. Basal intracellular calcium concentration was significantly lower in cells expressing hCaSR-wt and its gain of function variants compared to mock. In line, FRET studies using the D1ER probe, which detects [Ca2+]ER directly, demonstrated significantly higher calcium accumulation in cells expressing the gain of function CaSR variants compared to hCaSR-wt. Consistently, cells expressing activating CaSR variants showed a significant increase in SERCA activity and expression and a reduced PMCA expression. This combined parallel regulation in protein expression increases the ER to cytosol calcium gradient explaining the higher sensitivity of CaSR gain-of-function variants to external calcium. This control principle provides a general explanation of how cells reliably connect (and exacerbate receptor inputs to cell function.

  16. Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase.

    Kara R Barber

    2017-02-01

    Full Text Available Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

  17. The ethics of biosafety considerations in gain-of-function research resulting in the creation of potential pandemic pathogens.

    Evans, Nicholas Greig; Lipsitch, Marc; Levinson, Meira

    2015-11-01

    This paper proposes an ethical framework for evaluating biosafety risks of gain-of-function (GOF) experiments that create novel strains of influenza expected to be virulent and transmissible in humans, so-called potential pandemic pathogens (PPPs). Such research raises ethical concerns because of the risk that accidental release from a laboratory could lead to extensive or even global spread of a virulent pathogen. Biomedical research ethics has focused largely on human subjects research, while biosafety concerns about accidental infections, seen largely as a problem of occupational health, have been ignored. GOF/PPP research is an example of a small but important class of research where biosafety risks threaten public health, well beyond the small number of persons conducting the research.We argue that bioethical principles that ordinarily apply only to human subjects research should also apply to research that threatens public health, even if, as in GOF/PPP studies, the research involves no human subjects. Specifically we highlight the Nuremberg Code's requirements of 'fruitful results for the good of society, unprocurable by other methods', and proportionality of risk and humanitarian benefit, as broad ethical principles that recur in later documents on research ethics and should also apply to certain types of research not involving human subjects. We address several potential objections to this view, and conclude with recommendations for bringing these ethical considerations into policy development. 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/

  18. Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk.

    Chakhtoura, Zeina; Laki, Fatima; Bernadet, Marie; Cherifi, Ibtissem; Chiche, Aurélie; Pigat, Natascha; Bernichtein, Sophie; Courtillot, Carine; Boutillon, Florence; Bièche, Ivan; Vacher, Sophie; Tanguy, Marie-Laure; Bissery, Anne; Grouthier, Virginie; Camparo, Philippe; Foretz, Marc; Do Cruzeiro, Marcio; Pierre, Rémi; Rakotozafy, Fabienne; Tichet, Jean; Tejedor, Isabelle; Guidotti, Jacques-Emmanuel; Sigal-Zafrani, Brigitte; Goffin, Vincent; Touraine, Philippe

    2016-11-01

    In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLR I146L and PRLR I176V ). This study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis. This was an observational study and transgenic mouse model analysis. The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris. We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLR I146L or PRLR WT . We aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer. This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLR I146L exhibited very mild histological mammary phenotype but tumors were never observed. PRLR I146L and PRLR I176V variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.

  19. A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.

    Xiaoquan Zhu

    2014-10-01

    Full Text Available Distal arthrogryposis type 2B (DA2B is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del in troponin I type 2 (skeletal, fast (TNNI2, which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.

  20. Degree of handedness and priming: Further evidence for a distinction between production and identification priming mechanisms.

    Donna J. LaVoie

    2015-02-01

    Full Text Available The distinction between implicit and explicit forms of memory retrieval is long-standing, and important to the extent it reveals how different neural architecture supports different aspects of memory function. Similarly, distinctions have been made between kinds of repetition priming, a form of implicit memory retrieval. This study focuses on the production-identification priming distinction, which delineates priming tasks involving verification of stimulus features as compared to priming tasks that require use of a cue to guide response retrieval. Studies investigating this dissociation in dementia or similar patient populations indicate that these forms of priming may differ in their neural bases. The current study looks at degree of handedness as a way of investigating inferred neural architecture supporting these two forms of priming. A growing body of research indicates that degree of handedness (consistent, or CH, versus inconsistent, or ICH is associated with greater interhemispheric interaction and functional access to right hemisphere processing in ICH, with superior performance seen in ICH on memory tasks reliant on this processing. Arguments about the theoretical mechanisms underlying identification and production forms of perceptual priming tasks suggest that performance on these tasks will differ as a function of degree of handedness. We tested this question in a group of CH and ICH young adults, who were asked to study lists of words prior to performing a production priming task (word stem completion, a perceptual word identification task, and a word stem cued recall task. While both handedness groups exhibited reliable priming across tasks, word stem completion priming was greater in ICH than CH participants, with identification priming not differing between groups. This dissociation supports the argument that production and identification forms of priming have different underlying neural bases.

  1. β1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function

    Kruger, Larisa C.; O'Malley, Heather A.; Hull, Jacob M.; Kleeman, Amanda; Patino, Gustavo A.

    2016-01-01

    Voltage-gated sodium channel (VGSC) β subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, β subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell–cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC β1 and β1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of β1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b+/W) with mice heterozygous for the Scn1b-null allele (Scn1b+/−) to determine whether the C121W mutation results in loss-of-function in vivo. We found that Scn1b+/W mice were more susceptible than Scn1b+/− and Scn1b+/+ mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. β1-C121W subunits are expressed at the neuronal cell surface in vivo. However, despite this, β1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC α subunits in the brain. β1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1bW/W mice. These data, together with our previous results showing that β1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients. SIGNIFICANCE STATEMENT The mechanisms underlying genetic epilepsy syndromes are poorly understood. Closing this gap in knowledge is essential to the development of new medicines to treat epilepsy. We have used mouse models to

  2. Distinct Signaling Mechanisms in Multiple Developmental Pathways by the SCRAMBLED Receptor of Arabidopsis1[OPEN

    Kwak, Su-Hwan; Woo, Sooah; Lee, Myeong Min; Schiefelbein, John

    2014-01-01

    SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. PMID:25136062

  3. Distinct signaling mechanisms in multiple developmental pathways by the SCRAMBLED receptor of Arabidopsis.

    Kwak, Su-Hwan; Woo, Sooah; Lee, Myeong Min; Schiefelbein, John

    2014-10-01

    SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. © 2014 American Society of Plant Biologists. All Rights Reserved.

  4. Trimethylamine N-oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine

    Liao, Yi-Ting; Manson, Anthony C.; DeLyser, Michael R.; Noid, William G.; Cremer, Paul S.

    2017-01-01

    We report experimental and computational studies investigating the effects of three osmolytes, trimethylamine N-oxide (TMAO), betaine, and glycine, on the hydrophobic collapse of an elastin-like polypeptide (ELP). All three osmolytes stabilize collapsed conformations of the ELP and reduce the lower critical solution temperature (LSCT) linearly with osmolyte concentration. As expected from conventional preferential solvation arguments, betaine and glycine both increase the surface tension at the air–water interface. TMAO, however, reduces the surface tension. Atomically detailed molecular dynamics (MD) simulations suggest that TMAO also slightly accumulates at the polymer–water interface, whereas glycine and betaine are strongly depleted. To investigate alternative mechanisms for osmolyte effects, we performed FTIR experiments that characterized the impact of each cosolvent on the bulk water structure. These experiments showed that TMAO red-shifts the OH stretch of the IR spectrum via a mechanism that was very sensitive to the protonation state of the NO moiety. Glycine also caused a red shift in the OH stretch region, whereas betaine minimally impacted this region. Thus, the effects of osmolytes on the OH spectrum appear uncorrelated with their effects upon hydrophobic collapse. Similarly, MD simulations suggested that TMAO disrupts the water structure to the least extent, whereas glycine exerts the greatest influence on the water structure. These results suggest that TMAO stabilizes collapsed conformations via a mechanism that is distinct from glycine and betaine. In particular, we propose that TMAO stabilizes proteins by acting as a surfactant for the heterogeneous surfaces of folded proteins. PMID:28228526

  5. Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms.

    Achterberg, E J Marijke; Trezza, Viviana; Siviy, Stephen M; Schrama, Laurens; Schoffelmeer, Anton N M; Vanderschuren, Louk J M J

    2014-04-01

    Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated. In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats. The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine. Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.

  6. Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

    Beck, Michael W; Derrick, Jeffrey S; Kerr, Richard A; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D; Kim, Kwang S; Lee, Joo-Yong; Ruotolo, Brandon T; Lim, Mi Hee

    2016-10-13

    The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

  7. Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains.

    Pang, Xiaodong; Zhou, Huan-Xiang

    2014-05-01

    Protein phosphorylation is very common post-translational modification, catalyzed by kinases, for signaling and regulation. Phosphotyrosines frequently target SH2 domains. The spleen tyrosine kinase (Syk) is critical for tyrosine phosphorylation of multiple proteins and for regulation of important pathways. Phosphorylation of both Y342 and Y346 in Syk linker B is required for optimal signaling. The SH2 domains of Vav1 and PLC-γ both bind this doubly phosphorylated motif. Here we used a recently developed method to calculate the effects of Y342 and Y346 phosphorylation on the rate constants of a peptide from Syk linker B binding to the SH2 domains of Vav1 and PLC-γ. The predicted effects agree well with experimental observations. Moreover, we found that the same doubly phosphorylated peptide binds the two SH2 domains via distinct mechanisms, with apparent rigid docking for Vav1 SH2 and dock-and-coalesce for PLC-γ SH2.

  8. Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms

    Shedlock, Devon J.; Bailey, Michael A.; Popernack, Paul M.; Cunningham, James M.; Burton, Dennis R.; Sullivan, Nancy J.

    2010-01-01

    Human Ebola virus causes severe hemorrhagic fever disease with high mortality and there is no vaccine or treatment. Antibodies in survivors occur early, are sustained, and can delay infection when transferred into nonhuman primates. Monoclonal antibodies (mAbs) from survivors exhibit potent neutralizing activity in vitro and are protective in rodents. To better understand targets and mechanisms of neutralization, we investigated a panel of mAbs shown previously to react with the envelope glycoprotein (GP). While one non-neutralizing mAb recognized a GP epitope in the nonessential mucin-like domain, the rest were specific for GP1, were neutralizing, and could be further distinguished by reactivity with secreted GP. We show that survivor antibodies, human KZ52 and monkey JP3K11, were specific for conformation-dependent epitopes comprising residues in GP1 and GP2 and that neutralization occurred by two distinct mechanisms; KZ52 inhibited cathepsin cleavage of GP whereas JP3K11 recognized the cleaved, fusion-active form of GP.

  9. Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes.

    Borrego-Pinto, Joana; Somogyi, Kálmán; Karreman, Matthia A; König, Julia; Müller-Reichert, Thomas; Bettencourt-Dias, Mónica; Gönczy, Pierre; Schwab, Yannick; Lénárt, Péter

    2016-03-28

    Centriole elimination is an essential process that occurs in female meiosis of metazoa to reset centriole number in the zygote at fertilization. How centrioles are eliminated remains poorly understood. Here we visualize the entire elimination process live in starfish oocytes. Using specific fluorescent markers, we demonstrate that the two older, mother centrioles are selectively removed from the oocyte by extrusion into polar bodies. We show that this requires specific positioning of the second meiotic spindle, achieved by dynein-driven transport, and anchorage of the mother centriole to the plasma membrane via mother-specific appendages. In contrast, the single daughter centriole remaining in the egg is eliminated before the first embryonic cleavage. We demonstrate that these distinct elimination mechanisms are necessary because if mother centrioles are artificially retained, they cannot be inactivated, resulting in multipolar zygotic spindles. Thus, our findings reveal a dual mechanism to eliminate centrioles: mothers are physically removed, whereas daughters are eliminated in the cytoplasm, preparing the egg for fertilization. © 2016 Borrego-Pinto et al.

  10. Laboratory and 3-D-distinct element analysis of failure mechanism of slope under external surcharge

    Li, N.; Cheng, Y. M.

    2014-09-01

    Landslide is a major disaster resulting in considerable loss of human lives and property damages in hilly terrain in Hong Kong, China and many other countries. The factor of safety and the critical slip surface for slope stabilization are the main considerations for slope stability analysis in the past, while the detailed post-failure conditions of the slopes have not been considered in sufficient details. There are however increasing interest on the consequences after the initiation of failure which includes the development and propagation of the failure surfaces, the amount of failed mass and runoff and the affected region. To assess the development of slope failure in more details and to consider the potential danger of slopes after failure has initiated, the slope stability problem under external surcharge is analyzed by the distinct element method (DEM) and laboratory model test in the present research. A more refined study about the development of failure, microcosmic failure mechanism and the post-failure mechanism of slope will be carried out. The numerical modeling method and the various findings from the present work can provide an alternate method of analysis of slope failure which can give additional information not available from the classical methods of analysis.

  11. Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms.

    Siddiqui-Jain, Adam; Hoj, Jacob P; Hargiss, J Blade; Hoj, Taylor H; Payne, Carter J; Ritchie, Collin A; Herron, Steven R; Quinn, Colette; Schuler, Jeffrey T; Hansen, Marc D H

    2017-09-01

    Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents. We previously screened a small molecule library for compounds that block HGF-induced epithelial scattering. Most hits identified in this screen exhibit anti-mitotic properties. Here we assess the biological mechanism of a compound that blocks HGF-induced scattering with limited anti-mitotic activity. Analogs of this compound have one of two distinct activities: inhibiting either cell migration or cell proliferation with cell cycle arrest in G2/M. Each activity bears unique structure-activity relationships. The mechanism of action of anti-mitotic compounds is by inhibition of microtubule polymerization; these compounds entropically and enthalpically bind tubulin in the colchicine binding site, generating a conformational change in the tubulin dimer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes.

    Zhao, Junhua; Wang, Guliang; Del Mundo, Imee M; McKinney, Jennifer A; Lu, Xiuli; Bacolla, Albino; Boulware, Stephen B; Zhang, Changsheng; Zhang, Haihua; Ren, Pengyu; Freudenreich, Catherine H; Vasquez, Karen M

    2018-01-30

    Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Distinct Mechanism Evolved for Mycobacterial RNA Polymerase and Topoisomerase I Protein-Protein Interaction.

    Banda, Srikanth; Cao, Nan; Tse-Dinh, Yuk-Ching

    2017-09-15

    We report here a distinct mechanism of interaction between topoisomerase I and RNA polymerase in Mycobacterium tuberculosis and Mycobacterium smegmatis that has evolved independently from the previously characterized interaction between bacterial topoisomerase I and RNA polymerase. Bacterial DNA topoisomerase I is responsible for preventing the hyper-negative supercoiling of genomic DNA. The association of topoisomerase I with RNA polymerase during transcription elongation could efficiently relieve transcription-driven negative supercoiling. Our results demonstrate a direct physical interaction between the C-terminal domains of topoisomerase I (TopoI-CTDs) and the β' subunit of RNA polymerase of M. smegmatis in the absence of DNA. The TopoI-CTDs in mycobacteria are evolutionarily unrelated in amino acid sequence and three-dimensional structure to the TopoI-CTD found in the majority of bacterial species outside Actinobacteria, including Escherichia coli. The functional interaction between topoisomerase I and RNA polymerase has evolved independently in mycobacteria and E. coli, with distinctively different structural elements of TopoI-CTD utilized for this protein-protein interaction. Zinc ribbon motifs in E. coli TopoI-CTD are involved in the interaction with RNA polymerase. For M. smegmatis TopoI-CTD, a 27-amino-acid tail that is rich in basic residues at the C-terminal end is responsible for the interaction with RNA polymerase. Overexpression of recombinant TopoI-CTD in M. smegmatis competed with the endogenous topoisomerase I for protein-protein interactions with RNA polymerase. The TopoI-CTD overexpression resulted in decreased survival following treatment with antibiotics and hydrogen peroxide, supporting the importance of the protein-protein interaction between topoisomerase I and RNA polymerase during stress response of mycobacteria. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Feline immunodeficiency virus envelope glycoproteins antagonize tetherin through a distinctive mechanism that requires virion incorporation.

    Morrison, James H; Guevara, Rebekah B; Marcano, Adriana C; Saenz, Dyana T; Fadel, Hind J; Rogstad, Daniel K; Poeschla, Eric M

    2014-03-01

    also its Env protein, but the mechanism is distinctive. Unlike other tetherin antagonists, FIV Env cannot act in trans to rescue vpu-deficient HIV-1. It must be incorporated specifically into FIV virions to be active. Also unlike other retroviral antagonists, but similar to Ebola virus Env, it does not act by downregulating or degrading tetherin. FIV Env might exclude tetherin locally or direct assembly to tetherin-negative membrane domains. Other distinctive features are apparent, including evidence that this virus evolved an equilibrium in which tetherin is both restriction factor and cofactor, as FIV requires tetherin for optimal particle release.

  15. Beta2- and beta3-adrenoceptors activate glucose uptake in chick astrocytes by distinct mechanisms: a mechanism for memory enhancement?

    Hutchinson, Dana S; Summers, Roger J; Gibbs, Marie E

    2007-11-01

    Isoprenaline, acting at beta-adrenoceptors (ARs), enhances memory formation in single trial discriminated avoidance learning in day-old chicks by mechanisms involving alterations in glucose and glycogen metabolism. Earlier studies of memory consolidation in chicks indicated that beta3-ARs enhanced memory by increasing glucose uptake, whereas beta2-ARs enhance memory by increasing glycogenolysis. This study examines the ability of beta-ARs to increase glucose uptake in chick forebrain astrocytes. The beta-AR agonist isoprenaline increased glucose uptake in a concentration-dependent manner, as did insulin. Glucose uptake was increased by the beta2-AR agonist zinterol and the beta3-AR agonist CL316243, but not by the beta1-AR agonist RO363. In chick astrocytes, reverse transcription-polymerase chain reaction studies showed that beta1-, beta2-, and beta3-AR mRNA were present, whereas radioligand-binding studies showed the presence of only beta2- and beta3-ARs. beta-AR or insulin-mediated glucose uptake was inhibited by phosphatidylinositol-3 kinase and protein kinase C inhibitors, suggesting a possible interaction between the beta-AR and insulin pathways. However beta2- and beta3-ARs increase glucose uptake by two different mechanisms: beta2-ARs via a Gs-cAMP-protein kinase A-dependent pathway, while beta3-ARs via interactions with Gi. These results indicate that activation of beta2- and beta3-ARs causes glucose uptake in chick astrocytes by distinct mechanisms, which may be relevant for memory enhancement.

  16. Distinct mechanisms underlying tolerance to intermittent and constant hypoxia in Drosophila melanogaster.

    Priti Azad

    Full Text Available BACKGROUND: Constant hypoxia (CH and intermittent hypoxia (IH occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s in D. melanogaster after exposure to severe (1% O(2 intermittent or constant hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Our microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated in hypoxia tolerance (adult survival for longer periods (CH-7 days, IH-10 days under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70 led to a significant increase in adult survival (as compared to controls of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(208717 genes (P-element lines provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies. CONCLUSIONS/SIGNIFICANCE: We observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(208717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival.

  17. Therapeutic γ-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms

    Dai, Yan; Sangerman, Jose; Hong, Yuan Luo; Fuchareon, Suthat; Chui, David H.K.; Faller, Douglas V.; Perrine, Susan P.

    2015-01-01

    Pharmacologic augmentation of γ-globin expression sufficient to reduce anemia and clinical severity in patients with diverse hemoglobinopathies has been challenging. In studies here, representative molecules from four chemical classes, representing several distinct primary mechanisms of action, were investigated for effects on γ-globin transcriptional repressors, including components of the NuRD complex (LSD1 and HDACs 2-3), and the downstream repressor BCL11A, in erythroid progenitors from hemoglobinopathy patients. Two HDAC inhibitors (MS-275 and SB939), a short-chain fatty acid derivative (sodium dimethylbutyrate [SDMB]), and an agent identified in high-throughput screening, Benserazide, were studied. These therapeutics induced γ globin mRNA in progenitors above same subject controls up to 20-fold, and increased F-reticulocytes up to 20%. Cellular protein levels of BCL11A, LSD-1, and KLF1 were suppressed by the compounds. Chromatin immunoprecipitation assays demonstrated a 3.6-fold reduction in LSD1 and HDAC3 occupancy in the γ-globin gene promoter with Benserazide exposure, 3-fold reduction in LSD-1 and HDAC2 occupancy in the γ-globin gene promoter with SDMB exposure, while markers of gene activation (histone H3K9 acetylation and H3K4 demethylation), were enriched 5.7-fold. These findings identify clinical-stage oral therapeutics which inhibit or displace major co-repressors of γ-globin gene transcription and may suggest a rationale for combination therapy to produce enhanced efficacy. PMID:26603726

  18. Ire1 Has Distinct Catalytic Mechanisms for XBP1/HAC1 Splicing and RIDD

    Arvin B. Tam

    2014-11-01

    Full Text Available An evolutionarily conserved unfolded protein response (UPR component, IRE1, cleaves XBP1/HAC1 introns in order to generate spliced mRNAs that are translated into potent transcription factors. IRE1 also cleaves endoplasmic-reticulum-associated RNAs leading to their decay, an activity termed regulated IRE1-dependent decay (RIDD; however, the mechanism by which IRE1 differentiates intron cleavage from RIDD is not well understood. Using in vitro experiments, we found that IRE1 has two different modes of action: XBP1/HAC1 is cleaved by IRE1 subunits acting cooperatively within IRE1 oligomers, whereas a single subunit of IRE1 performs RIDD without cooperativity. Furthermore, these distinct activities can be separated by complementation of catalytically inactive IRE1 RNase and mutations at oligomerization interfaces. Using an IRE1 RNase inhibitor, STF-083010, selective inhibition of XBP1 splicing indicates that XBP1 promotes cell survival, whereas RIDD leads to cell death, revealing modulation of IRE1 activities as a drug-development strategy.

  19. Common and distinct neural mechanisms of attentional switching and response conflict.

    Kim, Chobok; Johnson, Nathan F; Gold, Brian T

    2012-08-21

    The human capacities for overcoming prepotent actions and flexibly switching between tasks represent cornerstones of cognitive control. Functional neuroimaging has implicated a diverse set of brain regions contributing to each of these cognitive control processes. However, the extent to which attentional switching and response conflict draw on shared or distinct neural mechanisms remains unclear. The current study examined the neural correlates of response conflict and attentional switching using event-related functional magnetic resonance imaging (fMRI) and a fully randomized 2×2 design. We manipulated an arrow-word version of the Stroop task to measure conflict and switching in the context of a single task decision, in response to a common set of stimuli. Under these common conditions, both behavioral and imaging data showed significant main effects of conflict and switching but no interaction. However, conjunction analyses identified frontal regions involved in both switching and response conflict, including the dorsal anterior cingulate cortex (dACC) and left inferior frontal junction. In addition, connectivity analyses demonstrated task-dependent functional connectivity patterns between dACC and inferior temporal cortex for attentional switching and between dACC and posterior parietal cortex for response conflict. These results suggest that the brain makes use of shared frontal regions, but can dynamically modulate the connectivity patterns of some of those regions, to deal with attentional switching and response conflict. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Motor learning in childhood reveals distinct mechanisms for memory retention and re-learning.

    Musselman, Kristin E; Roemmich, Ryan T; Garrett, Ben; Bastian, Amy J

    2016-05-01

    Adults can easily learn and access multiple versions of the same motor skill adapted for different conditions (e.g., walking in water, sand, snow). Following even a single session of adaptation, adults exhibit clear day-to-day retention and faster re-learning of the adapted pattern. Here, we studied the retention and re-learning of an adapted walking pattern in children aged 6-17 yr. We found that all children, regardless of age, showed adult-like patterns of retention of the adapted walking pattern. In contrast, children under 12 yr of age did not re-learn faster on the next day after washout had occurred-they behaved as if they had never adapted their walking before. Re-learning could be improved in younger children when the adaptation time on day 1 was increased to allow more practice at the plateau of the adapted pattern, but never to adult-like levels. These results show that the ability to store a separate, adapted version of the same general motor pattern does not fully develop until adolescence, and furthermore, that the mechanisms underlying the retention and rapid re-learning of adapted motor patterns are distinct. © 2016 Musselman et al.; Published by Cold Spring Harbor Laboratory Press.

  1. A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

    Fernández, S; Genis, L; Torres-Alemán, I

    2014-08-07

    Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

  2. Disseminated Tuberculosis and Chronic Mucocutaneous Candidiasis in a Patient with a Gain-of-Function Mutation in Signal Transduction and Activator of Transcription 1

    Sigifredo Pedraza-Sánchez

    2017-12-01

    Full Text Available In humans, recessive loss-of-function mutations in STAT1 are associated with mycobacterial and viral infections, whereas gain-of-function (GOF mutations in STAT1 are associated with a type of primary immunodeficiency related mainly, but not exclusively, to chronic mucocutaneous candidiasis (CMC. We studied and established a molecular diagnosis in a pediatric patient with mycobacterial infections, associated with CMC. The patient, daughter of a non-consanguineous mestizo Mexican family, had axillary adenitis secondary to BCG vaccination and was cured with resection of the abscess at 1-year old. At the age of 4 years, she had a supraclavicular abscess with acid-fast-staining bacilli identified in the soft tissue and bone, with clinical signs of disseminated infection and a positive Gene-X-pert test, which responded to anti-mycobacterial drugs. Laboratory tests of the IL-12/interferon gamma (IFN-γ circuit showed a higher production of IL-12p70 in the whole blood from the patient compared to healthy controls, when stimulated with BCG and BCG + IFN-γ. The whole blood of the patient produced 35% less IFN-γ compared to controls assessed by ELISA and flow cytometry, but IL-17 producing T cells from patient were almost absent in PBMC stimulated with PMA plus ionomycin. Signal transduction and activator of transcription 1 (STAT1 was hyperphosphorylated at tyrosine 701 in response to IFN-γ and -α, as demonstrated by flow cytometry and Western blotting in fresh blood mononuclear cells and in Epstein-Barr virus lymphoblastoid cell lines (EBV-LCLs; phosphorylation of STAT1 in EBV-LCLs from the patient was resistant to inhibition by staurosporine but sensitive to ruxolitinib, a Jak phosphorylation inhibitor. Genomic DNA sequencing showed a de novo mutation in STAT1 in cells from the patient, absent in her parents and brother; a known T385M missense mutation in the DNA-binding domain of the transcription factor was identified, and it is a GOF

  3. Hippocampus duality: Memory and novelty detection are subserved by distinct mechanisms.

    Barbeau, Emmanuel J; Chauvel, Patrick; Moulin, Christopher J A; Regis, Jean; Liégeois-Chauvel, Catherine

    2017-04-01

    The hippocampus plays a pivotal role both in novelty detection and in long-term memory. The physiological mechanisms underlying these behaviors have yet to be understood in humans. We recorded intracerebral evoked potentials within the hippocampus of epileptic patients (n = 10) during both memory and novelty detection tasks (targets in oddball tasks). We found that memory and detection tasks elicited late local field potentials in the hippocampus during the same period, but of opposite polarity (negative during novelty detection tasks, positive during memory tasks, ∼260-600 ms poststimulus onset, P < 0.05). Critically, these potentials had maximal amplitude on the same contact in the hippocampus for each patient. This pattern did not depend on the task as different types of memory and novelty detection tasks were used. It did not depend on the novelty of the stimulus or the difficulty of the task either. Two different hypotheses are discussed to account for this result: it is either due to the activation of CA1 pyramidal neurons by two different pathways such as the monosynaptic and trisynaptic entorhinal-hippocampus pathways, or to the activation of different neuronal populations, that is, differing either functionally (e.g., novelty/familiarity neurons) or located in different regions of the hippocampus (e.g., CA1/subiculum). In either case, these activities may integrate the activity of two distinct large-scale networks implementing externally or internally oriented, mutually exclusive, brain states. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms

    Leidgens, Verena; Seliger, Corinna; Jachnik, Birgit; Welz, Tobias; Leukel, Petra; Vollmann-Zwerenz, Arabel; Bogdahn, Ulrich; Kreutz, Marina; Grauer, Oliver M.; Hau, Peter

    2015-01-01

    Background Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells. Methods Glioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH-A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC. Results Ibuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration. Conclusions This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis. PMID:26485029

  5. Strength and Aerobic Exercises Improve Spatial Memory in Aging Rats Through Stimulating Distinct Neuroplasticity Mechanisms.

    Vilela, Thais Ceresér; Muller, Alexandre Pastoris; Damiani, Adriani Paganini; Macan, Tamires Pavei; da Silva, Sabrina; Canteiro, Paula Bortoluzzi; de Sena Casagrande, Alisson; Pedroso, Giulia Dos Santos; Nesi, Renata Tiscoski; de Andrade, Vanessa Moraes; de Pinho, Ricardo Aurino

    2017-12-01

    Aging is associated with impaired cognition and memory and increased susceptibility to neurodegenerative disorders. Physical exercise is neuroprotective; however, the major evidence of this effect involves studies of only aerobic training in young animals. The benefits of other exercise protocols such as strength training in aged animals remains unknown. Here, we investigated the effect of aerobic and strength training on spatial memory and hippocampal plasticity in aging rats. Aging Wistar rats performed aerobic or strength training for 50 min 3 to 4 days/week for 8 weeks. Spatial memory and neurotrophic and glutamatergic signaling in the hippocampus of aged rats were evaluated after aerobic or strength training. Both aerobic and strength training improved cognition during the performance of a spatial memory task. Remarkably, the improvement in spatial memory was accompanied by an increase in synaptic plasticity proteins within the hippocampus after exercise training, with some differences in the intracellular functions of those proteins between the two exercise protocols. Moreover, neurotrophic signaling (CREB, BDNF, and the P75 NTR receptor) increased after training for both exercise protocols, and aerobic exercise specifically increased glutamatergic proteins (NMDA receptor and PSD-95). We also observed a decrease in DNA damage after aerobic training. In contrast, strength training increased levels of PKCα and the proinflammatory factors TNF-α and IL-1β. Overall, our results show that both aerobic and strength training improved spatial memory in aging rats through inducing distinct molecular mechanisms of neuroplasticity. Our findings extend the idea that exercise protocols can be used to improve cognition during aging.

  6. TOPOISOMERASE1α Acts through Two Distinct Mechanisms to Regulate Stele and Columella Stem Cell Maintenance.

    Zhang, Yonghong; Zheng, Lanlan; Hong, Jing Han; Gong, Ximing; Zhou, Chun; Pérez-Pérez, José Manuel; Xu, Jian

    2016-05-01

    TOPOISOMERASE1 (TOP1), which releases DNA torsional stress generated during replication through its DNA relaxation activity, plays vital roles in animal and plant development. In Arabidopsis (Arabidopsis thaliana), TOP1 is encoded by two paralogous genes (TOP1α and TOP1β), of which TOP1α displays specific developmental functions that are critical for the maintenance of shoot and floral stem cells. Here, we show that maintenance of two different populations of root stem cells is also dependent on TOP1α-specific developmental functions, which are exerted through two distinct novel mechanisms. In the proximal root meristem, the DNA relaxation activity of TOP1α is critical to ensure genome integrity and survival of stele stem cells (SSCs). Loss of TOP1α function triggers DNA double-strand breaks in S-phase SSCs and results in their death, which can be partially reversed by the replenishment of SSCs mediated by ETHYLENE RESPONSE FACTOR115 In the quiescent center and root cap meristem, TOP1α is epistatic to RETINOBLASTOMA-RELATED (RBR) in the maintenance of undifferentiated state and the number of columella stem cells (CSCs). Loss of TOP1α function in either wild-type or RBR RNAi plants leads to differentiation of CSCs, whereas overexpression of TOP1α mimics and further enhances the effect of RBR reduction that increases the number of CSCs Taken together, these findings provide important mechanistic insights into understanding stem cell maintenance in plants. © 2016 American Society of Plant Biologists. All Rights Reserved.

  7. Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas

    Gisselsson David

    2007-09-01

    Full Text Available Abstract Background Neuroblastoma (NB is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process. Methods We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression. Results Tumours clustered in four sub-groups, dominated respectively by (1 gene amplification in double minute chromosomes and few other aberrations, (2 gene amplification and loss of 1p sequences, (3 loss of 1p and other structural aberrations including gain of 17q, and (4 whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1–3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number. Conclusion The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms.

  8. Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation

    Nielsen, Jonas Bille; Bentzen, Bo Hjorth; Olesen, Morten Salling

    2014-01-01

    Aims: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Disturbances in cardiac potassium conductance are considered as one of the disease mechanisms in AF. We aimed to investigate if mutations in potassium-channel β-subunits KCNE2 and KCNE3 are associated with early-onset lone AF. ...

  9. Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II-Induced Abdominal Aortic Aneurysms in C57BL/6 Mice-Brief Report.

    Lu, Hong; Howatt, Deborah A; Balakrishnan, Anju; Graham, Mark J; Mullick, Adam E; Daugherty, Alan

    2016-09-01

    Gain-of-function mutations of PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral (AAV) vector expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms. In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y). AAV at 3 doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose dependently in mice injected with AAV containing PCSK9D377Y mutation and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein receptor(-/-) mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent abdominal aortic aneurysmal formation, compared to low-density lipoprotein receptor(-/-) mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male low-density lipoprotein receptor(-/-) mice did not influence AngII-induced abdominal aortic aneurysms. AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting abdominal aortic aneurysms in C57BL/6 mice infused with Ang

  10. Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency.

    Ruparelia, Avnika A; Oorschot, Viola; Vaz, Raquel; Ramm, Georg; Bryson-Richardson, Robert J

    2014-12-01

    Mutations in the co-chaperone Bcl2-associated athanogene 3 (BAG3) can cause myofibrillar myopathy (MFM), a childhood-onset progressive muscle disease, characterized by the formation of protein aggregates and myofibrillar disintegration. In contrast to other MFM-causing proteins, BAG3 has no direct structural role, but regulates autophagy and the degradation of misfolded proteins. To investigate the mechanism of disease in BAG3-related MFM, we expressed wild-type BAG3 or the dominant MFM-causing BAG3 (BAG3(P209L)) in zebrafish. Expression of the mutant protein results in the formation of aggregates that contain wild-type BAG3. Through the stimulation and inhibition of autophagy, we tested the prevailing hypothesis that impaired autophagic function is responsible for the formation of protein aggregates. Contrary to the existing theory, our studies reveal that inhibition of autophagy is not sufficient to induce protein aggregation. Expression of the mutant protein, however, did not induce myofibrillar disintegration and we therefore examined the effect of knocking down Bag3 function. Loss of Bag3 resulted in myofibrillar disintegration, but not in the formation of protein aggregates. Remarkably, BAG3(P209L) is able to rescue the myofibrillar disintegration phenotype, further demonstrating that its function is not impaired. Together, our knockdown and overexpression experiments identify a mechanism whereby BAG3(P209L) aggregates form, gradually reducing the pool of available BAG3, which eventually results in BAG3 insufficiency and myofibrillar disintegration. This mechanism is consistent with the childhood onset and progressive nature of MFM and suggests that reducing aggregation through enhanced degradation or inhibition of nucleation would be an effective therapy for this disease.

  11. Brittle Fracture Mechanics of Snow : In Situ Testing and Distinct Element Modeling

    Faillettaz, J.; Daudon, D.; Louchet, F.

    A snow slab avalanche release usually results from the rupture of the snow cover at the interface between an upper layer (slab) and an underlying substrate. Amazingly, the models proposed so far to predict this kind of rupture were only based on continuum mechanics, as they did not take into account the existing cracks or cohesion defects at the interface between the two layers, and their possible unstable propagation that eventually triggers the avalanche. This is why the present work, essentially devoted to human triggered avalanches, is based instead on Griffith's fracture approach, widely used in modelling brittle fracture of materials. The possible rupture scenario involves a propagation in a shear mode of a "basal crack" nucleated and gradually grown at the interface by the skier's weight, followed by a mode I opening and propagation of a "crown crack" at the top of the sheared zone. Different avalanche sizes are predicted according whether the basal crack propagation reaches or not the Griffith's instabil- ity size before crown crack opening (Louchet 2000). Accurate predictions therefore require a precise knowledge of snow toughness values in both modes. A theoretical estimation of toughness considering snow as an ice foam was proposed by Kirchner and Michot (2000), but the question of whether these results may be extended to an assembly of sintered grains is still open. A mode I toughness measurement of snow was also published for the first time by Kirchner and Michot on samples gathered in the Vosges range. In the present work, we developed an experimental set similar to Michot's, in order to measure mode I toughness: a vertical crack of increasing size is gradually machined from the top surface in an horizontal snow beam until failure takes place under its own weight. The toughness value is computed from the snow weight and the crack length at the onset of rapid crack propagation. A similar device was designed for mode II testing, but is still under

  12. Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles

    Mario Sanhueza

    2013-12-01

    Amyotrophic Lateral Sclerosis (ALS is a motor neuron degenerative disease characterized by a progressive, and ultimately fatal, muscle paralysis. The human VAMP-Associated Protein B (hVAPB is the causative gene of ALS type 8. Previous studies have shown that a loss-of-function mechanism is responsible for VAPB-induced ALS. Recently, a novel mutation in hVAPB (V234I has been identified but its pathogenic potential has not been assessed. We found that neuronal expression of the V234I mutant allele in Drosophila (DVAP-V260I induces defects in synaptic structure and microtubule architecture that are opposite to those associated with DVAP mutants and transgenic expression of other ALS-linked alleles. Expression of DVAP-V260I also induces aggregate formation, reduced viability, wing postural defects, abnormal locomotion behavior, nuclear abnormalities, neurodegeneration and upregulation of the heat-shock-mediated stress response. Similar, albeit milder, phenotypes are associated with the overexpression of the wild-type protein. These data show that overexpressing the wild-type DVAP is sufficient to induce the disease and that DVAP-V260I is a pathogenic allele with increased wild-type activity. We propose that a combination of gain- and loss-of-function mechanisms is responsible for VAPB-induced ALS.

  13. Zif268/Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory.

    Penke, Zsuzsa; Morice, Elise; Veyrac, Alexandra; Gros, Alexandra; Chagneau, Carine; LeBlanc, Pascale; Samson, Nathalie; Baumgärtel, Karsten; Mansuy, Isabelle M; Davis, Sabrina; Laroche, Serge

    2014-01-05

    It is well established that Zif268/Egr1, a member of the Egr family of transcription factors, is critical for the consolidation of several forms of memory; however, it is as yet uncertain whether increasing expression of Zif268 in neurons can facilitate memory formation. Here, we used an inducible transgenic mouse model to specifically induce Zif268 overexpression in forebrain neurons and examined the effect on recognition memory and hippocampal synaptic transmission and plasticity. We found that Zif268 overexpression during the establishment of memory for objects did not change the ability to form a long-term memory of objects, but enhanced the capacity to form a long-term memory of the spatial location of objects. This enhancement was paralleled by increased long-term potentiation in the dentate gyrus of the hippocampus and by increased activity-dependent expression of Zif268 and selected Zif268 target genes. These results provide novel evidence that transcriptional mechanisms engaging Zif268 contribute to determining the strength of newly encoded memories.

  14. Distinction between added-energy and phase-resetting mechanisms in non-invasively detected somatosensory evoked responses.

    Fedele, T; Scheer, H-J; Burghoff, M; Waterstraat, G; Nikulin, V V; Curio, G

    2013-01-01

    Non-invasively recorded averaged event-related potentials (ERP) represent a convenient opportunity to investigate human brain perceptive and cognitive processes. Nevertheless, generative ERP mechanisms are still debated. Two previous approaches have been contested in the past: the added-energy model in which the response raises independently from the ongoing background activity, and the phase-reset model, based on stimulus-driven synchronization of oscillatory ongoing activity. Many criteria for the distinction of these two models have been proposed, but there is no definitive methodology to disentangle them, owing also to the limited information at the single trial level. Here, we propose a new approach combining low-noise EEG technology and multivariate decomposition techniques. We present theoretical analyses based on simulated data and identify in high-frequency somatosensory evoked responses an optimal target for the distinction between the two mechanisms.

  15. A nucleotide-analogue-induced gain of function corrects the error-prone nature of human DNA polymerase iota.

    Ketkar, Amit; Zafar, Maroof K; Banerjee, Surajit; Marquez, Victor E; Egli, Martin; Eoff, Robert L

    2012-06-27

    Y-family DNA polymerases participate in replication stress and DNA damage tolerance mechanisms. The properties that allow these enzymes to copy past bulky adducts or distorted template DNA can result in a greater propensity for them to make mistakes. Of the four human Y-family members, human DNA polymerase iota (hpol ι) is the most error-prone. In the current study, we elucidate the molecular basis for improving the fidelity of hpol ι through use of the fixed-conformation nucleotide North-methanocarba-2'-deoxyadenosine triphosphate (N-MC-dATP). Three crystal structures were solved of hpol ι in complex with DNA containing a template 2'-deoxythymidine (dT) paired with an incoming dNTP or modified nucleotide triphosphate. The ternary complex of hpol ι inserting N-MC-dATP opposite dT reveals that the adenine ring is stabilized in the anti orientation about the pseudo-glycosyl torsion angle, which mimics precisely the mutagenic arrangement of dGTP:dT normally preferred by hpol ι. The stabilized anti conformation occurs without notable contacts from the protein but likely results from constraints imposed by the bicyclo[3.1.0]hexane scaffold of the modified nucleotide. Unmodified dATP and South-MC-dATP each adopt syn glycosyl orientations to form Hoogsteen base pairs with dT. The Hoogsteen orientation exhibits weaker base-stacking interactions and is less catalytically favorable than anti N-MC-dATP. Thus, N-MC-dATP corrects the error-prone nature of hpol ι by preventing the Hoogsteen base-pairing mode normally observed for hpol ι-catalyzed insertion of dATP opposite dT. These results provide a previously unrecognized means of altering the efficiency and the fidelity of a human translesion DNA polymerase.

  16. A nucleotide analogue induced gain of function corrects the error-prone nature of human DNA polymerase iota

    Ketkar, Amit; Zafar, Maroof K.; Banerjee, Surajit; Marquez, Victor E.; Egli, Martin; Eoff, Robert L

    2012-01-01

    Y-family DNA polymerases participate in replication stress and DNA damage tolerance mechanisms. The properties that allow these enzymes to copy past bulky adducts or distorted template DNA can result in a greater propensity for them to make mistakes. Of the four human Y-family members, human DNA polymerase iota (hpol ι) is the most error-prone. In the current study, we elucidate the molecular basis for improving the fidelity of hpol ι through use of the fixed-conformation nucleotide North-methanocarba-2′-deoxyadenosine triphosphate (N-MC-dATP). Three crystal structures were solved of hpol ι in complex with DNA containing a template 2′-deoxythymidine (dT) paired with an incoming dNTP or modified nucleotide triphosphate. The ternary complex of hpol ι inserting N-MC-dATP opposite dT reveals that the adenine ring is stabilized in the anti orientation about the pseudo-glycosyl torsion angle (χ), which mimics precisely the mutagenic arrangement of dGTP:dT normally preferred by hpol ι. The stabilized anti conformation occurs without notable contacts from the protein but likely results from constraints imposed by the bicyclo[3.1.0]hexane scaffold of the modified nucleotide. Unmodified dATP and South-MC-dATP each adopt syn glycosyl orientations to form Hoogsteen base pairs with dT. The Hoogsteen orientation exhibits weaker base stacking interactions and is less catalytically favorable than anti N-MC-dATP. Thus, N-MC-dATP corrects the error-prone nature of hpol ι by preventing the Hoogsteen base-pairing mode normally observed for hpol ι-catalyzed insertion of dATP opposite dT. These results provide a previously unrecognized means of altering the efficiency and the fidelity of a human translesion DNA polymerase. PMID:22632140

  17. Commonalities and distinctions among mechanisms of addiction to alcohol and other drugs

    Ozburn, Angela R.; Janowsky, Aaron J.; Crabbe, John C.

    2015-01-01

    Alcohol abuse is comorbid with abuse of many other drugs, some with similar pharmacology and others quite different. This leads to the hypothesis of an underlying, unitary dysfunctional neurobiological basis for substance abuse risk and consequences. In this review, we discuss commonalities and distinctions of addiction to alcohol and other drugs. We focus on recent advances in pre-clinical studies using rodent models of drug self-administration. While there are specific behavioral and molecular manifestations common to alcohol, psychostimulant, opioid, and nicotine dependence, attempts to propose a unifying theory of the addictions inevitably face details where distinctions are found among classes of drugs. For alcohol, versus other drugs of abuse, we discuss and compare advances in: 1) neurocircuitry important for the different stages of drug dependence; 2) transcriptomics and genetical genomics; and 3) enduring effects. We note in particular the contributions of behavioral genetics and animal models: discussions of progress specifically relevant to treatment development can be found in the accompanying review (Karoly et al, this issue). PMID:26431116

  18. Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

    Lewis D. Evans

    2018-03-01

    Full Text Available Summary: In Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon. : In contrast with predictions that transfer of the microtubule-associated protein tau between neurons is a toxic gain-of-function process in dementia, Evans et al. show that healthy human neurons efficiently take up both normal and aggregated tau, by distinct but overlapping uptake mechanisms. Keywords: Alzheimer’s disease, frontotemporal dementia, Tau, MAPT, iPSC, endocytosis, human neurons, intracellular transport

  19. Structural plasticity mediates distinct GAP-dependent GTP hydrolysis mechanisms in Rab33 and Rab5.

    Majumdar, Soneya; Acharya, Abhishek; Prakash, Balaji

    2017-12-01

    The classical GTP hydrolysis mechanism, as seen in Ras, employs a catalytic glutamine provided in cis by the GTPase and an arginine supplied in trans by a GTPase activating protein (GAP). The key idea emergent from a large body of research on small GTPases is that GTPases employ a variety of different hydrolysis mechanisms; evidently, these variations permit diverse rates of GTPase inactivation, crucial for temporal regulation of different biological processes. Recently, we unified these variations and argued that a steric clash between active site residues (corresponding to positions 12 and 61 of Ras) governs whether a GTPase utilizes the cis-Gln or the trans-Gln (from the GAP) for catalysis. As the cis-Gln encounters a steric clash, the Rab GTPases employ the so-called dual finger mechanism where the interacting GAP supplies a trans-Gln for catalysis. Using experimental and computational methods, we demonstrate how the cis-Gln of Rab33 overcomes the steric clash when it is stabilized by a residue in the vicinity. In effect, this demonstrates how both cis-Gln- and trans-Gln-mediated mechanisms could operate in the same GTPase in different contexts, i.e. depending on the GAP that regulates its action. Interestingly, in the case of Rab5, which possesses a higher intrinsic GTP hydrolysis rate, a similar stabilization of the cis-Gln appears to overcome the steric clash. Taken together with the mechanisms seen for Rab1, it is evident that the observed variations in Rab and their GAP partners allow structural plasticity, or in other words, the choice of different catalytic mechanisms. © 2017 Federation of European Biochemical Societies.

  20. Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain of function mutations

    Galan-Diez, Marta; Isa, Adiba; Ponzetti, Marco

    2016-01-01

    of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5...... mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation...... of β-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM...

  1. Dominant Drop mutants are gain-of-function alleles of the muscle segment homeobox gene (msh) whose overexpression leads to the arrest of eye development.

    Mozer, B A

    2001-05-15

    Dominant Drop (Dr) mutations are nearly eyeless and have additional recessive phenotypes including lethality and patterning defects in eye and sensory bristles due to cis-regulatory lesions in the cell cycle regulator string (stg). Genetic analysis demonstrates that the dominant small eye phenotype is the result of separate gain-of-function mutations in the closely linked muscle segment homeobox (msh) gene, encoding a homeodomain transcription factor required for patterning of muscle and nervous system. Reversion of the Dr(Mio) allele was coincident with the generation of lethal loss-of-function mutations in msh in cis, suggesting that the dominant eye phenotype is the result of ectopic expression. Molecular genetic analysis revealed that two dominant Dr alleles contain lesions upstream of the msh transcription start site. In the Dr(Mio) mutant, a 3S18 retrotransposon insertion is the target of second-site mutations (P-element insertions or deletions) which suppress the dominant eye phenotype following reversion. The pattern of 3S18 expression and the absence of msh in eye imaginal discs suggest that transcriptional activation of the msh promoter accounts for ectopic expression. Dr dominant mutations arrest eye development by blocking the progression of the morphogenetic furrow leading to photoreceptor cell loss via apoptosis. Gal4-mediated ubiquitous expression of msh in third-instar larvae was sufficient to arrest the morphogenetic furrow in the eye imaginal disc and resulted in lethality prior to eclosion. Dominant mutations in the human msx2 gene, one of the vertebrate homologs of msh, are associated with craniosynostosis, a disease affecting cranial development. The Dr mutations are the first example of gain-of-function mutations in the msh/msx gene family identified in a genetically tractible model organism and may serve as a useful tool to identify additional genes that regulate this class of homeodomain proteins. Copyright 2001 Academic Press.

  2. Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

    Landor, S.; Mutvei, A.P.; Mamaeva, V.; Jin, S.; Busk, M.; Borra, R.; Grönroos, T.J.; Kronqvist, P.; Lendahl, U.; Sahlgren, C.M.

    2011-01-01

    A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular

  3. Overexpression of cypin alters dendrite morphology, single neuron activity, and network properties via distinct mechanisms

    Rodríguez, Ana R.; O'Neill, Kate M.; Swiatkowski, Przemyslaw; Patel, Mihir V.; Firestein, Bonnie L.

    2018-02-01

    Objective. This study investigates the effect that overexpression of cytosolic PSD-95 interactor (cypin), a regulator of synaptic PSD-95 protein localization and a core regulator of dendrite branching, exerts on the electrical activity of rat hippocampal neurons and networks. Approach. We cultured rat hippocampal neurons and used lipid-mediated transfection and lentiviral gene transfer to achieve high levels of cypin or cypin mutant (cypinΔPDZ PSD-95 non-binding) expression cellularly and network-wide, respectively. Main results. Our analysis revealed that although overexpression of cypin and cypinΔPDZ increase dendrite numbers and decrease spine density, cypin and cypinΔPDZ distinctly regulate neuronal activity. At the single cell level, cypin promotes decreases in bursting activity while cypinΔPDZ reduces sEPSC frequency and further decreases bursting compared to cypin. At the network level, by using the Fano factor as a measure of spike count variability, cypin overexpression results in an increase in variability of spike count, and this effect is abolished when cypin cannot bind PSD-95. This variability is also dependent on baseline activity levels and on mean spike rate over time. Finally, our spike sorting data show that overexpression of cypin results in a more complex distribution of spike waveforms and that binding to PSD-95 is essential for this complexity. Significance. Our data suggest that dendrite morphology does not play a major role in cypin action on electrical activity.

  4. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

    Chapuy, Bjoern; Stewart, Chip; Dunford, Andrew J; Kim, Jaegil; Kamburov, Atanas; Redd, Robert A; Lawrence, Mike S; Roemer, Margaretha G M; Li, Amy J; Ziepert, Marita; Staiger, Annette M; Wala, Jeremiah A; Ducar, Matthew D; Leshchiner, Ignaty; Rheinbay, Ester; Taylor-Weiner, Amaro; Coughlin, Caroline A; Hess, Julian M; Pedamallu, Chandra S; Livitz, Dimitri; Rosebrock, Daniel; Rosenberg, Mara; Tracy, Adam A; Horn, Heike; van Hummelen, Paul; Feldman, Andrew L; Link, Brian K; Novak, Anne J; Cerhan, James R; Habermann, Thomas M; Siebert, Reiner; Rosenwald, Andreas; Thorner, Aaron R; Meyerson, Matthew L; Golub, Todd R; Beroukhim, Rameen; Wulf, Gerald G; Ott, German; Rodig, Scott J; Monti, Stefano; Neuberg, Donna S; Loeffler, Markus; Pfreundschuh, Michael; Trümper, Lorenz; Getz, Gad; Shipp, Margaret A

    2018-04-30

    Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

  5. Medically important differences in snake venom composition are dictated by distinct postgenomic mechanisms.

    Casewell, Nicholas R; Wagstaff, Simon C; Wüster, Wolfgang; Cook, Darren A N; Bolton, Fiona M S; King, Sarah I; Pla, Davinia; Sanz, Libia; Calvete, Juan J; Harrison, Robert A

    2014-06-24

    Variation in venom composition is a ubiquitous phenomenon in snakes and occurs both interspecifically and intraspecifically. Venom variation can have severe outcomes for snakebite victims by rendering the specific antibodies found in antivenoms ineffective against heterologous toxins found in different venoms. The rapid evolutionary expansion of different toxin-encoding gene families in different snake lineages is widely perceived as the main cause of venom variation. However, this view is simplistic and disregards the understudied influence that processes acting on gene transcription and translation may have on the production of the venom proteome. Here, we assess the venom composition of six related viperid snakes and compare interspecific changes in the number of toxin genes, their transcription in the venom gland, and their translation into proteins secreted in venom. Our results reveal that multiple levels of regulation are responsible for generating variation in venom composition between related snake species. We demonstrate that differential levels of toxin transcription, translation, and their posttranslational modification have a substantial impact upon the resulting venom protein mixture. Notably, these processes act to varying extents on different toxin paralogs found in different snakes and are therefore likely to be as important as ancestral gene duplication events for generating compositionally distinct venom proteomes. Our results suggest that these processes may also contribute to altering the toxicity of snake venoms, and we demonstrate how this variability can undermine the treatment of a neglected tropical disease, snakebite.

  6. How space-number associations may be created in preliterate children: six distinct mechanisms

    Hans-Christoph eNuerk

    2015-03-01

    Full Text Available The directionality of space-number association (SNA is shaped by cultural experiences. It usually follows the culturally dominant reading direction. Smaller numbers are generally associated with the starting side for reading (left side in Western cultures, while larger numbers are associated with the right endpoint side. However, SNAs consistent with cultural reading directions are present before children can actually read and write. Therefore, these SNAs cannot only be shaped by the direction of children’s own reading/writing behavior. We propose six distinct processes - one biological and five cultural/educational - underlying directional space-number associations before formal reading acquisition: (i Brain lateralization (ii Monitoring adult reading behavior, (iii Pretend reading and writing, and rudimentary reading and writing skills, (iv Dominant attentional directional preferences in a society, not directly related to reading direction, (v Direct spatial-numerical learning, (vi Other spatial-directional processes independent of reading direction. In this mini-review, we will differentiate between these processes, elaborate when in development they might emerge, discuss how they may create the space-number associations observed in preliterate children and propose how they can be studied in the future.

  7. Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.

    Nahman-Averbuch, Hadas; Martucci, Katherine T; Granovsky, Yelena; Weissman-Fogel, Irit; Yarnitsky, David; Coghill, Robert C

    2014-12-01

    The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  8. BMPs regulate msx gene expression in the dorsal neuroectoderm of Drosophila and vertebrates by distinct mechanisms.

    Esteves, Francisco F; Springhorn, Alexander; Kague, Erika; Taylor, Erika; Pyrowolakis, George; Fisher, Shannon; Bier, Ethan

    2014-09-01

    In a broad variety of bilaterian species the trunk central nervous system (CNS) derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are expressed in corresponding non-overlapping patterns along the dorsal-ventral axis. While this conserved suite of "neural identity" gene expression strongly suggests a common ancestral origin for the patterning systems, it is unclear whether the original regulatory mechanisms establishing these patterns have been similarly conserved during evolution. In Drosophila, genetic evidence suggests that Bone Morphogenetic Proteins (BMPs) act in a dosage-dependent fashion to repress expression of neural identity genes. BMPs also play a dose-dependent role in patterning the dorsal and lateral regions of the vertebrate CNS, however, the mechanism by which they achieve such patterning has not yet been clearly established. In this report, we examine the mechanisms by which BMPs act on cis-regulatory modules (CRMs) that control localized expression of the Drosophila msh and zebrafish (Danio rerio) msxB in the dorsal central nervous system (CNS). Our analysis suggests that BMPs act differently in these organisms to regulate similar patterns of gene expression in the neuroectoderm: repressing msh expression in Drosophila, while activating msxB expression in the zebrafish. These findings suggest that the mechanisms by which the BMP gradient patterns the dorsal neuroectoderm have reversed since the divergence of these two ancient lineages.

  9. BMPs regulate msx gene expression in the dorsal neuroectoderm of Drosophila and vertebrates by distinct mechanisms.

    Francisco F Esteves

    2014-09-01

    Full Text Available In a broad variety of bilaterian species the trunk central nervous system (CNS derives from three primary rows of neuroblasts. The fates of these neural progenitor cells are determined in part by three conserved transcription factors: vnd/nkx2.2, ind/gsh and msh/msx in Drosophila melanogaster/vertebrates, which are expressed in corresponding non-overlapping patterns along the dorsal-ventral axis. While this conserved suite of "neural identity" gene expression strongly suggests a common ancestral origin for the patterning systems, it is unclear whether the original regulatory mechanisms establishing these patterns have been similarly conserved during evolution. In Drosophila, genetic evidence suggests that Bone Morphogenetic Proteins (BMPs act in a dosage-dependent fashion to repress expression of neural identity genes. BMPs also play a dose-dependent role in patterning the dorsal and lateral regions of the vertebrate CNS, however, the mechanism by which they achieve such patterning has not yet been clearly established. In this report, we examine the mechanisms by which BMPs act on cis-regulatory modules (CRMs that control localized expression of the Drosophila msh and zebrafish (Danio rerio msxB in the dorsal central nervous system (CNS. Our analysis suggests that BMPs act differently in these organisms to regulate similar patterns of gene expression in the neuroectoderm: repressing msh expression in Drosophila, while activating msxB expression in the zebrafish. These findings suggest that the mechanisms by which the BMP gradient patterns the dorsal neuroectoderm have reversed since the divergence of these two ancient lineages.

  10. Experimental acidification of two biogeochemically-distinct neotropical streams: Buffering mechanisms and macroinvertebrate drift

    Ardón, Marcelo; Duff, John H.; Ramírez, Alonso; Small, Gaston E.; Jackman, Alan P.; Triska, Frank J.; Pringle, Catherine M.

    2013-01-01

    Research into the buffering mechanisms and ecological consequences of acidification in tropical streams is lacking. We have documented seasonal and episodic acidification events in streams draining La Selva Biological Station, Costa Rica. Across this forested landscape, the severity in seasonal and episodic acidification events varies due to interbasin groundwater flow (IGF). Streams that receive IGF have higher concentrations of solutes and more stable pH (∼ 6) than streams that do not receive IGF (pH ∼ 5). To examine the buffering capacity and vulnerability of macroinvertebrates to short-term acidification events, we added hydrochloric acid to acidify a low-solute, poorly buffered (without IGF) and a high-solute, well buffered stream (with IGF). We hypothesized that: 1) protonation of bicarbonate (HCO 3 − ) would neutralize most of the acid added in the high-solute stream, while base cation release from the sediments would be the most important buffering mechanism in the low-solute stream; 2) pH declines would mobilize inorganic aluminum (Ali) from sediments in both streams; and 3) pH declines would increase macroinvertebrate drift in both streams. We found that the high-solute stream neutralized 745 μeq/L (96% of the acid added), while the solute poor stream only neutralized 27.4 μeq/L (40%). Protonation of HCO 3 − was an important buffering mechanism in both streams. Base cation, Fe 2+ , and Ali release from sediments and protonation of organic acids also provided buffering in the low-solute stream. We measured low concentrations of Ali release in both streams (2-9 μeq/L) in response to acidification, but the low-solute stream released double the amount Ali per 100 μeq of acid added than the high solute stream. Macroinvertebrate drift increased in both streams in response to acidification and was dominated by Ephemeroptera and Chironomidae. Our results elucidate the different buffering mechanisms in tropical streams and suggest that low

  11. Experimental acidification of two biogeochemically-distinct neotropical streams: Buffering mechanisms and macroinvertebrate drift

    Ardón, Marcelo, E-mail: ardonsayaom@ecu.edu [Department of Biology and North Carolina Center for Biodiversity, East Carolina University, Greenville, NC 27858 (United States); Duff, John H. [U.S. Geological Survey, Menlo Park, CA 94025 (United States); Ramírez, Alonso [Department of Environmental Sciences, University of Puerto Rico, San Juan, PR 00931 (Puerto Rico); Small, Gaston E. [Department of Ecology, Evolution, and Behavior, University of Minnesota, St. Paul, MN 55108 (United States); Jackman, Alan P. [University of California, Davis, CA 95616 (United States); Triska, Frank J. [U.S. Geological Survey, Menlo Park, CA 94025 (United States); Pringle, Catherine M. [Odum School of Ecology, University of Georgia, Athens, GA 30602 (United States)

    2013-01-15

    Research into the buffering mechanisms and ecological consequences of acidification in tropical streams is lacking. We have documented seasonal and episodic acidification events in streams draining La Selva Biological Station, Costa Rica. Across this forested landscape, the severity in seasonal and episodic acidification events varies due to interbasin groundwater flow (IGF). Streams that receive IGF have higher concentrations of solutes and more stable pH (∼ 6) than streams that do not receive IGF (pH ∼ 5). To examine the buffering capacity and vulnerability of macroinvertebrates to short-term acidification events, we added hydrochloric acid to acidify a low-solute, poorly buffered (without IGF) and a high-solute, well buffered stream (with IGF). We hypothesized that: 1) protonation of bicarbonate (HCO{sub 3}{sup −}) would neutralize most of the acid added in the high-solute stream, while base cation release from the sediments would be the most important buffering mechanism in the low-solute stream; 2) pH declines would mobilize inorganic aluminum (Ali) from sediments in both streams; and 3) pH declines would increase macroinvertebrate drift in both streams. We found that the high-solute stream neutralized 745 μeq/L (96% of the acid added), while the solute poor stream only neutralized 27.4 μeq/L (40%). Protonation of HCO{sub 3}{sup −} was an important buffering mechanism in both streams. Base cation, Fe{sup 2+}, and Ali release from sediments and protonation of organic acids also provided buffering in the low-solute stream. We measured low concentrations of Ali release in both streams (2-9 μeq/L) in response to acidification, but the low-solute stream released double the amount Ali per 100 μeq of acid added than the high solute stream. Macroinvertebrate drift increased in both streams in response to acidification and was dominated by Ephemeroptera and Chironomidae. Our results elucidate the different buffering mechanisms in tropical streams and

  12. Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

    Nowak, Jakub Stanislaw; Hobor, Fruzsina; Downie Ruiz Velasco, Angela; Choudhury, Nila Roy; Heikel, Gregory; Kerr, Alastair; Ramos, Andres; Michlewski, Gracjan

    2017-01-01

    Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3’-5’ exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We presen...

  13. C. elegans germline-deficient mutants respond to pathogen infection using shared and distinct mechanisms.

    Michael TeKippe

    2010-07-01

    Full Text Available Reproduction extracts a cost in resources that organisms are then unable to utilize to deal with a multitude of environmental stressors. In the nematode C. elegans, development of the germline shortens the lifespan of the animal and increases its susceptibility to microbial pathogens. Prior studies have demonstrated germline-deficient nematodes to have increased resistance to gram negative bacteria. We show that germline-deficient strains display increased resistance across a broad range of pathogens including gram positive and gram negative bacteria, and the fungal pathogen Cryptococcus neoformans. Furthermore, we show that the FOXO transcription factor DAF-16, which regulates longevity and immunity in C. elegans, appears to be crucial for maintaining longevity in both wild-type and germline-deficient backgrounds. Our studies indicate that germline-deficient mutants glp-1 and glp-4 respond to pathogen infection using common and different mechanisms that involve the activation of DAF-16.

  14. Marburg virus evades interferon responses by a mechanism distinct from ebola virus.

    Charalampos Valmas

    2010-01-01

    Full Text Available Previous studies have demonstrated that Marburg viruses (MARV and Ebola viruses (EBOV inhibit interferon (IFN-alpha/beta signaling but utilize different mechanisms. EBOV inhibits IFN signaling via its VP24 protein which blocks the nuclear accumulation of tyrosine phosphorylated STAT1. In contrast, MARV infection inhibits IFNalpha/beta induced tyrosine phosphorylation of STAT1 and STAT2. MARV infection is now demonstrated to inhibit not only IFNalpha/beta but also IFNgamma-induced STAT phosphorylation and to inhibit the IFNalpha/beta and IFNgamma-induced tyrosine phosphorylation of upstream Janus (Jak family kinases. Surprisingly, the MARV matrix protein VP40, not the MARV VP24 protein, has been identified to antagonize Jak and STAT tyrosine phosphorylation, to inhibit IFNalpha/beta or IFNgamma-induced gene expression and to inhibit the induction of an antiviral state by IFNalpha/beta. Global loss of STAT and Jak tyrosine phosphorylation in response to both IFNalpha/beta and IFNgamma is reminiscent of the phenotype seen in Jak1-null cells. Consistent with this model, MARV infection and MARV VP40 expression also inhibit the Jak1-dependent, IL-6-induced tyrosine phosphorylation of STAT1 and STAT3. Finally, expression of MARV VP40 is able to prevent the tyrosine phosphorylation of Jak1, STAT1, STAT2 or STAT3 which occurs following over-expression of the Jak1 kinase. In contrast, MARV VP40 does not detectably inhibit the tyrosine phosphorylation of STAT2 or Tyk2 when Tyk2 is over-expressed. Mutation of the VP40 late domain, essential for efficient VP40 budding, has no detectable impact on inhibition of IFN signaling. This study shows that MARV inhibits IFN signaling by a mechanism different from that employed by the related EBOV. It identifies a novel function for the MARV VP40 protein and suggests that MARV may globally inhibit Jak1-dependent cytokine signaling.

  15. Disrupting the cortical actin cytoskeleton points to two distinct mechanisms of yeast [PSI+] prion formation

    Speldewinde, Shaun H.; Tuite, Mick F.

    2017-01-01

    Mammalian and fungal prions arise de novo; however, the mechanism is poorly understood in molecular terms. One strong possibility is that oxidative damage to the non-prion form of a protein may be an important trigger influencing the formation of its heritable prion conformation. We have examined the oxidative stress-induced formation of the yeast [PSI+] prion, which is the altered conformation of the Sup35 translation termination factor. We used tandem affinity purification (TAP) and mass spectrometry to identify the proteins which associate with Sup35 in a tsa1 tsa2 antioxidant mutant to address the mechanism by which Sup35 forms the [PSI+] prion during oxidative stress conditions. This analysis identified several components of the cortical actin cytoskeleton including the Abp1 actin nucleation promoting factor, and we show that deletion of the ABP1 gene abrogates oxidant-induced [PSI+] prion formation. The frequency of spontaneous [PSI+] prion formation can be increased by overexpression of Sup35 since the excess Sup35 increases the probability of forming prion seeds. In contrast to oxidant-induced [PSI+] prion formation, overexpression-induced [PSI+] prion formation was only modestly affected in an abp1 mutant. Furthermore, treating yeast cells with latrunculin A to disrupt the formation of actin cables and patches abrogated oxidant-induced, but not overexpression-induced [PSI+] prion formation, suggesting a mechanistic difference in prion formation. [PIN+], the prion form of Rnq1, localizes to the IPOD (insoluble protein deposit) and is thought to influence the aggregation of other proteins. We show Sup35 becomes oxidized and aggregates during oxidative stress conditions, but does not co-localize with Rnq1 in an abp1 mutant which may account for the reduced frequency of [PSI+] prion formation. PMID:28369054

  16. Distinct mechanisms of DNA repair in mycobacteria and their implications in attenuation of the pathogen growth.

    Kurthkoti, Krishna; Varshney, Umesh

    2012-04-01

    About a third of the human population is estimated to be infected with Mycobacterium tuberculosis. Emergence of drug resistant strains and the protracted treatment strategies have compelled the scientific community to identify newer drug targets, and to develop newer vaccines. In the host macrophages, the bacterium survives within an environment rich in reactive nitrogen and oxygen species capable of damaging its genome. Therefore, for its successful persistence in the host, the pathogen must need robust DNA repair mechanisms. Analysis of M. tuberculosis genome sequence revealed that it lacks mismatch repair pathway suggesting a greater role for other DNA repair pathways such as the nucleotide excision repair, and base excision repair pathways. In this article, we summarize the outcome of research involving these two repair pathways in mycobacteria focusing primarily on our own efforts. Our findings, using Mycobacterium smegmatis model, suggest that deficiency of various DNA repair functions in single or in combinations severely compromises their DNA repair capacity and attenuates their growth under conditions typically encountered in macrophages. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  17. Cell adhesion over two distinct surfaces varied with chemical and mechanical properties

    Huang, Chih-Ling; Liao, Jiunn-Der; Yang, Chia-Fen; Chang, Chia-Wei; Ju, Ming-Shaung; Lin, Chou-Ching K.

    2009-01-01

    Chitosan is widely recognized as a natural and proper scaffold material; however, as a base substrate, it shows little promotion effect for the growth of cultured fibroblast cells. In this study, chitosan in a film form was prepared and used as a cell-culturing matrix, followed by patterning the evaporated Au upon it. Micro-scale Au clusters of ∼ 150 μm in diameter and ∼ 20 nm in thickness were then patterned and adhered upon the chitosan matrix. Physical and chemical properties of Au/chitosan were characterized. In particular, nano-indentation with dynamic contact module was applied to measure the nano-hardness of the tailored surfaces on Au/chitosan. Fibroblast cells were thereafter cultured on Au/chitosan. Experimental results demonstrated that as compared with the chitosan matrix, Au clusters and their boundary area exhibited favorable to promote cell adhesion, spreading, and growth. As well, nano-hardness on the boundary area of Au/chitosan significantly enhanced, while the cultured fibroblast cells aggregated upon Au clusters and the boundary area. In combination with the possible chemical and mechanical changes resulted by the evaporation of Au clusters upon the chitosan matrix, a selectively-enhanced Au/chitosan to promote fibroblast cells proliferation was created. Such design is anticipated for enabling a surface for scaffold materials with the cell-guidable function.

  18. Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control

    Daniela Strobbe

    2018-03-01

    Full Text Available The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in PARK7, encoding DJ-1, are associated with early-onset familial Parkinson’s disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein–protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation. We report that the DJ-1M26I mutant influences DJ-1 interactions with SUMO-1, in turn enhancing removal of mitochondria and conferring increased cellular susceptibility to dopamine toxicity. By contrast, the DJ-1D149A mutant does not influence mitophagy, but instead impairs Ca2+ dynamics and free radical homeostasis by disrupting DJ-1 interactions with a mitochondrial accessory protein known as DJ-1-binding protein (DJBP/EFCAB6. Thus, individual DJ-1 mutations have different effects on mitochondrial function and quality control, implying mutation-specific pathomechanisms converging on impaired mitochondrial homeostasis.

  19. AAA-ATPase FIDGETIN-LIKE 1 and Helicase FANCM Antagonize Meiotic Crossovers by Distinct Mechanisms.

    Chloe Girard

    2015-07-01

    Full Text Available Meiotic crossovers (COs generate genetic diversity and are critical for the correct completion of meiosis in most species. Their occurrence is tightly constrained but the mechanisms underlying this limitation remain poorly understood. Here we identified the conserved AAA-ATPase FIDGETIN-LIKE-1 (FIGL1 as a negative regulator of meiotic CO formation. We show that Arabidopsis FIGL1 limits CO formation genome-wide, that FIGL1 controls dynamics of the two conserved recombinases DMC1 and RAD51 and that FIGL1 hinders the interaction between homologous chromosomes, suggesting that FIGL1 counteracts DMC1/RAD51-mediated inter-homologue strand invasion to limit CO formation. Further, depleting both FIGL1 and the previously identified anti-CO helicase FANCM synergistically increases crossover frequency. Additionally, we showed that the effect of mutating FANCM on recombination is much lower in F1 hybrids contrasting from the phenotype of inbred lines, while figl1 mutation equally increases crossovers in both contexts. This shows that the modes of action of FIGL1 and FANCM are differently affected by genomic contexts. We propose that FIGL1 and FANCM represent two successive barriers to CO formation, one limiting strand invasion, the other disassembling D-loops to promote SDSA, which when both lifted, leads to a large increase of crossovers, without impairing meiotic progression.

  20. FTIR characterization ans chemo-mechanical distinction of reted kenaf fibres

    Emannuel Omenna

    2017-12-01

    Full Text Available Inadequate information on the binding characteristics of kenaf biomass at the molecular level has adversely affected the modifications of its cellulose-hemicellulose-lignin structure. This study was undertaken to assess the characteristic features and chemo-mechanical properties of kenaf fibres retted under three different media namely: tank, stream and ribbon. Fourier transform infra-red (FTIR spectra analysis as well as the ASTM standard for tensile tests were applied. The results showed that the broad bands occurred at the range of 3312- 3420 cm−1 for all the retted fibres were due to the presence of hydroxyl (–OH group while the peaks were obtained at 1635.76, 1635.34, and 1730.69 cm−1 for stream, tank and ribbon retted fibres respectively. However, tank retted fibres had the most broad band intensity at 3419.78cm-1 while ribbon fibres had the highest absorption peak of 1730.69cm-1 corresponding to C=O stretching of the acetyl group in hemi-cellulose. Stream retted Kenaf fibres had the highest tensile strength followed by the tank retted fibres while ribbon fibres had the least. Furthermore, there was no significant difference between stream and tank retted Kenaf fibres in terms of tensile modulus and this was significantly higher than that of ribbon fibre. The α-cellulose content of stream retted fibres was slightly higher than that of ribbon fibres while tank retted fibres had the least. From the results, tank retted Kenaf fibre was ranked as ‘the best fibre’ with the most intensive broad bands and least in lignin and hemi-cellulose content which were regarded as the impurities, gummy and waxy materials, responsible for an easy deformation of the fibre cellular networks.

  1. Distinct mechanisms are responsible for osteopenia and growth retardation in OASIS-deficient mice.

    Murakami, Tomohiko; Hino, Shin-Ichiro; Nishimura, Riko; Yoneda, Toshiyuki; Wanaka, Akio; Imaizumi, Kazunori

    2011-03-01

    Old astrocyte specifically induced substance (OASIS), which is a new type of endoplasmic reticulum (ER) stress transducer, is a basic leucine zipper transcription factor of the CREB/ATF family that contains a transmembrane domain and is processed by regulated intramembrane proteolysis in response to ER stress. OASIS is selectively expressed in certain types of cells such as astrocytes and osteoblasts. We have previously demonstrated that OASIS activates transcription of the type I collagen gene Col1a1 and contributes to the secretion of bone matrix proteins in osteoblasts, and that OASIS-/- mice exhibit osteopenia and growth retardation. In the present study, we examined whether osteopenia in OASIS-/- mice is rescued by OASIS introduction into osteoblasts. We generated OASIS-/- mice that specifically expressed OASIS in osteoblasts using a 2.3-kb osteoblast-specific type I collagen promoter (OASIS-/-;Tg mice). Histological analysis of OASIS-/-;Tg mice revealed that osteopenia in OASIS-/- mice was rescued by osteoblast-specific expression of the OASIS transgene. The decreased expression levels of type I collagen mRNAs in the bone tissues of OASIS-/- mice were recovered by the OASIS transgene accompanied by the rescue of an abnormal expansion of the rough ER in OASIS-/- osteoblasts. In contrast, growth retardation in OASIS-/- mice did not improve in OASIS-/-;Tg mice. Interestingly, the serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-1 were downregulated in OASIS-/- mice compared with those in wild-type mice. These decreased GH and IGF-1 levels in OASIS-/- mice did not change when OASIS was introduced into osteoblasts. Taken together, these results indicate that OASIS regulates skeletal development by osteoblast-dependent and -independent mechanisms. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms

    Borbulevych, Oleg Y.; Santhanagopolan, Sujatha M.; Hossain, Moushumi; Baker, Brian M. (Notre)

    2013-09-18

    T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART-1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross-reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity.

  3. Suppressive versus augmenting effect of the same pretreatment regimen in two murine tumor systems with distinct effector mechanisms

    Fujiwara, Hiromi; Hamaoka, Toshiyuki; Kitagawa, Masayasu

    1978-01-01

    The effect of presensitization with x-irradiated tumor cells on the development of host's immune resistance against the tumor-associated transplantation antigens (TATA) was investigated in two syngeneic tumor systems with distinct effector mechanisms. When X5563 plasmacytoma, to which immune resistance was mediated exclusively by killer T lymphocytes, was intravenously inoculated into syngeneic C3H/He mice with lower number after 7000 R x-irradiation, the mice failed to exhibit any protective immunity against the subsequent challenge with viable tumor cells. Moreover, these mice lost their capability to develop any immune resistance even after an appropriate immunization procedure. The immunodepression induced by such a pretreatment regimen was specific for X5563 tumor. While no suppressor cell activity was detected in the above pretreated mice, serum factor(s) from these mice was virtually responsible for this suppression. When the serum factor mediating this tumor-specific suppression was fractionated on the Sephadex G-200 column, the suppressive activity was found in albumin-corresponding fraction, free of any immunoglobulin component. In contrast, in MM102 mammary tumor system, in which immune resistance is solely mediated by tumor-specific antibody, the pretreatment with x-irradiated MM102 cells augmented the induction of anti-tumor immunity. These results indicate that while tumor antigens given in the form of x-irradiated tumor cells suppress the induction of killer T cell-mediated immunity in one system, the same presensitization regimen of tumor antigens augments the antibody-mediated immunity in another system, thus giving a divergent effect on the distinct effector mechanisms of syngeneic tumor immunity. (author)

  4. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.

    Matsushita, Masaki; Hasegawa, Satoru; Kitoh, Hiroshi; Mori, Kensaku; Ohkawara, Bisei; Yasoda, Akihiro; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2015-02-01

    Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH.

  5. Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants.

    Kagawa, Reiko; Fujiki, Ryoji; Tsumura, Miyuki; Sakata, Sonoko; Nishimura, Shiho; Itan, Yuval; Kong, Xiao-Fei; Kato, Zenichiro; Ohnishi, Hidenori; Hirata, Osamu; Saito, Satoshi; Ikeda, Maiko; El Baghdadi, Jamila; Bousfiha, Aziz; Fujiwara, Kaori; Oleastro, Matias; Yancoski, Judith; Perez, Laura; Danielian, Silvia; Ailal, Fatima; Takada, Hidetoshi; Hara, Toshiro; Puel, Anne; Boisson-Dupuis, Stéphanie; Bustamante, Jacinta; Casanova, Jean-Laurent; Ohara, Osamu; Okada, Satoshi; Kobayashi, Masao

    2017-07-01

    Germline heterozygous mutations in human signal transducer and activator of transcription 1 (STAT1) can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases, or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis. LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil domain (CCD) and DNA-binding domain (DBD). Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants. We estimated variations in the CCD/DBD of STAT1. We mutagenized 342 individual wild-type amino acids in the CCD/DBD (45.6% of full-length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity. Of these 342 mutants, 201 were neutral, 30 were LOF, and 111 were GOF mutations in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in the CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the effect of 2 hypomorphic and dominant negative mutations, E157K and G250E, in the CCD of STAT1 that we found in 2 unrelated patients with Mendelian susceptibility to mycobacterial diseases. The systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  6. Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms.

    Carlin, Jesse Lea; Jain, Shalini; Gizewski, Elizabeth; Wan, Tina C; Tosh, Dilip K; Xiao, Cuiying; Auchampach, John A; Jacobson, Kenneth A; Gavrilova, Oksana; Reitman, Marc L

    2017-03-01

    Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1 -/- , Adora3 -/- ) mice. Confirming prior data, stimulation of the A 3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H 1 receptors. In contrast, A 1 AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A 1 AR agonists, including N 6 -cyclopentyladenosine (CPA), N 6 -cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A 1 AR and A 3 AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N 6 -endo-norbornyladenosine], or using Adora3 -/- mice allowed selective stimulation of A 1 AR. AMP-stimulated hypothermia can occur independently of A 1 AR, A 3 AR, and mast cells. A 1 AR and A 3 AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A 1 AR nor A 3 AR was required for fasting-induced torpor. A 1 AR and A 3 AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms. Published by Elsevier Ltd.

  7. Laboratory and 3-D distinct element analysis of the failure mechanism of a slope under external surcharge

    Li, N.; Cheng, Y. M.

    2015-01-01

    Landslide is a major disaster resulting in considerable loss of human lives and property damages in hilly terrain in Hong Kong, China and many other countries. The factor of safety and the critical slip surface for slope stabilization are the main considerations for slope stability analysis in the past, while the detailed post-failure conditions of the slopes have not been considered in sufficient detail. There is however increasing interest in the consequences after the initiation of failure that includes the development and propagation of the failure surfaces, the amount of failed mass and runoff and the affected region. To assess the development of slope failure in more detail and to consider the potential danger of slopes after failure has initiated, the slope stability problem under external surcharge is analyzed by the distinct element method (DEM) and a laboratory model test in the present research. A more refined study about the development of failure, microcosmic failure mechanisms and the post-failure mechanisms of slopes will be carried out. The numerical modeling method and the various findings from the present work can provide an alternate method of analysis of slope failure, which can give additional information not available from the classical methods of analysis.

  8. Vaccine and Wild-Type Strains of Yellow Fever Virus Engage Distinct Entry Mechanisms and Differentially Stimulate Antiviral Immune Responses.

    Fernandez-Garcia, Maria Dolores; Meertens, Laurent; Chazal, Maxime; Hafirassou, Mohamed Lamine; Dejarnac, Ophélie; Zamborlini, Alessia; Despres, Philippe; Sauvonnet, Nathalie; Arenzana-Seisdedos, Fernando; Jouvenet, Nolwenn; Amara, Ali

    2016-02-09

    The live attenuated yellow fever virus (YFV) vaccine 17D stands as a "gold standard" for a successful vaccine. 17D was developed empirically by passaging the wild-type Asibi strain in mouse and chicken embryo tissues. Despite its immense success, the molecular determinants for virulence attenuation and immunogenicity of the 17D vaccine are poorly understood. 17D evolved several mutations in its genome, most of which lie within the envelope (E) protein. Given the major role played by the YFV E protein during virus entry, it has been hypothesized that the residues that diverge between the Asibi and 17D E proteins may be key determinants of attenuation. In this study, we define the process of YFV entry into target cells and investigate its implication in the activation of the antiviral cytokine response. We found that Asibi infects host cells exclusively via the classical clathrin-mediated endocytosis, while 17D exploits a clathrin-independent pathway for infectious entry. We demonstrate that the mutations in the 17D E protein acquired during the attenuation process are sufficient to explain the differential entry of Asibi versus 17D. Interestingly, we show that 17D binds to and infects host cells more efficiently than Asibi, which culminates in increased delivery of viral RNA into the cytosol and robust activation of the cytokine-mediated antiviral response. Overall, our study reveals that 17D vaccine and Asibi enter target cells through distinct mechanisms and highlights a link between 17D attenuation, virus entry, and immune activation. The yellow fever virus (YFV) vaccine 17D is one of the safest and most effective live virus vaccines ever developed. The molecular determinants for virulence attenuation and immunogenicity of 17D are poorly understood. 17D was generated by serially passaging the virulent Asibi strain in vertebrate tissues. Here we examined the entry mechanisms engaged by YFV Asibi and the 17D vaccine. We found the two viruses use different entry

  9. TLR2-dependent inhibition of macrophage responses to IFN-gamma is mediated by distinct, gene-specific mechanisms.

    Sarah A Benson

    2009-07-01

    Full Text Available Mycobacterium tuberculosis uses multiple mechanisms to avoid elimination by the immune system. We have previously shown that M. tuberculosis can inhibit selected macrophage responses to IFN-gamma through TLR2-dependent and -independent mechanisms. To specifically address the role of TLR2 signaling in mediating this inhibition, we stimulated macrophages with the specific TLR2/1 ligand Pam(3CSK(4 and assayed responses to IFN-gamma. Pam(3CSK(4 stimulation prior to IFN-gamma inhibited transcription of the unrelated IFN-gamma-inducible genes, CIITA and CXCL11. Surface expression of MHC class II and secretion of CXCL11 were greatly reduced as well, indicating that the reduction in transcripts had downstream effects. Inhibition of both genes required new protein synthesis. Using chromatin immunoprecipitation, we found that TLR2 stimulation inhibited IFN-gamma-induced RNA polymerase II binding to the CIITA and CXCL11 promoters. Furthermore, TATA binding protein was unable to bind the TATA box of the CXCL11 promoter, suggesting that assembly of transcriptional machinery was disrupted. However, TLR2 stimulation affected chromatin modifications differently at each of the inhibited promoters. Histone H3 and H4 acetylation was reduced at the CIITA promoter but unaffected at the CXCL11 promoter. In addition, NF-kappaB signaling was required for inhibition of CXCL11 transcription, but not for inhibition of CIITA. Taken together, these results indicate that TLR2-dependent inhibition of IFN-gamma-induced gene expression is mediated by distinct, gene-specific mechanisms that disrupt binding of the transcriptional machinery to the promoters.

  10. Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

    Juan Liu

    2016-04-01

    Full Text Available Although dasatinib is effective in most imatinib mesylate (IMT-resistant chronic myeloid leukemia (CML patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562RIMT. Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt/ mammalian target of rapamycin (mTOR signaling and autophagic activity were increased significantly in K562RIMT cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN was responsible for the increased Akt/mTOR activities in K562RIMT cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562RIMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562RIMT cells. In summary, in K562RIMT cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells.

  11. Gain-of-function R225W mutation in human AMPKgamma(3 causing increased glycogen and decreased triglyceride in skeletal muscle.

    Sheila R Costford

    Full Text Available BACKGROUND: AMP-activated protein kinase (AMPK is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3 subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations. Here we report the first gain-of-function mutation in the muscle-specific regulatory gamma(3 subunit in humans. METHODS AND FINDINGS: We sequenced the exons and splice junctions of the AMPK gamma(3 gene (PRKAG3 in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The gamma(3 R225W mutation is homologous in location to the gamma(2R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the gamma(3R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN- pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a approximately 90% increase of skeletal muscle glycogen content and a approximately 30% decrease in intramuscular triglyceride (IMTG. CONCLUSIONS: We have identified for the first time a mutation in the skeletal muscle-specific regulatory gamma(3 subunit of AMPK in humans. The gamma(3R225W mutation has significant functional effects as demonstrated by increases in basal and AMP

  12. Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations.

    Galán-Díez, Marta; Isa, Adiba; Ponzetti, Marco; Nielsen, Morten Frost; Kassem, Moustapha; Kousteni, Stavroula

    2016-03-01

    Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of β-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of β-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require β-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of β-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate β-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. Published

  13. A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8.

    Bouhy, Delphine; Juneja, Manisha; Katona, Istvan; Holmgren, Anne; Asselbergh, Bob; De Winter, Vicky; Hochepied, Tino; Goossens, Steven; Haigh, Jody J; Libert, Claude; Ceuterick-de Groote, Chantal; Irobi, Joy; Weis, Joachim; Timmerman, Vincent

    2018-01-01

    Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces

  14. Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines

    Rodríguez, Teresa; Méndez, Rosa; Del Campo, Ana; Jiménez, Pilar; Aptsiauri, Natalia; Garrido, Federico; Ruiz-Cabello, Francisco

    2007-01-01

    The inability of cancer cells to present antigen on the cell surface via MHC class I molecules is one of the mechanisms by which tumor cells evade anti-tumor immunity. Alterations of Jak-STAT components of interferon (IFN)-mediated signaling can contribute to the mechanism of cell resistance to IFN, leading to lack of MHC class I inducibility. Hence, the identification of IFN-γ-resistant tumors may have prognostic and/or therapeutic relevance. In the present study, we investigated a mechanism of MHC class I inducibility in response to IFN-γ treatment in human melanoma cell lines. Basal and IFN-induced expression of HLA class I antigens was analyzed by means of indirect immunofluorescence flow cytometry, Western Blot, RT-PCR, and quantitative real-time RT-PCR (TaqMan ® Gene Expression Assays). In demethylation studies cells were cultured with 5-aza-2'-deoxycytidine. Electrophoretic Mobility Shift Assay (EMSA) was used to assay whether IRF-1 promoter binding activity is induced in IFN-γ-treated cells. Altered IFN-γ mediated HLA-class I induction was observed in two melanoma cells lines (ESTDAB-004 and ESTDAB-159) out of 57 studied, while treatment of these two cell lines with IFN-α led to normal induction of HLA class I antigen expression. Examination of STAT-1 in ESTDAB-004 after IFN-γ treatment demonstrated that the STAT-1 protein was expressed but not phosphorylated. Interestingly, IFN-α treatment induced normal STAT-1 phosphorylation and HLA class I expression. In contrast, the absence of response to IFN-γ in ESTDAB-159 was found to be associated with alterations in downstream components of the IFN-γ signaling pathway. We observed two distinct mechanisms of loss of IFN-γ inducibility of HLA class I antigens in two melanoma cell lines. Our findings suggest that loss of HLA class I induction in ESTDAB-004 cells results from a defect in the earliest steps of the IFN-γ signaling pathway due to absence of STAT-1 tyrosine-phosphorylation, while absence

  15. Radial frequency stimuli and sine-wave gratings seem to be processed by distinct contrast brain mechanisms

    M.L.B. Simas

    2005-03-01

    Full Text Available An assumption commonly made in the study of visual perception is that the lower the contrast threshold for a given stimulus, the more sensitive and selective will be the mechanism that processes it. On the basis of this consideration, we investigated contrast thresholds for two classes of stimuli: sine-wave gratings and radial frequency stimuli (i.e., j0 targets or stimuli modulated by spherical Bessel functions. Employing a suprathreshold summation method, we measured the selectivity of spatial and radial frequency filters using either sine-wave gratings or j0 target contrast profiles at either 1 or 4 cycles per degree of visual angle (cpd, as the test frequencies. Thus, in a forced-choice trial, observers chose between a background spatial (or radial frequency alone and the given background stimulus plus the test frequency (1 or 4 cpd sine-wave grating or radial frequency. Contrary to our expectations, the results showed elevated thresholds (i.e., inhibition for sine-wave gratings and decreased thresholds (i.e., summation for radial frequencies when background and test frequencies were identical. This was true for both 1- and 4-cpd test frequencies. This finding suggests that sine-wave gratings and radial frequency stimuli are processed by different quasi-linear systems, one working at low luminance and contrast level (sine-wave gratings and the other at high luminance and contrast levels (radial frequency stimuli. We think that this interpretation is consistent with distinct foveal only and foveal-parafoveal mechanisms involving striate and/or other higher visual areas (i.e., V2 and V4.

  16. Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins

    Takeru Hayashi

    2017-09-01

    Full Text Available Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory “relaxed” and inhibitory “squeezed” states, which is fixed upon high-affinity CagA binding to the “relaxed” state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.

  17. Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively.

    Nowak, Jakub Stanislaw; Hobor, Fruzsina; Downie Ruiz Velasco, Angela; Choudhury, Nila Roy; Heikel, Gregory; Kerr, Alastair; Ramos, Andres; Michlewski, Gracjan

    2017-03-01

    Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3'-5' exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We present evidence that Dis3l2 controls miRNA-9 production. Finally, we show that the constitutive expression of untagged Lin28a during neuronal differentiation in vitro positively and negatively affects numerous other miRNAs. Our findings shed light on the role of Lin28a in differentiating cells and on the ways in which one RNA-binding protein can perform multiple roles in the regulation of RNA processing. © 2017 Nowak et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  18. Staying green postharvest: how three mutations in the Arabidopsis chlorophyll b reductase gene NYC1 delay degreening by distinct mechanisms.

    Jibran, Rubina; Sullivan, Kerry L; Crowhurst, Ross; Erridge, Zoe A; Chagné, David; McLachlan, Andrew R G; Brummell, David A; Dijkwel, Paul P; Hunter, Donald A

    2015-11-01

    Stresses such as energy deprivation, wounding and water-supply disruption often contribute to rapid deterioration of harvested tissues. To uncover the genetic regulation behind such stresses, a simple assessment system was used to detect senescence mutants in conjunction with two rapid mapping techniques to identify the causal mutations. To demonstrate the power of this approach, immature inflorescences of Arabidopsis plants that contained ethyl methanesulfonate-induced lesions were detached and screened for altered timing of dark-induced senescence. Numerous mutant lines displaying accelerated or delayed timing of senescence relative to wild type were discovered. The underlying mutations in three of these were identified using High Resolution Melting analysis to map to a chromosomal arm followed by a whole-genome sequencing-based mapping method, termed 'Needle in the K-Stack', to identify the causal lesions. All three mutations were single base pair changes and occurred in the same gene, NON-YELLOW COLORING1 (NYC1), a chlorophyll b reductase of the short-chain dehydrogenase/reductase (SDR) superfamily. This was consistent with the mutants preferentially retaining chlorophyll b, although substantial amounts of chlorophyll b were still lost. The single base pair mutations disrupted NYC1 function by three distinct mechanisms, one by producing a termination codon, the second by interfering with correct intron splicing and the third by replacing a highly conserved proline with a non-equivalent serine residue. This non-synonymous amino acid change, which occurred in the NADPH binding domain of NYC1, is the first example of such a mutation in an SDR protein inhibiting a physiological response in plants. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Vaccine and Wild-Type Strains of Yellow Fever Virus Engage Distinct Entry Mechanisms and Differentially Stimulate Antiviral Immune Responses

    Maria Dolores Fernandez-Garcia

    2016-02-01

    Full Text Available The live attenuated yellow fever virus (YFV vaccine 17D stands as a “gold standard” for a successful vaccine. 17D was developed empirically by passaging the wild-type Asibi strain in mouse and chicken embryo tissues. Despite its immense success, the molecular determinants for virulence attenuation and immunogenicity of the 17D vaccine are poorly understood. 17D evolved several mutations in its genome, most of which lie within the envelope (E protein. Given the major role played by the YFV E protein during virus entry, it has been hypothesized that the residues that diverge between the Asibi and 17D E proteins may be key determinants of attenuation. In this study, we define the process of YFV entry into target cells and investigate its implication in the activation of the antiviral cytokine response. We found that Asibi infects host cells exclusively via the classical clathrin-mediated endocytosis, while 17D exploits a clathrin-independent pathway for infectious entry. We demonstrate that the mutations in the 17D E protein acquired during the attenuation process are sufficient to explain the differential entry of Asibi versus 17D. Interestingly, we show that 17D binds to and infects host cells more efficiently than Asibi, which culminates in increased delivery of viral RNA into the cytosol and robust activation of the cytokine-mediated antiviral response. Overall, our study reveals that 17D vaccine and Asibi enter target cells through distinct mechanisms and highlights a link between 17D attenuation, virus entry, and immune activation.

  20. Characterization of Trichome-Expressed BAHD Acyltransferases in Petunia axillaris Reveals Distinct Acylsugar Assembly Mechanisms within the Solanaceae1[OPEN

    Uebler, Joseph B.; Liu, Xiaoxiao

    2017-01-01

    Acylsugars are synthesized in the glandular trichomes of the Solanaceae family and are implicated in protection against abiotic and biotic stress. Acylsugars are composed of either sucrose or glucose esterified with varying numbers of acyl chains of differing length. In tomato (Solanum lycopersicum), acylsugar assembly requires four acylsugar acyltransferases (ASATs) of the BAHD superfamily. Tomato ASATs catalyze the sequential esterification of acyl-coenzyme A thioesters to the R4, R3, R3ʹ, and R2 positions of sucrose, yielding a tetra-acylsucrose. Petunia spp. synthesize acylsugars that are structurally distinct from those of tomato. To explore the mechanisms underlying this chemical diversity, a Petunia axillaris transcriptome was mined for trichome preferentially expressed BAHDs. A combination of phylogenetic analyses, gene silencing, and biochemical analyses coupled with structural elucidation of metabolites revealed that acylsugar assembly is not conserved between tomato and petunia. In P. axillaris, tetra-acylsucrose assembly occurs through the action of four ASATs, which catalyze sequential addition of acyl groups to the R2, R4, R3, and R6 positions. Notably, in P. axillaris, PaxASAT1 and PaxASAT4 catalyze the acylation of the R2 and R6 positions of sucrose, respectively, and no clear orthologs exist in tomato. Similarly, petunia acylsugars lack an acyl group at the R3ʹ position, and congruently, an ortholog of SlASAT3, which catalyzes acylation at the R3ʹ position in tomato, is absent in P. axillaris. Furthermore, where putative orthologous relationships of ASATs are predicted between tomato and petunia, these are not supported by biochemical assays. Overall, these data demonstrate the considerable evolutionary plasticity of acylsugar biosynthesis. PMID:28701351

  1. Characterization of Trichome-Expressed BAHD Acyltransferases in Petunia axillaris Reveals Distinct Acylsugar Assembly Mechanisms within the Solanaceae.

    Nadakuduti, Satya Swathi; Uebler, Joseph B; Liu, Xiaoxiao; Jones, A Daniel; Barry, Cornelius S

    2017-09-01

    Acylsugars are synthesized in the glandular trichomes of the Solanaceae family and are implicated in protection against abiotic and biotic stress. Acylsugars are composed of either sucrose or glucose esterified with varying numbers of acyl chains of differing length. In tomato ( Solanum lycopersicum ), acylsugar assembly requires four acylsugar acyltransferases (ASATs) of the BAHD superfamily. Tomato ASATs catalyze the sequential esterification of acyl-coenzyme A thioesters to the R4, R3, R3', and R2 positions of sucrose, yielding a tetra-acylsucrose. Petunia spp. synthesize acylsugars that are structurally distinct from those of tomato. To explore the mechanisms underlying this chemical diversity, a Petunia axillaris transcriptome was mined for trichome preferentially expressed BAHDs. A combination of phylogenetic analyses, gene silencing, and biochemical analyses coupled with structural elucidation of metabolites revealed that acylsugar assembly is not conserved between tomato and petunia. In P. axillaris , tetra-acylsucrose assembly occurs through the action of four ASATs, which catalyze sequential addition of acyl groups to the R2, R4, R3, and R6 positions. Notably, in P. axillaris , PaxASAT1 and PaxASAT4 catalyze the acylation of the R2 and R6 positions of sucrose, respectively, and no clear orthologs exist in tomato. Similarly, petunia acylsugars lack an acyl group at the R3' position, and congruently, an ortholog of SlASAT3, which catalyzes acylation at the R3' position in tomato, is absent in P. axillaris Furthermore, where putative orthologous relationships of ASATs are predicted between tomato and petunia, these are not supported by biochemical assays. Overall, these data demonstrate the considerable evolutionary plasticity of acylsugar biosynthesis. © 2017 American Society of Plant Biologists. All Rights Reserved.

  2. Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice

    Deng, Wei; Mayford, Mark; Gage, Fred H

    2013-01-01

    eLife digest Being able to keep memories of similar events separate in your mind is an essential part of remembering. If you use the same carpark every day, recalling where you left your car this morning is challenging, not because you have to remember an event from long ago, but because you have to distinguish between many similar memories. Keeping memories distinct is one of the functions of a subregion of the hippocampus called the dentate gyrus. The process of taking complex memories and ...

  3. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

    Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

    2007-12-01

    Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At 50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

  4. Arbuscular mycorrhizal fungi reveal distinct patterns of anastomosis formation and hyphal healing mechanisms between different phylogenic groups

    De Souza, F.A.; Fernández, F.; Delmas, N.S.; Declerck, S.

    2005-01-01

    The significance of anastomosis formation and the hyphal healing mechanism (HHM) for functionality and integrity of the arbuscular mycorrhizal (AM) fungal mycelial network remains poorly documented. Four Glomeraceae and three Gigasporaceae were cultured monoxenically. Anastomosis formation was

  5. Azadirachtin(A) distinctively modulates subdomain 2 of actin - novel mechanism to induce depolymerization revealed by molecular dynamics study.

    Pravin Kumar, R; Roopa, L; Sudheer Mohammed, M M; Kulkarni, Naveen

    2016-12-01

    Azadirachtin(A) (AZA), a potential insecticide from neem, binds to actin and induces depolymerization in Drosophila. AZA binds to the pocket same as that of Latrunculin A (LAT), but LAT inhibits actin polymerization by stiffening the actin structure and affects the ADP-ATP exchange. The mechanism by which AZA induces actin depolymerization is not clearly understood. Therefore, different computational experiments were conducted to delineate the precise mechanism of AZA-induced actin depolymerization. Molecular dynamics studies showed that AZA strongly interacted with subdomain 2 and destabilized the interactions between subdomain 2 of one actin and subdomains 1 and 4 of the adjacent actin, causing the separation of actin subunits. The separation was observed between subdomain 3 of subunit n and subdomain 4 of subunit n + 2. However, the specific triggering point for the separation of the subunits was the destabilization of direct interactions between subdomain 2 of subunit n (Arg39, Val45, Gly46 and Arg62) and subdomain 4 of subunit n + 2 (Asp286, Ile287, Asp288, Ile289, Asp244 and Lys291). These results reveal a unique mechanism of an actin filament modulator that induces depolymerization. This mechanism of AZA can be used to design similar molecules against mammalian actins for cancer therapy.

  6. Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making.

    Clarke, Hannah F; Horst, Nicole K; Roberts, Angela C

    2015-03-31

    Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety and mood disorders, but the specific contributions of each region are unknown, including how they gate the impact of threat on decision making. To address this, the effects of GABAergic inactivation of these regions were studied in marmoset monkeys performing an instrumental approach-avoidance decision-making task that is sensitive to changes in anxiety. Inactivation of either region induced a negative bias away from punishment that could be ameliorated with anxiolytic treatment. However, whereas the effects of ventrolateral prefrontal cortex inactivation on punishment avoidance were seen immediately, those of orbitofrontal cortex inactivation were delayed and their expression was dependent upon an amygdala-anterior hippocampal circuit. We propose that these negative biases result from deficits in attentional control and punishment prediction, respectively, and that they provide the basis for understanding how distinct regional prefrontal dysregulation contributes to the heterogeneity of anxiety disorders with implications for cognitive-behavioral treatment strategies.

  7. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

    Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.; Cruchaga, Carlos; Colonna, Marco; Holtzman, Michael J.; Brett, Thomas J. (WU-MED)

    2016-12-20

    Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.

  8. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity?

    Fantegrossi, William E.; Moran, Jeffery H.; Radominska-Pandya, Anna; Prather, Paul L.

    2013-01-01

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a “safe” and “legal” alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed “advantages” have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. PMID:24084047

  9. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

    Fantegrossi, William E; Moran, Jeffery H; Radominska-Pandya, Anna; Prather, Paul L

    2014-02-27

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. © 2013.

  10. Modeling PCN-61 and PCN-66: Isostructural rht -Metal–Organic Frameworks with Distinct CO 2 Sorption Mechanisms

    Pham, Tony; Forrest, Katherine A.; McDonald, Kyle; Space, Brian

    2014-01-01

    © 2014 American Chemical Society. Simulations of CO2 sorption were performed in two members of the highly tunable rht-metal-organic framework (MOF) platform: PCN-61 and PCN-66. These MOFs differ only in the triisophthalate ligand used to synthesize the respective MOFs. In PCN-61, the center of the ligand contains a benzene ring; this ring is substituted with a triphenylamine group in PCN-66. There are two chemically distinct Cu2+ ions that comprise the copper paddlewheels, [Cu2(O2CR)4], in all rht-MOFs. One type of Cu2+ ion, denoted Cu1, projects into the truncated tetrahedral (T-Td) and truncated octahedral (T-Oh) cages, while the other Cu2+ ion, denoted Cu2, projects into the cuboctahedral (cub-Oh) cages. Electronic structure calculations revealed that, in PCN-61, the Cu2 ions have a significantly higher partial positive charge than the Cu1 ions, whereas the opposite was observed in PCN-66. The simulations revealed that the CO2 molecules sorb initially onto the Cu2+ ions that have the higher partial positive charge, i.e., the Cu2 ions in PCN-61 and the Cu1 ions in PCN-66. This was demonstrated by examining the radial distribution function, g(r), about both Cu2+ ions and the modeled structure at low loading for both MOFs. This study provided insights into how differences in the charge distributions about the copper paddlewheels between two isostructural MOFs, arising from the choice of functionality on the ligand, can lead to different CO2 binding sites at low loading and suggests a more general conceptual framework for controlling sorption through the tuning of MOF electronics.

  11. Modeling PCN-61 and PCN-66: Isostructural rht -Metal–Organic Frameworks with Distinct CO 2 Sorption Mechanisms

    Pham, Tony

    2014-11-05

    © 2014 American Chemical Society. Simulations of CO2 sorption were performed in two members of the highly tunable rht-metal-organic framework (MOF) platform: PCN-61 and PCN-66. These MOFs differ only in the triisophthalate ligand used to synthesize the respective MOFs. In PCN-61, the center of the ligand contains a benzene ring; this ring is substituted with a triphenylamine group in PCN-66. There are two chemically distinct Cu2+ ions that comprise the copper paddlewheels, [Cu2(O2CR)4], in all rht-MOFs. One type of Cu2+ ion, denoted Cu1, projects into the truncated tetrahedral (T-Td) and truncated octahedral (T-Oh) cages, while the other Cu2+ ion, denoted Cu2, projects into the cuboctahedral (cub-Oh) cages. Electronic structure calculations revealed that, in PCN-61, the Cu2 ions have a significantly higher partial positive charge than the Cu1 ions, whereas the opposite was observed in PCN-66. The simulations revealed that the CO2 molecules sorb initially onto the Cu2+ ions that have the higher partial positive charge, i.e., the Cu2 ions in PCN-61 and the Cu1 ions in PCN-66. This was demonstrated by examining the radial distribution function, g(r), about both Cu2+ ions and the modeled structure at low loading for both MOFs. This study provided insights into how differences in the charge distributions about the copper paddlewheels between two isostructural MOFs, arising from the choice of functionality on the ligand, can lead to different CO2 binding sites at low loading and suggests a more general conceptual framework for controlling sorption through the tuning of MOF electronics.

  12. Two Silene vulgaris copper transporters residing in different cellular compartments confer copper hypertolerance by distinct mechanisms when expressed in Arabidopsis thaliana.

    Li, Yanbang; Iqbal, Mazhar; Zhang, Qianqian; Spelt, Cornelis; Bliek, Mattijs; Hakvoort, Henk W J; Quattrocchio, Francesca M; Koes, Ronald; Schat, Henk

    2017-08-01

    Silene vulgaris is a metallophyte of calamine, cupriferous and serpentine soils all over Europe. Its metallicolous populations are hypertolerant to zinc (Zn), cadmium (Cd), copper (Cu) or nickel (Ni), compared with conspecific nonmetallicolous populations. These hypertolerances are metal-specific, but the underlying mechanisms are poorly understood. We investigated the role of HMA5 copper transporters in Cu-hypertolerance of a S. vulgaris copper mine population. Cu-hypertolerance in Silene is correlated and genetically linked with enhanced expression of two HMA5 paralogs, SvHMA5I and SvHMA5II, each of which increases Cu tolerance when expressed in Arabidopsis thaliana. Most Spermatophytes, except Brassicaceae, possess homologs of SvHMA5I and SvHMA5II, which originate from an ancient duplication predating the appearance of spermatophytes. SvHMA5II and the A. thaliana homolog AtHMA5 localize in the endoplasmic reticulum and upon Cu exposure move to the plasma membrane, from where they are internalized and degraded in the vacuole. This resembles trafficking of mammalian homologs and is apparently an extremely ancient mechanism. SvHMA5I, instead, neofunctionalized and always resides on the tonoplast, likely sequestering Cu in the vacuole. Adaption of Silene to a Cu-polluted soil is at least in part due to upregulation of two distinct HMA5 transporters, which contribute to Cu hypertolerance by distinct mechanisms. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  13. Distinct toxicological characteristics and mechanisms of Hg2+ and MeHg in Tetrahymena under low concentration exposure.

    Liu, Cheng-Bin; Qu, Guang-Bo; Cao, Meng-Xi; Liang, Yong; Hu, Li-Gang; Shi, Jian-Bo; Cai, Yong; Jiang, Gui-Bin

    2017-12-01

    Inorganic divalent mercury complexes (Hg 2+ ) and monomethylmercury complexes (MeHg) are the main mercury species in aquatic systems and their toxicity to aquatic organisms is of great concern. Tetrahymena is a type of unicellular eukaryotic protozoa located at the bottom of food chain that plays a fundamental role in the biomagnification of mercury. In this work, the dynamic accumulation properties, toxicological characteristics and mechanisms of Hg 2+ and MeHg in five Tetrahymena species were evaluated in detail. The results showed that both Hg 2+ and MeHg were ingested and exhibited inhibitory effects on the proliferation or survival of Tetrahymena species. However, the ingestion rate of MeHg was significantly higher than that of Hg 2+ . The mechanisms responsible for the toxicity of MeHg and Hg 2+ were different, although both chemicals altered mitochondrial membrane potential (MMP). MeHg disrupted the integrity of membranes while Hg 2+ had detrimental effects on Tetrahymena as a result of the increased generation of reactive oxygen species (ROS). In addition, the five Tetrahymena species showed different capacities in accumulating Hg 2+ and MeHg, with T. corlissi exhibiting the highest accumulations. The study also found significant growth-promoting effect on T. corlissi under low concentration exposure (0.003 and 0.01μg Hg/mL (15 and 50nM)), suggesting different effect and mechanism that should be more closely examined when assessing the bioaccumulation and toxicity of mercury in aquatic ecosystems. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion.

    John J Worthington

    2013-01-01

    Full Text Available Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor α receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFα during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection.

  15. Binding of the cSH3 domain of Grb2 adaptor to two distinct RXXK motifs within Gab1 docker employs differential mechanisms.

    McDonald, Caleb B; Seldeen, Kenneth L; Deegan, Brian J; Bhat, Vikas; Farooq, Amjad

    2011-01-01

    A ubiquitous component of cellular signaling machinery, Gab1 docker plays a pivotal role in routing extracellular information in the form of growth factors and cytokines to downstream targets such as transcription factors within the nucleus. Here, using isothermal titration calorimetry (ITC) in combination with macromolecular modeling (MM), we show that although Gab1 contains four distinct RXXK motifs, designated G1, G2, G3, and G4, only G1 and G2 motifs bind to the cSH3 domain of Grb2 adaptor and do so with distinct mechanisms. Thus, while the G1 motif strictly requires the PPRPPKP consensus sequence for high-affinity binding to the cSH3 domain, the G2 motif displays preference for the PXVXRXLKPXR consensus. Such sequential differences in the binding of G1 and G2 motifs arise from their ability to adopt distinct polyproline type II (PPII)- and 3(10) -helical conformations upon binding to the cSH3 domain, respectively. Collectively, our study provides detailed biophysical insights into a key protein-protein interaction involved in a diverse array of signaling cascades central to health and disease. Copyright © 2010 John Wiley & Sons, Ltd.

  16. Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes

    Gual, Philippe; Gonzalez, Teresa; Grémeaux, Thierry

    2003-01-01

    . Furthermore, the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the osmotic shock-induced phosphorylation of IRS-1 on Ser307. The inhibition of mTOR completely reversed the inhibitory effect of hyperosmotic stress on insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase activation......In 3T3-L1 adipocytes, hyperosmotic stress was found to inhibit insulin signaling, leading to an insulin-resistant state. We show here that, despite normal activation of insulin receptor, hyperosmotic stress inhibits both tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1....... In addition, prolonged osmotic stress enhanced the degradation of IRS proteins through a rapamycin-insensitive pathway and a proteasome-independent process. These data support evidence of new mechanisms involved in osmotic stress-induced cellular insulin resistance. Short-term osmotic stress induces...

  17. The 11S Proteasomal Activator REGγ Impacts Polyglutamine-Expanded Androgen Receptor Aggregation and Motor Neuron Viability through Distinct Mechanisms

    Jill M. Yersak

    2017-05-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is caused by expression of a polyglutamine (polyQ-expanded androgen receptor (AR. The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28γ (also referred to as REGγ is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28α, PA28β counterparts. To clarify the role of REGγ in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA. Overexpression of REGγ in a PC12 cell model of SBMA increased polyQ-expanded AR aggregation and contributed to polyQ-expanded AR toxicity in the presence of dihydrotestosterone (DHT. These effects of REGγ were independent of its association with the proteasome and may be due, in part, to the decreased binding of polyQ-expanded AR by the E3 ubiquitin-ligase MDM2. Unlike its effects in PC12 cells, REGγ overexpression rescued transgenic SBMA motor neurons from DHT-induced toxicity in a proteasome binding-dependent manner, suggesting that the degradation of a specific 11S proteasome substrate or substrates promotes motor neuron viability. One potential substrate that we found to play a role in mutant AR toxicity is the splicing factor SC35. These studies reveal that, depending on the cellular context, two biological roles for REGγ impact cell viability in the face of polyQ-expanded AR; a proteasome binding-independent mechanism directly promotes mutant AR aggregation while a proteasome binding-dependent mechanism promotes cell viability. The balance between these functions likely determines REGγ effects on polyQ-expanded AR-expressing cells.

  18. Distinctive Citizenship

    Kaur, Ravinder

    2009-01-01

    The refugee, in India's Partition history, appears as an enigmatic construct - part pitiful, part heroic, though mostly shorn of agency - representing the surface of the human tragedy of Partition. Yet this archetype masks the undercurrent of social distinctions that produced hierarchies of post...

  19. The metabolically active subpopulation in Pseudomonas aeruginosa biofilms survives exposure to membrane-targeting antimicrobials via distinct molecular mechanisms

    Chiang, Wen-Chi; Pamp, Sünje Johanna; Nilsson, Martin

    2012-01-01

    encoding lipopolysaccharide modification enzymes, as well as on the mexAB-oprM, mexCD-oprJ, and muxABC-opmB genes encoding antimicrobial efflux pumps, but does not depend on the mexPQ-opmE efflux pump genes. Development of chlorhexidine-tolerant subpopulations was found to depend on the mexCD-oprJ genes......, but does not depend on the pmr, mexAB-oprM, mexPQ-opmE, or muxABC-opmB genes. Tolerance to SDS and EDTA in P. aeruginosa biofilms is linked to metabolically active cells, but does not depend on the pmr, mexAB, mexCD, mexPQ, or muxABC genes. Our data suggest that the active subpopulation in P. aeruginosa......-targeting compounds colistin, EDTA, SDS, and chlorhexidine resulted in the same spatial distribution of live and dead bacteria, we investigated whether tolerance to these compounds originated from the same molecular mechanisms. Development of colistin-tolerant subpopulations was found to depend on the pmr genes...

  20. Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Nef Proteins Show Distinct Patterns and Mechanisms of Src Kinase Activation

    Greenway, Alison L.; Dutartre, Hélène; Allen, Kelly; McPhee, Dale A.; Olive, Daniel; Collette, Yves

    1999-01-01

    The nef gene from human and simian immunodeficiency viruses (HIV and SIV) regulates cell function and viral replication, possibly through binding of the nef product to cellular proteins, including Src family tyrosine kinases. We show here that the Nef protein encoded by SIVmac239 interacts with and also activates the human Src kinases Lck and Hck. This is in direct contrast to the inhibitory effect of HIV type 1 (HIV-1) Nef on Lck catalytic activity. Unexpectedly, however, the interaction of SIV Nef with human Lck or Hck is not mediated via its consensus proline motif, which is known to mediate HIV-1 Nef binding to Src homology 3 (SH3) domains, and various experimental analyses failed to show significant interaction of SIV Nef with the SH3 domain of either kinase. Instead, SIV Nef can bind Lck and Hck SH2 domains, and its N-terminal 50 amino acid residues are sufficient for Src kinase binding and activation. Our results provide evidence for multiple mechanisms by which Nef binds to and regulates Src kinases. PMID:10364375

  1. Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss; imatinib provides selective protection only against cisplatin.

    Stephanie Morgan

    Full Text Available Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001 and doxorubicin (3 fold, p<0.01. TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01 but not against doxorubicin treatment.Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s the patient is exposed to.

  2. Retention in the Golgi apparatus and expression on the cell surface of Cfr/Esl-1/Glg-1/MG-160 are regulated by two distinct mechanisms.

    Miyaoka, Yuichiro; Kato, Hidenori; Ebato, Kazuki; Saito, Shigeru; Miyata, Naoko; Imamura, Toru; Miyajima, Atsushi

    2011-11-15

    Cfr (cysteine-rich fibroblast growth factor receptor) is an Fgf (fibroblast growth factor)-binding protein without a tyrosine kinase. We have shown previously that Cfr is involved in Fgf18 signalling via Fgf receptor 3c. However, as Cfr is also known as Glg (Golgi apparatus protein)-1 or MG-160 and occurs in the Golgi apparatus, it remains unknown how the distribution of Cfr is regulated. In the present study, we performed a mutagenic analysis of Cfr to show that two distinct regions contribute to its distribution and stability. First, the C-terminal region retains Cfr in the Golgi apparatus. Secondly, the Cfr repeats in the extracellular juxtamembrane region destabilizes Cfr passed through the Golgi apparatus. This destabilization does not depend on the cleavage and secretion of the extracellular domain of Cfr. Furthermore, we found that Cfr with a GPI (glycosylphosphatidylinositol) anchor was predominantly expressed on the cell surface in Ba/F3 cells and affected Fgf18 signalling in a similar manner to the full-length Cfr, indicating that the interaction of Cfr with Fgfs on the cell surface is important for its function in Fgf signalling. These results suggest that the expression of Cfr in the Golgi apparatus and on the plasma membrane is finely tuned through two distinct mechanisms for exhibiting different functions.

  3. Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms

    Weixiang Guo

    2015-06-01

    Full Text Available Fragile X mental retardation protein (FMRP and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2 is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.

  4. Distinct uptake mechanisms but similar intracellular processing of two different toll-like receptor ligand-peptide conjugates in dendritic cells.

    Khan, Selina; Bijker, Martijn S; Weterings, Jimmy J; Tanke, Hans J; Adema, Gosse J; van Hall, Thorbald; Drijfhout, Jan W; Melief, Cornelis J M; Overkleeft, Hermen S; van der Marel, Gijsbert A; Filippov, Dmitri V; van der Burg, Sjoerd H; Ossendorp, Ferry

    2007-07-20

    Covalent conjugation of Toll-like receptor ligands (TLR-L) to synthetic antigenic peptides strongly improves antigen presentation in vitro and T lymphocyte priming in vivo. These molecularly well defined TLR-L-peptide conjugates, constitute an attractive vaccination modality, sharing the peptide antigen and a defined adjuvant in one single molecule. We have analyzed the intracellular trafficking and processing of two TLR-L conjugates in dendritic cells (DCs). Long synthetic peptides containing an ovalbumin cytotoxic T-cell epitope were chemically conjugated to two different TLR-Ls the TLR2 ligand, Pam(3)CysSK(4) (Pam) or the TLR9 ligand CpG. Rapid and enhanced uptake of both types of TLR-L-conjugated peptide occurred in DCs. Moreover, TLR-L conjugation greatly enhanced antigen presentation, a process that was dependent on endosomal acidification, proteasomal cleavage, and TAP translocation. The uptake of the CpG approximately conjugate was independent of endosomally-expressed TLR9 as reported previously. Unexpectedly, we found that Pam approximately conjugated peptides were likewise internalized independently of the expression of cell surface-expressed TLR2. Further characterization of the uptake mechanisms revealed that TLR2-L employed a different uptake route than TLR9-L. Inhibition of clathrin- or caveolin-dependent endocytosis greatly reduced uptake and antigen presentation of the Pam-conjugate. In contrast, internalization and antigen presentation of CpG approximately conjugates was independent of clathrin-coated pits but partly dependent on caveolae formation. Importantly, in contrast to the TLR-independent uptake of the conjugates, TLR expression and downstream TLR signaling was required for dendritic cell maturation and for priming of naïve CD8(+) T-cells. Together, our data show that targeting to two distinct TLRs requires distinct uptake mechanism but follows similar trafficking and intracellular processing pathways leading to optimal antigen

  5. Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.

    Shahar-Gold, Hadar; Gur, Rotem; Wagner, Shlomo

    2013-01-01

    Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM) can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP). In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.

  6. Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.

    Hadar Shahar-Gold

    Full Text Available Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP. In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.

  7. Indicine N-oxide binds to tubulin at a distinct site and inhibits the assembly of microtubules: a mechanism for its cytotoxic activity.

    Appadurai, Prakash; Rathinasamy, Krishnan

    2014-02-10

    Indicine N-oxide, a pyrrolizidine alkaloid present in the plant Heliotropium indicum had shown promising cytotoxic activity in various tumor models. The compound exhibited severe toxicity to hepatocytes and bone marrow cells. The present work was aimed to evaluate the molecular mechanism of the toxicity of indicine N-oxide. We found that indicine N-oxide inhibited the proliferation of various cancer cell lines in a concentration dependent manner with IC50 ranging from 46 to 100 μM. At the half maximal inhibitory concentration it blocked the cell cycle progression at mitosis without significantly altering the organization of the spindle and interphase microtubules. The toxicities of the compound at higher concentrations are attributed to its severe depolymerizing effect on both the interphase and spindle microtubules. Binding studies using purified goat brain tubulin indicated that indicine N-oxide binds to tubulin at a distinct site not shared by colchicine or taxol. It decreased the polymer mass of both purified tubulin and MAP-rich tubulin. It was found to induce cleavage of DNA using pUC18 plasmid. The interactions of indicine N-oxide on DNA were also confirmed by computational analysis; which predicted its binding site at the minor groove of DNA. These studies bring to light that the toxicities of indicine N-oxide were due to its DNA damaging effects and depolymerization of microtubules. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  8. A comparative study on Ca content and distribution in two Gesneriaceae species reveals distinctive mechanisms to cope with high rhizospheric soluble calcium

    Wenlong eLi

    2014-11-01

    Full Text Available Excessive Ca is toxic to plants thus significantly affects plant growth and species distribution in Ca-rich karst areas. To understand how plants survive high Ca soil, laboratory experiments were established to compare the physiological responses and internal Ca distribution in organ, tissue, cell and intracellular levels under different Ca levels for Lysionotus pauciflorus and Boea hygrometrica, two karst habitant Gesneriaceae species in Southwest China. In the controlled condition, L. pauciflorus could survive as high as 200 mM rhizospheric soluble Ca, attributed to a series of physiological responses and preferential storage that limited Ca accumulation in chloroplasts of palisade cells. In contrast, B. hygrometrica could survive only 20 mM rhizospheric soluble Ca, but accumulated a high level of internal Ca in both palisade and spongy cells without disturbance on photosynthetic activity. By phenotype screening of transgenic plants expressing high Ca-inducible genes from B. hygrometrica, the expression of BhDNAJC2 in A. thaliana was found to enhance plant growth and photosynthesis under high soluble Ca stress. BhDNAJC2 encodes a recently reported heat shock protein (HSP 40 family DnaJ-domain protein. The Ca-resistant phenotype of BhDNAJC2 highlights the important role of chaperone-mediated protein quality control in Ca tolerance in B. hygrometrica. Taken together, our results revealed that distinctive mechanisms were employed in the two Gesneriaceae karst habitants to cope with a high Ca environment.

  9. Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization.

    Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N; Leonard, Christopher S

    2016-09-28

    Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca(2+) release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca(2+) influx and Ca(2+)-induced-Ca(2+) release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events. Orexin peptides are known to excite neurons via slow postsynaptic depolarizations. Here we elucidate a significant new orexin action that increases and prolongs the postspike

  10. Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein

    Sekigawa Akio

    2012-09-01

    Full Text Available Abstract Background Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD and dementia with Lewy bodies (DLB. Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg mice expressing DLB-linked P123H β-synuclein (P123H βS were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules. Therefore, the objectives of this study were to evaluate α-synuclein (αS-immunoreactive axonal swellings (αS-globules in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice. Results In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE. In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2, the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules. Conclusions Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein

  11. Dominant gain-of-function mutations in transmembrane domain III of ERS1 and ETR1 suggest a novel role for this domain in regulating the magnitude of ethylene response in Arabidopsis.

    Deslauriers, Stephen D; Alvarez, Ashley A; Lacey, Randy F; Binder, Brad M; Larsen, Paul B

    2015-10-01

    Prior work resulted in identification of an Arabidopsis mutant, eer5-1, with extreme ethylene response in conjunction with failure to induce a subset of ethylene-responsive genes, including AtEBP. EER5, which is a TREX-2 homolog that is part of a nucleoporin complex, functions as part of a cryptic aspect of the ethylene signaling pathway that is required for regulating the magnitude of ethylene response. A suppressor mutagenesis screen was carried out to identify second site mutations that could restore the growth of ethylene-treated eer5-1 to wild-type levels. A dominant gain-of-function mutation in the ethylene receptor ETHYLENE RESPONSE SENSOR 1 (ERS1) was identified, with the ers1-4 mutation being located in transmembrane domain III at a point nearly equivalent to the previously described etr1-2 mutation in the other Arabidopsis subfamily I ethylene receptor, ETHYLENE RESPONSE 1 (ETR1). Although both ers1-4 and etr1-2 partially suppress the ethylene hypersensitivity of eer5-1 and are at least in part REVERSION TO ETHYLENE SENSITIVITY 1 (RTE1)-dependent, ers1-4 was additionally found to restore the expression of AtEBP in ers1-4;eer5-1 etiolated seedlings after ethylene treatment in an EIN3-dependent manner. Our work indicates that ERS1-regulated expression of a subset of ethylene-responsive genes is related to controlling the magnitude of ethylene response, with hyperinduction of these genes correlated with reduced ethylene-dependent growth inhibition. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  12. Vascular defects in gain-of-function fps/fes transgenic mice correlate with PDGF- and VEGF-induced activation of mutant Fps/Fes kinase in endothelial cells.

    Sangrar, W; Mewburn, J D; Vincent, S G; Fisher, J T; Greer, P A

    2004-05-01

    Fps/Fes is a cytoplasmic tyrosine kinase that is abundantly expressed in the myeloid, endothelial, epithelial, neuronal and platelet lineages. Genetic manipulation in mice has uncovered potential roles for this kinase in hematopoiesis, innate immunity, inflammation and angiogenesis. We have utilized a genetic approach to explore the role of Fps/Fes in angiogenesis. A hypervascular line of mice generated by expression of a 'gain-of-function' human fps/fes transgene (fps(MF)) encoding a myristoylated variant of Fps (MFps) was used in these studies. The hypervascular phenotype of this line was extensively characterized by intravital microscopy and biochemical approaches. fps(MF) mice exhibited 1.6-1.7-fold increases in vascularity which was attributable to increases in the number of secondary vessels. Vessels were larger, exhibited varicosities and disorganized patterning, and were found to have defects in histamine-induced permeability. Biochemical characterization of endothelial cell (EC) lines derived from fps(MF) mice revealed that MFps was hypersensitive to activation by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). MFps mediates enhanced sensitization to VEGF and PDGF signaling in ECs. We propose that this hypersensitization contributes to excessive angiogenic signaling and that this underlies the observed hypervascular phenotype of fps(MF) mice. These phenotypes recapitulate important aspects of the vascular defects observed in both VEGF and angiopoietin-1 transgenic mice. The fps/fes proto-oncogene product therefore represents a novel player in the regulation of angiogenesis, and the fps(MF) line of mice constitutes a unique new murine model for the study of this process.

  13. Distinct mechanisms underlie adaptation of proximal tubule Na+/H+ exchanger isoform 3 in response to chronic metabolic and respiratory acidosis.

    Silva, Pedro Henrique Imenez; Girardi, Adriana Castello Costa; Neri, Elida Adalgisa; Rebouças, Nancy Amaral

    2012-04-01

    The Na(+/)H(+) exchanger isoform 3 (NHE3) is essential for HCO(3)(-) reabsorption in renal proximal tubules. The expression and function of NHE3 must adapt to acid-base conditions. The goal of this study was to elucidate the mechanisms responsible for higher proton secretion in proximal tubules during acidosis and to evaluate whether there are differences between metabolic and respiratory acidosis with regard to NHE3 modulation and, if so, to identify the relevant parameters that may trigger these distinct adaptive responses. We achieved metabolic acidosis by lowering HCO(3)(-) concentration in the cell culture medium and respiratory acidosis by increasing CO(2) tension in the incubator chamber. We found that cell-surface NHE3 expression was increased in response to both forms of acidosis. Mild (pH 7.21 ± 0.02) and severe (6.95 ± 0.07) metabolic acidosis increased mRNA levels, at least in part due to up-regulation of transcription, whilst mild (7.11 ± 0.03) and severe (6.86 ± 0.01) respiratory acidosis did not up-regulate NHE3 expression. Analyses of the Nhe3 promoter region suggested that the regulatory elements sensitive to metabolic acidosis are located between -466 and -153 bp, where two consensus binding sites for SP1, a transcription factor up-regulated in metabolic acidosis, were localised. We conclude that metabolic acidosis induces Nhe3 promoter activation, which results in higher mRNA and total protein level. At the plasma membrane surface, NHE3 expression was increased in metabolic and respiratory acidosis alike, suggesting that low pH is responsible for NHE3 displacement to the cell surface.

  14. The Hippo pathway controls border cell migration through distinct mechanisms in outer border cells and polar cells of the Drosophila ovary.

    Lin, Tzu-Huai; Yeh, Tsung-Han; Wang, Tsu-Wei; Yu, Jenn-Yah

    2014-11-01

    The Hippo pathway is a key signaling cascade in controlling organ size. The core components of this pathway are two kinases, Hippo (Hpo) and Warts (Wts), and a transcriptional coactivator, Yorkie (Yki). Yes-associated protein (YAP, a Yki homolog in mammals) promotes epithelial-mesenchymal transition and cell migration in vitro. Here, we use border cells in the Drosophila ovary as a model to study Hippo pathway functions in cell migration in vivo. During oogenesis, polar cells secrete Unpaired (Upd), which activates JAK/STAT signaling of neighboring cells and specifies them into outer border cells. The outer border cells form a cluster with polar cells and undergo migration. We find that hpo and wts are required for migration of the border cell cluster. In outer border cells, overexpression of hpo disrupts polarization of the actin cytoskeleton and attenuates migration. In polar cells, knockdown of hpo and wts or overexpression of yki impairs border cell induction and disrupts migration. These manipulations in polar cells reduce JAK/STAT activity in outer border cells. Expression of upd-lacZ is increased and decreased in yki and hpo mutant polar cells, respectively. Furthermore, forced expression of upd in polar cells rescues defects of border cell induction and migration caused by wts knockdown. These results suggest that Yki negatively regulates border cell induction by inhibiting JAK/STAT signaling. Together, our data elucidate two distinct mechanisms of the Hippo pathway in controlling border cell migration: (1) in outer border cells, it regulates polarized distribution of the actin cytoskeleton; (2) in polar cells, it regulates upd expression to control border cell induction and migration. Copyright © 2014 by the Genetics Society of America.

  15. Crystal Structures and Thermodynamic Analysis Reveal Distinct Mechanisms of CD28 Phosphopeptide Binding to the Src Homology 2 (SH2) Domains of Three Adaptor Proteins*

    Inaba, Satomi; Numoto, Nobutaka; Ogawa, Shuhei; Morii, Hisayuki; Ikura, Teikichi; Abe, Ryo; Ito, Nobutoshi; Oda, Masayuki

    2017-01-01

    Full activation of T cells and differentiation into effector T cells are essential for many immune responses and require co-stimulatory signaling via the CD28 receptor. Extracellular ligand binding to CD28 recruits protein-tyrosine kinases to its cytoplasmic tail, which contains a YMNM motif. Following phosphorylation of the tyrosine, the proteins growth factor receptor-bound protein 2 (Grb2), Grb2-related adaptor downstream of Shc (Gads), and p85 subunit of phosphoinositide 3-kinase may bind to pYMNM (where pY is phosphotyrosine) via their Src homology 2 (SH2) domains, leading to downstream signaling to distinct immune pathways. These three adaptor proteins bind to the same site on CD28 with variable affinity, and all are important for CD28-mediated co-stimulatory function. However, the mechanism of how these proteins recognize and compete for CD28 is unclear. To visualize their interactions with CD28, we have determined the crystal structures of Gads SH2 and two p85 SH2 domains in complex with a CD28-derived phosphopeptide. The high resolution structures obtained revealed that, whereas the CD28 phosphopeptide bound to Gads SH2 is in a bent conformation similar to that when bound to Grb2 SH2, it adopts a more extended conformation when bound to the N- and C-terminal SH2 domains of p85. These differences observed in the peptide-protein interactions correlated well with the affinity and other thermodynamic parameters for each interaction determined by isothermal titration calorimetry. The detailed insight into these interactions reported here may inform the development of compounds that specifically inhibit the association of CD28 with these adaptor proteins to suppress excessive T cell responses, such as in allergies and autoimmune diseases. PMID:27927989

  16. Crystal Structures and Thermodynamic Analysis Reveal Distinct Mechanisms of CD28 Phosphopeptide Binding to the Src Homology 2 (SH2) Domains of Three Adaptor Proteins.

    Inaba, Satomi; Numoto, Nobutaka; Ogawa, Shuhei; Morii, Hisayuki; Ikura, Teikichi; Abe, Ryo; Ito, Nobutoshi; Oda, Masayuki

    2017-01-20

    Full activation of T cells and differentiation into effector T cells are essential for many immune responses and require co-stimulatory signaling via the CD28 receptor. Extracellular ligand binding to CD28 recruits protein-tyrosine kinases to its cytoplasmic tail, which contains a YMNM motif. Following phosphorylation of the tyrosine, the proteins growth factor receptor-bound protein 2 (Grb2), Grb2-related adaptor downstream of Shc (Gads), and p85 subunit of phosphoinositide 3-kinase may bind to pYMNM (where pY is phosphotyrosine) via their Src homology 2 (SH2) domains, leading to downstream signaling to distinct immune pathways. These three adaptor proteins bind to the same site on CD28 with variable affinity, and all are important for CD28-mediated co-stimulatory function. However, the mechanism of how these proteins recognize and compete for CD28 is unclear. To visualize their interactions with CD28, we have determined the crystal structures of Gads SH2 and two p85 SH2 domains in complex with a CD28-derived phosphopeptide. The high resolution structures obtained revealed that, whereas the CD28 phosphopeptide bound to Gads SH2 is in a bent conformation similar to that when bound to Grb2 SH2, it adopts a more extended conformation when bound to the N- and C-terminal SH2 domains of p85. These differences observed in the peptide-protein interactions correlated well with the affinity and other thermodynamic parameters for each interaction determined by isothermal titration calorimetry. The detailed insight into these interactions reported here may inform the development of compounds that specifically inhibit the association of CD28 with these adaptor proteins to suppress excessive T cell responses, such as in allergies and autoimmune diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. A Bystander Mechanism Explains the Specific Phenotype of a Broadly Expressed Misfolded Protein.

    Lauren Klabonski

    2016-12-01

    Full Text Available Misfolded proteins in transgenic models of conformational diseases interfere with proteostasis machinery and compromise the function of many structurally and functionally unrelated metastable proteins. This collateral damage to cellular proteins has been termed 'bystander' mechanism. How a single misfolded protein overwhelms the proteostasis, and how broadly-expressed mutant proteins cause cell type-selective phenotypes in disease are open questions. We tested the gain-of-function mechanism of a R37C folding mutation in an endogenous IGF-like C.elegans protein DAF-28. DAF-28(R37C is broadly expressed, but only causes dysfunction in one specific neuron, ASI, leading to a distinct developmental phenotype. We find that this phenotype is caused by selective disruption of normal biogenesis of an unrelated endogenous protein, DAF-7/TGF-β. The combined deficiency of DAF-28 and DAF-7 biogenesis, but not of DAF-28 alone, explains the gain-of-function phenotype-deficient pro-growth signaling by the ASI neuron. Using functional, fluorescently-tagged protein, we find that, in animals with mutant DAF-28/IGF, the wild-type DAF-7/TGF-β is mislocalized to and accumulates in the proximal axon of the ASI neuron. Activation of two different branches of the unfolded protein response can modulate both the developmental phenotype and DAF-7 mislocalization in DAF-28(R37C animals, but appear to act through divergent mechanisms. Our finding that bystander targeting of TGF-β explains the phenotype caused by a folding mutation in an IGF-like protein suggests that, in conformational diseases, bystander misfolding may specify the distinct phenotypes caused by different folding mutations.

  18. Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms.

    Alexander, Matthew R; Murgai, Meera; Moehle, Christopher W; Owens, Gary K

    2012-04-02

    Smooth muscle cell (SMC) phenotypic modulation in atherosclerosis and in response to PDGF in vitro involves repression of differentiation marker genes and increases in SMC proliferation, migration, and matrix synthesis. However, SMCs within atherosclerotic plaques can also express a number of proinflammatory genes, and in cultured SMCs the inflammatory cytokine IL-1β represses SMC marker gene expression and induces inflammatory gene expression. Studies herein tested the hypothesis that IL-1β modulates SMC phenotype to a distinct inflammatory state relative to PDGF-DD. Genome-wide gene expression analysis of IL-1β- or PDGF-DD-treated SMCs revealed that although both stimuli repressed SMC differentiation marker gene expression, IL-1β distinctly induced expression of proinflammatory genes, while PDGF-DD primarily induced genes involved in cell proliferation. Promoters of inflammatory genes distinctly induced by IL-1β exhibited over-representation of NF-κB binding sites, and NF-κB inhibition in SMCs reduced IL-1β-induced upregulation of proinflammatory genes as well as repression of SMC differentiation marker genes. Interestingly, PDGF-DD-induced SMC marker gene repression was not NF-κB dependent. Finally, immunofluorescent staining of mouse atherosclerotic lesions revealed the presence of cells positive for the marker of an IL-1β-stimulated inflammatory SMC, chemokine (C-C motif) ligand 20 (CCL20), but not the PDGF-DD-induced gene, regulator of G protein signaling 17 (RGS17). Results demonstrate that IL-1β- but not PDGF-DD-induced phenotypic modulation of SMC is characterized by NF-κB-dependent activation of proinflammatory genes, suggesting the existence of a distinct inflammatory SMC phenotype. In addition, studies provide evidence for the possible utility of CCL20 and RGS17 as markers of inflammatory and proliferative state SMCs within atherosclerotic plaques in vivo.

  19. Quantitative sensory testing somatosensory profiles in patients with cervical radiculopathy are distinct from those in patients with nonspecific neck-arm pain.

    Tampin, Brigitte; Slater, Helen; Hall, Toby; Lee, Gabriel; Briffa, Noelle Kathryn

    2012-12-01

    The aim of this study was to establish the somatosensory profiles of patients with cervical radiculopathy and patients with nonspecific neck-arm pain associated with heightened nerve mechanosensitivity (NSNAP). Sensory profiles were compared to healthy control (HC) subjects and a positive control group comprising patients with fibromyalgia (FM). Quantitative sensory testing (QST) of thermal and mechanical detection and pain thresholds, pain sensitivity and responsiveness to repetitive noxious mechanical stimulation was performed in the maximal pain area, the corresponding dermatome and foot of 23 patients with painful C6 or C7 cervical radiculopathy, 8 patients with NSNAP in a C6/7 dermatomal pain distribution, 31 HC and 22 patients with FM. For both neck-arm pain groups, all QST parameters were within the 95% confidence interval of HC data. Patients with cervical radiculopathy were characterised by localised loss of function (thermal, mechanical, vibration detection Ppain area and dermatome (thermal detection, vibration detection, pressure pain sensitivity Ppain groups demonstrated increased cold sensitivity in their maximal pain area (Ppain groups differed from patients with FM, the latter characterised by a widespread gain of function in most nociceptive parameters (thermal, pressure, mechanical pain sensitivity Ppain characteristics between the 2 neck-arm pain groups, distinct sensory profiles were demonstrated for each group. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  20. Specific cerebral heat shock proteins and histamine receptor cross-talking mechanisms promote distinct lead-dependent neurotoxic responses in teleosts

    Giusi, Giuseppina; Alo, Raffaella; Crudo, Michele; Facciolo, Rosa Maria; Canonaco, Marcello

    2008-01-01

    Recent interests are beginning to be directed towards toxic neurobiological dysfunctions caused by lead (Pb) in aquatic vertebrates. In the present work, treatment with a maximum acceptable toxic concentration of this heavy metal was responsible for highly significant (p 2 R) antagonist cimetidine (Cim), as shown by the very robust (p 3 R) thioperamide (Thio), instead, blocked Pb-dependent up-regulatory trends of both chaperones in mostly hypothalamic areas. Moreover, intense neuronal damages of the above brain regions coincided with altered expressions of HSP70 and HSP90 when treated only with Cim. Overall these first results show that distinct H n R are able to exert a net neuroprotective role arising from their interaction with chaperones in fish exposed to Pb-dependent stressful conditions making this a potentially key interaction especially for T. pavo, aquatic species which plays an important ecological role towards the survival of other commercially vital fishes

  1. Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation.

    Winkler, I G; Pettit, A R; Raggatt, L J; Jacobsen, R N; Forristal, C E; Barbier, V; Nowlan, B; Cisterne, A; Bendall, L J; Sims, N A; Lévesque, J-P

    2012-07-01

    The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide (CYP) as adjuvant to granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) for autologous transplants in patients who failed prior mobilization with G-CSF alone. It has recently emerged that G-CSF mediates HSC mobilization and inhibits bone formation via specific bone marrow (BM) macrophages. We compared the effect of these three mobilizing agents on BM macrophages, bone formation, osteoblasts, HSC niches and HSC reconstitution potential. Both G-CSF and CYP suppressed niche-supportive macrophages and osteoblasts, and inhibited expression of endosteal cytokines resulting in major impairment of HSC reconstitution potential remaining in the mobilized BM. In sharp contrast, although AMD3100 was effective at mobilizing HSC, it did not suppress osteoblasts, endosteal cytokine expression or reconstitution potential of HSC remaining in the mobilized BM. In conclusion, although G-CSF, CYP and AMD3100 efficiently mobilize HSC into the blood, their effects on HSC niches and bone formation are distinct with both G-CSF and CYP targeting HSC niche function and bone formation, whereas AMD3100 directly targets HSC without altering niche function or bone formation.

  2. The Memory Trace Supporting Lose-Shift Responding Decays Rapidly after Reward Omission and Is Distinct from Other Learning Mechanisms in Rats.

    Gruber, Aaron J; Thapa, Rajat

    2016-01-01

    The propensity of animals to shift choices immediately after unexpectedly poor reinforcement outcomes is a pervasive strategy across species and tasks. We report here that the memory supporting such lose-shift responding in rats rapidly decays during the intertrial interval and persists throughout training and testing on a binary choice task, despite being a suboptimal strategy. Lose-shift responding is not positively correlated with the prevalence and temporal dependence of win-stay responding, and it is inconsistent with predictions of reinforcement learning on the task. These data provide further evidence that win-stay and lose-shift are mediated by dissociated neural mechanisms and indicate that lose-shift responding presents a potential confound for the study of choice in the many operant choice tasks with short intertrial intervals. We propose that this immediate lose-shift responding is an intrinsic feature of the brain's choice mechanisms that is engaged as a choice reflex and works in parallel with reinforcement learning and other control mechanisms to guide action selection.

  3. Dissecting the Photoprotective Mechanism Encoded by the flv4-2 Operon: a Distinct Contribution of Sll0218 in Photosystem II Stabilization.

    Bersanini, Luca; Allahverdiyeva, Yagut; Battchikova, Natalia; Heinz, Steffen; Lespinasse, Maija; Ruohisto, Essi; Mustila, Henna; Nickelsen, Jörg; Vass, Imre; Aro, Eva-Mari

    2017-03-01

    In Synechocystis sp. PCC 6803, the flv4-2 operon encodes the flavodiiron proteins Flv2 and Flv4 together with a small protein, Sll0218, providing photoprotection for Photosystem II (PSII). Here, the distinct roles of Flv2/Flv4 and Sll0218 were addressed, using a number of flv4-2 operon mutants. In the ∆sll0218 mutant, the presence of Flv2/Flv4 rescued PSII functionality as compared with ∆sll0218-flv2, where neither Sll0218 nor the Flv2/Flv4 heterodimer are expressed. Nevertheless, both the ∆sll0218 and ∆sll0218-flv2 mutants demonstrated deficiency in accumulation of PSII proteins suggesting a role for Sll0218 in PSII stabilization, which was further supported by photoinhibition experiments. Moreover, the accumulation of PSII assembly intermediates occurred in Sll0218-lacking mutants. The YFP-tagged Sll0218 protein localized in a few spots per cell at the external side of the thylakoid membrane, and biochemical membrane fractionation revealed clear enrichment of Sll0218 in the PratA-defined membranes, where the early biogenesis steps of PSII occur. Further, the characteristic antenna uncoupling feature of the ∆flv4-2 operon mutants is shown to be related to PSII destabilization in the absence of Sll0218. It is concluded that the Flv2/Flv4 heterodimer supports PSII functionality, while the Sll0218 protein assists PSII assembly and stabilization, including optimization of light harvesting. © 2016 The Authors. Plant, Cell & Enviroment Published by John Wiley & Sons Ltd.

  4. Evolution of Enzymatic Activities in the Enolase Superfamily: Stereochemically Distinct Mechanisms in Two Families of cis,cis-Muconate Lactonizing Enzymes

    Sakai, A.; Fedorov, A; Fedorov, E; Schnoes, A; Glasner, M; Burley, S; Babbitt, P; Almo, S; Gerlt, J

    2009-01-01

    The mechanistically diverse enolase superfamily is a paradigm for elucidating Nature's strategies for divergent evolution of enzyme function. Each of the different reactions catalyzed by members of the superfamily is initiated by abstraction of the a-proton of a carboxylate substrate that is coordinated to an essential Mg2+. The muconate lactonizing enzyme (MLE) from Pseudomonas putida, a member of a family that catalyzes the syn-cycloisomerization of cis,cis-muconate to (4S)-muconolactone in the e-ketoadipate pathway, has provided critical insights into the structural bases for evolution of function within the superfamily. A second, divergent family of homologous MLEs that catalyzes anti-cycloisomerization has been identified. Structures of members of both families liganded with the common (4S)-muconolactone product (syn, Pseudomonas fluorescens, gi 70731221; anti, Mycobacterium smegmatis, gi 118470554) document that the conserved Lys at the end of the second e-strand in the (e/a)7e-barrel domain serves as the acid catalyst in both reactions. The different stereochemical courses (syn and anti) result from different structural strategies for determining substrate specificity: although the distal carboxylate group of the cis,cis-muconate substrate attacks the same face of the proximal double bond, opposite faces of the resulting enolate anion intermediate are presented to the conserved Lys acid catalyst. The discovery of two families of homologous, but stereochemically distinct, MLEs likely provides an example of 'pseudoconvergent' evolution of the same function from different homologous progenitors within the enolase superfamily, in which different spatial arrangements of active site functional groups and substrate specificity determinants support catalysis of the same reaction.

  5. Evolution of Enzymatic Activities in the Enolase Superfamily: Stereochemically Distinct Mechanisms in Two Families of cis,cis-Muconate Lactonizing Enzymes†

    Sakai, Ayano; Fedorov, Alexander A.; Fedorov, Elena V.; Schnoes, Alexandra M.; Glasner, Margaret E.; Brown, Shoshana; Rutter, Marc E.; Bain, Kevin; Chang, Shawn; Gheyi, Tarun; Sauder, J. Michael; Burley, Stephen K.; Babbitt, Patricia C.; Almo, Steven C.; Gerlt, John A.

    2009-01-01

    The mechanistically diverse enolase superfamily is a paradigm for elucidating Nature’s strategies for divergent evolution of enzyme function. Each of the different reactions catalyzed by members of the superfamily is initiated by abstraction of the α-proton of a carboxylate substrate that is coordinated to an essential Mg2+. The muconate lactonizing enzyme (MLE) from Pseudomonas putida, a member of a family that catalyzes the syn-cycloisomerization of cis,cis-muconate to (4S)-muconolactone in the β-ketoadipate pathway, has provided critical insights into the structural bases for evolution of function within the superfamily. A second, divergent family of homologues MLEs that catalyzes anti-cycloisomerization has been identified. Structures of members of both families liganded with the common (4S)-muconolactone product (syn, Pseudomonas fluorescens, GI:70731221; anti, Mycobacterium smegmatis, GI:118470554) document that the conserved Lys at the end of the second β-strand in the (β/α)7β-barrel domain serves as the acid catalyst in both reactions. The different stereochemical courses (syn and anti) result from different structural strategies for determining substrate specificity: although the distal carboxylate group of the cis,cis-muconate substrate attacks the same face of the proximal double bond, opposite faces of the resulting enolate anion intermediate are presented to the conserved Lys acid catalyst. The discovery of two families of homologous, but stereochemically distinct, MLEs likely provides an example of “pseudoconvergent” evolution of the same function from different homologous progenitors within the enolase superfamily, in which different spatial arrangements of active site functional groups and substrate specificity determinants support catalysis of the same reaction. PMID:19220063

  6. Quantum Distinction: Quantum Distinctiones!

    Zeps, Dainis

    2009-01-01

    10 pages; How many distinctions, in Latin, quantum distinctiones. We suggest approach of anthropic principle based on anthropic reference system which should be applied equally both in theoretical physics and in mathematics. We come to principle that within reference system of life subject of mathematics (that of thinking) should be equated with subject of physics (that of nature). For this reason we enter notions of series of distinctions, quantum distinction, and argue that quantum distinct...

  7. The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder.

    Malki, Karim; Keers, Robert; Tosto, Maria Grazia; Lourdusamy, Anbarasu; Carboni, Lucia; Domenici, Enrico; Uher, Rudolf; McGuffin, Peter; Schalkwyk, Leonard C

    2014-05-07

    distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.

  8. Distinct Mechanisms of Recognizing Endosomal Sorting Complex Required for Transport III (ESCRT-III) Protein IST1 by Different Microtubule Interacting and Trafficking (MIT) Domains*

    Guo, Emily Z.; Xu, Zhaohui

    2015-01-01

    The endosomal sorting complex required for transport (ESCRT) machinery is responsible for membrane remodeling in a number of biological processes including multivesicular body biogenesis, cytokinesis, and enveloped virus budding. In mammalian cells, efficient abscission during cytokinesis requires proper function of the ESCRT-III protein IST1, which binds to the microtubule interacting and trafficking (MIT) domains of VPS4, LIP5, and Spartin via its C-terminal MIT-interacting motif (MIM). Here, we studied the molecular interactions between IST1 and the three MIT domain-containing proteins to understand the structural basis that governs pairwise MIT-MIM interaction. Crystal structures of the three molecular complexes revealed that IST1 binds to the MIT domains of VPS4, LIP5, and Spartin using two different mechanisms (MIM1 mode versus MIM3 mode). Structural comparison revealed that structural features in both MIT and MIM contribute to determine the specific binding mechanism. Within the IST1 MIM sequence, two phenylalanine residues were shown to be important in discriminating MIM1 versus MIM3 binding. These observations enabled us to deduce a preliminary binding code, which we applied to provide CHMP2A, a protein that normally only binds the MIT domain in the MIM1 mode, the additional ability to bind the MIT domain of Spartin in the MIM3 mode. PMID:25657007

  9. Distinct mechanisms of recognizing endosomal sorting complex required for transport III (ESCRT-III) protein IST1 by different microtubule interacting and trafficking (MIT) domains.

    Guo, Emily Z; Xu, Zhaohui

    2015-03-27

    The endosomal sorting complex required for transport (ESCRT) machinery is responsible for membrane remodeling in a number of biological processes including multivesicular body biogenesis, cytokinesis, and enveloped virus budding. In mammalian cells, efficient abscission during cytokinesis requires proper function of the ESCRT-III protein IST1, which binds to the microtubule interacting and trafficking (MIT) domains of VPS4, LIP5, and Spartin via its C-terminal MIT-interacting motif (MIM). Here, we studied the molecular interactions between IST1 and the three MIT domain-containing proteins to understand the structural basis that governs pairwise MIT-MIM interaction. Crystal structures of the three molecular complexes revealed that IST1 binds to the MIT domains of VPS4, LIP5, and Spartin using two different mechanisms (MIM1 mode versus MIM3 mode). Structural comparison revealed that structural features in both MIT and MIM contribute to determine the specific binding mechanism. Within the IST1 MIM sequence, two phenylalanine residues were shown to be important in discriminating MIM1 versus MIM3 binding. These observations enabled us to deduce a preliminary binding code, which we applied to provide CHMP2A, a protein that normally only binds the MIT domain in the MIM1 mode, the additional ability to bind the MIT domain of Spartin in the MIM3 mode. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Molecular mechanisms of protein-cholesterol interactions in plasma membranes: Functional distinction between topological (tilted) and consensus (CARC/CRAC) domains.

    Fantini, Jacques; Di Scala, Coralie; Baier, Carlos J; Barrantes, Francisco J

    2016-09-01

    The molecular mechanisms that control the multiple possible modes of protein association with membrane cholesterol are remarkably convergent. These mechanisms, which include hydrogen bonding, CH-π stacking and dispersion forces, are used by a wide variety of extracellular proteins (e.g. microbial or amyloid) and membrane receptors. Virus fusion peptides penetrate the membrane of host cells with a tilted orientation that is compatible with a transient interaction with cholesterol; this tilted orientation is also characteristic of the process of insertion of amyloid proteins that subsequently form oligomeric pores in the plasma membrane of brain cells. Membrane receptors that are associated with cholesterol generally display linear consensus binding motifs (CARC and CRAC) characterized by a triad of basic (Lys/Arg), aromatic (Tyr/phe) and aliphatic (Leu/Val) amino acid residues. In some cases, the presence of both CARC and CRAC within the same membrane-spanning domain allows the simultaneous binding of two cholesterol molecules, one in each membrane leaflet. In this review the molecular basis and the functional significance of the different modes of protein-cholesterol interactions in plasma membranes are discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Mutations Phe785Leu and Thr618Met in Na+, K+-ATPase, Associated with Familial Rapid-Onset Dystonia Parkinsonism, Interfere with Na+ Interaction by Distinct Mechanisms

    Schack, Vivien Rodacker; Toustrup-Jensen, Mads Schak; Vilsen, Bente

    The Na+, K+-ATPase plays key roles in brain function. Recently, missense mutations in the Na+, K+-ATPase were found associated with familial rapid-onset dystonia parkinsonism (FRDP). Here, we have characterized the functional consequences of FRDP mutations Phe785Leu and Thr618Met. Both mutations...... lead to functionally altered, but active, Na+, K+-pumps that display reduced apparent affinity for cytoplasmic Na+, but the underlying mechanism differs between the mutants. In Phe785Leu, the interaction of the E1 form with Na+ is defective, and the E1-E2 equilibrium is not displaced. In Thr618Met......, the Na+ affinity is reduced because of displacement of the conformational equilibrium in favor of the K+-occluded E2(K2) form. In both mutants, K+ interaction at the external activating sites of the E2P phosphoenzyme is normal. The change of cellular Na+ homeostasis is likely a major factor contributing...

  12. Mutations Phe785Leu and Thr618Met in Na+, K+-ATPase, Associated with Familial Rapid-Onset Dystonia Parkinsonism, Interfere with Na+ Interaction by Distinct Mechanisms

    Schack, Vivien Rodacker; Toustrup-Jensen, Mads Schak; Vilsen, Bente

    The Na+, K+-ATPase plays key roles in brain function. Recently, missense mutations in the Na+, K+-ATPase were found associated with familial rapid-onset dystonia parkinsonism (FRDP). We have characterized the functional consequences of FRDP mutations Phe785Leu and Thr618Met. Both mutations lead...... to functionally altered, but active, Na+, K+-pumps that display reduced apparent affinity for cytoplasmic Na+, but the underlying mechanism differs between the mutants. In Phe785Leu, the interaction of the E1 form with Na+ is defective, and the E1-E2 equilibrium is not displaced. In Thr618Met, the Na+ affinity...... is reduced because of displacement of the conformational equilibrium in favor of the K+-occluded E2(K2) form. In both mutants, K+ interaction at the external activating sites of the E2P phosphoenzyme is normal. The change of cellular Na+ homeostasis is likely a major factor contributing to the development...

  13. Distinct kinetics and mechanisms of mZVI particles aging in saline and fresh groundwater: H2 evolution and surface passivation.

    Xin, Jia; Tang, Fenglin; Zheng, Xilai; Shao, Haibing; Kolditz, Olaf; Lu, Xin

    2016-09-01

    Application of microscale zero-valent iron (mZVI) is a promising technology for in-situ contaminated groundwater remediation; however, its longevity is negatively impacted by surface passivation, especially in saline groundwater. In this study, the aging behavior of mZVI particles was investigated in three media (milli-Q water, fresh groundwater and saline groundwater) using batch experiments to evaluate their potential corrosion and passivation performance under different field conditions. The results indicated that mZVI was reactive for 0-7 days of exposure to water and then gradually lost H2-generating capacity over the next hundred days in all of the tested media. In comparison, mZVI in saline groundwater exhibited the fastest corrosion rate during the early phase (0-7 d), followed by the sharpest kinetic constant decline in the latter phases. The SEM-EDS and XPS analyses demonstrated that in the saline groundwater, a thin and compact oxide film was immediately formed on the surface and significantly shielded the iron reactive site. Nevertheless, in fresh groundwater and milli-Q water, a passive layer composed of loosely and unevenly distributed precipitates slowly formed, with abundant reactive sites available to support continuous iron corrosion. These findings provide insight into the molecular-scale mechanism that governs mZVI passivation and provide implications for long-term mZVI application in saline contaminated groundwater. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. DsrA regulatory RNA represses both hns and rbsD mRNAs through distinct mechanisms in Escherichia coli.

    Lalaouna, David; Morissette, Audrey; Carrier, Marie-Claude; Massé, Eric

    2015-10-01

    The 87 nucleotide long DsrA sRNA has been mostly studied for its translational activation of the transcriptional regulator RpoS. However, it also represses hns mRNA, which encodes H-NS, a major regulator that affects expression of nearly 5% of Escherichia coli genes. A speculative model previously suggested that DsrA would block hns mRNA translation by binding simultaneously to start and stop codon regions of hns mRNA (coaxial model). Here, we show that DsrA efficiently blocked translation of hns mRNA by base-pairing immediately downstream of the start codon. In addition, DsrA induced hns mRNA degradation by actively recruiting the RNA degradosome complex. Data presented here led to a model of DsrA action on hns mRNA, which supports a canonical mechanism of sRNA-induced mRNA degradation by binding to the translation initiation region. Furthermore, using MS2-affinity purification coupled with RNA sequencing technology (MAPS), we also demonstrated that DsrA targets rbsD mRNA, involved in ribose utilization. Surprisingly, DsrA base pairs far downstream of rbsD start codon and induces rapid degradation of the transcript. Thus, our study enables us to draw an extended DsrA targetome. © 2015 John Wiley & Sons Ltd.

  15. Distinct Mechanism of Cysteine Oxidation-Dependent Activation and Cold Sensitization of Human Transient Receptor Potential Ankyrin 1 Channel by High and Low Oxaliplatin

    Takahito Miyake

    2017-11-01

    Full Text Available Oxaliplatin, a third-generation platinum-based chemotherapeutic agent, displays unique acute peripheral neuropathy triggered or enhanced by cold, and accumulating evidence suggests that transient receptor potential ankyrin 1 (TRPA1 is responsible. TRPA1 is activated by oxaliplatin via a glutathione-sensitive mechanism. However, oxaliplatin interrupts hydroxylation of a proline residue located in the N-terminal region of TRPA1 via inhibition of prolyl hydroxylase (PHD, which causes sensitization of TRPA1 to reactive oxygen species (ROS. Furthermore, PHD inhibition endows cold-insensitive human TRPA1 (hTRPA1 with ROS-dependent cold sensitivity. Since cysteine oxidation and proline hydroxylation regulate its activity, their association with oxaliplatin-induced TRPA1 activation and acquirement of cold sensitivity were investigated in the present study. A high concentration of oxaliplatin (1 mM induced outward-rectifier whole-cell currents and increased the intracellular Ca2+ concentration in hTRPA1-expressing HEK293 cells, but did not increase the probability of hTRPA1 channel opening in the inside-out configuration. Oxaliplatin also induced the rapid generation of hydrogen peroxide, and the resultant Ca2+ influx was prevented in the presence of glutathione and in cysteine-mutated hTRPA1 (Cys641Ser-expressing cells, whereas proline-mutated hTRPA1 (Pro394Ala-expressing cells showed similar whole-cell currents and Ca2+ influx. By contrast, a lower concentration of oxaliplatin (100 μM did not increase the intracellular Ca2+ concentration but did confer cold sensitivity on hTRPA1-expressing cells, and this was inhibited by PHD2 co-overexpression. Cold sensitivity was abolished by the mitochondria-targeting ROS scavenger mitoTEMPO and was minimal in cysteine-mutated hTRPA1 (Cys641Ser or Cys665Ser-expressing cells. Thus, high oxaliplatin evokes ROS-mediated cysteine oxidation-dependent hTRPA1 activation independent of PHD activity, while a lower

  16. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells.

    Ana Juknat

    Full Text Available Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS to activate BV-2 microglial cells, we examined how Δ(9-tetrahydrocannabinol (THC, the major psychoactive component of marijuana, and cannabidiol (CBD the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p≤0.005. Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2, cell cycle related (Cdkn2b, Gadd45a as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1. The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFκB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress

  17. Social conformity despite individual preferences for distinctiveness.

    Smaldino, Paul E; Epstein, Joshua M

    2015-03-01

    We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.

  18. Mechanics

    Hartog, J P Den

    1961-01-01

    First published over 40 years ago, this work has achieved the status of a classic among introductory texts on mechanics. Den Hartog is known for his lively, discursive and often witty presentations of all the fundamental material of both statics and dynamics (and considerable more advanced material) in new, original ways that provide students with insights into mechanical relationships that other books do not always succeed in conveying. On the other hand, the work is so replete with engineering applications and actual design problems that it is as valuable as a reference to the practicing e

  19. Touch communicates distinct emotions.

    Hertenstein, Matthew J; Keltner, Dacher; App, Betsy; Bulleit, Brittany A; Jaskolka, Ariane R

    2006-08-01

    The study of emotional signaling has focused almost exclusively on the face and voice. In 2 studies, the authors investigated whether people can identify emotions from the experience of being touched by a stranger on the arm (without seeing the touch). In the 3rd study, they investigated whether observers can identify emotions from watching someone being touched on the arm. Two kinds of evidence suggest that humans can communicate numerous emotions with touch. First, participants in the United States (Study 1) and Spain (Study 2) could decode anger, fear, disgust, love, gratitude, and sympathy via touch at much-better-than-chance levels. Second, fine-grained coding documented specific touch behaviors associated with different emotions. In Study 3, the authors provide evidence that participants can accurately decode distinct emotions by merely watching others communicate via touch. The findings are discussed in terms of their contributions to affective science and the evolution of altruism and cooperation. (c) 2006 APA, all rights reserved

  20. Mechanics

    Chester, W

    1979-01-01

    When I began to write this book, I originally had in mind the needs of university students in their first year. May aim was to keep the mathematics simple. No advanced techniques are used and there are no complicated applications. The emphasis is on an understanding of the basic ideas and problems which require expertise but do not contribute to this understanding are not discussed. How­ ever, the presentation is more sophisticated than might be considered appropri­ ate for someone with no previous knowledge of the subject so that, although it is developed from the beginning, some previous acquaintance with the elements of the subject would be an advantage. In addition, some familiarity with element­ ary calculus is assumed but not with the elementary theory of differential equations, although knowledge of the latter would again be an advantage. It is my opinion that mechanics is best introduced through the motion of a particle, with rigid body problems left until the subject is more fully developed. Howev...

  1. Counselor Identity: Conformity or Distinction?

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

  2. Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway

    Dorssers, Lambert CJ; Agthoven, Ton van; Brinkman, Arend; Veldscholte, Jos; Smid, Marcel; Dechering, Koen J

    2005-01-01

    Tamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling. We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made. Relatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours. The direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway

  3. Distinction

    2010-01-01

    Pr Serge Haroche La Médaille d’or 2009 du CNRS est décernée au Pr Serge Haroche, titulaire de la chaire de Physique quantique depuis 2001. Serge Haroche est spécialiste de physique atomique et d’optique quantique. Il est l’un des fondateurs de l’électrodynamique quantique en cavité, domaine qui permet, par des expériences conceptuellement simples, d’éclairer les fondements de la théorie quantique et de réaliser des prototypes de systèmes de traitement quantique de l’information. Serge Haroche...

  4. Bax-mediated mitochondrial outer membrane permeabilization (MOMP), distinct from the mitochondrial permeability transition, is a key mechanism in diclofenac-induced hepatocyte injury: Multiple protective roles of cyclosporin A.

    Siu, Woen Ping; Pun, Pamela Boon Li; Latchoumycandane, Calivarathan; Boelsterli, Urs A

    2008-03-15

    Diclofenac, a widely used nonsteroidal anti-inflammatory drug, has been associated with rare but severe cases of clinical hepatotoxicity. Diclofenac causes concentration-dependent cell death in human hepatocytes (after 24-48 h) by mitochondrial permeabilization via poorly defined mechanisms. To explore whether the cyclophilin D (CyD)-dependent mitochondrial permeability transition (mPT) and/or the mitochondrial outer membrane permeabilization (MOMP) was primarily involved in mediating cell death, we exposed immortalized human hepatocytes (HC-04) to apoptogenic concentrations of diclofenac (>500 microM) in the presence or absence of inhibitors of upstream mediators. The CyD inhibitor, cyclosporin A (CsA, 2 microM) fully inhibited diclofenac-induced cell injury, suggesting that mPT was involved. However, CyD gene silencing using siRNA left the cells susceptible to diclofenac toxicity, and CsA still protected the CyD-negative cells from lethal injury. Diclofenac induced early (9 h) activation of Bax and Bak and caused mitochondrial translocation of Bax, indicating that MOMP was involved in cell death. Inhibition of Bax protein expression by using siRNA significantly protected HC-04 from diclofenac-induced cell injury. Diclofenac also induced early Bid activation (tBid formation, 6 h), which is an upstream mechanism that initiates Bax activation and mitochondrial translocation. Bid activation was sensitive to the Ca2+ chelator, BAPTA. In conclusion, we found that Bax/Bak-mediated MOMP is a key mechanism of diclofenac-induced lethal cell injury in human hepatocytes, and that CsA can prevent MOMP through inhibition of Bax activation. These data support our concept that the Ca2+-Bid-Bax-MOMP axis is a critical pathway in diclofenac (metabolite)-induced hepatocyte injury.

  5. Bax-mediated mitochondrial outer membrane permeabilization (MOMP), distinct from the mitochondrial permeability transition, is a key mechanism in diclofenac-induced hepatocyte injury: Multiple protective roles of cyclosporin A

    Siu, W.P.; Pun, Pamela Boon Li; Latchoumycandane, Calivarathan; Boelsterli, Urs A.

    2008-01-01

    Diclofenac, a widely used nonsteroidal anti-inflammatory drug, has been associated with rare but severe cases of clinical hepatotoxicity. Diclofenac causes concentration-dependent cell death in human hepatocytes (after 24-48 h) by mitochondrial permeabilization via poorly defined mechanisms. To explore whether the cyclophilin D (CyD)-dependent mitochondrial permeability transition (mPT) and/or the mitochondrial outer membrane permeabilization (MOMP) was primarily involved in mediating cell death, we exposed immortalized human hepatocytes (HC-04) to apoptogenic concentrations of diclofenac (> 500 μM) in the presence or absence of inhibitors of upstream mediators. The CyD inhibitor, cyclosporin A (CsA, 2 μM) fully inhibited diclofenac-induced cell injury, suggesting that mPT was involved. However, CyD gene silencing using siRNA left the cells susceptible to diclofenac toxicity, and CsA still protected the CyD-negative cells from lethal injury. Diclofenac induced early (9 h) activation of Bax and Bak and caused mitochondrial translocation of Bax, indicating that MOMP was involved in cell death. Inhibition of Bax protein expression by using siRNA significantly protected HC-04 from diclofenac-induced cell injury. Diclofenac also induced early Bid activation (tBid formation, 6 h), which is an upstream mechanism that initiates Bax activation and mitochondrial translocation. Bid activation was sensitive to the Ca 2+ chelator, BAPTA. In conclusion, we found that Bax/Bak-mediated MOMP is a key mechanism of diclofenac-induced lethal cell injury in human hepatocytes, and that CsA can prevent MOMP through inhibition of Bax activation. These data support our concept that the Ca 2+ -Bid-Bax-MOMP axis is a critical pathway in diclofenac (metabolite)-induced hepatocyte injury

  6. Defining poverty as distinctively human

    H.P.P. Lötter

    2007-05-01

    Full Text Available While it is relatively easy for most people to identify human beings suffering from poverty, it is rather more difficult to come to a proper understanding of poverty. In this article the author wants to deepen our understanding of poverty by interpreting the conventional definitions of poverty in a new light. The article starts with a defence of a claim that poverty is a concept uniquely applicable to humans. It then present a critical discussion of the distinction between absolute and relative poverty and it is then argued that a revision of this distinction can provide general standards applicable to humans everywhere.

  7. Regulation of T cell activation by HIV-1 accessory proteins: Vpr acts via distinct mechanisms to cooperate with Nef in NFAT-directed gene expression and to promote transactivation by CREB

    Lahti, Anna L.; Manninen, Aki; Saksela, Kalle

    2003-01-01

    Nef and Vpr are lentiviral accessory proteins that have been implicated in regulation of cellular gene expression. We noticed that Vpr can potentiate Nef-induced activation of nuclear factor of activated T cells (NFAT)-dependent transcription. Unlike Nef, which stimulated calcium signaling to activate NFAT, Vpr functioned farther downstream. Similar to the positive effects of Vpr on most of the transcriptional test systems that we used, potentiation of NFAT-directed gene expression was relatively modest in magnitude (two- to threefold) and depended on the cell cycle-arresting capacity of Vpr. By contrast, we found that Vpr could cause more than fivefold upregulation of cyclic AMP response element (CRE)-directed transcription via a mechanism that did not require Vpr-induced G2/M arrest. This effect, however, was only evident under suboptimal conditions known to lead to serine phosphorylation of the CRE binding factor (CREB) but not to CREB-dependent gene expression. This suggested that Vpr may act by stabilizing interactions with CREB and its transcriptional cofactor CREB binding protein (CBP). Indeed, this effect could be blocked by cotransfection of the adenoviral CBP inhibitor E1A. These results provide additional evidence for cell cycle-independent regulation of gene expression by Vpr and implicate CREB as a potentially important target for Vpr action in HIV-infected host cells

  8. A Novel Algorithm for the Generation of Distinct Kinematic Chain

    Medapati, Sreenivasa Reddy; Kuchibhotla, Mallikarjuna Rao; Annambhotla, Balaji Srinivasa Rao

    2016-07-01

    Generation of distinct kinematic chains is an important topic in the design of mechanisms for various industrial applications i.e., robotic manipulator, tractor, crane etc. Many researchers have intently focused on this area and explained various processes of generating distinct kinematic chains which are laborious and complex. It is desirable to enumerate the kinematic chains systematically to know the inherent characteristics of a chain related to its structure so that all the distinct chains can be analyzed in depth, prior to the selection of a chain for a purpose. This paper proposes a novel and simple method with set of rules defined to eliminate isomorphic kinematic chains generating distinct kinematic chains. Also, this method simplifies the process of generating distinct kinematic chains even at higher levels i.e., 10-link, 11-link with single and multiple degree of freedom.

  9. MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression.

    Christopher R Shaler

    2017-06-01

    Full Text Available Superantigens (SAgs are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS. Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB; ii the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT or γδ T cells, and is characterized by production of interferon (IFN-γ, tumor necrosis factor (TNF-α and interleukin (IL-2, but not IL-17A; iii high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1 participation, is required for MAIT cell activation; iv MAIT cell responses to SEB can occur in a T cell receptor (TCR Vβ-specific manner but are largely contributed by IL-12 and IL-18; v as MAIT cells are primed by SAgs, they also begin to

  10. Presidential address: distinction or extinction.

    Pressman, Barry D

    2008-10-01

    Despite its continuing scientific successes in imaging, radiology as a specialty is faced with a very difficult and competitive environment. Nonradiologists are more and more interested in vertically integrating imaging into their practices, while teleradiology and picture archiving and communication systems are resulting in the greater isolation of radiologists. Commoditization is a realistic and devastating threat to the survival and professionalism of the specialty. To remain viable as a specialty, radiologists must elevate their practice by subspecializing, becoming more involved with clinical care, and actively interacting with patients and referring clinicians. Distinction will prevent extinction.

  11. Pseudomonas piscicida kills vibrios by two distinct mechanisms

    Pseudoalteromonas piscicida is a naturally-occurring marine bacterium which kills competing bacteria, including vibrios. In studies by Richards et al. (AEM00175-17), three strains of P. piscicida were isolated and characterized. Strains secreted proteolytic enzymes which likely killed competing or...

  12. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

    Le Billan, Florian; Amazit, Larbi; Bleakley, Kevin; Xue, Qiong-Yao; Pussard, Eric; Lhadj, Christophe; Kolkhof, Peter; Viengchareun, Say; Fagart, Jérôme; Lombès, Marc

    2018-05-07

    Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling. Here, we decipher the transcriptional regulatory mechanisms that underlie selective effects of MRs and GRs on shared genomic targets in a human renal cellular model. Kinetic, serial, and sequential chromatin immunoprecipitation approaches were performed on the period circadian protein 1 ( PER1) target gene, providing evidence that both receptors dynamically and cyclically interact at the same target promoter in a specific and distinct transcriptional signature. During this process, both receptors regulate PER1 gene by binding as homo- or heterodimers to the same promoter region. Our results suggest a novel level of MR-GR target gene regulation, which should be considered for a better and integrated understanding of corticosteroid-related pathophysiology.-Le Billan, F., Amazit, L., Bleakley, K., Xue, Q.-Y., Pussard, E., Lhadj, C., Kolkhof, P., Viengchareun, S., Fagart, J., Lombès, M. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

  13. NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies.

    Wallace, John L

    2012-01-01

    The mechanisms underlying the ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through suppression of gastric acid secretion (mainly with proton pump inhibitors). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs is less well understood, involving more complex mechanisms than those in the stomach and proximal duodenum. There is clear evidence for important contributions to NSAID enteropathy of enteric bacteria, bile and enterohepatic recirculation of the NSAID. There is no evidence that suppression of gastric acid secretion will reduce the incidence or severity of NSAID enteropathy. Indeed, clinical data suggest little, if any, benefit. Animal studies suggest a significant exacerbation of NSAID enteropathy when proton pump inhibitors are co-administered with the NSAID. This worsening of damage appears to be linked to changes in the number and types of bacteria in the small intestine during proton pump inhibitor therapy. The distinct mechanisms of NSAID-induced injury in the stomach/proximal duodenum versus the more distal small intestine likely dictate distinct strategies for prevention. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  14. Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma.

    Terra Vleeshouwer-Neumann

    Full Text Available Embryonal rhabdomyosarcoma (ERMS is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

  15. Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy.

    Faber, C.G.; Hoeijmakers, J.G.; Ahn, H.S.; Cheng, X.; Han, C.; Choi, J.S.; Estacion, M.; Lauria, G.; Vanhoutte, E.K.; Gerrits, M.M.; Dib-Hajj, S.; Drenth, J.P.H.; Waxman, S.G.; Merkies, I.S.

    2012-01-01

    OBJECTIVE: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations

  16. Gain-of-function KCNJ6 Mutation in a Severe Hyperkinetic Movement Disorder Phenotype.

    Horvath, Gabriella A; Zhao, Yulin; Tarailo-Graovac, Maja; Boelman, Cyrus; Gill, Harinder; Shyr, Casper; Lee, James; Blydt-Hansen, Ingrid; Drögemöller, Britt I; Moreland, Jacqueline; Ross, Colin J; Wasserman, Wyeth W; Masotti, Andrea; Slesinger, Paul A; van Karnebeek, Clara D M

    2018-05-29

    Here, we describe a fourth case of a human with a de novo KCNJ6 (GIRK2) mutation, who presented with clinical findings of severe hyperkinetic movement disorder and developmental delay, similar to the Keppen-Lubinsky syndrome but without lipodystrophy. Whole-exome sequencing of the patient's DNA revealed a heterozygous de novo variant in the KCNJ6 (c.512T>G, p.Leu171Arg). We conducted in vitro functional studies to determine if this Leu-to-Arg mutation alters the function of GIRK2 channels. Heterologous expression of the mutant GIRK2 channel alone produced an aberrant basal inward current that lacked G protein activation, lost K + selectivity and gained Ca 2+ permeability. Notably, the inward current was inhibited by the Na + channel blocker QX-314, similar to the previously reported weaver mutation in murine GIRK2. Expression of a tandem dimer containing GIRK1 and GIRK2(p.Leu171Arg) did not lead to any currents, suggesting heterotetramers are not functional. In neurons expressing p.Leu171Arg GIRK2 channels, these changes in channel properties would be expected to generate a sustained depolarization, instead of the normal G protein-gated inhibitory response, which could be mitigated by expression of other GIRK subunits. The identification of the p.Leu171Arg GIRK2 mutation potentially expands the Keppen-Lubinsky syndrome phenotype to include severe dystonia and ballismus. Our study suggests screening for dominant KCNJ6 mutations in the evaluation of patients with severe movement disorders, which could provide evidence to support a causal role of KCNJ6 in neurological channelopathies. Copyright © 2018. Published by Elsevier Ltd.

  17. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

    Vincent Runtuwene

    2011-05-01

    Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.

  18. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

    Runtuwene, V.J.; van Eekelen, M.J.L.; Overvoorde, J.; Rehmann, H.; Yntema, H.G.; Nillesen, W.M.; van Haeringen, A.; van der Burgt, I.; Burgering, B.; den Hertog, J.

    2011-01-01

    Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS

  19. Processes of fungal proteome evolution and gain of function: gene duplication and domain rearrangement

    Cohen-Gihon, Inbar; Nussinov, Ruth; Sharan, Roded

    2011-01-01

    During evolution, organisms have gained functional complexity mainly by modifying and improving existing functioning systems rather than creating new ones ab initio. Here we explore the interplay between two processes which during evolution have had major roles in the acquisition of new functions: gene duplication and protein domain rearrangements. We consider four possible evolutionary scenarios: gene families that have undergone none of these event types; only gene duplication; only domain rearrangement, or both events. We characterize each of the four evolutionary scenarios by functional attributes. Our analysis of ten fungal genomes indicates that at least for the fungi clade, species significantly appear to gain complexity by gene duplication accompanied by the expansion of existing domain architectures via rearrangements. We show that paralogs gaining new domain architectures via duplication tend to adopt new functions compared to paralogs that preserve their domain architectures. We conclude that evolution of protein families through gene duplication and domain rearrangement is correlated with their functional properties. We suggest that in general, new functions are acquired via the integration of gene duplication and domain rearrangements rather than each process acting independently

  20. A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

    Rutsch, Frank; Macdougall, Mary; Lu, Changming; Buers, Insa; Mamaeva, Olga; Nitschke, Yvonne; Rice, Gillian I.; Erlandsen, Heidi; Kehl, Hans Gerd; Thiele, Holger; Nürnberg, Peter; Höhne, Wolfgang; Crow, Yanick J.; Feigenbaum, Annette; Hennekam, Raoul C.

    2015-01-01

    Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of

  1. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

    Runtuwene, Vincent; van Eekelen, Mark; Overvoorde, John; Rehmann, Holger; Yntema, Helger G.; Nillesen, Willy M.; van Haeringen, Arie; van der Burgt, Ineke; Burgering, Boudewijn; den Hertog, Jeroen

    2011-01-01

    SUMMARY Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome. PMID:21263000

  2. Gain-of-function screen for genes that affect Drosophila muscle pattern formation.

    Nicole Staudt

    2005-10-01

    Full Text Available This article reports the production of an EP-element insertion library with more than 3,700 unique target sites within the Drosophila melanogaster genome and its use to systematically identify genes that affect embryonic muscle pattern formation. We designed a UAS/GAL4 system to drive GAL4-responsive expression of the EP-targeted genes in developing apodeme cells to which migrating myotubes finally attach and in an intrasegmental pattern of cells that serve myotubes as a migration substrate on their way towards the apodemes. The results suggest that misexpression of more than 1.5% of the Drosophila genes can interfere with proper myotube guidance and/or muscle attachment. In addition to factors already known to participate in these processes, we identified a number of enzymes that participate in the synthesis or modification of protein carbohydrate side chains and in Ubiquitin modifications and/or the Ubiquitin-dependent degradation of proteins, suggesting that these processes are relevant for muscle pattern formation.

  3. Rolie-Poly fluid flowing through constrictions: Two distinct instabilities

    Reis, T.; Wilson, H.J.

    2013-01-01

    Elastic instabilities of entangled polymer melts are common in industrial processes but the physics responsible is not well understood. We present a numerical linear stability study of a molecular based constitutive model which grants us physical insight into the underlying mechanics involved. Two constriction flows are considered - one shear dominated, the other extension dominated - and two distinct instabilities are found. The influence of the molecular structure and the behaviour of the polymer dynamics are investigated and in both cases chain relaxation and orientation play a crucial role. This suggests a molecular-based physical interpretation of the underlying mechanisms responsible for flow instabilities. © 2013 Elsevier B.V.

  4. Rolie-Poly fluid flowing through constrictions: Two distinct instabilities

    Reis, T.

    2013-05-01

    Elastic instabilities of entangled polymer melts are common in industrial processes but the physics responsible is not well understood. We present a numerical linear stability study of a molecular based constitutive model which grants us physical insight into the underlying mechanics involved. Two constriction flows are considered - one shear dominated, the other extension dominated - and two distinct instabilities are found. The influence of the molecular structure and the behaviour of the polymer dynamics are investigated and in both cases chain relaxation and orientation play a crucial role. This suggests a molecular-based physical interpretation of the underlying mechanisms responsible for flow instabilities. © 2013 Elsevier B.V.

  5. Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy.

    Wei, Feng; Yan, Li-Min; Su, Tao; He, Na; Lin, Zhi-Jian; Wang, Jie; Shi, Yi-Wu; Yi, Yong-Hong; Liao, Wei-Ping

    2017-08-01

    Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations. Eleven genes featured loss-of-function mutations and six had gain-of-function mutations. Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.

  6. Amnesia, rehearsal, and temporal distinctiveness models of recall.

    Brown, Gordon D A; Della Sala, Sergio; Foster, Jonathan K; Vousden, Janet I

    2007-04-01

    Classical amnesia involves selective memory impairment for temporally distant items in free recall (impaired primacy) together with relative preservation of memory for recency items. This abnormal serial position curve is traditionally taken as evidence for a distinction between different memory processes, with amnesia being associated with selectively impaired long-term memory. However recent accounts of normal serial position curves have emphasized the importance of rehearsal processes in giving rise to primacy effects and have suggested that a single temporal distinctiveness mechanism can account for both primacy and recency effects when rehearsal is considered. Here we explore the pattern of strategic rehearsal in a patient with very severe amnesia. When the patient's rehearsal pattern is taken into account, a temporal distinctiveness model can account for the serial position curve in both amnesic and control free recall. The results are taken as consistent with temporal distinctiveness models of free recall, and they motivate an emphasis on rehearsal patterns in understanding amnesic deficits in free recall.

  7. Validity of Sensory Systems as Distinct Constructs

    Su, Chia-Ting; Parham, L. Diane

    2014-01-01

    Confirmatory factor analysis testing whether sensory questionnaire items represented distinct sensory system constructs found, using data from two age groups, that such constructs can be measured validly using questionnaire data.

  8. Visual distinctiveness can enhance recency effects.

    Bornstein, B H; Neely, C B; LeCompte, D C

    1995-05-01

    Experimental efforts to meliorate the modality effect have included attempts to make the visual stimulus more distinctive. McDowd and Madigan (1991) failed to find an enhanced recency effect in serial recall when the last item was made more distinct in terms of its color. In an attempt to extend this finding, three experiments were conducted in which visual distinctiveness was manipulated in a different manner, by combining the dimensions of physical size and coloration (i.e., whether the stimuli were solid or outlined in relief). Contrary to previous findings, recency was enhanced when the size and coloration of the last item differed from the other items in the list, regardless of whether the "distinctive" item was larger or smaller than the remaining items. The findings are considered in light of other research that has failed to obtain a similar enhanced recency effect, and their implications for current theories of the modality effect are discussed.

  9. Distinctiveness of Saudi Arabian EFL Learners

    Manssour Habbash

    2016-04-01

    Full Text Available In view of the increasing concern among English language teachers dealing with students from Saudi Arabia, as it manifests in TESOL community discussions, about the uniqueness of Saudi Arabian EFL learners, this paper attempts to document the outcome of a study of their distinctiveness from the perspective of expatriate teachers working for PYPs (Preparatory Year Programs in Saudi Arabia. This study examines the distinctiveness with regard to the learning attitudes of Saudi students that are often cultivated by the culture and academic environment in their homeland. Employing an emic approach for collecting the required data an analysis was carried out in light of the other studies on ‘education’ in Saudi Arabia that have particular reference to the factors that can positively influence student motivation, student success and the academic environment. The findings were used in constructing the rationale behind such distinctiveness. Assuming that the outcome of the discussion on the findings of this exploration can be helpful for teachers in adapting their teaching methodology and improving their teacher efficacy in dealing with students both from the kingdom and in the kingdom, some recommendations are made. Keywords: China Distinctiveness, Saudi Arabian University context, Expatriate teachers’ perspective, Distinctiveness Theory

  10. On Hobbes’s distinction of accidents

    Lupoli Agostino

    2012-06-01

    Full Text Available An interpolation introduced by K. Schuhmann in his critical edition of "De corpore" (chap. VI, § 13 diametrically overturns the meaning of Hobbes’s doctrine of distinction of accidents in comparison with all previous editions. The article focuses on the complexity of this crucial juncture in "De corpore" argument on which depends the interpretation of Hobbes’s whole conception of science. It discusses the reasons pro and contra Schuhmann’s interpolation and concludes against it, because it is not compatible with the rationale underlying the complex architecture of "De corpore", which involves a symmetry between the ‘logical’ distinction of accidents and the ‘metaphysical’ distinction of phantasms.

  11. What makes health promotion research distinct?

    Woodall, James; Warwick-Booth, Louise; South, Jane; Cross, Ruth

    2018-02-01

    There have been concerns about the decline of health promotion as a practice and discipline and, alongside this, calls for a clearer articulation of health promotion research and what, if anything, makes it distinct. This discussion paper, based on a review of the literature, the authors' own experiences in the field, and a workshop delivered by two of the authors at the 8th Nordic Health Promotion Conference, seeks to state the reasons why health promotion research is distinctive. While by no means exhaustive, the paper suggests four distinctive features. The paper hopes to be a catalyst to enable health promotion researchers to be explicit in their practice and to begin the process of developing an agreed set of research principles.

  12. Intergroup Leadership Across Distinct Subgroups and Identities.

    Rast, David E; Hogg, Michael A; van Knippenberg, Daan

    2018-03-01

    Resolving intergroup conflict is a significant and often arduous leadership challenge, yet existing theory and research rarely, if ever, discuss or examine this situation. Leaders confront a significant challenge when they provide leadership across deep divisions between distinct subgroups defined by self-contained identities-The challenge is to avoid provoking subgroup identity distinctiveness threat. Drawing on intergroup leadership theory, three studies were conducted to test the core hypothesis that, where identity threat exists, leaders promoting an intergroup relational identity will be better evaluated and are more effective than leaders promoting a collective identity; in the absence of threat, leaders promoting a collective identity will prevail. Studies 1 and 2 ( N = 170; N = 120) supported this general proposition. Study 3 ( N = 136) extended these findings, showing that leaders promoting an intergroup relational identity, but not a collective identity, improved intergroup attitudes when participants experienced an identity distinctiveness threat.

  13. Distinctive Dynamic Capabilities for New Business Creation

    Rosenø, Axel; Enkel, Ellen; Mezger, Florian

    2013-01-01

    This study examines the distinctive dynamic capabilities for new business creation in established companies. We argue that these are very different from those for managing incremental innovation within a company's core business. We also propose that such capabilities are needed in both slow...... and fast-paced industries, and that similarities exist across industries. Hence, the study contributes to dynamic capabilities literature by: 1) identifying the distinctive dynamic capabilities for new business creation; 2) shifting focus away from dynamic capabilities in environments characterised by high...... clock-speed and uncertainty towards considering dynamic capabilities for the purpose of developing new businesses, which also implies a high degree of uncertainty. Based on interviews with 33 companies, we identify distinctive dynamic capabilities for new business creation, find that dynamic...

  14. Fermionic bound states in distinct kinklike backgrounds

    Bazeia, D. [Universidade Federal da Paraiba, Departamento de Fisica, Joao Pessoa, Paraiba (Brazil); Mohammadi, A. [Universidade Federal de Campina Grande, Departamento de Fisica, Caixa Postal 10071, Campina Grande, Paraiba (Brazil)

    2017-04-15

    This work deals with fermions in the background of distinct localized structures in the two-dimensional spacetime. Although the structures have a similar topological character, which is responsible for the appearance of fractionally charged excitations, we want to investigate how the geometric deformations that appear in the localized structures contribute to the change in the physical properties of the fermionic bound states. We investigate the two-kink and compact kinklike backgrounds, and we consider two distinct boson-fermion interactions, one motivated by supersymmetry and the other described by the standard Yukawa coupling. (orig.)

  15. Common and distinct components in data fusion

    Smilde, Age Klaas; Mage, Ingrid; Næs, Tormod

    2016-01-01

    and understanding their relative merits. This paper provides a unifying framework for this subfield of data fusion by using rigorous arguments from linear algebra. The most frequently used methods for distinguishing common and distinct components are explained in this framework and some practical examples are given...

  16. Knowledge Affords Distinctive Processing in Memory

    Hunt, R. Reed; Rawson, Katherine A.

    2011-01-01

    The effect of knowledge on memory generally is processing. However, both conceptual and empirical reasons exist to suspect that the organizational account is incomplete. Recently a revised version of that account has been proposed under the rubric of distinctiveness theory (Rawson & Van Overschelde, 2008). The goal of the experiments reported…

  17. Distinctiveness of Saudi Arabian EFL Learners

    Habbash, Manssour; Idapalapati, Srinivasa Rao

    2016-01-01

    In view of the increasing concern among English language teachers dealing with students from Saudi Arabia, as it manifests in TESOL community discussions, about the uniqueness of Saudi Arabian EFL learners, this paper attempts to document the outcome of a study of their distinctiveness from the perspective of expatriate teachers working for PYPs…

  18. Keeping conceptual boundaries distinct between decision making and learning is necessary to understand social influence.

    Le Mens, Gaël

    2014-02-01

    Bentley et al. make the deliberate choice to blur the distinction between learning and decision making. This obscures the social influence mechanisms that operate in the various empirical settings that their map aims to categorize. Useful policy prescriptions, however, require an accurate understanding of the social influence mechanisms that underlie the dynamics of popularity.

  19. Embarrassment: its distinct form and appeasement functions.

    Keltner, D; Buswell, B N

    1997-11-01

    The authors address 2 questions about embarrassment. First, Is embarrassment a distinct emotion? The evidence indicates that the antecedents, experience, and display of embarrassment, and to a limited extent its autonomic physiology, are distinct from shame, guilt, and amusement and share the dynamic, temporal characteristics of emotion. Second, What are the theoretical accounts of embarrassment? Three accounts focus on the causes of embarrassment, positioning that it follows the loss of self-esteem, concern for others' evaluations, or absence of scripts to guide interactions. A fourth account focuses on the effects of the remedial actions of embarrassment, which correct preceding transgressions. A fifth account focuses on the functional parallels between embarrassment and nonhuman appeasement. The discussion focuses on unanswered questions about embarrassment.

  20. Distinctive skeletal dysplasia in Cockayne syndrome

    Silengo, M.C.; Franceschini, P.; Bianco, R.; Biagioli, M.; Pastorin, L.; Vista, N.; Baldassar, A.; Benso, L.

    1986-01-01

    Cockayne syndrom is a well-known autosomal recessive form of dwarfism with senile-like appearance. Skeletal changes such as flattening of vertebral bodies, ivory epiphyses and thickening of cranial vault, have been observed in some patients with this condition. We describe here a 5.5-year-old girl with the typical clinical signs of Cockayne syndrome and a distinctive form of bone dysplasia with major involvment of the spine. (orig.)

  1. Distinctive skeletal dysplasia in Cockayne syndrome

    Silengo, M.C.; Franceschini, P.; Bianco, R.; Biagioli, M.; Pastorin, L.; Vista, N.; Baldassar, A.; Benso, L.

    1986-03-01

    Cockayne syndrome is a well-known autosomal recessive form of dwarfism with senile-like appearance. Skeletal changes such as flattening of vertebral bodies, ivory epiphyses and thickening of cranial vault, have been observed in some patients with this condition. We describe here a 5.5-year-old girl with the typical clinical signs of Cockayne syndrome and a distinctive form of bone dysplasia with major involvement of the spine.

  2. Army nurses in wartime: distinction and pride.

    Higgins, L P

    1996-08-01

    Nurses have served with distinction in wartime since Florence Nightingale went to the Crimea. Women often accompanied their husbands to battle during the Revolutionary and Civil Wars, caring for the sick and wounded. Although not officially given officer status until 1920, Army nurses served in the Spanish-American War and World War I. As officers, thousands of nurses served in subsequent wars, distinguishing themselves by their heroism, devotion to duty, and sheer tenacity of spirit.

  3. The origin of the distinction between microscopic formulas for stress and Cauchy stress

    Chen, Youping

    2016-01-01

    Stress is calculated routinely in atomistic simulations. The widely used microscopic stress formulas derived from classical or quantum mechanics, however, are distinct from the concept of Cauchy stress, i.e., the true mechanical tress. This work examines various atomistic stress formulations and their inconsistencies. Using standard mathematic theorems and the law of mechanics, we show that Cauchy stress results unambiguously from the definition of internal force density, thereby removing the...

  4. A distinction of two discourses concerning wellbeing

    Wistoft, Karen; Qvortrup, Lars

    2017-01-01

    and behavioral mental health interventions, while the latter defines wellbeing in positive terms with a focus on wellbeing as the result of learning and with pedagogical interventions that only indirectly can support the individual’s learning activity. The former sees wellbeing as the result of a “wellbeing cure......The article concerns the current discourses concerning well-being with the point that it is important to make a distinction between a healthcare oriented discourse and a learning oriented discourse. The former defines wellbeing in negative terms and looks at causally oriented aspects of wellbeing......”, while the latter sees wellbeing as the result of wellbeing learning processes....

  5. Approaching the Distinction between Intuition and Insight.

    Zhang, Zhonglu; Lei, Yi; Li, Hong

    2016-01-01

    Intuition and insight share similar cognitive and neural basis. Though, there are still some essential differences between the two. Here in this short review, we discriminated between intuition, and insight in two aspects. First, intuition, and insight are toward different aspects of information processing. Whereas intuition involves judgment about "yes or no," insight is related to "what" is the solution. Second, tacit knowledge play different roles in between intuition and insight. On the one hand, tacit knowledge is conducive to intuitive judgment. On the other hand, tacit knowledge may first impede but later facilitate insight occurrence. Furthermore, we share theoretical, and methodological views on how to access the distinction between intuition and insight.

  6. The neural signatures of distinct psychopathic traits.

    Carré, Justin M; Hyde, Luke W; Neumann, Craig S; Viding, Essi; Hariri, Ahmad R

    2013-01-01

    Recent studies suggest that psychopathy may be associated with dysfunction in the neural circuitry supporting both threat- and reward-related processes. However, these studies have involved small samples and often focused on extreme groups. Thus, it is unclear to what extent current findings may generalize to psychopathic traits in the general population. Furthermore, no studies have systematically and simultaneously assessed associations between distinct psychopathy facets and both threat- and reward-related brain function in the same sample of participants. Here, we examined the relationship between threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity and variation in four facets of self-reported psychopathy in a sample of 200 young adults. Path models indicated that amygdala reactivity to fearful facial expressions is negatively associated with the interpersonal facet of psychopathy, whereas amygdala reactivity to angry facial expressions is positively associated with the lifestyle facet. Furthermore, these models revealed that differential VS reactivity to positive versus negative feedback is negatively associated with the lifestyle facet. There was suggestive evidence for gender-specific patterns of association between brain function and psychopathy facets. Our findings are the first to document differential associations between both threat- and reward-related neural processes and distinct facets of psychopathy and thus provide a more comprehensive picture of the pattern of neural vulnerabilities that may predispose to maladaptive outcomes associated with psychopathy.

  7. The Distinction Between Curative and Assistive Technology.

    Stramondo, Joseph A

    2018-05-01

    Disability activists have sometimes claimed their disability has actually increased their well-being. Some even say they would reject a cure to keep these gains. Yet, these same activists often simultaneously propose improvements to the quality and accessibility of assistive technology. However, for any argument favoring assistive over curative technology (or vice versa) to work, there must be a coherent distinction between the two. This line is already vague and will become even less clear with the emergence of novel technologies. This paper asks and tries to answer the question: what is it about the paradigmatic examples of curative and assistive technologies that make them paradigmatic and how can these defining features help us clarify the hard cases? This analysis will begin with an argument that, while the common views of this distinction adequately explain the paradigmatic cases, they fail to accurately pick out the relevant features of those technologies that make them paradigmatic and to provide adequate guidance for parsing the hard cases. Instead, it will be claimed that these categories of curative or assistive technologies are defined by the role the technologies play in establishing a person's relational narrative identity as a member of one of two social groups: disabled people or non-disabled people.

  8. Distinct types of eigenvector localization in networks

    Pastor-Satorras, Romualdo; Castellano, Claudio

    2016-01-01

    The spectral properties of the adjacency matrix provide a trove of information about the structure and function of complex networks. In particular, the largest eigenvalue and its associated principal eigenvector are crucial in the understanding of nodes’ centrality and the unfolding of dynamical processes. Here we show that two distinct types of localization of the principal eigenvector may occur in heterogeneous networks. For synthetic networks with degree distribution P(q) ~ q-γ, localization occurs on the largest hub if γ > 5/2 for γ < 5/2 a new type of localization arises on a mesoscopic subgraph associated with the shell with the largest index in the K-core decomposition. Similar evidence for the existence of distinct localization modes is found in the analysis of real-world networks. Our results open a new perspective on dynamical processes on networks and on a recently proposed alternative measure of node centrality based on the non-backtracking matrix.

  9. Network analysis reveals distinct clinical syndromes underlying acute mountain sickness.

    David P Hall

    Full Text Available Acute mountain sickness (AMS is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS, we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25. These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes.

  10. Stalled replication forks generate a distinct mutational signature in yeast

    Larsen, Nicolai B.; Liberti, Sascha E.; Vogel, Ivan

    2017-01-01

    Proliferating cells acquire genome alterations during the act of DNA replication. This leads to mutation accumulation and somatic cell mosaicism in multicellular organisms, and is also implicated as an underlying cause of aging and tumorigenesis. The molecular mechanisms of DNA replication...... Escherichia coli Tus/Ter complex) engineered into the yeast genome. We demonstrate that transient stalling at this barrier induces a distinct pattern of genome rearrangements in the newly replicated region behind the stalled fork, which primarily consist of localized losses and duplications of DNA sequences....... These genetic alterations arise through the aberrant repair of a single-stranded DNA gap, in a process that is dependent on Exo1- and Shu1-dependent homologous recombination repair (HRR). Furthermore, aberrant processing of HRR intermediates, and elevated HRR-associated mutagenesis, is detectable in a yeast...

  11. Entrepreneurship research in Spain: developments and distinctiveness.

    Sánchez, José C; Gutiérrez, Andrea

    2011-08-01

    This article presents a review of research on entrepreneurship in Spain, paying particular attention to its beginnings, nature and main focus of interest. We have developed a database based on the review of 471 works produced between 1977 and 2009, including articles published in national and international journals and dissertations (read in Spain) that allowed us to extract the following results. There is a preference for qualitative methods, conceptual contributions and the entrepreneurial process as the privileged research theme. There is also a strong focus of interest on micro and small enterprises. These characteristics of Spanish research in areas of entrepreneurship can make a distinctive contribution to international research. However, the dissemination of knowledge and inadequate strategies for international publication limit the diffusion of Spanish research in entrepreneurship. Lastly, we discuss the implications for future research.

  12. 10 distinct stellar populations in omega Centauri.

    Bellini, Andrea; Anderson, Jay; Bedin, Luigi R.; Cool, Adrienne; King, Ivan R.; van der marel, roeland p.

    2015-08-01

    We are constructing the most comprehensive catalog of photometry and proper motions ever assembled for a globular cluster. The core of omega Centauri has been imaged over 600 times through WFC3’s UVIS and IR channels for the purposes of detector calibration. There exist ~30 exposures each for 26 filters, stretching uniformly from F225W in the UV to F160W in the infrared. Furthermore, the 12-year baseline between this data and a 2002 ACS survey will more than triple both the accuracy and the number of well-measured stars compared to previous studies.This totally unprecedented complete spectral coverage for over 400,000 stars, from the red-giant branch down to the white dwarfs, provides the best chance yet to understand the multiple-population phenomenon in any globular cluster. A preliminary analysis of the color-magnitude diagrams in different bands already allows us to identify 10 distinct sequences.

  13. Anticancer properties of distinct antimalarial drug classes.

    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  14. Anticancer Properties of Distinct Antimalarial Drug Classes

    Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

    2013-01-01

    We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

  15. Neurophysiological Distinction between Schizophrenia and Schizoaffective Disorder

    Mathalon, Daniel H.; Hoffman, Ralph E.; Watson, Todd D.; Miller, Ryan M.; Roach, Brian J.; Ford, Judith M.

    2009-01-01

    Schizoaffective disorder (SA) is distinguished from schizophrenia (SZ) based on the presence of prominent mood symptoms over the illness course. Despite this clinical distinction, SA and SZ patients are often combined in research studies, in part because data supporting a distinct pathophysiological boundary between the disorders are lacking. Indeed, few studies have addressed whether neurobiological abnormalities associated with SZ, such as the widely replicated reduction and delay of the P300 event-related potential (ERP), are also present in SA. Scalp EEG was acquired from patients with DSM-IV SA (n = 15) or SZ (n = 22), as well as healthy controls (HC; n = 22) to assess the P300 elicited by infrequent target (15%) and task-irrelevant distractor (15%) stimuli in separate auditory and visual ”oddball” tasks. P300 amplitude was reduced and delayed in SZ, relative to HC, consistent with prior studies. These SZ abnormalities did not interact with stimulus type (target vs. task-irrelevant distractor) or modality (auditory vs. visual). Across sensory modality and stimulus type, SA patients exhibited normal P300 amplitudes (significantly larger than SZ patients and indistinguishable from HC). However, P300 latency and reaction time were both equivalently delayed in SZ and SA patients, relative to HC. P300 differences between SA and SZ patients could not be accounted for by variation in symptom severity, socio-economic status, education, or illness duration. Although both groups show similar deficits in processing speed, SA patients do not exhibit the P300 amplitude deficits evident in SZ, consistent with an underlying pathophysiological boundary between these disorders. PMID:20140266

  16. The pursuit of optimal distinctiveness and consumer preferences.

    He, Lingnan; Cong, Feng; Liu, Yanping; Zhou, Xinyue

    2010-10-01

    This article investigates the effect of optimal distinctiveness on consumer product consumption. The authors argue that consumers acquire and display material possessions to restore their optimal levels of distinctiveness. Results showed that placing consumers in a state of low distinctiveness increased desire to acquire distinctive products, whereas perceptions of high distinctiveness reduced desire to acquire such products. Consumers' desire for distinctiveness-related products held true for various consumer choices, including willingness to pay more for limited-edition products and preference for unpopular gifts. This finding has implications for understanding consumer choice in expressing identity. © 2010 The Authors. Scandinavian Journal of Psychology © 2010 The Scandinavian Psychological Associations.

  17. Distribution of Disease-Associated Copy Number Variants across Distinct Disorders of Cognitive Development

    Pescosolido, Matthew F.; Gamsiz, Ece D.; Nagpal, Shailender; Morrow, Eric M.

    2013-01-01

    Objective: The purpose of the present study was to discover the extent to which distinct "DSM" disorders share large, highly recurrent copy number variants (CNVs) as susceptibility factors. We also sought to identify gene mechanisms common to groups of diagnoses and/or specific to a given diagnosis based on associations with CNVs. Method:…

  18. Endpoint distinctiveness facilitates analogical mapping in pigeons.

    Hagmann, Carl Erick; Cook, Robert G

    2015-03-01

    Analogical thinking necessitates mapping shared relations across two separate domains. We investigated whether pigeons could learn faster with ordinal mapping of relations across two physical dimensions (circle size & choice spatial position) relative to random mapping of these relations. Pigeons were trained to relate six circular samples of different sizes to horizontally positioned choice locations in a six alternative matching-to-sample task. Three pigeons were trained in a mapped condition in which circle size mapped directly onto choice spatial position. Three other pigeons were trained in a random condition in which the relations between size and choice position were arbitrarily assigned. The mapped group showed an advantage over the random group in acquiring this task. In a subsequent second phase, relations between the dimensions were ordinally reversed for the mapped group and re-randomized for the random group. There was no difference in how quickly matching accuracy re-emerged in the two groups, although the mapped group eventually performed more accurately. Analyses suggested this mapped advantage was likely due to endpoint distinctiveness and the benefits of proximity errors during choice responding rather than a conceptual or relational advantage attributable to the common or ordinal mapping of the two dimensions. This potential difficulty in mapping relations across dimensions may limit the pigeons' capacity for more advanced types of analogical reasoning. This article is part of a Special Issue entitled: Tribute to Tom Zentall. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Endpoint Distinctiveness Facilitates Analogical Mapping in Pigeons

    Hagmann, Carl Erick; Cook, Robert G.

    2015-01-01

    Analogical thinking necessitates mapping shared relations across two separate domains. We investigated whether pigeons could learn faster with ordinal mapping of relations across two physical dimensions (circle size & choice spatial position) relative to random mapping of these relations. Pigeons were trained to relate six circular samples of different sizes to horizontally positioned choice locations in a six alternative matching-to-sample task. Three pigeons were trained in a mapped condition in which circle size mapped directly onto choice spatial position. Three other pigeons were trained in a random condition in which the relations between size and choice position were arbitrarily assigned. The mapped group showed an advantage over the random group in acquiring this task. In a subsequent second phase, reassignment, relations between the dimensions were ordinally reversed for the mapped group and re-randomized for the random group. There was no difference in how quickly matching accuracy re-emerged in the two groups, although the mapped group eventually performed more accurately. Analyses suggested this mapped advantage was likely due endpoint distinctiveness and the benefits of proximity errors during choice responding rather than a conceptual or relational advantage attributable to the common or ordinal map of the two dimensions. This potential difficulty in mapping relations across dimensions may limit the pigeons’ capacity for more advanced types of analogical reasoning. PMID:25447511

  20. Reservoir floodplains support distinct fish assemblages

    Miranda, Leandro E.; Wigen, S. L.; Dagel, Jonah D.

    2014-01-01

    Reservoirs constructed on floodplain rivers are unique because the upper reaches of the impoundment may include extensive floodplain environments. Moreover, reservoirs that experience large periodic water level fluctuations as part of their operational objectives seasonally inundate and dewater floodplains in their upper reaches, partly mimicking natural inundations of river floodplains. In four flood control reservoirs in Mississippi, USA, we explored the dynamics of connectivity between reservoirs and adjacent floodplains and the characteristics of fish assemblages that develop in reservoir floodplains relative to those that develop in reservoir bays. Although fish species richness in floodplains and bays were similar, species composition differed. Floodplains emphasized fish species largely associated with backwater shallow environments, often resistant to harsh environmental conditions. Conversely, dominant species in bays represented mainly generalists that benefit from the continuous connectivity between the bay and the main reservoir. Floodplains in the study reservoirs provided desirable vegetated habitats at lower water level elevations, earlier in the year, and more frequently than in bays. Inundating dense vegetation in bays requires raising reservoir water levels above the levels required to reach floodplains. Therefore, aside from promoting distinct fish assemblages within reservoirs and helping promote diversity in regulated rivers, reservoir floodplains are valued because they can provide suitable vegetated habitats for fish species at elevations below the normal pool, precluding the need to annually flood upland vegetation that would inevitably be impaired by regular flooding. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

  1. Health and morality: two conceptually distinct categories?

    Tengland, Per-Anders

    2012-03-01

    When seeing immoral actions, criminal or not, we sometimes deem the people who perform them unhealthy. This is especially so if the actions are of a serious nature, e.g. involving murder, assault, or rape. We turn our moral evaluation into an evaluation about health and illness. This tendency is partly supported by some diagnoses found in the DMS-IV, such as Antisocial personality disorder, and the ICD-10, such as Dissocial personality disorder. The aim of the paper is to answer the question: How analytically sound is the inclusion of morality into a theory of health? The holistic theory of Lennart Nordenfelt is used as a starting point, and it is used as an example of a theory where morality and health are conceptually distinct categories. Several versions of a pluralistic holistic theory are then discussed in order to see if, and if so, how, morality can be conceptually related to health. It is concluded that moral abilities (and dispositions) can be seen as being part of the individual's health. It is harder to incorporate moral virtues and moral actions into such a theory. However, if immoral actions "cluster" in an individual, and are of a severe kind, causing serious harm to other people, it is more likely that the person, for those reasons only, be deemed unhealthy.

  2. Are empathy and concern psychologically distinct?

    Jordan, Matthew R; Amir, Dorsa; Bloom, Paul

    2016-12-01

    Researchers have long been interested in the relationship between feeling what you believe others feel-often described as empathy-and caring about the welfare of others-often described as compassion or concern. Many propose that empathy is a prerequisite for concern and is therefore the ultimate motivator of prosocial actions. To assess this hypothesis, the authors developed the Empathy Index, which consists of 2 novel scales, and explored their relationship to a measure of concern as well as to measures of cooperative and altruistic behavior. A series of factor analyses reveal that empathy and concern consistently load on different factors. Furthermore, they show that empathy and concern motivate different behaviors: concern for others is a uniquely positive predictor of prosocial action whereas empathy is either not predictive or negatively predictive of prosocial actions. Together these studies suggest that empathy and concern are psychologically distinct and empathy plays a more limited role in our moral lives than many believe. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  3. Medical student empathy: interpersonal distinctions and correlates.

    Jordan, Kevin D; Foster, Penni Smith

    2016-12-01

    Attention to interpersonal behaviors, communication, and relational factors is taking on increasing importance in medical education. Medical student empathy is one aspect of the physician-patient relationship that is often involved in beneficial interactions leading to improved clinical outcomes and patient satisfaction. As an interpersonal quality, empathy is a social behavior well-suited to be examined from an interpersonal perspective. The present study used the interpersonal theory of clinical, personality, and social psychology to examine the construct of empathy and theorize about likely interpersonal correlates. One hundred and sixty-three students from an academic health center in the southeastern United States participated in this study. The medical student version of the Jefferson Scale of Empathy was used to assess empathy and its factors: Perspective taking, compassionate care, and walking in the patient's shoes. Interpersonal assessments included the International Personality Item Pool-Interpersonal Circumplex, the Interpersonal Support Evaluation List, and the UCLA Loneliness Scale. Distinct interpersonal styles and correlates emerged among empathy and its factors. While all factors of empathy were related to interpersonal warmth, perspective taking and compassionate care were also associated with submissiveness. Of note, only walking in the patient's shoes was correlated with both social support and less loneliness. These findings are discussed in light of interpersonal theory with particular attention paid to the implications for medical education and professional development.

  4. Biophysics of cancer progression and high-throughput mechanical characterization of biomaterials

    Osborne, Lukas Dylan

    Cancer metastasis involves a series of events known as the metastatic cascade. In this complex progression, cancer cells detach from the primary tumor, invade the surrounding stromal space, transmigrate the vascular system, and establish secondary tumors at distal sites. Specific mechanical phenotypes are likely adopted to enable cells to successfully navigate the mechanical environments encountered during metastasis. To examine the role of cell mechanics in cancer progression, I employed force-consistent biophysical and biochemical assays to characterize the mechanistic links between stiffness, stiffness response and cell invasion during the epithelial to mesenchymal transition (EMT). EMT is an essential physiological process, whose abnormal reactivation has been implicated in the detachment of cancer cells from epithelial tissue and their subsequent invasion into stromal tissue. I demonstrate that epithelial-state cells respond to force by evoking a stiffening response, and that after EMT, mesenchymal-state cells have reduced stiffness but also lose the ability to increase their stiffness in response to force. Using loss and gain of function studies, two proteins are established as functional connections between attenuated stiffness and stiffness response and the increased invasion capacity acquired after EMT. To enable larger scale assays to more fully explore the connection between biomechanics and cancer, I discuss the development of an automated array high throughput (AHT) microscope. The AHT system is shown to implement passive microbead rheology to accurately characterize the mechanical properties of biomaterials. Compared to manually performed mechanical characterizations, the AHT system executes experiments in two orders of magnitude less time. Finally, I use the AHT microscope to study the effect of gain of function oncogenic molecules on cell stiffness. I find evidence that our assay can identify alterations in cell stiffness due to constitutive

  5. The evolution of compositionally and functionally distinct actin filaments.

    Gunning, Peter W; Ghoshdastider, Umesh; Whitaker, Shane; Popp, David; Robinson, Robert C

    2015-06-01

    The actin filament is astonishingly well conserved across a diverse set of eukaryotic species. It has essentially remained unchanged in the billion years that separate yeast, Arabidopsis and man. In contrast, bacterial actin-like proteins have diverged to the extreme, and many of them are not readily identified from sequence-based homology searches. Here, we present phylogenetic analyses that point to an evolutionary drive to diversify actin filament composition across kingdoms. Bacteria use a one-filament-one-function system to create distinct filament systems within a single cell. In contrast, eukaryotic actin is a universal force provider in a wide range of processes. In plants, there has been an expansion of the number of closely related actin genes, whereas in fungi and metazoa diversification in tropomyosins has increased the compositional variety in actin filament systems. Both mechanisms dictate the subset of actin-binding proteins that interact with each filament type, leading to specialization in function. In this Hypothesis, we thus propose that different mechanisms were selected in bacteria, plants and metazoa, which achieved actin filament compositional variation leading to the expansion of their functional diversity. © 2015. Published by The Company of Biologists Ltd.

  6. Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice

    Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M.J.M.; Pietrobon, Daniela

    2014-01-01

    Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca2+] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory–inhibitory balance in FHM1. PMID:24907493

  7. Distinct cardiac transcriptional profiles defining pregnancy and exercise.

    Eunhee Chung

    Full Text Available BACKGROUND: Although the hypertrophic responses of the heart to pregnancy and exercise are both considered to be physiological processes, they occur in quite different hormonal and temporal settings. In this study, we have compared the global transcriptional profiles of left ventricular tissues at various time points during the progression of hypertrophy in exercise and pregnancy. METHODOLOGY/PRINCIPAL FINDINGS: The following groups of female mice were analyzed: non-pregnant diestrus cycle sedentary control, mid-pregnant, late-pregnant, and immediate-postpartum, and animals subjected to 7 and 21 days of voluntary wheel running. Hierarchical clustering analysis shows that while mid-pregnancy and both exercise groups share the closest relationship and similar gene ontology categories, late pregnancy and immediate post-partum are quite different with high representation of secreted/extracellular matrix-related genes. Moreover, pathway-oriented ontological analysis shows that metabolism regulated by cytochrome P450 and chemokine pathways are the most significant signaling pathways regulated in late pregnancy and immediate-postpartum, respectively. Finally, increases in expression of components of the proteasome observed in both mid-pregnancy and immediate-postpartum also result in enhanced proteasome activity. Interestingly, the gene expression profiles did not correlate with the degree of cardiac hypertrophy observed in the animal groups, suggesting that distinct pathways are employed to achieve similar amounts of cardiac hypertrophy. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that cardiac adaptation to the later stages of pregnancy is quite distinct from both mid-pregnancy and exercise. Furthermore, it is very dynamic since, by 12 hours post-partum, the heart has already initiated regression of cardiac growth, and 50 genes have changed expression significantly in the immediate-postpartum compared to late-pregnancy. Thus, pregnancy

  8. Distinctiveness of Initial Preform Properties in Renovation

    V. M. Yaroslavtsev

    2015-01-01

    Full Text Available Technologies of renovation form a special group of resource-and energy saving technological processes as they are, by definition, already aimed either at increasing resource of the objects satisfying needs of the society life support and practical activities in different spheres, or at extension of their life cycle including a reuse of material from which they are made. Renovation is used where there is a material object, which does not meet requirements of standard or technical documentation.A characteristic feature of the renovation technologies is lack of procedure for a choice of the preform as in all cases an initial preform is the renovation object itself. Thus each object, acting as an initial preform, has the exclusively individual properties, including technological ones.Distinctiveness of renovation object properties is correlated, first of all, with the personified conditions of formation and (or change of condition of their properties in time at all stages of life cycle (production – transportation – warehousing – operation starting with a preform material when manufacturing under all types of loadings (technological and operational. As a result each object forms its "history" of loading and damages and, therefore, its information base which has to consider the phenomenon of “heredity of life cycle”. The term "heredity of life cycle" characterizes information support of object at any moment under review, including both information of technological inheritance, and data of operational heredity.As a result at every moment of time we have a product with a set of new, uncertain properties caused by the phenomena of heredity of life cycle. These properties are individual for each object to be renovated, which changed its status for the status of initial preform for different types of renovation technologies. This is one of the most important distinctions of renovation technology from the technology used to manufacture a new

  9. Peptidomic and transcriptomic profiling of four distinct spider venoms.

    Vera Oldrati

    Full Text Available Venom based research is exploited to find novel candidates for the development of innovative pharmacological tools, drug candidates and new ingredients for cosmetic and agrochemical industries. Moreover, venomics, as a well-established approach in systems biology, helps to elucidate the genetic mechanisms of the production of such a great molecular biodiversity. Today the advances made in the proteomics, transcriptomics and bioinformatics fields, favor venomics, allowing the in depth study of complex matrices and the elucidation even of minor compounds present in minute biological samples. The present study illustrates a rapid and efficient method developed for the elucidation of venom composition based on NextGen mRNA sequencing of venom glands and LC-MS/MS venom proteome profiling. The analysis of the comprehensive data obtained was focused on cysteine rich peptide toxins from four spider species originating from phylogenetically distant families for comparison purposes. The studied species were Heteropoda davidbowie (Sparassidae, Poecilotheria formosa (Theraphosidae, Viridasius fasciatus (Viridasiidae and Latrodectus mactans (Theridiidae. This led to a high resolution profiling of 284 characterized cysteine rich peptides, 111 of which belong to the Inhibitor Cysteine Knot (ICK structural motif. The analysis of H. davidbowie venom revealed a high richness in term of venom diversity: 95 peptide sequences were identified; out of these, 32 peptides presented the ICK structural motif and could be classified in six distinct families. The profiling of P. formosa venom highlighted the presence of 126 peptide sequences, with 52 ICK toxins belonging to three structural distinct families. V. fasciatus venom was shown to contain 49 peptide sequences, out of which 22 presented the ICK structural motif and were attributed to five families. The venom of L. mactans, until now studied for its large neurotoxins (Latrotoxins, revealed the presence of 14

  10. Distinct genetic alterations in colorectal cancer.

    Hassan Ashktorab

    Full Text Available BACKGROUND: Colon cancer (CRC development often includes chromosomal instability (CIN leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities. METHODOLOGY/PRINCIPAL FINDINGS: We applied genome-wide array comparative genome hybridization (aCGH using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes. There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. CONCLUSIONS/SIGNIFICANCE: Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs.

  11. Municipal solid waste landfills harbor distinct microbiomes

    Stamps, Blake W.; Lyles, Christopher N.; Suflita, Joseph M.; Masoner, Jason R.; Cozzarelli, Isabelle M.; Kolpin, Dana W.; Stevenson, Bradley S.

    2016-01-01

    Landfills are the final repository for most of the discarded material from human society and its “built environments.” Microorganisms subsequently degrade this discarded material in the landfill, releasing gases (largely CH4 and CO2) and a complex mixture of soluble chemical compounds in leachate. Characterization of “landfill microbiomes” and their comparison across several landfills should allow the identification of environmental or operational properties that influence the composition of these microbiomes and potentially their biodegradation capabilities. To this end, the composition of landfill microbiomes was characterized as part of an ongoing USGS national survey studying the chemical composition of leachates from 19 non-hazardous landfills across 16 states in the continental U.S. The landfills varied in parameters such as size, waste composition, management strategy, geography, and climate zone. The diversity and composition of bacterial and archaeal populations in leachate samples were characterized by 16S rRNA gene sequence analysis, and compared against a variety of physical and chemical parameters in an attempt to identify their impact on selection. Members of the Epsilonproteobacteria, Gammaproteobacteria, Clostridia, and candidate division OP3 were the most abundant. The distribution of the observed phylogenetic diversity could best be explained by a combination of variables and was correlated most strongly with the concentrations of chloride and barium, rate of evapotranspiration, age of waste, and the number of detected household chemicals. This study illustrates how leachate microbiomes are distinct from those of other natural or built environments, and sheds light on the major selective forces responsible for this microbial diversity.

  12. Municipal Solid Waste Landfills Harbor Distinct Microbiomes

    Blake Warren Stamps

    2016-04-01

    Full Text Available Landfills are the final repository for most of the discarded material from human society and its built environments. Microorganisms subsequently degrade this discarded material in the landfill, releasing gases (largely CH4 and CO2 and a complex mixture of soluble chemical compounds in leachate. Characterization of landfill microbiomes and their comparison across several landfills should allow the identification of environmental or operational properties that influence the composition of these microbiomes and potentially their biodegradation capabilities. To this end, the composition of landfill microbiomes was characterized as part of an ongoing USGS national survey studying the chemical composition of leachates from 19 non-hazardous landfills across 16 states in the continental U.S. The landfills varied in parameters such as size, waste composition, management strategy, geography, and climate zone. The diversity and composition of bacterial and archaeal populations in leachate samples were characterized by 16S rRNA gene sequence analysis, and compared against a variety of physical and chemical parameters in an attempt to identify their impact on selection. Members of the Epsilonproteobacteria, Gammaproteobacteria, Clostridia, and candidate division OP3 were the most abundant. The distribution of the observed phylogenetic diversity could best be explained by a combination of variables and was correlated most strongly with the concentrations of chloride and barium, rate of evapotranspiration, age of waste, and the number of detected household chemicals. This study illustrates how leachate microbiomes are distinct from those of other natural or built environments, and sheds light on the major selective forces responsible for this microbial diversity.

  13. Distinction between epigenic and hypogenic maze caves

    Palmer, Arthur N.

    2011-11-01

    Certain caves formed by dissolution of bedrock have maze patterns composed of closed loops in which many intersecting fractures or pores have enlarged simultaneously. Their origin can be epigenic (by shallow circulation of meteoric groundwater) or hypogenic (by rising groundwater or production of deep-seated solutional aggressiveness). Epigenic mazes form by diffuse infiltration through a permeable insoluble caprock or by floodwater supplied by sinking streams. Most hypogenic caves involve deep sources of aggressiveness. Transverse hypogenic cave origin is a recently proposed concept in which groundwater of mainly meteoric origin rises across strata in the distal portions of large flow systems, to form mazes in soluble rock sandwiched between permeable but insoluble strata. The distinction between maze types is debated and is usually based on examination of diagnostic cave features and relation of caves to their regional setting. In this paper, the principles of mass transfer are applied to clarify the limits of each model, to show how cave origin is related to groundwater discharge, dissolution rate, and time. The results show that diffuse infiltration and floodwater can each form maze caves at geologically feasible rates (typically within 500 ka). Transverse hypogenic mazes in limestone, to enlarge significantly within 1 Ma, require an unusually high permeability of the non-carbonate beds (generally ≥ 10-4 cm/s), large discharge, and calcite saturation no greater than 90%, which is rare in deep diffuse flow in sedimentary rocks. Deep sources of aggressiveness are usually required. The origin of caves by transverse hypogenic flow is much more favorable in evaporite rocks than in carbonate rocks.

  14. Both differences in encoding processes and monitoring at retrieval reduce false alarms when distinctive information is studied.

    Hanczakowski, Maciej; Mazzoni, Giuliana

    2011-04-01

    A reduction in false alarms to critical lures is observed in the DRM paradigm (Roediger & McDermott, 1995) when distinctive information is presented at encoding. Two mechanisms have been proposed to account for this reduction. According to the monitoring theory (e.g., the distinctiveness heuristic), lack of diagnostic recollection serves as a basis for discarding non-presented lures. According to the encoding theory, presenting distinctive information at study leads to impoverished relational processing, which results in a reduction in memorial information elicited by critical lures. In the present study a condition was created in which the use of the distinctiveness heuristic was precluded by associating, within the same study, lures with distinctive information in a context different from the study session. Under that condition reduction in false alarms to distinctive critical lures was still observed. This result supports the predictions of the encoding theory. However, when in the same study the use of the distinctiveness heuristic was not precluded, reductions in false alarms to unrelated lures were also observed when distinctive information was presented at study, indicating that both mechanisms are likely to contribute to the rejection of false memories.

  15. 1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action.

    Pirotte, Bernard; de Tullio, Pascal; Florence, Xavier; Goffin, Eric; Somers, Fabian; Boverie, Stéphane; Lebrun, Philippe

    2013-04-25

    The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.

  16. Fast micrographia: An unusual but distinctive sign

    Umaiorubahan Meenakshisundaram

    2013-01-01

    Full Text Available Fast micrographia is a rare clinical sign, which is reported in patients with pallidal pathology. A 68-year-old male presented with hypophonia and short shuffling gait with decreased arm swing. About 3 weeks before, he had an acute myocardial infarction and a period of hemodynamic and respiratory distress during which he required mechanical ventilatory support. He was found to have a fast handwriting with micrographia from the outset. His rapid alternating hand and finger movements were normal. Magnetic resonance imaging (MRI of the brain showed features of hypoxic ischemic encephalopathy including hyperintensities on T1 and T2 weighted images in the globus pallidus, and putamen bilaterally.

  17. Two distinct origins for Archean greenstone belts

    Smithies, R. Hugh; Ivanic, Tim J.; Lowrey, Jack R.; Morris, Paul A.; Barnes, Stephen J.; Wyche, Stephen; Lu, Yong-Jun

    2018-04-01

    Applying the Th/Yb-Nb/Yb plot of Pearce (2008) to the well-studied Archean greenstone sequences of Western Australia shows that individual volcanic sequences evolved through one of two distinct processes reflecting different modes of crust-mantle interaction. In the Yilgarn Craton, the volcanic stratigraphy of the 2.99-2.71 Ga Youanmi Terrane mainly evolved through processes leading to Th/Yb-Nb/Yb trends with a narrow range of Th/Nb ('constant-Th/Nb' greenstones). In contrast, the 2.71-2.66 Ga volcanic stratigraphy of the Eastern Goldfields Superterrane evolved through processes leading to Th/Yb-Nb/Yb trends showing a continuous range in Th/Nb ('variable-Th/Nb' greenstones). Greenstone sequences of the Pilbara Craton show a similar evolution, with constant-Th/Nb greenstone evolution between 3.13 and 2.95 Ga and variable-Th/Nb greenstone evolution between 3.49 and 3.23 Ga and between 2.77 and 2.68 Ga. The variable-Th/Nb trends dominate greenstone sequences in Australia and worldwide, and are temporally associated with peaks in granite magmatism, which promoted crustal preservation. The increasing Th/Nb in basalts correlates with decreasing εNd, reflecting variable amounts of crustal assimilation during emplacement of mantle-derived magmas. These greenstones are typically accompanied in the early stages by komatiite, and can probably be linked to mantle plume activity. Thus, regions such as the Eastern Goldfields Superterrane simply developed as plume-related rifts over existing granite-greenstone crust - in this case the Youanmi Terrane. Their Th/Nb trends are difficult to reconcile with modern-style subduction processes. The constant-Th/Nb trends may reflect derivation from a mantle source already with a high and constant Th/Nb ratio. This, and a lithological association including boninite-like lavas, basalts, and calc-alkaline andesites, all within a narrow Th/Nb range, resembles compositions typical of modern-style subduction settings. These greenstones are very

  18. Refractory versus resistant hypertension: Novel distinctive phenotypes

    Dudenbostel, Tanja; Siddiqui, Mohammed; Gharpure, Nitin; Calhoun, David A.

    2017-01-01

    Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is defined as blood pressure (BP) >140/90 mmHg treated with ≥3 antihypertensive medications, including a diuretic, if tolerated. Refractory hypertension is a novel phenotype of severe antihypertensive treatment failure. The proposed definition for refractory hypertension, i.e. BP >140/90 mmHg with use of ≥5 different antihypertensive medications, including a diuretic and a mineralocorticoid receptor antagonist (MRA) has been applied inconsistently. In comparison to RHTN, refractory hypertension seems to be less prevalent than RHTN. This review focuses on current knowledge about this novel phenotype compared with RHTN including definition, prevalence, mechanisms, characteristics and comorbidities, including cardiovascular risk. In patients with RHTN excess fluid retention is thought to be a common mechanism for the development of RHTN. Recently, evidence has emerged suggesting that refractory hypertension may be more of neurogenic etiology due to increased sympathetic activity as opposed to excess fluid retention. Treatment recommendations for RHTN are generally based on use and intensification of diuretic therapy, especially with the combination of a long-acting thiazide-like diuretic and an MRA. Based on findings from available studies, such an approach does not seem to be a successful strategy to control BP in patients with refractory hypertension and effective sympathetic inhibition in such patients, either with medications and/or device based approaches may be needed. PMID:29034321

  19. Grain distinct stratified nanolayers in aluminium alloys

    Donatus, U., E-mail: uyimedonatus@yahoo.com [School of Materials, The University of Manchester, Manchester, M13 9PL, England (United Kingdom); Thompson, G.E.; Zhou, X.; Alias, J. [School of Materials, The University of Manchester, Manchester, M13 9PL, England (United Kingdom); Tsai, I.-L. [Oxford Instruments NanoAnalysis, HP12 2SE, High Wycombe (United Kingdom)

    2017-02-15

    The grains of aluminium alloys have stratified nanolayers which determine their mechanical and chemical responses. In this study, the nanolayers were revealed in the grains of AA6082 (T6 and T7 conditions), AA5083-O and AA2024-T3 alloys by etching the alloys in a solution comprising 20 g Cr{sub 2}O{sub 3} + 30 ml HPO{sub 3} in 1 L H{sub 2}O. Microstructural examination was conducted on selected grains of interest using scanning electron microscopy and electron backscatter diffraction technique. It was observed that the nanolayers are orientation dependent and are parallel to the {100} planes. They have ordered and repeated tunnel squares that are flawed at the sides which are aligned in the <100> directions. These flawed tunnel squares dictate the tunnelling corrosion morphology as well as appearing to have an affect on the arrangement and sizes of the precipitation hardening particles. The inclination of the stratified nanolayers, their interpacing, and the groove sizes have significant influence on the corrosion behaviour and seeming influence on the strengthening mechanism of the investigated aluminium alloys. - Highlights: • Stratified nanolayers in aluminium alloy grains. • Relationship of the stratified nanolayers with grain orientation. • Influence of the inclinations of the stratified nanolayers on corrosion. • Influence of the nanolayers interspacing and groove sizes on hardness and corrosion.

  20. Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa.

    La Rosa, Ruggero; Johansen, Helle Krogh; Molin, Søren

    2018-04-10

    Evolution by natural selection under complex and dynamic environmental conditions occurs through intricate and often counterintuitive trajectories affecting many genes and metabolic solutions. To study short- and long-term evolution of bacteria in vivo , we used the natural model system of cystic fibrosis (CF) infection. In this work, we investigated how and through which trajectories evolution of Pseudomonas aeruginosa occurs when migrating from the environment to the airways of CF patients, and specifically, we determined reduction of growth rate and metabolic specialization as signatures of adaptive evolution. We show that central metabolic pathways of three distinct Pseudomonas aeruginosa lineages coevolving within the same environment become restructured at the cost of versatility during long-term colonization. Cell physiology changes from naive to adapted phenotypes resulted in (i) alteration of growth potential that particularly converged to a slow-growth phenotype, (ii) alteration of nutritional requirements due to auxotrophy, (iii) tailored preference for carbon source assimilation from CF sputum, (iv) reduced arginine and pyruvate fermentation processes, and (v) increased oxygen requirements. Interestingly, although convergence was evidenced at the phenotypic level of metabolic specialization, comparative genomics disclosed diverse mutational patterns underlying the different evolutionary trajectories. Therefore, distinct combinations of genetic and regulatory changes converge to common metabolic adaptive trajectories leading to within-host metabolic specialization. This study gives new insight into bacterial metabolic evolution during long-term colonization of a new environmental niche. IMPORTANCE Only a few examples of real-time evolutionary investigations in environments outside the laboratory are described in the scientific literature. Remembering that biological evolution, as it has progressed in nature, has not taken place in test tubes, it is not

  1. Gain-of-function analysis of poplar CLE genes in Arabidopsis by exogenous application and over-expression assays.

    Liu, Yisen; Yang, Shaohui; Song, Yingjin; Men, Shuzhen; Wang, Jiehua

    2016-04-01

    Among 50 CLE gene family members in the Populus trichocarpa genome, three and six PtCLE genes encode a CLE motif sequence highly homologous to Arabidopsis CLV3 and TDIF peptides, respectively, which potentially make them functional equivalents. To test and compare their biological activity, we first chemically synthesized each dodecapeptide and analysed itsi n vitro bioactivity on Arabidopsis seedlings. Similarly, but to a different extent, three types of poplar CLV3-related peptides caused root meristem consumption, phyllotaxis disorder, anthocyanin accumulation and failure to enter the bolting stage. In comparison, application of two poplar TDIF-related peptides led to root length promotion in a dose-dependent manner with an even stronger effect observed for poplar TDIF-like peptide than TDIF. Next, we constructed CaMV35S:PtCLE transgenic plants for each of the nine PtCLE genes. Phenotypic abnormalities exemplified by arrested shoot apical meristem and abnormal flower structure were found to be more dominant and severe in 35S:PtCLV3 and 35S:PtCLV3-like2 lines than in the 35S:PtCLV3-like line. Disordered vasculature was detected in both stem and hypocotyl cross-sections in Arabidopsis plants over-expressing poplar TDIF-related genes with the most defective vascular patterning observed for TDIF2 and two TDIF-like genes. Phenotypic difference consistently observed in peptide application assay and transgenic analysis indicated the functional diversity of nine poplar PtCLE genes under investigation. This work represents the first report on the functional analysis of CLE genes in a tree species and constitutes a basis for further study of the CLE peptide signalling pathway in tree development. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. The late flowering phenotype of fwa mutants is caused by gain-of-function epigenetic alleles of a homeodomain gene

    Soppe, W.J.J.; Jacobsen, S.E.; Alonso-Blanco, C.; Jackson, J.P.; Kakutani, T.; Koornneef, M.; Peeters, A.J.M.

    2000-01-01

    The transition to flowering in Arabidopsis thaliana is delayed in fwa mutant plants. FWA was identified by loss-of-function mutations in normally flowering revertants of the fwa mutant, and it encodes a homeodomain-containing transcription factor. The DNA sequence of wild-type and fwa mutant alleles

  3. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease

    Alfonso, Stephanie I.; Callender, Julia A.; Hooli, Basavaraj; Antal, Corina E.; Mullin, Kristina; Sherman, Mathew A.; Lesné, Sylvain E.; Leitges, Michael; Newton, Alexandra C.; Tanzi, Rudolph E.; Malinow, Roberto

    2016-01-01

    Alzheimer’s disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes protein kinase Cα (PKCα), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKCα as assessed in live-cell imaging experiments using a genetically encoded PKC activity reporter. Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the Aβ precursor CT100 revealed that PKCα was required for the reduced synaptic activity caused by Aβ. In PRKCA−/− neurons expressing CT100, introduction of PKCα, but not PKCα lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKCα to the synapse is required for its mediation of the effects of Aβ. Thus, enhanced PKCα activity may contribute to AD, possibly by mediating the actions of Aβ on synapses. In contrast, reduced PKCα activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme. PMID:27165780

  4. Coexistence of gain-of-function JAK2 germ line mutations with JAK2(V617F) in polycythemia vera

    Láníková, Lucie; Babošová, Oľga; Swierczek, S.; Wang, L.; Wheeler, D.A.; Divoky, V.; Kořínek, Vladimír; Prchal, J.T.

    2016-01-01

    Roč. 128, č. 18 (2016), s. 2266-2270 ISSN 0006-4971 R&D Projects: GA ČR GJ15-18046Y; GA MŠk LO1419 Institutional support: RVO:68378050 Keywords : JAK2 mutations * polycythemia vera Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 13.164, year: 2016

  5. FoxO1 gain of function in the pancreas causes glucose intolerance, polycystic pancreas, and islet hypervascularization.

    Osamu Kikuchi

    Full Text Available Genetic studies revealed that the ablation of insulin/IGF-1 signaling in the pancreas causes diabetes. FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling. We previously reported that FoxO1 haploinsufficiency restored β cell mass and rescued diabetes in IRS2 knockout mice. However, it is still unclear whether FoxO1 dysregulation in the pancreas could be the cause of diabetes. To test this hypothesis, we generated transgenic mice overexpressing constitutively active FoxO1 specifically in the pancreas (TG. TG mice had impaired glucose tolerance and some of them indeed developed diabetes due to the reduction of β cell mass, which is associated with decreased Pdx1 and MafA in β cells. We also observed increased proliferation of pancreatic duct epithelial cells in TG mice and some mice developed a polycystic pancreas as they aged. Furthermore, TG mice exhibited islet hypervascularities due to increased VEGF-A expression in β cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.

  6. The Gain-of-Function Integrin β3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.

    Dohn, Michael R; Kooker, Christopher G; Bastarache, Lisa; Jessen, Tammy; Rinaldi, Capria; Varney, Seth; Mazalouskas, Matthew D; Pan, Hope; Oliver, Kendra H; Velez Edwards, Digna R; Sutcliffe, James S; Denny, Joshua C; Carneiro, Ana M D

    2017-11-15

    Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism Leu33Pro (rs5918, Pl A2 ) produces hyperactive αvβ3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an Itgb3 variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders. SIGNIFICANCE STATEMENT The integrin β3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine integrin β3 recapitulates the sex-dependent neurochemical and behavioral attributes of ASD. Using state-of-the-art techniques, we show that presynaptic 5-HT function is altered in these mice, and that the localization of 5-HT transporters to specific compartments within the synapse, disrupted by the integrin β3 Pro33 mutation, is critical for appropriate reuptake of 5-HT. Our studies provide fundamental insight into the genetic network regulating 5-HT neurotransmission in the CNS that is also associated with ASD risk. Copyright © 2017 the authors 0270-6474/17/3711272-14$15.00/0.

  7. Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint

    Kleiblová, P.; Shaltiel, I.A.; Benada, Jan; Ševčík, J.; Pecháčková, Soňa; Pohlreich, P.; Voest, E.E.; Dundr, P.; Bartek, Jiří; Kleibl, Z.; Medema, R.H.; Macůrek, Libor

    2013-01-01

    Roč. 201, č. 4 (2013), s. 511-521 ISSN 0021-9525 R&D Projects: GA ČR GAP301/10/1525; GA ČR GAP305/12/2485; GA ČR GA13-18392S Grant - others:GA MZd(CZ) NT13343; EK(XE) 223575; EK(XE) ED0030/01/01 Institutional support: RVO:68378050 Keywords : DNA damage * cell cycle * cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 9.688, year: 2013

  8. Auxin-binding pocket of ABP1 is crucial for its gain-of-function cellular and developmental roles

    Grones, P.; Chen, X.; Simon, S.; Kaufmann, W.A.; De Rycke, R.; Nodzyński, T.; Zažímalová, Eva; Friml, J.

    2015-01-01

    Roč. 66, č. 16 (2015), s. 5055-5065 ISSN 0022-0957 Institutional support: RVO:61389030 Keywords : Auxin * ABP1 * Auxin binding Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.677, year: 2015

  9. Two distinct ballistic processes in graphene

    Lewkowicz, M; Rosenstein, B; Nghiem, D

    2012-01-01

    A dynamical approach to ballistic transport in mesoscopic graphene samples of finite length Land contact potential difference with leads U is developed. It is shown that at ballistic times shorter than both relevant time scales, t L = L/v g (v g - Fermi velocity) and t u = ħ/(eU), the major effect of electric field is to creates the electron - hole pairs, namely causes interband transitions. At ballistic times lager than the two scales the mechanism is very different. The conductivity has its “nonrelativistic” or intraband value equal to the one obtained within the Landauer-Butticker approach for the barrier Uresulting from evanescent waves tunneling through the barrier.

  10. Mechanics without mechanisms

    Eisenthal, Joshua

    2018-05-01

    At the time of Heinrich Hertz's premature death in 1894, he was regarded as one of the leading scientists of his generation. However, the posthumous publication of his treatise in the foundations of physics, Principles of Mechanics, presents a curious historical situation. Although Hertz's book was widely praised and admired, it was also met with a general sense of dissatisfaction. Almost all of Hertz's contemporaries criticized Principles for the lack of any plausible way to construct a mechanism from the "hidden masses" that are particularly characteristic of Hertz's framework. This issue seemed especially glaring given the expectation that Hertz's work might lead to a model of the underlying workings of the ether. In this paper I seek an explanation for why Hertz seemed so unperturbed by the difficulties of constructing such a mechanism. In arriving at this explanation, I explore how the development of Hertz's image-theory of representation framed the project of Principles. The image-theory brings with it an austere view of the "essential content" of mechanics, only requiring a kind of structural isomorphism between symbolic representations and target phenomena. I argue that bringing this into view makes clear why Hertz felt no need to work out the kinds of mechanisms that many of his readers looked for. Furthermore, I argue that a crucial role of Hertz's hypothesis of hidden masses has been widely overlooked. Far from acting as a proposal for the underlying structure of the ether, I show that Hertz's hypothesis ruled out knowledge of such underlying structure.

  11. Two Groups of Thellungiella salsuginea RAVs Exhibit Distinct Responses and Sensitivity to Salt and ABA in Transgenic Arabidopsis.

    Shaohui Yang

    Full Text Available Containing both AP2 domain and B3 domain, RAV (Related to ABI3/VP1 transcription factors are involved in diverse functions in higher plants. A total of eight TsRAV genes were isolated from the genome of Thellungiella salsuginea and could be divided into two groups (A- and B-group based on their sequence similarity. The mRNA abundance of all Thellungiella salsuginea TsRAVs followed a gradual decline during seed germination. In Thellungiella salsuginea seedling, transcripts of TsRAVs in the group A (A-TsRAVs were gradually and moderately reduced by salt treatment but rapidly and severely repressed by ABA treatment. In comparison, with a barely detectable constitutive expression, the transcriptional level of TsRAVs in the group B (B-TsRAVs exhibited a moderate induction in cotyledons when confronted with ABA. We then produced the "gain-of-function" transgenic Arabidopsis plants for each TsRAV gene and found that only 35S:A-TsRAVs showed weak growth retardation including reduced root elongation, suggesting their roles in negatively controlling plant growth. Under normal conditions, the germination process of all TsRAVs overexpressing transgenic seeds was inhibited with a stronger effect observed in 35S:A-TsRAVs seeds than in 35S:B-TsRAVs seeds. With the presence of NaCl, seed germination and seedling root elongation of all plants including wild type and 35S:TsRAVs plants were retarded and a more severe inhibition occurred to the 35S:A-TsRAV transgenic plants. ABA treatment only negatively affected the germination rates of 35S:A-TsRAV transgenic seeds but not those of 35S:B-TsRAV transgenic seeds. All 35S:TsRAVs transgenic plants showed a similar degree of reduction in root growth compared with untreated seedlings in the presence of ABA. Furthermore, the cotyledon greening/expansion was more severely inhibited 35S:A-TsRAVs than in 35S:B-TsRAVs seedlings. Upon water deficiency, with a wider opening of stomata, 35S:A-TsRAVs plants experienced a faster

  12. Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma.

    Francesco Abate

    2015-10-01

    Full Text Available Endemic Burkitt lymphoma (eBL is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%, in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL, we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF. We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.

  13. Social Media Blurred the Distinction Between Author and Reader

    Lambiotte, Renaud

    The last few years have seen the emergence of the sharing economy. As social media blurred the distinction between author and reader, everyone can now offer or receive services thanks to the networking tools provided by new technological companies. Take Uber, and its billion of journeys in 2015 alone, with tens of thousands of vehicles crawling every moment in the globe's biggest cities. As often, when confronted with a technological change, we observe a polarization of society, and the search for an equilibrium characterized by new norms, rights, and obligations. Understanding the mechanisms behind this re-organization requires an integrated, interdisciplinary approach, covering an intricate web of legal, societal, economical, and computational issues which, we believe, could benefit from a complex systems perspective. As a first step, we are currently studying the dynamics of pricing in Uber. In this new de-regulated world, journey prices fluctuate in time depending on traffic but also on the service's perceived balance of passenger demand and driver supply...

  14. Different Selection Pressures Give Rise to Distinct Ethnic Phenomena

    Moya, Cristina; Boyd, Robert

    2015-01-01

    Many accounts of ethnic phenomena imply that processes such as stereotyping, essentialism, ethnocentrism, and intergroup hostility stem from a unitary adaptation for reasoning about groups. This is partly justified by the phenomena’s co-occurrence in correlational studies. Here we argue that these behaviors are better modeled as functionally independent adaptations that arose in response to different selection pressures throughout human evolution. As such, different mechanisms may be triggered by different group boundaries within a single society. We illustrate this functionalist framework using ethnographic work from the Quechua-Aymara language boundary in the Peruvian Altiplano. We show that different group boundaries motivate different ethnic phenomena. For example, people have strong stereotypes about socioeconomic categories, which are not cooperative units, whereas they hold fewer stereotypes about communities, which are the primary focus of cooperative activity. We also show that, despite the cross-cultural importance of ethnolinguistic boundaries, the Quechua-Aymara linguistic distinction does not strongly motivate any of these intergroup processes. PMID:25731969

  15. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum?

    Aastha Chawla

    2016-01-01

    Full Text Available Diabetes and related complications are associated with long-term damage and failure of various organ systems. The line of demarcation between the pathogenic mechanisms of microvascular and macrovascular complications of diabetes and differing responses to therapeutic interventions is blurred. Diabetes induces changes in the microvasculature, causing extracellular matrix protein synthesis, and capillary basement membrane thickening which are the pathognomic features of diabetic microangiopathy. These changes in conjunction with advanced glycation end products, oxidative stress, low grade inflammation, and neovascularization of vasa vasorum can lead to macrovascular complications. Hyperglycemia is the principal cause of microvasculopathy but also appears to play an important role in causation of macrovasculopathy. There is thought to be an intersection between micro and macro vascular complications, but the two disorders seem to be strongly interconnected, with micro vascular diseases promoting atherosclerosis through processes such as hypoxia and changes in vasa vasorum. It is thus imperative to understand whether microvascular complications distinctly precede macrovascular complications or do both of them progress simultaneously as a continuum. This will allow re-focusing on the clinical issues with a unifying perspective which can improve type 2 diabetes mellitus outcomes.

  16. Distinct frontal regions for processing sentence syntax and story grammar.

    Sirigu, A; Cohen, L; Zalla, T; Pradat-Diehl, P; Van Eeckhout, P; Grafman, J; Agid, Y

    1998-12-01

    Time is a fundamental dimension of cognition. It is expressed in the sequential ordering of individual elements in a wide variety of activities such as language, motor control or in the broader domain of long range goal-directed actions. Several studies have shown the importance of the frontal lobes in sequencing information. The question addressed in this study is whether this brain region hosts a single supramodal sequence processor, or whether separate mechanisms are required for different kinds of temporally organised knowledge structures such as syntax and action knowledge. Here we show that so-called agrammatic patients, with lesions in Broca's area, ordered word groups correctly to form a logical sequence of actions but they were severely impaired when similar word groups had to be ordered as a syntactically well-formed sentence. The opposite performance was observed in patients with dorsolateral prefrontal lesions, that is, while their syntactic processing was intact at the sentence level, they demonstrated a pronounced deficit in producing temporally coherent sequences of actions. Anatomical reconstruction of lesions from brain scans revealed that the sentence and action grammar deficits involved distinct, non-overlapping sites within the frontal lobes. Finally, in a third group of patients whose lesions encompassed both Broca's area and the prefrontal cortex, the two types of deficits were found. We conclude that sequence processing is specific to knowledge domains and involves different networks within the frontal lobes.

  17. Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma.

    Abate, Francesco; Ambrosio, Maria Raffaella; Mundo, Lucia; Laginestra, Maria Antonella; Fuligni, Fabio; Rossi, Maura; Zairis, Sakellarios; Gazaneo, Sara; De Falco, Giulia; Lazzi, Stefano; Bellan, Cristiana; Rocca, Bruno Jim; Amato, Teresa; Marasco, Elena; Etebari, Maryam; Ogwang, Martin; Calbi, Valeria; Ndede, Isaac; Patel, Kirtika; Chumba, David; Piccaluga, Pier Paolo; Pileri, Stefano; Leoncini, Lorenzo; Rabadan, Raul

    2015-10-01

    Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.

  18. Bacterial protease uses distinct thermodynamic signatures for substrate recognition.

    Bezerra, Gustavo Arruda; Ohara-Nemoto, Yuko; Cornaciu, Irina; Fedosyuk, Sofiya; Hoffmann, Guillaume; Round, Adam; Márquez, José A; Nemoto, Takayuki K; Djinović-Carugo, Kristina

    2017-06-06

    Porphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate considerable interest. Surprisingly, these two microorganisms do not ferment carbohydrates; rather they use proteinaceous substrates as carbon and energy sources. However, the underlying biochemical mechanisms of their energy metabolism remain unknown. Here, we show that dipeptidyl peptidase 11 (DPP11), a central metabolic enzyme in these bacteria, undergoes a conformational change upon peptide binding to distinguish substrates from end products. It binds substrates through an entropy-driven process and end products in an enthalpy-driven fashion. We show that increase in protein conformational entropy is the main-driving force for substrate binding via the unfolding of specific regions of the enzyme ("entropy reservoirs"). The relationship between our structural and thermodynamics data yields a distinct model for protein-protein interactions where protein conformational entropy modulates the binding free-energy. Further, our findings provide a framework for the structure-based design of specific DPP11 inhibitors.

  19. Distinctive characters of Nostoc genomes in cyanolichens.

    Gagunashvili, Andrey N; Andrésson, Ólafur S

    2018-06-05

    Cyanobacteria of the genus Nostoc are capable of forming symbioses with a wide range of organism, including a diverse assemblage of cyanolichens. Only certain lineages of Nostoc appear to be able to form a close, stable symbiosis, raising the question whether symbiotic competence is determined by specific sets of genes and functionalities. We present the complete genome sequencing, annotation and analysis of two lichen Nostoc strains. Comparison with other Nostoc genomes allowed identification of genes potentially involved in symbioses with a broad range of partners including lichen mycobionts. The presence of additional genes necessary for symbiotic competence is likely reflected in larger genome sizes of symbiotic Nostoc strains. Some of the identified genes are presumably involved in the initial recognition and establishment of the symbiotic association, while others may confer advantage to cyanobionts during cohabitation with a mycobiont in the lichen symbiosis. Our study presents the first genome sequencing and genome-scale analysis of lichen-associated Nostoc strains. These data provide insight into the molecular nature of the cyanolichen symbiosis and pinpoint candidate genes for further studies aimed at deciphering the genetic mechanisms behind the symbiotic competence of Nostoc. Since many phylogenetic studies have shown that Nostoc is a polyphyletic group that includes several lineages, this work also provides an improved molecular basis for demarcation of a Nostoc clade with symbiotic competence.

  20. Creating fair lineups for suspects with distinctive features

    Zarkadi, Theodora; Wade, Kimberley A.; Stewart, Neil

    2009-01-01

    In their descriptions, eyewitnesses often refer to a culprit's distinctive facial features. However, in a police lineup, selecting the only member with the described distinctive feature is unfair to the suspect and provides the police with little further information. For fair and informative lineups, the distinctive feature should be either replicated across foils or concealed on the target. In the present experiments, replication produced more correct identifications in target-present lineup...

  1. Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation.

    Guoshi Li

    2017-10-01

    Full Text Available The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh and norepinephrine (NE and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.

  2. Molecular polymorphism of a cell surface proteoglycan: distinct structures on simple and stratified epithelia.

    Sanderson, R D; Bernfield, M

    1988-12-01

    Epithelial cells are organized into either a single layer (simple epithelia) or multiple layers (stratified epithelia). Maintenance of these cellular organizations requires distinct adhesive mechanisms involving many cell surface molecules. One such molecule is a cell surface proteoglycan, named syndecan, that contains both heparan sulfate and chondroitin sulfate chains. This proteoglycan binds cells to fibrillar collagens and fibronectin and thus acts as a receptor for interstitial matrix. The proteoglycan is restricted to the basolateral surface of simple epithelial cells, but is located over the entire surface of stratified epithelial cells, even those surfaces not contacting matrix. We now show that the distinct localization in simple and stratified epithelia correlates with a distinct proteoglycan structure. The proteoglycan from simple epithelia (modal molecular size, 160 kDa) is larger than that from stratified epithelia (modal molecular size, 92 kDa), but their core proteins are identical in size and immunoreactivity. The proteoglycan from simple epithelia has more and larger heparan sulfate and chondroitin sulfate chains than the proteoglycan from stratified epithelia. Thus, the cell surface proteoglycan shows a tissue-specific structural polymorphism due to distinct posttranslational modifications. This polymorphism likely reflects distinct proteoglycan functions in simple and stratified epithelia, potentially meeting the different adhesive requirements of the cells in these different organizations.

  3. Similarities and distinctions of CIR and Sheath

    Yermolaev, Yuri; Lodkina, Irina; Nikolaeva, Nadezhda; Yermolaev, Michael

    2016-04-01

    On the basis of OMNI data and our catalog of large scale solar wind (SW) streams during 1976-2000 [Yermolaev et al., 2009] we study the average temporal profiles for two types of compressed regions: CIR (corotating interaction region - compressed region before High Speed Stream (HSS)) and Sheath (compressed region before fast Interplanetary CMEs (ICMEs), including Magnetic Cloud (MC) and Ejecta). As have been shown by Nikolaeva et al, [2015], the efficiency of magnetic storm generation is ~50% higher for Sheath and CIR than for ICME (MC and Ejecta), i.e. reaction magnetosphere depends on type of driver. To take into account the different durations of SW types, we use the double superposed epoch analysis (DSEA) method: rescaling the duration of the interval for all types in such a manner that, respectively, beginning and end for all intervals of selected type coincide [Yermolaev et al., 2010; 2015]. Obtained data allows us to suggest that the formation of all types of compression regions has the same physical mechanism irrespective of piston (HSS or ICME) type and differences are connected with geometry and full jumps of speed in edges of compression regions. If making the natural assumption that the gradient of speed is directed approximately on normal to the piston, CIR has the largest angle between the gradient of speed and the direction of average SW speed, and ICME - the smallest angle. The work was supported by the Russian Foundation for Basic Research, projects 13-02-00158, 16-02-00125 and by Program of Presidium of the Russian Academy of Sciences. References: Nikolaeva, N. S. , Yu. I. Yermolaev, and I. G. Lodkina (2015), Modeling of the Corrected Dst* Index Temporal Profile on the Main Phase of the Magnetic Storms Generated by Different Types of Solar Wind, Cosmic Research, Vol. 53, No. 2, pp. 119-127. Yermolaev, Yu. I., N. S. Nikolaeva, I. G. Lodkina, and M. Yu. Yermolaev (2009), Catalog of Large-Scale Solar Wind Phenomena during 1976-2000, Cosmic Research

  4. Fracture Mechanics

    Jang, Dong Il; Jeong, Gyeong Seop; Han, Min Gu

    1992-08-01

    This book introduces basic theory and analytical solution of fracture mechanics, linear fracture mechanics, non-linear fracture mechanics, dynamic fracture mechanics, environmental fracture and fatigue fracture, application on design fracture mechanics, application on analysis of structural safety, engineering approach method on fracture mechanics, stochastic fracture mechanics, numerical analysis code and fracture toughness test and fracture toughness data. It gives descriptions of fracture mechanics to theory and analysis from application of engineering.

  5. Identity-specific motivation: How distinct identities direct self-regulation across distinct situations.

    Browman, Alexander S; Destin, Mesmin; Molden, Daniel C

    2017-12-01

    Research on self-regulation has traditionally emphasized that people's thoughts and actions are guided by either (a) domain-general motivations that emerge from a cumulative history of life experiences, or (b) situation-specific motivations that emerge in immediate response to the incentives present in a particular context. However, more recent studies have illustrated the importance of understanding the interplay between such domain-general and situation-specific motivations across the types of contexts people regularly encounter. The present research, therefore, expands existing perspectives on self-regulation by investigating how people's identities -the internalized roles, relationships, and social group memberships that define who they are-systemically guide when and how different domain-general motivations are activated within specific types of situations. Using the motivational framework described by regulatory focus theory (Higgins, 1997), Studies 1 and 2 demonstrate that people indeed have distinct, identity-specific motivations that uniquely influence their current self-regulation when such identities are active. Studies 3-5 then begin to explore how identity-specific motivations are situated within people's larger self-concept. Studies 3a and 3b demonstrate that the less compatible people's specific identities, the more distinct are the motivations connected to those identities. Studies 4-5 then provide some initial, suggestive evidence that identity-specific motivations are not a separate, superordinate feature of people's identities that then alter how they pursue any subordinate, identity-relevant traits, but instead that such motivations emerge from the cumulative motivational significance of the subordinate traits to which the identities themselves become attached. Implications for understanding the role of the self-concept in self-regulation are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  6. Variable mechanical ventilation.

    Fontela, Paula Caitano; Prestes, Renata Bernardy; Forgiarini, Luiz Alberto; Friedman, Gilberto

    2017-01-01

    To review the literature on the use of variable mechanical ventilation and the main outcomes of this technique. Search, selection, and analysis of all original articles on variable ventilation, without restriction on the period of publication and language, available in the electronic databases LILACS, MEDLINE®, and PubMed, by searching the terms "variable ventilation" OR "noisy ventilation" OR "biologically variable ventilation". A total of 36 studies were selected. Of these, 24 were original studies, including 21 experimental studies and three clinical studies. Several experimental studies reported the beneficial effects of distinct variable ventilation strategies on lung function using different models of lung injury and healthy lungs. Variable ventilation seems to be a viable strategy for improving gas exchange and respiratory mechanics and preventing lung injury associated with mechanical ventilation. However, further clinical studies are necessary to assess the potential of variable ventilation strategies for the clinical improvement of patients undergoing mechanical ventilation.

  7. Distinct Signaling Roles of cIMP, cCMP, and cUMP.

    Seifert, Roland

    2016-10-04

    The cyclic purine nucleotide cIMP and the cyclic pyrimidine nucleotides cCMP and cUMP are emerging second messengers. These cNMPs show different biological effects, but the molecular mechanisms remain elusive. In this issue of Structure, Ng et al. (2016) provide structural evidence for distinct interactions of cIMP, cCMP, and cUMP with ion channels. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Distinctiveness of Encoding and Memory for Learning Tasks.

    Glover, John A.; And Others

    1982-01-01

    A distinctiveness of encoding hypothesis, as applied to the facilitative effects that higher order objectives have on readers' prose recall, was evaluated in three experiments. Results suggest that distinctiveness of encoding may offer a theoretical basis for the effects of adjunct aids as well as a guide to their construction. (Author/GK)

  9. Tagging like Humans: Diverse and Distinct Image Annotation

    Wu, Baoyuan

    2018-03-31

    In this work we propose a new automatic image annotation model, dubbed {\\\\bf diverse and distinct image annotation} (D2IA). The generative model D2IA is inspired by the ensemble of human annotations, which create semantically relevant, yet distinct and diverse tags. In D2IA, we generate a relevant and distinct tag subset, in which the tags are relevant to the image contents and semantically distinct to each other, using sequential sampling from a determinantal point process (DPP) model. Multiple such tag subsets that cover diverse semantic aspects or diverse semantic levels of the image contents are generated by randomly perturbing the DPP sampling process. We leverage a generative adversarial network (GAN) model to train D2IA. Extensive experiments including quantitative and qualitative comparisons, as well as human subject studies, on two benchmark datasets demonstrate that the proposed model can produce more diverse and distinct tags than the state-of-the-arts.

  10. Distinct metal-exchange pathways of doped Ag25 nanoclusters

    Bootharaju, Megalamane Siddaramappa

    2016-09-09

    Atomically precise metal nanoclusters (NCs) containing more than one type of metal atom (i.e., doped or alloyed), due to synergistic effects, open new avenues for engineering the catalytic and optical properties of NCs in a manner that homometal NCs cannot. Unfortunately, it is still a major challenge to controllably introduce multimetallic dopants in NCs, understanding the dopants\\' positions, mechanism, and synergistic effects. To overcome these challenges, we designed a metal-exchange approach involving NCs as molecular templates and metal ions as the source of the incoming dopant. In particular, two structurally similar monodoped silver-rich NCs, [MAg24(SR)(18)](2-) (M = Pd/Pt and SR: thiolate), were synthesized as templates to study their mechanistic transformation in response to the introduction of gold atoms. The controllable incorporation of Au atoms into the MAg24 framework facilitated the elucidation of distinct doping pathways through high-resolution mass spectrometry, optical spectroscopy and elemental analysis. Interestingly, gold replaced the central Pd atom of [PdAg24(SR)(18)](2-) clusters to produce predominantly bimetallic [AuAg24(SR)(18)](-) clusters along with a minor product of an [Au2Ag23(SR)(18)](-) cluster. In contrast, the central Pt atom remained intact in [PtAg24(SR)(18)](2-) clusters, and gold replaced the noncentral Ag atoms to form trimetallic [AuxPtAg24-x(SR)(18)](2-) NCs, where x = 1-2, with a portion of the starting [PtAg24(SR)(18)](2-) NCs remaining. This study reveals some of the unusual metal-exchange pathways of doped NCs and the important role played by the initial metal dopant in directing the position of a second dopant in the final product.

  11. Origin of chemically distinct discs in the Auriga cosmological simulations

    Grand, Robert J. J.; Bustamante, Sebastián; Gómez, Facundo A.; Kawata, Daisuke; Marinacci, Federico; Pakmor, Rüdiger; Rix, Hans-Walter; Simpson, Christine M.; Sparre, Martin; Springel, Volker

    2018-03-01

    The stellar disc of the Milky Way shows complex spatial and abundance structure that is central to understanding the key physical mechanisms responsible for shaping our Galaxy. In this study, we use six very high resolution cosmological zoom-in simulations of Milky Way-sized haloes to study the prevalence and formation of chemically distinct disc components. We find that our simulations develop a clearly bimodal distribution in the [α/Fe]-[Fe/H] plane. We find two main pathways to creating this dichotomy, which operate in different regions of the galaxies: (a) an early (z > 1) and intense high-[α/Fe] star formation phase in the inner region (R ≲ 5 kpc) induced by gas-rich mergers, followed by more quiescent low-[α/Fe] star formation; and (b) an early phase of high-[α/Fe] star formation in the outer disc followed by a shrinking of the gas disc owing to a temporarily lowered gas accretion rate, after which disc growth resumes. In process (b), a double-peaked star formation history around the time and radius of disc shrinking accentuates the dichotomy. If the early star formation phase is prolonged (rather than short and intense), chemical evolution proceeds as per process (a) in the inner region, but the dichotomy is less clear. In the outer region, the dichotomy is only evident if the first intense phase of star formation covers a large enough radial range before disc shrinking occurs; otherwise, the outer disc consists of only low-[α/Fe] sequence stars. We discuss the implication that both processes occurred in the Milky Way.

  12. Puzzling Mechanisms

    van Deventer, M. Oskar

    2009-01-01

    The basis of a good mechanical puzzle is often a puzzling mechanism. This article will introduce some new puzzling mechanisms, like two knots that engage like gears, a chain whose links can be interchanged, and flat gears that do not come apart. It illustrates how puzzling mechanisms can be transformed into real mechanical puzzles, e.g., by…

  13. Distinct Element modeling of geophysical signatures during sinkhole collapse

    Al-Halbouni, Djamil; Holohan, Eoghan P.; Taheri, Abbas; Dahm, Torsten

    2017-04-01

    A sinkhole forms due to the collapse of rocks or soil near the Earth's surface into an underground cavity. Such cavities represent large secondary pore spaces derived by dissolution and subrosion in the underground. By changing the stress field in the surrounding material, the growth of cavities can lead to a positive feedback, in which expansion and mechanical instability in the surrounding material increases or generates new secondary pore space (e.g. by fracturing), which in turn increases the cavity size, etc. A sinkhole forms due to the eventual subsidence or collapse of the overburden that becomes destabilized and fails all the way to the Earth's surface. Both natural processes like (sub)surface water movement and earthquakes, and human activities, such as mining, construction and groundwater extraction, intensify such feedbacks. The development of models for the mechanical interaction of a growing cavity and fracturing of its surrounding material, thus capturing related precursory geophysical signatures, has been limited, however. Here we report on the advances of a general, simplified approach to simulating cavity growth and sinkhole formation by using 2D Distinct Element Modeling (DEM) PFC5.0 software and thereby constraining pre-, syn- and post-collapse geophysical and geodetic signatures. This physically realistic approach allows for spontaneous cavity development and dislocation of rock mass to be simulated by bonded particle formulation of DEM. First, we present calibration and validation of our model. Surface subsidence above an instantaneously excavated circular cavity is tracked and compared with an incrementally increasing dissolution zone both for purely elastic and non-elastic material.This validation is important for the optimal choice of model dimensions and particles size with respect to simulation time. Second, a cavity growth approach is presented and compared to a well-documented case study, the deliberately intensified sinkhole collapse at

  14. Auditory Selective Attention: an introduction and evidence for distinct facilitation and inhibition mechanisms

    Mikyska, Constanze Elisabeth Anna

    2012-01-01

    Objective Auditory selective attention is a complex brain function that is still not completely understood. The classic example is the so-called “cocktail party effect” (Cherry, 1953), which describes the impressive ability to focus one’s attention on a single voice from a multitude of voices. This means that particular stimuli in the environment are enhanced in contrast to other ones of lower priority that are ignored. To be able to understand how attention can influence the perception and p...

  15. Mechanism of transient force augmentation varying with two distinct timescales for interacting vortex rings

    Fu, Zhidong; Qin, Suyang; Liu, Hong

    2014-01-01

    The dynamics of dual vortex ring flows is studied experimentally and numerically in a model system that consists of a piston-cylinder apparatus. The flows are generated by double identical strokes which have the velocity profile characterized by the sinusoidal function of half the period. By calculating the total wake impulse in two strokes in the experiments, it is found that the average propulsive force increases by 50% in the second stroke for the sufficiently small stroke length, compared with the first stroke. In the numerical simulations, two types of transient force augmentation are revealed, there being the transient force augmentation for the small stroke lengths and the absolute transient force augmentation for the large stroke lengths. The relative transient force augmentation increases to 78% for L/D = 1, while the absolute transient force augmentation for L/D = 4 is twice as much as that for L/D = 1. Further investigation demonstrates that the force augmentation is attributed to the interaction between vortex rings, which induces transport of vortex impulse and more evident fluid entrainment. The critical situation of vortex ring separation is defined and indicated, with vortex spacing falling in a narrow gap when the stroke lengths vary. A new model is proposed concerning the limiting process of impulse, further suggesting that apart from vortex formation timescale, vortex spacing should be interpreted as an independent timescale to reflect the dynamics of vortex interaction.

  16. Distinct mechanisms of relaxation to bioactive components from chamomile species in porcine isolated blood vessels

    Roberts, R.E.; Allen, S.; Chang, A.P.Y.; Henderson, H.; Hobson, G.C.; Karania, B.; Morgan, K.N.; Pek, A.S.Y.; Raghvani, K.; Shee, C.Y.; Shikotra, J.; Street, E.; Abbas, Z.; Ellis, K.; Heer, J.K.; Alexander, S.P.H.

    2013-01-01

    German chamomile (Matricaria recutita L.), a widely-used herbal medicine, has been reported to have a wide range of biological effects, including smooth muscle relaxation. The aim of this study was to compare the effects of representative compounds from chamomile (apigenin, luteolin, (−)-α-bisabolol, farnesene, umbelliferone; 3–30 μM) on vascular tone using porcine coronary and splenic arteries mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane-mimetic U46619. Apigenin, luteolin, and (−)-α-bisabolol produced slow, concentration-dependent relaxations in both the coronary and splenic arteries that were not blocked by inhibition of nitric oxide synthase or potassium channels. Removal of extracellular calcium inhibited the relaxations to all three compounds, and these compounds also inhibited calcium re-addition-evoked contractions, indicating that the relaxation response may be mediated through inhibition of calcium influx. Apigenin and luteolin, but not (−)-α-bisabolol, enhanced the relaxation to the nitric oxide donor sodium nitroprusside, indicating that apigenin and luteolin may act to regulate cyclic GMP levels. Umbelliferone produced a rapid, transient relaxation in the splenic artery, but not the coronary artery, that was inhibited by L-NAME and removal of the endothelium, suggesting an influence on nitric oxide production. Farnesene, at concentrations up to 30 μM, was without effect in either blood vessel. In conclusion, hydroxylated compounds (apigenin, luteolin and (−)-α-bisabolol) found in chamomile all caused a slow relaxation of isolated blood vessels through an effect on calcium influx. Umbelliferone, on the other hand, produced a rapid, transient relaxation dependent upon release of nitric oxide from the endothelium. - Highlights: • Apigenin, luteolin, and (-)-α-bisabolol are present in chamomile. • They produced slow, concentration-dependent relaxations in arteries. • These relaxations were associated with an inhibition of calcium entry. • Farnesene, at concentrations up to 30 μM, was without effect in either blood vessel. • Umbelliferone produced a rapid, transient nitric oxide-dependent relaxation

  17. The drive to eat: comparisons and distinctions between mechanisms of food reward and drug addiction.

    DiLeone, Ralph J; Taylor, Jane R; Picciotto, Marina R

    2012-10-01

    The growing rates of obesity have prompted comparisons between the uncontrolled intake of food and drugs; however, an evaluation of the equivalence of food- and drug-related behaviors requires a thorough understanding of the underlying neural circuits driving each behavior. Although it has been attractive to borrow neurobiological concepts from addiction to explore compulsive food seeking, a more integrated model is needed to understand how food and drugs differ in their ability to drive behavior. In this Review, we will examine the commonalities and differences in the systems-level and behavioral responses to food and to drugs of abuse, with the goal of identifying areas of research that would address gaps in our understanding and ultimately identify new treatments for obesity or drug addiction.

  18. Evidence for distinct mechanisms underlying attentional priming and sensory memory for bistable perception.

    Brinkhuis, M A B; Kristjánsson, Á; Brascamp, J W

    2015-08-01

    Attentional selection in visual search paradigms and perceptual selection in bistable perception paradigms show functional similarities. For example, both are sensitive to trial history: They are biased toward previously selected targets or interpretations. We investigated whether priming by target selection in visual search and sensory memory for bistable perception are related. We did this by presenting two trial types to observers. We presented either ambiguous spheres that rotated over a central axis and could be perceived as rotating in one of two directions, or search displays in which the unambiguously rotating target and distractor spheres closely resembled the two possible interpretations of the ambiguous stimulus. We interleaved both trial types within experiments, to see whether priming by target selection during search trials would affect the perceptual outcome of bistable perception and, conversely, whether sensory memory during bistable perception would affect target selection times during search. Whereas we found intertrial repetition effects among consecutive search trials and among consecutive bistable trials, we did not find cross-paradigm effects. Thus, even though we could ascertain that our experiments robustly elicited processes of both search priming and sensory memory for bistable perception, these same experiments revealed no interaction between the two.

  19. KIF7 Controls the Proliferation of Cells of the Respiratory Airway through Distinct Microtubule Dependent Mechanisms.

    Garry L Coles

    2015-10-01

    Full Text Available The cell cycle must be tightly coordinated for proper control of embryonic development and for the long-term maintenance of organs such as the lung. There is emerging evidence that Kinesin family member 7 (Kif7 promotes Hedgehog (Hh signaling during embryonic development, and its misregulation contributes to diseases such as ciliopathies and cancer. Kif7 encodes a microtubule interacting protein that controls Hh signaling through regulation of microtubule dynamics within the primary cilium. However, whether Kif7 has a function in nonciliated cells remains largely unknown. The role Kif7 plays in basic cell biological processes like cell proliferation or cell cycle progression also remains to be elucidated. Here, we show that Kif7 is required for coordination of the cell cycle, and inactivation of this gene leads to increased cell proliferation in vivo and in vitro. Immunostaining and transmission electron microscopy experiments show that Kif7dda/dda mutant lungs are hyperproliferative and exhibit reduced alveolar epithelial cell differentiation. KIF7 depleted C3H10T1/2 fibroblasts and Kif7dda/dda mutant mouse embryonic fibroblasts have increased growth rates at high cellular densities, suggesting that Kif7 may function as a general regulator of cellular proliferation. We ascertained that in G1, Kif7 and microtubule dynamics regulate the expression and activity of several components of the cell cycle machinery known to control entry into S phase. Our data suggest that Kif7 may function to regulate the maintenance of the respiratory airway architecture by controlling cellular density, cell proliferation, and cycle exit through its role as a microtubule associated protein.

  20. Distinct effects on diversifying selection by two mechanisms of immunity against Streptococcus pneumoniae.

    Yuan Li

    Full Text Available Antigenic variation to evade host immunity has long been assumed to be a driving force of diversifying selection in pathogens. Colonization by Streptococcus pneumoniae, which is central to the organism's transmission and therefore evolution, is limited by two arms of the immune system: antibody- and T cell- mediated immunity. In particular, the effector activity of CD4(+ T(H17 cell mediated immunity has been shown to act in trans, clearing co-colonizing pneumococci that do not bear the relevant antigen. It is thus unclear whether T(H17 cell immunity allows benefit of antigenic variation and contributes to diversifying selection. Here we show that antigen-specific CD4(+ T(H17 cell immunity almost equally reduces colonization by both an antigen-positive strain and a co-colonized, antigen-negative strain in a mouse model of pneumococcal carriage, thus potentially minimizing the advantage of escape from this type of immunity. Using a proteomic screening approach, we identified a list of candidate human CD4(+ T(H17 cell antigens. Using this list and a previously published list of pneumococcal Antibody antigens, we bioinformatically assessed the signals of diversifying selection among the identified antigens compared to non-antigens. We found that Antibody antigen genes were significantly more likely to be under diversifying selection than the T(H17 cell antigen genes, which were indistinguishable from non-antigens. Within the Antibody antigens, epitopes recognized by human antibodies showed stronger evidence of diversifying selection. Taken together, the data suggest that T(H17 cell-mediated immunity, one form of T cell immunity that is important to limit carriage of antigen-positive pneumococcus, favors little diversifying selection in the targeted antigen. The results could provide new insight into pneumococcal vaccine design.

  1. C-terminal substitution of MDM2 interacting peptides modulates binding affinity by distinctive mechanisms.

    Christopher J Brown

    Full Text Available The complex between the proteins MDM2 and p53 is a promising drug target for cancer therapy. The residues 19-26 of p53 have been biochemically and structurally demonstrated to be a most critical region to maintain the association of MDM2 and p53. Variation of the amino acid sequence in this range obviously alters the binding affinity. Surprisingly, suitable substitutions contiguous to this region of the p53 peptides can yield tightly binding peptides. The peptide variants may differ by a single residue that vary little in their structural conformations and yet are characterized by large differences in their binding affinities. In this study a systematic analysis into the role of single C-terminal mutations of a 12 residue fragment of the p53 transactivation domain (TD and an equivalent phage optimized peptide (12/1 were undertaken to elucidate their mechanistic and thermodynamic differences in interacting with the N-terminal of MDM2. The experimental results together with atomistically detailed dynamics simulations provide insight into the principles that govern peptide design protocols with regard to protein-protein interactions and peptidomimetic design.

  2. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms

    Rohde, Mikkel; Daugaard, Mads; Jensen, Mette Hartvig

    2005-01-01

    Whereas the stress-inducible heat-shock protein 70 (Hsp70) has gained plenty of attention as a putative target for tumor therapy, little is known about the role of other Hsp70 proteins in cancer. Here we present the first thorough analysis of the expression and function of the cytosolic Hsp70...... proteins in human cancer cells and identify Hsp70-2, a protein essential for spermatogenesis, as an important regulator of cancer cell growth. Targeted knock-down of the individual family members by RNA interference revealed that both Hsp70 and Hsp70-2 were required for cancer cell growth, whereas...

  3. RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms.

    Farias Luz, Nivea; Balaji, Sakthi; Okuda, Kendi; Barreto, Aline Silva; Bertin, John; Gough, Peter J; Gazzinelli, Ricardo; Almeida, Roque P; Bozza, Marcelo T; Borges, Valeria M; Chan, Francis Ka-Ming

    2016-06-15

    Leishmaniasis is an important parasitic disease found in the tropics and subtropics. Cutaneous and visceral leishmaniasis affect an estimated 1.5 million people worldwide. Despite its human health relevance, relatively little is known about the cell death pathways that control Leishmania replication in the host. Necroptosis is a recently identified form of cell death with potent antiviral effects. Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptosis downstream of death receptors and TLRs. Heme, a product of hemoglobin catabolism during certain intracellular pathogen infections, is also a potent inducer of macrophage necroptosis. We found that human visceral leishmaniasis patients exhibit elevated serum levels of heme. Therefore, we examined the impact of heme and necroptosis on Leishmania replication. Indeed, heme potently inhibited Leishmania replication in bone marrow-derived macrophages. Moreover, we found that inhibition of RIPK1 kinase activity also enhanced parasite replication in the absence of heme. We further found that the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), a putative downstream effector of RIPK1, was also required for inhibition of Leishmania replication. In mouse infection, both PGAM5 and RIPK1 kinase activity are required for IL-1β expression in response to Leishmania However, PGAM5, but not RIPK1 kinase activity, was directly responsible for Leishmania-induced IL-1β secretion and NO production in bone marrow-derived macrophages. Collectively, these results revealed that RIPK1 and PGAM5 function independently to exert optimal control of Leishmania replication in the host. Copyright © 2016 by The American Association of Immunologists, Inc.

  4. Computations Underlying Social Hierarchy Learning: Distinct Neural Mechanisms for Updating and Representing Self-Relevant Information.

    Kumaran, Dharshan; Banino, Andrea; Blundell, Charles; Hassabis, Demis; Dayan, Peter

    2016-12-07

    Knowledge about social hierarchies organizes human behavior, yet we understand little about the underlying computations. Here we show that a Bayesian inference scheme, which tracks the power of individuals, better captures behavioral and neural data compared with a reinforcement learning model inspired by rating systems used in games such as chess. We provide evidence that the medial prefrontal cortex (MPFC) selectively mediates the updating of knowledge about one's own hierarchy, as opposed to that of another individual, a process that underpinned successful performance and involved functional interactions with the amygdala and hippocampus. In contrast, we observed domain-general coding of rank in the amygdala and hippocampus, even when the task did not require it. Our findings reveal the computations underlying a core aspect of social cognition and provide new evidence that self-relevant information may indeed be afforded a unique representational status in the brain. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Distinct Feedforward and Feedback Effects of Microstimulation in Visual Cortex Reveal Neural Mechanisms of Texture Segregation.

    Klink, P Christiaan; Dagnino, Bruno; Gariel-Mathis, Marie-Alice; Roelfsema, Pieter R

    2017-07-05

    The visual cortex is hierarchically organized, with low-level areas coding for simple features and higher areas for complex ones. Feedforward and feedback connections propagate information between areas in opposite directions, but their functional roles are only partially understood. We used electrical microstimulation to perturb the propagation of neuronal activity between areas V1 and V4 in monkeys performing a texture-segregation task. In both areas, microstimulation locally caused a brief phase of excitation, followed by inhibition. Both these effects propagated faithfully in the feedforward direction from V1 to V4. Stimulation of V4, however, caused little V1 excitation, but it did yield a delayed suppression during the late phase of visually driven activity. This suppression was pronounced for the V1 figure representation and weaker for background representations. Our results reveal functional differences between feedforward and feedback processing in texture segregation and suggest a specific modulating role for feedback connections in perceptual organization. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment

    Holáň, Vladimír; Heřmánková, Barbora; Boháčová, Pavla; Kössl, Jan; Chudíčková, Milada; Hájková, Michaela; Krulová, Magdaléna; Zajícová, Alena; Javorková, Eliška

    2016-01-01

    Roč. 12, č. 6 (2016), s. 654-663 ISSN 1550-8943 R&D Projects: GA ČR(CZ) GA14-12580S; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LO1508; GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : mesenchymal stem cells * regulatory B cells * cytokine environment Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.967, year: 2016

  7. Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy

    Stuart, Sarah A; Butler, Paul; Munafò, Marcus R; Nutt, David J; Robinson, Emma SJ

    2015-01-01

    The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats’ choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid-onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate–reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine. PMID:25740288

  8. Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms

    Spangler, J.; Tomala, Jakub; Luca, V.C.; Jude, K.M.; Dong, S.; Ring, A.M.; Votavová, Petra; Pepper, M.; Kovář, Marek; Garcia, K.Ch.

    2015-01-01

    Roč. 42, č. 5 (2015), s. 815-825 ISSN 1074-7613 R&D Projects: GA ČR GA13-12885S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 Keywords : IN-VIVO EXPANSION * AUTOIMMUNE-DISEASE * SMALL-MOLECULE Subject RIV: EC - Immunology Impact factor: 24.082, year: 2015

  9. Distinct mechanisms of relaxation to bioactive components from chamomile species in porcine isolated blood vessels

    Roberts, R.E., E-mail: Richard.roberts@nottingham.ac.uk; Allen, S.; Chang, A.P.Y.; Henderson, H.; Hobson, G.C.; Karania, B.; Morgan, K.N.; Pek, A.S.Y.; Raghvani, K.; Shee, C.Y.; Shikotra, J.; Street, E.; Abbas, Z.; Ellis, K.; Heer, J.K.; Alexander, S.P.H., E-mail: steve.alexander@nottingham.ac.uk

    2013-11-01

    German chamomile (Matricaria recutita L.), a widely-used herbal medicine, has been reported to have a wide range of biological effects, including smooth muscle relaxation. The aim of this study was to compare the effects of representative compounds from chamomile (apigenin, luteolin, (−)-α-bisabolol, farnesene, umbelliferone; 3–30 μM) on vascular tone using porcine coronary and splenic arteries mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane-mimetic U46619. Apigenin, luteolin, and (−)-α-bisabolol produced slow, concentration-dependent relaxations in both the coronary and splenic arteries that were not blocked by inhibition of nitric oxide synthase or potassium channels. Removal of extracellular calcium inhibited the relaxations to all three compounds, and these compounds also inhibited calcium re-addition-evoked contractions, indicating that the relaxation response may be mediated through inhibition of calcium influx. Apigenin and luteolin, but not (−)-α-bisabolol, enhanced the relaxation to the nitric oxide donor sodium nitroprusside, indicating that apigenin and luteolin may act to regulate cyclic GMP levels. Umbelliferone produced a rapid, transient relaxation in the splenic artery, but not the coronary artery, that was inhibited by L-NAME and removal of the endothelium, suggesting an influence on nitric oxide production. Farnesene, at concentrations up to 30 μM, was without effect in either blood vessel. In conclusion, hydroxylated compounds (apigenin, luteolin and (−)-α-bisabolol) found in chamomile all caused a slow relaxation of isolated blood vessels through an effect on calcium influx. Umbelliferone, on the other hand, produced a rapid, transient relaxation dependent upon release of nitric oxide from the endothelium. - Highlights: • Apigenin, luteolin, and (-)-α-bisabolol are present in chamomile. • They produced slow, concentration-dependent relaxations in arteries. • These relaxations were associated with an inhibition of calcium entry. • Farnesene, at concentrations up to 30 μM, was without effect in either blood vessel. • Umbelliferone produced a rapid, transient nitric oxide-dependent relaxation.

  10. Mechanisms of distinct activated carbon and biochar amendment effects on petroleum vapour biofiltration in soil.

    Bushnaf, Khaled M; Mangse, George; Meynet, Paola; Davenport, Russell J; Cirpka, Olaf A; Werner, David

    2017-10-18

    We studied the effects of two percent by weight activated carbon versus biochar amendments in 93 cm long sand columns on the biofiltration of petroleum vapours released by a non-aqueous phase liquid (NAPL) source. Activated carbon greatly enhanced, whereas biochar slightly reduced, the biofiltration of volatile petroleum hydrocarbons (VPHs) over 430 days. Sorbent amendment benefitted the VPH biofiltration by retarding breakthrough during the biodegradation lag phase. Subsequently, sorbent amendment briefly reduced the mineralization of petroleum hydrocarbons by limiting their bioavailability. During the last and longest study period, when conditions became less supportive of microbial growth, because of inorganic nutrient scarcity, the sorbents again improved the pollution attenuation by preventing the degrading microorganisms from being overloaded with VPHs. A 16S rRNA gene based analysis showed sorbent amendment effects on soil microbial communities. Nocardioidaceae benefitted the most from petroleum hydrocarbons in activated carbon amended soil, whereas Pseudomonadacea predominated in unamended soil. Whilst the degrading microorganisms were overloaded with VPHs in the unamended soil, the reduced mobility and bioavailability of VPHs in the activated carbon amended soil led to the emergence of communities with higher specific substrate affinity, which removed bioavailable VPHs effectively at low concentrations. A numerical pollutant fate model reproduced these experimental observations by considering sorption effects on the pollutant migration and bioavailability for growth of VPH degrading biomass, which is limited by a maximum soil biomass carrying capacity. Activated carbon was a much stronger sorbent for VPHs than biochar, which explained the diverging effects of the two sorbents in this study.

  11. Aubergine Controls Germline Stem Cell Self-Renewal and Progeny Differentiation via Distinct Mechanisms.

    Ma, Xing; Zhu, Xiujuan; Han, Yingying; Story, Benjamin; Do, Trieu; Song, Xiaoqing; Wang, Su; Zhang, Ying; Blanchette, Marco; Gogol, Madelaine; Hall, Kate; Peak, Allison; Anoja, Perera; Xie, Ting

    2017-04-24

    Piwi family protein Aubergine (Aub) maintains genome integrity in late germ cells of the Drosophila ovary through Piwi-associated RNA-mediated repression of transposon activities. Although it is highly expressed in germline stem cells (GSCs) and early progeny, it remains unclear whether it plays any roles in early GSC lineage development. Here we report that Aub promotes GSC self-renewal and GSC progeny differentiation. RNA-iCLIP results show that Aub binds the mRNAs encoding self-renewal and differentiation factors in cultured GSCs. Aub controls GSC self-renewal by preventing DNA-damage-induced Chk2 activation and by translationally controlling the expression of self-renewal factors. It promotes GSC progeny differentiation by translationally controlling the expression of differentiation factors, including Bam. Therefore, this study reveals a function of Aub in GSCs and their progeny, which promotes translation of self-renewal and differentiation factors by directly binding to its target mRNAs and interacting with translational initiation factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Neural Mechanisms Underlying Visual Short-Term Memory Gain for Temporally Distinct Objects.

    Ihssen, Niklas; Linden, David E J; Miller, Claire E; Shapiro, Kimron L

    2015-08-01

    Recent research has shown that visual short-term memory (VSTM) can substantially be improved when the to-be-remembered objects are split in 2 half-arrays (i.e., sequenced) or the entire array is shown twice (i.e., repeated), rather than presented simultaneously. Here we investigate the hypothesis that sequencing and repeating displays overcomes attentional "bottlenecks" during simultaneous encoding. Using functional magnetic resonance imaging, we show that sequencing and repeating displays increased brain activation in extrastriate and primary visual areas, relative to simultaneous displays (Study 1). Passively viewing identical stimuli did not increase visual activation (Study 2), ruling out a physical confound. Importantly, areas of the frontoparietal attention network showed increased activation in repetition but not in sequential trials. This dissociation suggests that repeating a display increases attentional control by allowing attention to be reallocated in a second encoding episode. In contrast, sequencing the array poses fewer demands on control, with competition from nonattended objects being reduced by the half-arrays. This idea was corroborated by a third study in which we found optimal VSTM for sequential displays minimizing attentional demands. Importantly these results provide support within the same experimental paradigm for the role of stimulus-driven and top-down attentional control aspects of biased competition theory in setting constraints on VSTM. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Distinct mechanisms of nuclear accumulation regulate the functional consequence of E2F transcription factors

    Allen, K.E.; Luna, S. de la; Kerkhoven, R.M.; Bernards, R.A.; Thangue, N.B. La

    1997-01-01

    Transcription factor E2F plays an important role in coordinating and integrating early cell cycle progression with the transcription apparatus. It is known that physiological E2F arises when a member of two families of proteins, E2F and DP, interact as E2F/DP heterodimers and that transcriptional

  14. Mechanism for multiplicity of steady states with distinct cell concentration in continuous culture of mammalian cells.

    Yongky, Andrew; Lee, Jongchan; Le, Tung; Mulukutla, Bhanu Chandra; Daoutidis, Prodromos; Hu, Wei-Shou

    2015-07-01

    Continuous culture for the production of biopharmaceutical proteins offers the possibility of steady state operations and thus more consistent product quality and increased productivity. Under some conditions, multiplicity of steady states has been observed in continuous cultures of mammalian cells, wherein with the same dilution rate and feed nutrient composition, steady states with very different cell and product concentrations may be reached. At those different steady states, cells may exhibit a high glycolysis flux with high lactate production and low cell concentration, or a low glycolysis flux with low lactate and high cell concentration. These different steady states, with different cell concentration, also have different productivity. Developing a mechanistic understanding of the occurrence of steady state multiplicity and devising a strategy to steer the culture toward the desired steady state is critical. We establish a multi-scale kinetic model that integrates a mechanistic intracellular metabolic model and cell growth model in a continuous bioreactor. We show that steady state multiplicity exists in a range of dilution rate in continuous culture as a result of the bistable behavior in glycolysis. The insights from the model were used to devise strategies to guide the culture to the desired steady state in the multiple steady state region. The model provides a guideline principle in the design of continuous culture processes of mammalian cells. © 2015 Wiley Periodicals, Inc.

  15. Unified treatment of the classical and quantum mechanics

    Shirokov, Yu.M.

    1979-01-01

    Classical and Quantum Mechanics are unified in the sense that almost all axioms of both mechanics are identical. The only distinction is the explicit form of one algebraic identity. The unified theory is applied to scattering problem. (Z.M.)

  16. Many-Objective Distinct Candidates Optimization using Differential Evolution

    Justesen, Peter; Ursem, Rasmus Kjær

    2010-01-01

    for each objective. The Many-Objective Distinct Candidates Optimization using Differential Evolution (MODCODE) algorithm takes a novel approach by focusing search using a user-defined number of subpopulations each returning a distinct optimal solution within the preferred region of interest. In this paper......, we present the novel MODCODE algorithm incorporating the ROD measure to measure and control candidate distinctiveness. MODCODE is tested against GDE3 on three real world centrifugal pump design problems supplied by Grundfos. Our algorithm outperforms GDE3 on all problems with respect to all...

  17. Creating fair lineups for suspects with distinctive features.

    Zarkadi, Theodora; Wade, Kimberley A; Stewart, Neil

    2009-12-01

    In their descriptions, eyewitnesses often refer to a culprit's distinctive facial features. However, in a police lineup, selecting the only member with the described distinctive feature is unfair to the suspect and provides the police with little further information. For fair and informative lineups, the distinctive feature should be either replicated across foils or concealed on the target. In the present experiments, replication produced more correct identifications in target-present lineups--without increasing the incorrect identification of foils in target-absent lineups--than did concealment. This pattern, and only this pattern, is predicted by the hybrid-similarity model of recognition.

  18. The rhetorician's craft, distinctions in science, and political morality

    Sadler, John Z

    2006-01-01

    In his response to Szasz' Secular Humanism and Scientific Psychiatry, the author considers the use of rhetorical devices in Szasz' work, Szasz' avoidance of acknowledging psychiatry's scientific distinctions, and Szaszian libertarianism versus liberalism. PMID:16759356

  19. Education and Training: Is There Any Longer a Useful Distinction?

    Hager, Paul; Laurent, John

    1990-01-01

    Although education and training were distinct concepts when Taylorism dominated the workplace, it is no longer appropriate to separate them. Today's highly competitive environment requires the education of a flexible, multiskilled workforce, not training for narrowly defined employment tasks. (SK)

  20. The rhetorician's craft, distinctions in science, and political morality

    Sadler, John Z

    2006-01-01

    Abstract In his response to Szasz' Secular Humanism and Scientific Psychiatry, the author considers the use of rhetorical devices in Szasz' work, Szasz' avoidance of acknowledging psychiatry's scientific distinctions, and Szaszian libertarianism versus liberalism.

  1. The rhetorician's craft, distinctions in science, and political morality

    Sadler John Z

    2006-05-01

    Full Text Available Abstract In his response to Szasz' Secular Humanism and Scientific Psychiatry, the author considers the use of rhetorical devices in Szasz' work, Szasz' avoidance of acknowledging psychiatry's scientific distinctions, and Szaszian libertarianism versus liberalism.

  2. Tagging like Humans: Diverse and Distinct Image Annotation

    Wu, Baoyuan; Chen, Weidong; Sun, Peng; Liu, Wei; Ghanem, Bernard; Lyu, Siwei

    2018-01-01

    including quantitative and qualitative comparisons, as well as human subject studies, on two benchmark datasets demonstrate that the proposed model can produce more diverse and distinct tags than the state-of-the-arts.

  3. Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

    Teo, Minyuen

    2013-03-01

    A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes.

  4. Fetterman-House: A Process Use Distinction and a Theory.

    Fetterman, David

    2003-01-01

    Discusses the concept of process use as an important distinction between the evaluation theories of E. House and D. Fetterman, thus helping to explain the discordant results of C. Christie for these two theories. (SLD)

  5. 29 CFR 549.3 - Distinction between plan and trust.

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Distinction between plan and trust. 549.3 Section 549.3 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR REGULATIONS REQUIREMENTS OF A âBONA FIDE PROFIT-SHARING PLAN OR TRUSTâ § 549.3 Distinction between plan and trust. As used in this part: (a) Profit-sharing plan...

  6. An Adult Developmental Approach to Perceived Facial Attractiveness and Distinctiveness

    Natalie C. Ebner; Natalie C. Ebner; Natalie C. Ebner; Joerg Luedicke; Manuel C. Voelkle; Manuel C. Voelkle; Michaela Riediger; Michaela Riediger; Tian Lin; Ulman Lindenberger; Ulman Lindenberger

    2018-01-01

    Attractiveness and distinctiveness constitute facial features with high biological and social relevance. Bringing a developmental perspective to research on social-cognitive face perception, we used a large set of faces taken from the FACES Lifespan Database to examine effects of face and perceiver characteristics on subjective evaluations of attractiveness and distinctiveness in young (20–31 years), middle-aged (44–55 years), and older (70–81 years) men and women. We report novel findings su...

  7. Quantum mechanics

    Anon.

    1990-01-01

    The book is on quantum mechanics. The emphasis is on the basic concepts and the methodology. The chapters include: Breakdown of classical concepts; Quantum mechanical concepts; Basic postulates of quantum mechanics; solution of problems in quantum mechanics; Simple harmonic oscillator; and Angular Momentum

  8. Continuum mechanics

    Spencer, A J M

    2004-01-01

    The mechanics of fluids and the mechanics of solids represent the two major areas of physics and applied mathematics that meet in continuum mechanics, a field that forms the foundation of civil and mechanical engineering. This unified approach to the teaching of fluid and solid mechanics focuses on the general mechanical principles that apply to all materials. Students who have familiarized themselves with the basic principles can go on to specialize in any of the different branches of continuum mechanics. This text opens with introductory chapters on matrix algebra, vectors and Cartesian ten

  9. Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.

    Haradhvala, N J; Kim, J; Maruvka, Y E; Polak, P; Rosebrock, D; Livitz, D; Hess, J M; Leshchiner, I; Kamburov, A; Mouw, K W; Lawrence, M S; Getz, G

    2018-05-01

    Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures.

  10. A Distinct Population of Microglia Supports Adult Neurogenesis in the Subventricular Zone

    Ribeiro Xavier, Anna L.; Kress, Benjamin T.; Goldman, Steven A.

    2015-01-01

    found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low...... STATEMENT: Microglial cells are a specialized population of macrophages in the CNS, playing key roles as immune mediators. As integral components in the CNS, the microglia stand out for using the same mechanisms, phagocytosis and cytochemokine release, to promote homeostasis, synaptic pruning, and neural...... toward olfactory bulb layers. In addition to other unique populations residing in the SVZ niche, microglia display distinct morphofunctional properties that boost neuronal progenitor survival and migration in the mammalian brain....

  11. Circuit mechanisms of sensorimotor learning

    Makino, Hiroshi; Hwang, Eun Jung; Hedrick, Nathan G.; Komiyama, Takaki

    2016-01-01

    SUMMARY The relationship between the brain and the environment is flexible, forming the foundation for our ability to learn. Here we review the current state of our understanding of the modifications in the sensorimotor pathway related to sensorimotor learning. We divide the process in three hierarchical levels with distinct goals: 1) sensory perceptual learning, 2) sensorimotor associative learning, and 3) motor skill learning. Perceptual learning optimizes the representations of important sensory stimuli. Associative learning and the initial phase of motor skill learning are ensured by feedback-based mechanisms that permit trial-and-error learning. The later phase of motor skill learning may primarily involve feedback-independent mechanisms operating under the classic Hebbian rule. With these changes under distinct constraints and mechanisms, sensorimotor learning establishes dedicated circuitry for the reproduction of stereotyped neural activity patterns and behavior. PMID:27883902

  12. Distinctions, Affiliations, and Professional Knowledge in Financial Reform Commissions

    Seabrooke, Leonard; Tsingou, Eleni

    the different stresses in reports with and without clear mandates, and the role of important members of the policy community in promoting particular reform ideas. The article finds that differences in ideas emerging from the financial reform expert groups reflect nested power relationships in the commissioning...... the reports. Fractal distinctions, such as between ‘behavior’ or ‘system’ as a reform focus, allow us to locate the object of regulation within expert groups, experts’ professional context, and the politics behind the commissioning of work. Analyzing fractal distinctions provides a useful way to understand...... of work, constituent audiences, and reform priorities among governing institutions, rather than distinct ‘European’ and ‘American’ ideas....

  13. Distinctions, Affiliations, and Professional Knowledge in Financial Reform Expert Groups

    Seabrooke, Leonard; Tsingou, Eleni

    2014-01-01

    to understand the different stresses in reports with and without clear mandates, and the role of important members of the policy community in promoting particular reform ideas. The contribution finds that differences in ideas emerging from the financial reform expert groups reflect nested power relationships...... the reports. Fractal distinctions, such as between ‘behaviour’ or ‘system’ as a reform focus, allow us to locate the object of regulation within expert groups, the experts' professional context and the politics behind the commissioning of work. Analysing fractal distinctions provides a useful way...... in the commissioning of work, constituent audiences and reform priorities among governing institutions, rather than distinct ‘European’ and ‘American’ ideas....

  14. Liquidity spillover in international stock markets through distinct time scales.

    Righi, Marcelo Brutti; Vieira, Kelmara Mendes

    2014-01-01

    This paper identifies liquidity spillovers through different time scales based on a wavelet multiscaling method. We decompose daily data from U.S., British, Brazilian and Hong Kong stock markets indices in order to calculate the scale correlation between their illiquidities. The sample is divided in order to consider non-crisis, sub-prime crisis and Eurozone crisis. We find that there are changes in correlations of distinct scales and different periods. Association in finest scales is smaller than in coarse scales. There is a rise on associations in periods of crisis. In frequencies, there is predominance for significant distinctions involving the coarsest scale, while for crises periods there is predominance for distinctions on the finest scale.

  15. Load and distinctness interact in working memory for lexical manual gestures

    Mary eRudner

    2015-08-01

    Full Text Available The Ease of Language Understanding model (ELU, Rönnberg et al., 2013 predicts that decreasing the distinctness of language stimuli increases working memory load; in the speech domain this notion is supported by empirical evidence. Our aim was to determine whether such an over-additive interaction can be generalized to sign processing in sign-naïve individuals and whether it is modulated by experience of computer gaming. Twenty young adults with no knowledge of sign language performed an n-back working memory task based on manual gestures lexicalized in sign language; the visual resolution of the signs and working memory load were manipulated. Performance was poorer when load was high and resolution was low. These two effects interacted over-additively, demonstrating that reducing the resolution of signed stimuli increases working memory load when there is no pre-existing semantic representation. This suggests that load and distinctness are handled by a shared amodal mechanism which can be revealed empirically when stimuli are degraded and load is high, even without pre-existing semantic representation. There was some evidence that the mechanism is influenced by computer gaming experience. Future work should explore how the shared mechanism is influenced by pre-existing semantic representation and sensory factors together with computer gaming experience.

  16. Load and distinctness interact in working memory for lexical manual gestures.

    Rudner, Mary; Toscano, Elena; Holmer, Emil

    2015-01-01

    The Ease of Language Understanding model (Rönnberg et al., 2013) predicts that decreasing the distinctness of language stimuli increases working memory load; in the speech domain this notion is supported by empirical evidence. Our aim was to determine whether such an over-additive interaction can be generalized to sign processing in sign-naïve individuals and whether it is modulated by experience of computer gaming. Twenty young adults with no knowledge of sign language performed an n-back working memory task based on manual gestures lexicalized in sign language; the visual resolution of the signs and working memory load were manipulated. Performance was poorer when load was high and resolution was low. These two effects interacted over-additively, demonstrating that reducing the resolution of signed stimuli increases working memory load when there is no pre-existing semantic representation. This suggests that load and distinctness are handled by a shared amodal mechanism which can be revealed empirically when stimuli are degraded and load is high, even without pre-existing semantic representation. There was some evidence that the mechanism is influenced by computer gaming experience. Future work should explore how the shared mechanism is influenced by pre-existing semantic representation and sensory factors together with computer gaming experience.

  17. Implement of the Owner Distinction Function for Healing-Type Pet Robots

    Nambo, Hidetaka; Kimura, Haruhiko; Hirose, Sadaki

    In recent years, a robotics technology is extremely progressive, and robots are widely applied in many fields. One of the most typical robots is a pet robot. The pet robot is based on an animal pet, such as a dog or a cat. Also, it is known that an animal pet has a healing effect. Therefore, the study to apply pet robots to Animal Assisted Therapy instead of an animal pet has begun to be investigated. We, also, have investigated a method of an owner distinction for pet robot, to emphasize a healing effect of pet robots. In this paper, taking account of implementation into pet robots, a real-time owner distinction method is proposed. In the concrete, the method provides a real-time matching algorithm and an oblivion mechanism. The real-time matching means that a matching and a data acquisition are processed simultaneously. The oblivion mechanism is deleting features of owners in the database of the pet robots. Additionally, the mechanism enables to reduce matching costs or size of database and it enables to follow a change of owners. Furthermore, effectivity and a practicality of the method are evaluated by experiments.

  18. Mechanical Ventilation

    ... ventilation is a life support treatment. A mechanical ventilator is a machine that helps people breathe when ... to breathe enough on their own. The mechanical ventilator is also called a ventilator , respirator, or breathing ...

  19. The Dirac equation in classical statistical mechanics

    Ord, G.N.

    2002-01-01

    The Dirac equation, usually obtained by 'quantizing' a classical stochastic model is here obtained directly within classical statistical mechanics. The special underlying space-time geometry of the random walk replaces the missing analytic continuation, making the model 'self-quantizing'. This provides a new context for the Dirac equation, distinct from its usual context in relativistic quantum mechanics

  20. Mechanisms of Interaction in Speech Production

    Baese-Berk, Melissa; Goldrick, Matthew

    2009-01-01

    Many theories predict the presence of interactive effects involving information represented by distinct cognitive processes in speech production. There is considerably less agreement regarding the precise cognitive mechanisms that underlie these interactive effects. For example, are they driven by purely production-internal mechanisms (e.g., Dell,…

  1. What History Tells Us about the Distinct Nature of Chemistry.

    Chang, Hasok

    2017-11-01

    Attention to the history of chemistry can help us recognise the characteristics of chemistry that have helped to maintain it as a separate scientific discipline with a unique identity. Three such features are highlighted in this paper. First, chemistry has maintained a distinct type of theoretical thinking, independent from that of physics even in the era of quantum chemistry. Second, chemical research has always been shaped by its ineliminable practical relevance and usefulness. Third, the lived experience of chemistry, spanning the laboratory, the classroom and everyday life, is distinctive in its multidimensional sensuousness. Furthermore, I argue that the combination of these three features makes chemistry an exemplary science.

  2. Revitalizing the “civic” and “ethnic” distinction

    Larsen, Christian Albrekt

    2017-01-01

    This article describes how contemporary publics think about the nation along Kohn’s classic distinction between “civic” and “ethnic” nationalism. The article makes three contributes to the existing literature. Firstly, it introduces a new statistical tool, multi-classification-analysis, to establ......This article describes how contemporary publics think about the nation along Kohn’s classic distinction between “civic” and “ethnic” nationalism. The article makes three contributes to the existing literature. Firstly, it introduces a new statistical tool, multi...

  3. Grammar-Lexicon Distinction in a Neurocognitive Context

    Ishkhanyan, Byurakn

    hypotheses and testing them through using various methods. The grammar-lexicon distinction and working memory are thus central topics of this thesis. The results suggest a potential for a successful integration of the two theories. The findings further provide evidence for Boye & Harder’s (2012......) understanding of the grammar-lexicon distinction, and for the involvement of working memory in language production, as the REF-model would predict. As a starting point for integrating the two theories, the present thesis gives directions for future research on the neurocognitive underpinning of language and its...... relation to working memory....

  4. Mechanical design

    Risitano, Antonino

    2011-01-01

    METHODOLOGICAL STATEMENT OF ENGINEERING DESIGNApproaches to product design and developmentMechanical design and environmental requirementsPROPERTIES OF ENGINEERING MATERIALSMaterials for mechanical designCharacterization of metalsStress conditionsFatigue of materialsOptimum material selection in mechanical designDESIGN OF MECHANICAL COMPONENTS AND SYSTEMSFailure theoriesHertz theoryLubrificationShafts and bearingsSplines and keysSpringsFlexible machine elementsSpur gearsPress and shrink fitsPressure tubesCouplingsClutchesBrakes

  5. NLC Mechanical

    text only Mechanical Systems.gif (14697 bytes) NLC Home Page NLC Technical SLAC Permanent Magnets Organization Overview The Mechanical Systems Group Organization is shown on the NLC Project Group Organization Chart (Next Linear Collider Technical Web Page). The Mechanical Systems Group operates on a matrixed

  6. Mechanical Kinesiology.

    Barham, Jerry N.

    Mechanical kinesiology is defined as a study of the mechanical factors affecting human movement, i.e., applying the physical laws of mechanics to the study of human motor behavior. This textbook on the subject is divided into thirty lessons. Each lesson is organized into three parts: a part on the text proper; a part entitled "study…

  7. Mechanisms Design

    Restrepo-Giraldo, John Dairo

    2006-01-01

    Most products and machines involve some kind of controlled movement. From window casements to DVD players, from harbor cranes to the shears to prune your garden, all these machines require mechanisms to move. This course intends to provide the analytical and conceptual tools to design such mechan......Most products and machines involve some kind of controlled movement. From window casements to DVD players, from harbor cranes to the shears to prune your garden, all these machines require mechanisms to move. This course intends to provide the analytical and conceptual tools to design...... using criteria such as size, performance parameters, operation environment, etc. Content: Understanding Mechanisms Design (2 weeks) Definitions, mechanisms representations, kinematic diagrams, the four bar linkage, mobility, applications of mechanisms, types of mechanisms, special mechanisms, the design......: equations for various mechanisms. At the end of this module you will be able to analyze existing mechanisms and to describe their movement. Designing mechanisms (7 weeks) Type synthesis and dimensional synthesis, function generation, path generation, three precision points in multi-loop mechanisms...

  8. Agricultural mechanization policy and strategy : the case of Thailand

    Rijk, A.G.

    1989-01-01

    The role of agricultural mechanization in a developing economy is examined in order to enhance the formulation of mechanization policy and strategy. As a result of the review and assessment of the mechanization process, seven distinct stages in the mechanization process are specified and

  9. Monoclonal Antibodies Follow Distinct Aggregation Pathways During Production-Relevant Acidic Incubation and Neutralization

    Pedersen, Thomas Skamris; Tian, Xinsheng; Thorolfsson, Matthias

    2016-01-01

    and orthogonal analytical methods, including small-angle X-ray scattering and dynamic light scattering and supplemented the experimental data with crystal structure-based spatial aggregation propensity (SAP) calculations. RESULTS: We revealed distinct solution behaviors between the three mAb models: At acidic p......PURPOSE: Aggregation aspects of therapeutic monoclonal antibodies (mAbs) are of common concern to the pharmaceutical industry. Low pH treatment is applied during affinity purification and to inactivate endogenous retroviruses, directing interest to the mechanisms of acid-induced antibody...... distinguish between reversible and irreversible mAb aggregation pathways at early stages of acidic treatment....

  10. EGL-13/SoxD Specifies Distinct O2 and CO2 Sensory Neuron Fates in Caenorhabditis elegans

    Gramstrup Petersen, Jakob; Rojo Romanos, Teresa; Juozaityte, Vaida

    2013-01-01

    that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms......Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral...

  11. Discrete mechanics

    Caltagirone, Jean-Paul

    2014-01-01

    This book presents the fundamental principles of mechanics to re-establish the equations of Discrete Mechanics. It introduces physics and thermodynamics associated to the physical modeling.  The development and the complementarity of sciences lead to review today the old concepts that were the basis for the development of continuum mechanics. The differential geometry is used to review the conservation laws of mechanics. For instance, this formalism requires a different location of vector and scalar quantities in space. The equations of Discrete Mechanics form a system of equations where the H

  12. Discrete mechanics

    Lee, T.D.

    1985-01-01

    This paper reviews the role of time throughout all phases of mechanics: classical mechanics, non-relativistic quantum mechanics, and relativistic quantum theory. As an example of the relativistic quantum field theory, the case of a massless scalar field interacting with an arbitrary external current is discussed. The comparison between the new discrete theory and the usual continuum formalism is presented. An example is given of a two-dimensional random lattice and its duel. The author notes that there is no evidence that the discrete mechanics is more appropriate than the usual continuum mechanics

  13. Tp53 gene mediates distinct dopaminergic neuronal damage in different dopaminergic neurotoxicant models

    Tao Lu

    2017-01-01

    Full Text Available Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson's disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic (DA neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by pharmacological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal terminal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuronal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.

  14. Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1.

    Han, Jingyan; Shuvaev, Vladimir V; Davies, Peter F; Eckmann, David M; Muro, Silvia; Muzykantov, Vladimir R

    2015-07-28

    Targeting nanocarriers (NC) to endothelial cell adhesion molecules including Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1 or CD31) improves drug delivery and pharmacotherapy of inflammation, oxidative stress, thrombosis and ischemia in animal models. Recent studies unveiled that hydrodynamic conditions modulate endothelial endocytosis of NC targeted to PECAM-1, but the specificity and mechanism of effects of flow remain unknown. Here we studied the effect of flow on endocytosis by human endothelial cells of NC targeted by monoclonal antibodies Ab62 and Ab37 to distinct epitopes on the distal extracellular domain of PECAM. Flow in the range of 1-8dyn/cm(2), typical for venous vasculature, stimulated the uptake of spherical Ab/NC (~180nm diameter) carrying ~50 vs 200 Ab62 and Ab37 per NC, respectively. Effect of flow was inhibited by disruption of cholesterol-rich plasmalemma domains and deletion of PECAM-1 cytosolic tail. Flow stimulated endocytosis of Ab62/NC and Ab37/NC via eliciting distinct signaling pathways mediated by RhoA/ROCK and Src Family Kinases, respectively. Therefore, flow stimulates endothelial endocytosis of Ab/NC in a PECAM-1 epitope specific manner. Using ligands of binding to distinct epitopes on the same target molecule may enable fine-tuning of intracellular delivery based on the hemodynamic conditions in the vascular area of interest. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Dynamic Changes in Amygdala Psychophysiological Connectivity Reveal Distinct Neural Networks for Facial Expressions of Basic Emotions.

    Diano, Matteo; Tamietto, Marco; Celeghin, Alessia; Weiskrantz, Lawrence; Tatu, Mona-Karina; Bagnis, Arianna; Duca, Sergio; Geminiani, Giuliano; Cauda, Franco; Costa, Tommaso

    2017-03-27

    The quest to characterize the neural signature distinctive of different basic emotions has recently come under renewed scrutiny. Here we investigated whether facial expressions of different basic emotions modulate the functional connectivity of the amygdala with the rest of the brain. To this end, we presented seventeen healthy participants (8 females) with facial expressions of anger, disgust, fear, happiness, sadness and emotional neutrality and analyzed amygdala's psychophysiological interaction (PPI). In fact, PPI can reveal how inter-regional amygdala communications change dynamically depending on perception of various emotional expressions to recruit different brain networks, compared to the functional interactions it entertains during perception of neutral expressions. We found that for each emotion the amygdala recruited a distinctive and spatially distributed set of structures to interact with. These changes in amygdala connectional patters characterize the dynamic signature prototypical of individual emotion processing, and seemingly represent a neural mechanism that serves to implement the distinctive influence that each emotion exerts on perceptual, cognitive, and motor responses. Besides these differences, all emotions enhanced amygdala functional integration with premotor cortices compared to neutral faces. The present findings thus concur to reconceptualise the structure-function relation between brain-emotion from the traditional one-to-one mapping toward a network-based and dynamic perspective.

  16. Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses.

    Montefusco, David J; Chen, Lujia; Matmati, Nabil; Lu, Songjian; Newcomb, Benjamin; Cooper, Gregory F; Hannun, Yusuf A; Lu, Xinghua

    2013-10-29

    Ceramide, the central molecule of sphingolipid metabolism, is an important bioactive molecule that participates in various cellular regulatory events and that has been implicated in disease. Deciphering ceramide signaling is challenging because multiple ceramide species exist, and many of them may have distinct functions. We applied systems biology and molecular approaches to perturb ceramide metabolism in the yeast Saccharomyces cerevisiae and inferred causal relationships between ceramide species and their potential targets by combining lipidomic, genomic, and transcriptomic analyses. We found that during heat stress, distinct metabolic mechanisms controlled the abundance of different groups of ceramide species and provided experimental support for the importance of the dihydroceramidase Ydc1 in mediating the decrease in dihydroceramides during heat stress. Additionally, distinct groups of ceramide species, with different N-acyl chains and hydroxylations, regulated different sets of functionally related genes, indicating that the structural complexity of these lipids produces functional diversity. The transcriptional modules that we identified provide a resource to begin to dissect the specific functions of ceramides.

  17. Neural correlates of the food/non-food visual distinction.

    Tsourides, Kleovoulos; Shariat, Shahriar; Nejati, Hossein; Gandhi, Tapan K; Cardinaux, Annie; Simons, Christopher T; Cheung, Ngai-Man; Pavlovic, Vladimir; Sinha, Pawan

    2016-03-01

    An evolutionarily ancient skill we possess is the ability to distinguish between food and non-food. Our goal here is to identify the neural correlates of visually driven 'edible-inedible' perceptual distinction. We also investigate correlates of the finer-grained likability assessment. Our stimuli depicted food or non-food items with sub-classes of appealing or unappealing exemplars. Using data-classification techniques drawn from machine-learning, as well as evoked-response analyses, we sought to determine whether these four classes of stimuli could be distinguished based on the patterns of brain activity they elicited. Subjects viewed 200 images while in a MEG scanner. Our analyses yielded two successes and a surprising failure. The food/non-food distinction had a robust neural counterpart and emerged as early as 85 ms post-stimulus onset. The likable/non-likable distinction too was evident in the neural signals when food and non-food stimuli were grouped together, or when only the non-food stimuli were included in the analyses. However, we were unable to identify any neural correlates of this distinction when limiting the analyses only to food stimuli. Taken together, these positive and negative results further our understanding of the substrates of a set of ecologically important judgments and have clinical implications for conditions like eating-disorders and anhedonia. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Magnetic mirror fusion systems: Characteristics and distinctive features

    Post, R.F.

    1987-01-01

    A tutorial account is given of the main characteristics and distinctive features of conceptual magnetic fusion systems employing the magnetic mirror principle. These features are related to the potential advantages that mirror-based fusion systems may exhibit for the generation of economic fusion power

  19. Visual Distinctiveness and the Development of Children's False Memories

    Howe, Mark L.

    2008-01-01

    Distinctiveness effects in children's (5-, 7-, and 11-year-olds) false memory illusions were examined using visual materials. In Experiment 1, developmental trends (increasing false memories with age) were obtained using Deese-Roediger-McDermott lists presented as words and color photographs but not line drawings. In Experiment 2, when items were…

  20. Effectiveness, Improvement and Educational Change: A Distinctively Canadian Approach?

    Hargreaves, Andy; Fink, Dean

    1998-01-01

    A distinctive Canadian school of thought on educational change is inclined to synthesize diverse bodies of work and integrate nonrational and emotional dimensions with rational and technically effective ones in a socially critical way. Highlights the Canadian perspective through discussions about complex systems, contexts of change, critical…

  1. Distinct patterns of epigenetic marks and transcription factor binding ...

    Distinct patterns of epigenetic marks and transcription factor binding sites across promoters of sense-intronic long noncoding RNAs. Sourav Ghosh, Satish Sati, Shantanu Sengupta and Vinod Scaria. J. Genet. 94, 17–25. Gencode V9 lncRNA gene : 11004. Known lncRNA : 1175. Novel lncRNA : 5898. Putative lncRNA :.

  2. Genetic Determinism and the Innate-Acquired Distinction in Medicine

    2009-01-01

    This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate–acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate–acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate–acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature–nurture debates. PMID:20234831

  3. Are there distinctive indigenous methods of inquiry? | Le Grange ...

    This article explores whether there are methods that might be referred to as being distinctly indigenous. In doing so the nature of method is examined and it is concluded that method is not universal and neutral, but rather situated and performative. The upshot of this is that research methods can be transformed and that ...

  4. Blurring Boundaries : Carnap, Quine, and the Internal-External Distinction

    Verhaegh, Sander

    Quine is routinely perceived as saving metaphysics from Carnapian positivism. Where Carnap rejects metaphysical existence claims as meaningless, Quine is taken to restore their intelligibility by dismantling the former's internal-external distinction. The problem with this picture, however, is that

  5. 48 CFR 307.7001 - Distinction between acquisition and assistance.

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Distinction between acquisition and assistance. 307.7001 Section 307.7001 Federal Acquisition Regulations System HEALTH AND HUMAN... barter, of property or services for the direct benefit or use of the Government; or (2) Government...

  6. MAGDM linear-programming models with distinct uncertain preference structures.

    Xu, Zeshui S; Chen, Jian

    2008-10-01

    Group decision making with preference information on alternatives is an interesting and important research topic which has been receiving more and more attention in recent years. The purpose of this paper is to investigate multiple-attribute group decision-making (MAGDM) problems with distinct uncertain preference structures. We develop some linear-programming models for dealing with the MAGDM problems, where the information about attribute weights is incomplete, and the decision makers have their preferences on alternatives. The provided preference information can be represented in the following three distinct uncertain preference structures: 1) interval utility values; 2) interval fuzzy preference relations; and 3) interval multiplicative preference relations. We first establish some linear-programming models based on decision matrix and each of the distinct uncertain preference structures and, then, develop some linear-programming models to integrate all three structures of subjective uncertain preference information provided by the decision makers and the objective information depicted in the decision matrix. Furthermore, we propose a simple and straightforward approach in ranking and selecting the given alternatives. It is worth pointing out that the developed models can also be used to deal with the situations where the three distinct uncertain preference structures are reduced to the traditional ones, i.e., utility values, fuzzy preference relations, and multiplicative preference relations. Finally, we use a practical example to illustrate in detail the calculation process of the developed approach.

  7. Differential Recruitment of Distinct Amygdalar Nuclei across Appetitive Associative Learning

    Cole, Sindy; Powell, Daniel J.; Petrovich, Gorica D.

    2013-01-01

    The amygdala is important for reward-associated learning, but how distinct cell groups within this heterogeneous structure are recruited during appetitive learning is unclear. Here we used Fos induction to map the functional amygdalar circuitry recruited during early and late training sessions of Pavlovian appetitive conditioning. We found that a…

  8. An Objective Approach to Identify Spectral Distinctiveness for Hearing Impairment

    Yeou-Jiunn Chen

    2013-01-01

    Full Text Available To facilitate the process of developing speech perception, speech-language pathologists have to teach a subject with hearing loss the differences between two syllables by manually enhancing acoustic cues of speech. However, this process is time consuming and difficult. Thus, this study proposes an objective approach to automatically identify the regions of spectral distinctiveness between two syllables, which is used for speech-perception training. To accurately represent the characteristics of speech, mel-frequency cepstrum coefficients are selected as analytical parameters. The mismatch between two syllables in time domain is handled by dynamic time warping. Further, a filter bank is adopted to estimate the components in different frequency bands, which are also represented as mel-frequency cepstrum coefficients. The spectral distinctiveness in different frequency bands is then easily estimated by using Euclidean metrics. Finally, a morphological gradient operator is applied to automatically identify the regions of spectral distinctiveness. To evaluate the proposed approach, the identified regions are manipulated and then the manipulated syllables are measured by a close-set based speech-perception test. The experimental results demonstrated that the identified regions of spectral distinctiveness are very useful in speech perception, which indeed can help speech-language pathologists in speech-perception training.

  9. Distinctiveness and Bidirectional Effects in Input Enhancement for Vocabulary Learning

    Barcroft, Joe

    2003-01-01

    This study examined input enhancement and second language (L2) vocabulary learning while exploring the role of "distinctiveness," the degree to which an item in the input diverges from the form in which other items in the input are presented, with regard to the nature and direction of the effects of enhancement. In this study,…

  10. BMP signalling differentially regulates distinct haematopoietic stem cell types

    M. Crisan (Mihaela); P. Solaimani Kartalaei (Parham); C.S. Vink (Chris); T. Yamada-Inagawa (Tomoko); K. Bollerot (Karine); W.F.J. van IJcken (Wilfred); R. Van Der Linden (Reinier); S.C. de Sousa Lopes (Susana Chuva); R. Monteiro (Rui); C.L. Mummery (Christine); E.A. Dzierzak (Elaine)

    2015-01-01

    textabstractAdult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they

  11. An Adult Developmental Approach to Perceived Facial Attractiveness and Distinctiveness

    Natalie C. Ebner

    2018-05-01

    Full Text Available Attractiveness and distinctiveness constitute facial features with high biological and social relevance. Bringing a developmental perspective to research on social-cognitive face perception, we used a large set of faces taken from the FACES Lifespan Database to examine effects of face and perceiver characteristics on subjective evaluations of attractiveness and distinctiveness in young (20–31 years, middle-aged (44–55 years, and older (70–81 years men and women. We report novel findings supporting variations by face and perceiver age, in interaction with gender and emotion: although older and middle-aged compared to young perceivers generally rated faces of all ages as more attractive, young perceivers gave relatively higher attractiveness ratings to young compared to middle-aged and older faces. Controlling for variations in attractiveness, older compared to young faces were viewed as more distinctive by young and middle-aged perceivers. Age affected attractiveness more negatively for female than male faces. Furthermore, happy faces were rated as most attractive, while disgusted faces were rated as least attractive, particularly so by middle-aged and older perceivers and for young and female faces. Perceivers largely agreed on distinctiveness ratings for neutral and happy emotions, but older and middle-aged compared to young perceivers rated faces displaying negative emotions as more distinctive. These findings underscore the importance of a lifespan perspective on perception of facial characteristics and suggest possible effects of age on goal-directed perception, social motivation, and in-group bias. This publication makes available picture-specific normative data for experimental stimulus selection.

  12. Axiomatic electrodynamics and microscopic mechanics

    Yussouff, M.

    1981-04-01

    A new approach to theoretical physics, along with the basic formulation of a new MICROSCOPIC MECHANICS for the motion of small charged particles is described in this set of lecture notes. Starting with the classical (Newtonian) mechanics and classical fields, the important but well known properties of Classical Electromagnetic field are discussed up to section 4. The next nection describes the usual radiation damping theory and its difficulties. It is argued that the usual treatment of radiation damping is not valid for small space and time intervals and the true description of motion requires a new type of mechanics - the MICROSCOPIC MECHANICS: Section 6 and 7 are devoted to showing that not only the new microscopic mechanics goes over to Newtonian mechanics in the proper limit, but also it is closely connected with Quantum Mechanics. All the known results of the Schroedinger theory can be reproduced by microscopic mechanics which also gives a clear physical picture. It removes Einstein's famous objections against Quantum Theory and provides a clear distinction between classical and Quantum behavior. Seven Axioms (three on Classical Mechanics, two for Maxwell's theory, one for Relativity and a new Axiom on Radiation damping) are shown to combine Classical Mechanics, Maxwellian Electrodynamics, Relativity and Schroedinger's Quantum Theory within a single theoretical framework under Microscopic Mechanics which awaits further development at the present time. (orig.)

  13. Learning-performance distinction and memory processes for motor skills: a focused review and perspective.

    Kantak, Shailesh S; Winstein, Carolee J

    2012-03-01

    Behavioral research in cognitive psychology provides evidence for an important distinction between immediate performance that accompanies practice and long-term performance that reflects the relative permanence in the capability for the practiced skill (i.e. learning). This learning-performance distinction is strikingly evident when challenging practice conditions may impair practice performance, but enhance long-term retention of motor skills. A review of motor learning studies with a specific focus on comparing differences in performance between that at the end of practice and at delayed retention suggests that the delayed retention or transfer performance is a better indicator of motor learning than the performance at (or end of) practice. This provides objective evidence for the learning-performance distinction. This behavioral evidence coupled with an understanding of the motor memory processes of encoding, consolidation and retrieval may provide insight into the putative mechanism that implements the learning-performance distinction. Here, we propose a simplistic empirically-based framework--motor behavior-memory framework--that integrates the temporal evolution of motor memory processes with the time course of practice and delayed retention frequently used in behavioral motor learning paradigms. In the context of the proposed framework, recent research has used noninvasive brain stimulation to decipher the role of each motor memory process, and specific cortical brain regions engaged in motor performance and learning. Such findings provide beginning insights into the relationship between the time course of practice-induced performance changes and motor memory processes. This in turn has promising implications for future research and practical applications. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Mechanical drawing

    Cho, Ho Seon; Lee, Geun Hui

    2004-04-15

    This book deals with how to read and draw the mechanical drawing, which includes the basic of drawing like purpose, kinds, and criterion, projection, special projection drawing, omission of the figure, section, and types of section, dimensioning method, writing way of allowable limit size, tolerance of regular size, parts list and assembling drawing, fitting, mechanical elements like screw, key, pin, rivet, spring, bearing, pipe, valve, welding, geometric tolerance and mechanical materials.

  15. Classical mechanics

    Benacquista, Matthew J

    2018-01-01

    This textbook provides an introduction to classical mechanics at a level intermediate between the typical undergraduate and advanced graduate level. This text describes the background and tools for use in the fields of modern physics, such as quantum mechanics, astrophysics, particle physics, and relativity. Students who have had basic undergraduate classical mechanics or who have a good understanding of the mathematical methods of physics will benefit from this book.

  16. Mechanical science

    Bolton, W C

    2013-01-01

    This book gives comprehensive coverage of mechanical science for HNC/HND students taking mechanical engineering courses, including all topics likely to be covered in both years of such courses, as well as for first year undergraduate courses in mechanical engineering. It features 500 problems with answers and 200 worked examples. The third edition includes a new section on power transmission and an appendix on mathematics to help students with the basic notation of calculus and solution of differential equations.

  17. Chlamydia infection across host species boundaries promotes distinct sets of transcribed anti-apoptotic factors.

    Joshua eMessinger

    2015-12-01

    Full Text Available Chlamydiae, obligate intracellular bacteria, cause significant human and veterinary associated diseases. Having emerged an estimated 700-million years ago, these bacteria have twice adapted to humans as a host species, causing sexually transmitted infection (C. trachomatis and respiratory associated disease (C. pneumoniae. The principle mechanism of host cell defense against these intracellular bacteria is the induction of cell death via apoptosis. However, in the arms race of co-evolution, Chlamydiae have developed mechanisms to promote cell viability and inhibit cell death. Herein we examine the impact of Chlamydiae infection across multiple host species on transcription of anti-apoptotic genes. We found mostly distinct patterns of gene expression (Mcl1 and cIAPs elicited by each pathogen-host pair indicating Chlamydiae infection across host species boundaries does not induce a universally shared host response. Understanding species specific host-pathogen interactions is paramount to deciphering how potential pathogens become emerging diseases.

  18. Continuum Mechanics

    Romano, Antonio

    2010-01-01

    This book offers a broad overview of the potential of continuum mechanics to describe a wide range of macroscopic phenomena in real-world problems. Building on the fundamentals presented in the authors' previous book, Continuum Mechanics using Mathematica(R), this new work explores interesting models of continuum mechanics, with an emphasis on exploring the flexibility of their applications in a wide variety of fields.Specific topics, which have been chosen to show the power of continuum mechanics to characterize the experimental behavior of real phenomena, include: * various aspects of nonlin

  19. Facets of contextual realism in quantum mechanics

    Pan, Alok Kumar; Home, Dipankar

    2011-01-01

    In recent times, there is an upsurge of interest in demonstrating the quantum contextuality. In this proceedings, we explore the two different forms of arguments that have been used for showing the contextual character of quantum mechanics. First line of study concerns the violations of the noncontextual realist models by quantum mechanics, where second line of study that is qualitatively distinct from the earlier one, demonstrates the contextuality within the formalism of quantum mechanics.

  20. Distinct transmitter release properties determine differences in short-term plasticity at functional and silent synapses.

    Cabezas, Carolina; Buño, Washington

    2006-05-01

    Recent evidence suggests that functional and silent synapses are not only postsynaptically different but also presynaptically distinct. The presynaptic differences may be of functional importance in memory formation because a proposed mechanism for long-term potentiation is the conversion of silent synapses into functional ones. However, there is little direct experimentally evidence of these differences. We have investigated the transmitter release properties of functional and silent Schaffer collateral synapses and show that on the average functional synapses displayed a lower percentage of failures and higher excitatory postsynaptic current (EPSC) amplitudes than silent synapses at +60 mV. Moreover, functional but not silent synapses show paired-pulse facilitation (PPF) at +60 mV and thus presynaptic short-term plasticity will be distinct in the two types of synapse. We examined whether intraterminal endoplasmic reticulum Ca2+ stores influenced the release properties of these synapses. Ryanodine (100 microM) and thapsigargin (1 microM) increased the percentage of failures and decreased both the EPSC amplitude and PPF in functional synapses. Caffeine (10 mM) had the opposite effects. In contrast, silent synapses were insensitive to both ryanodine and caffeine. Hence we have identified differences in the release properties of functional and silent synapses, suggesting that synaptic terminals of functional synapses express regulatory molecular mechanisms that are absent in silent synapses.

  1. Distinction of Fly Artifacts from Human Blood using Immunodetection.

    Rivers, David B; Acca, Gillian; Fink, Marc; Brogan, Rebecca; Chen, Dorothy; Schoeffield, Andrew

    2018-02-21

    Insect stains produced by necrophagous flies are indistinguishable morphologically from human bloodstains. At present, no diagnostic tests exist to overcome this deficiency. As the first step toward developing a chemical test to recognize fly artifacts, polyclonal antisera were generated in rats against three distinct antigenic sequences of fly cathepsin D-like proteinase, an enzyme that is structurally distinct in cyclorrhaphous Diptera from other animals. The resulting rat antisera bound to artifacts produced by Protophormia terraenovae and synthetic peptides used to generate the polyclonal antisera, but not with any type of mammalian blood tested in immunoassays. Among the three antisera, anti-md3 serum displayed the highest reactivity for fly stains, demonstrated cross-reactivity for all synthetic peptides representing antigenic sequences of the mature fly enzyme, and bound artifacts originating from the fly digestive tract. Further work is needed to determine whether the antisera are suitable for non-laboratory conditions. © 2018 American Academy of Forensic Sciences.

  2. Morphological distinctiveness of Javan Tupaia hypochrysa (Scandentia, Tupaiidae)

    Sargis, Eric J.; Woodman, Neal; Morningstar, Natalie C.; Reese, Aspen T.; Olson, Link E.

    2013-01-01

    The common treeshrew, Tupaia glis, represents a species complex with a complicated taxonomic history. It is distributed mostly south of the Isthmus of Kra on the Malay Peninsula and surrounding islands. In our recent revision of a portion of this species complex, we did not fully assess the population from Java (T. “glis” hypochrysa) because of our limited sample. Herein, we revisit this taxon using multivariate analyses in comparisons with T. glis, T. chrysogaster of the Mentawai Islands, and T. ferruginea from Sumatra. Analyses of both the manus and skull of Javan T. “glis” hypochrysa show it to be most similar to T. chrysogaster and distinct from both T. glis and T. ferruginea. Yet, the Javan population and T. chrysogaster have different mammae counts, supporting recognition of T. hypochrysa as a distinct species. The change in taxonomic status of T. hypochrysa has conservation implications for both T. glis and this Javan endemic.

  3. Neonatal lethal dwarfism with distinct skeletal malformations - a separate entity?

    Rosendahl, K.; Maurseth, K.; Olsen, Oe.E. [Dept. of Paediatric Radiology, Haukeland University Hospital, Bergen (Norway); Halvorsen, O.J. [Dept. of Pathology, Haukeland University Hospital, Bergen (Norway); Gjelland, K. [Dept. of Gynaecology, Haukeland University Hospital, Bergen (Norway); Engebretsen, L. [Dept. of Genetics, Haukeland University Hospital, Bergen (Norway)

    2001-09-01

    We describe a case of neonatal lethal dwarfism characterised by short trunk, short, stick-like tubular bones, deficient ossification of the axial skeleton and broad, sclerotic horizontal ribs. Two similar cases have previously been reported as examples of the Neu-Laxova syndrome. However, the radiological findings of the Neu-Laxova syndrome, as reported in 16 out of 40 documented cases, show a heterogeneous pattern of minor features, which differ distinctively from those found in the previous two cases and by us. A literature research did not reveal similar cases, and we therefore suggest that our case, together with the two previous cases, may represent a new distinctive form of neonatal lethal dwarfism. (orig.)

  4. Neonatal lethal dwarfism with distinct skeletal malformations - a separate entity?

    Rosendahl, K.; Maurseth, K.; Olsen, Oe.E.; Halvorsen, O.J.; Gjelland, K.; Engebretsen, L.

    2001-01-01

    We describe a case of neonatal lethal dwarfism characterised by short trunk, short, stick-like tubular bones, deficient ossification of the axial skeleton and broad, sclerotic horizontal ribs. Two similar cases have previously been reported as examples of the Neu-Laxova syndrome. However, the radiological findings of the Neu-Laxova syndrome, as reported in 16 out of 40 documented cases, show a heterogeneous pattern of minor features, which differ distinctively from those found in the previous two cases and by us. A literature research did not reveal similar cases, and we therefore suggest that our case, together with the two previous cases, may represent a new distinctive form of neonatal lethal dwarfism. (orig.)

  5. Distinctive safety aspects of the CANDU-PHW reactor design

    Kugler, G.

    1980-01-01

    Two lectures are presented in this report. They were prepared in response to a request from IAEA to provide information on the 'Special characteristics of the safety analysis of heavy water reactors' to delegates from member states attending the Interregional Training Course on Safety Analysis Review, held at Karlsruhe, November 19 to December 20, 1979. The CANDU-PHW reactor is used as a model for discussion. The first lecture describes the distinctive features of the CANDU reactor and how they impact on reactor safety. In the second lecture the Canadian safety philosophy, the safety design objective, and other selected topics on reactor safety analysis are discussed. The material in this report was selected with a view to assisting those not familiar with the CANDU heavy water reactor design in evaluating the distinctive safety aspects of these reactors. (auth)

  6. Mapping Phylogenetic Trees to Reveal Distinct Patterns of Evolution.

    Kendall, Michelle; Colijn, Caroline

    2016-10-01

    Evolutionary relationships are frequently described by phylogenetic trees, but a central barrier in many fields is the difficulty of interpreting data containing conflicting phylogenetic signals. We present a metric-based method for comparing trees which extracts distinct alternative evolutionary relationships embedded in data. We demonstrate detection and resolution of phylogenetic uncertainty in a recent study of anole lizards, leading to alternate hypotheses about their evolutionary relationships. We use our approach to compare trees derived from different genes of Ebolavirus and find that the VP30 gene has a distinct phylogenetic signature composed of three alternatives that differ in the deep branching structure. phylogenetics, evolution, tree metrics, genetics, sequencing. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  7. A distinct bacterial dysbiosis associated skin inflammation in ovine footrot

    Maboni, Grazieli; Blanchard, Adam; Frosth, Sara; Stewart, Ceri; Emes, Richard; Tötemeyer, Sabine

    2017-03-01

    Ovine footrot is a highly prevalent bacterial disease caused by Dichelobacter nodosus and characterised by the separation of the hoof horn from the underlying skin. The role of innate immune molecules and other bacterial communities in the development of footrot lesions remains unclear. This study shows a significant association between the high expression of IL1β and high D. nodosus load in footrot samples. Investigation of the microbial population identified distinct bacterial populations in the different disease stages and also depending on the level of inflammation. Treponema (34%), Mycoplasma (29%) and Porphyromonas (15%) were the most abundant genera associated with high levels of inflammation in footrot. In contrast, Acinetobacter (25%), Corynebacteria (17%) and Flavobacterium (17%) were the most abundant genera associated with high levels of inflammation in healthy feet. This demonstrates for the first time there is a distinct microbial community associated with footrot and high cytokine expression.

  8. The emotional memory effect: differential processing or item distinctiveness?

    Schmidt, Stephen R; Saari, Bonnie

    2007-12-01

    A color-naming task was followed by incidental free recall to investigate how emotional words affect attention and memory. We compared taboo, nonthreatening negative-affect, and neutral words across three experiments. As compared with neutral words, taboo words led to longer color-naming times and better memory in both within- and between-subjects designs. Color naming of negative-emotion nontaboo words was slower than color naming of neutral words only during block presentation and at relatively short interstimulus intervals (ISIs). The nontaboo emotion words were remembered better than neutral words following blocked and random presentation and at both long and short ISIs, but only in mixed-list designs. Our results support multifactor theories of the effects of emotion on attention and memory. As compared with neutral words, threatening stimuli received increased attention, poststimulus elaboration, and benefit from item distinctiveness, whereas nonthreatening emotional stimuli benefited only from increased item distinctiveness.

  9. Pseudomonas aeruginosa diversity in distinct paediatric patient groups

    Tramper-Stranders, G.A.; Ent, C.K. van der; Wolfs, T.F.

    2008-01-01

    the other groups. A group of clonal isolates was observed among patients from the CF-chronic and CF-1 groups. These or different clonal isolates were not encountered among the three other patient groups. No characteristic resistance pattern could be identified among isolates from the distinct patient groups......Pseudomonas aeruginosa is a pathogen that often infects patients who are either immunocompromised or have local defects in host defences. It is known that cystic fibrosis (CF) patients are sometimes infected with certain clonal isolates. It is not clear whether these clonal isolates also infect non......-CF patients and whether clonality of isolates occurs in other patient groups. The aim of this study was to investigate P. aeruginosa diversity and the occurrence of clones within five distinct paediatric patient groups susceptible to P. aeruginosa infection. P. aeruginosa isolates were cultured from 157...

  10. The True Self: A Psychological Concept Distinct From the Self.

    Strohminger, Nina; Knobe, Joshua; Newman, George

    2017-07-01

    A long tradition of psychological research has explored the distinction between characteristics that are part of the self and those that lie outside of it. Recently, a surge of research has begun examining a further distinction. Even among characteristics that are internal to the self, people pick out a subset as belonging to the true self. These factors are judged as making people who they really are, deep down. In this paper, we introduce the concept of the true self and identify features that distinguish people's understanding of the true self from their understanding of the self more generally. In particular, we consider recent findings that the true self is perceived as positive and moral and that this tendency is actor-observer invariant and cross-culturally stable. We then explore possible explanations for these findings and discuss their implications for a variety of issues in psychology.

  11. Two distinct forms of functional lateralization in the human brain

    Gotts, Stephen J.; Jo, Hang Joon; Wallace, Gregory L.; Saad, Ziad S.; Cox, Robert W.; Martin, Alex

    2013-01-01

    The hemispheric lateralization of certain faculties in the human brain has long been held to be beneficial for functioning. However, quantitative relationships between the degree of lateralization in particular brain regions and the level of functioning have yet to be established. Here we demonstrate that two distinct forms of functional lateralization are present in the left vs. the right cerebral hemisphere, with the left hemisphere showing a preference to interact more exclusively with itself, particularly for cortical regions involved in language and fine motor coordination. In contrast, right-hemisphere cortical regions involved in visuospatial and attentional processing interact in a more integrative fashion with both hemispheres. The degree of lateralization present in these distinct systems selectively predicted behavioral measures of verbal and visuospatial ability, providing direct evidence that lateralization is associated with enhanced cognitive ability. PMID:23959883

  12. New approach to equipment quality evaluation method with distinct functions

    Milisavljević Vladimir M.

    2016-01-01

    Full Text Available The paper presents new approach for improving method for quality evaluation and selection of equipment (devices and machinery by applying distinct functions. Quality evaluation and selection of devices and machinery is a multi-criteria problem which involves the consideration of numerous parameters of various origins. Original selection method with distinct functions is based on technical parameters with arbitrary evaluation of each parameter importance (weighting. Improvement of this method, presented in this paper, addresses the issue of weighting of parameters by using Delphi Method. Finally, two case studies are provided, which included quality evaluation of standard boilers for heating and evaluation of load-haul-dump (LHD machines, to demonstrate applicability of this approach. Analytical Hierarchical Process (AHP is used as a control method.

  13. Recognition of distinctive patterns of gallium-67 distribution in sarcoidosis

    Sulavik, S.B.; Spencer, R.P.; Weed, D.A.; Shapiro, H.R.; Shiue, S.T.; Castriotta, R.J.

    1990-01-01

    Assessment of gallium-67 ( 67 Ga) uptake in the salivary and lacrimal glands and intrathoracic lymph nodes was made in 605 consecutive patients including 65 with sarcoidosis. A distinctive intrathoracic lymph node 67 Ga uptake pattern, resembling the Greek letter lambda, was observed only in sarcoidosis (72%). Symmetrical lacrimal gland and parotid gland 67 Ga uptake (panda appearance) was noted in 79% of sarcoidosis patients. A simultaneous lambda and panda pattern (62%) or a panda appearance with radiographic bilateral, symmetrical, hilar lymphadenopathy (6%) was present only in sarcoidosis patients. The presence of either of these patterns was particularly prevalent in roentgen Stages I (80%) or II (74%). We conclude that simultaneous (a) lambda and panda images, or (b) a panda image with bilateral symmetrical hilar lymphadenopathy on chest X-ray represent distinctive patterns which are highly specific for sarcoidosis, and may obviate the need for invasive diagnostic procedures

  14. The influence of context on distinct facial expressions of disgust.

    Reschke, Peter J; Walle, Eric A; Knothe, Jennifer M; Lopez, Lukas D

    2018-06-11

    Face perception is susceptible to contextual influence and perceived physical similarities between emotion cues. However, studies often use structurally homogeneous facial expressions, making it difficult to explore how within-emotion variability in facial configuration affects emotion perception. This study examined the influence of context on the emotional perception of categorically identical, yet physically distinct, facial expressions of disgust. Participants categorized two perceptually distinct disgust facial expressions, "closed" (i.e., scrunched nose, closed mouth) and "open" (i.e., scrunched nose, open mouth, protruding tongue), that were embedded in contexts comprising emotion postures and scenes. Results demonstrated that the effect of nonfacial elements was significantly stronger for "open" disgust facial expressions than "closed" disgust facial expressions. These findings provide support that physical similarity within discrete categories of facial expressions is mutable and plays an important role in affective face perception. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  15. Automotive Mechanics.

    Linder, Ralph C.; And Others

    This curriculum guide, which was validated by vocational teachers and mechanics in the field, describes the competencies needed by entry-level automotive mechanics. This guide lists 15 competencies; for each competency, various tasks with their performance objective, student learning experiences, suggested instructional techniques, instructional…

  16. Ethical distinctions between different kinds of plant breeding

    Myskja, B.K.; Schouten, H.J.; Gjerris, Mickey

    2015-01-01

    The article discusses whether there are ethically significant distinctions between different forms of plant breeding. We distinguish different forms of plant breeding according to the kind of technology and degree of human intervention compared to plant reproduction occurring in nature. According...... differences between plant breeding methods. The framework can contribute to an improved dialogue between the scientific community and the wider public by making the scepticism towards GM-technology more intelligible....

  17. Parakeratosis pustulosa - a distinct but less familiar disease

    Pandhi Deepika

    2003-01-01

    Full Text Available Parakeratosis pustulosa (PP is a distinct but less commonly known skin disease, which is frequently seen, in young girls. We describe the clinical and histological features of PP in a 7 month old female baby. Further, it is stressed that unless carefully looked for, this entity may be easily misdiagnosed as chronic paronychia, acrodermatitis of Hallopeau, pustular psoriasis, atopic dermatitis, tinea pedis or dry fissured eczematoid dermatitis and mistreated subsequently.

  18. Early- versus Late-Onset Dysthymia: A Meaningful Clinical Distinction?

    Sansone, Randy A.; Sansone, Lori A.

    2009-01-01

    In the current Diagnostic and Statistical Manual of Mental Disorders, dysthymic disorder is categorized as either early-onset or late-onset, based upon the emergence of symptoms before or after the age of 21, respectively. Does this diagnostic distinction have any meaningful clinical implications? In this edition of The Interface, we present empirical studies that have, within a single study, compared individuals with early-versus late-onset dysthymia. In this review, we found that, compared ...

  19. Distinct types of glial cells populate the Drosophila antenna

    Jhaveri Dhanisha

    2005-11-01

    Full Text Available Abstract Background The development of nervous systems involves reciprocal interactions between neurons and glia. In the Drosophila olfactory system, peripheral glial cells arise from sensory lineages specified by the basic helix-loop-helix transcription factor, Atonal. These glia wrap around the developing olfactory axons early during development and pattern the three distinct fascicles as they exit the antenna. In the moth Manduca sexta, an additional set of central glia migrate to the base of the antennal nerve where axons sort to their glomerular targets. In this work, we have investigated whether similar types of cells exist in the Drosophila antenna. Results We have used different P(Gal4 lines to drive Green Fluorescent Protein (GFP in distinct populations of cells within the Drosophila antenna. Mz317::GFP, a marker for cell body and perineural glia, labels the majority of peripheral glia. An additional ~30 glial cells detected by GH146::GFP do not derive from any of the sensory lineages and appear to migrate into the antenna from the brain. Their appearance in the third antennal segment is regulated by normal function of the Epidermal Growth Factor receptor and small GTPases. We denote these distinct populations of cells as Mz317-glia and GH146-glia respectively. In the adult, processes of GH146-glial cells ensheath the olfactory receptor neurons directly, while those of the Mz317-glia form a peripheral layer. Ablation of GH146-glia does not result in any significant effects on the patterning of the olfactory receptor axons. Conclusion We have demonstrated the presence of at least two distinct populations of glial cells within the Drosophila antenna. GH146-glial cells originate in the brain and migrate to the antenna along the newly formed olfactory axons. The number of cells populating the third segment of the antenna is regulated by signaling through the Epidermal Growth Factor receptor. These glia share several features of the sorting

  20. Is fuel poverty in Ireland a distinct type of deprivation?

    Watson, Dorothy; Maitre, Bertrand

    2014-01-01

    In this paper, we draw on the Central Statistics Office SILC data for Ireland to ask whether fuel poverty is a distinctive type of deprivation that warrants a fundamentally different policy response than poverty in general. We examine the overlap between fuel poverty (based on three self-report items) and poverty in general – with a particular emphasis on the national indicator of basic deprivation which is used in the measurement of poverty for policy purposes in Ireland. We examine changes ...

  1. Distinctively human motivation and another view on human evolution

    Prudkov, Pavel N.

    2006-01-01

    Human evolution is a multidisciplinary problem, one of its aspects is the origin and development of distinctively human psychological features. Cognitive properties (language, symbolic thinking) are considered as such features and numerous authors hypothesize its evolution. We suggest that the most important human characteristic is connected with motivation rather than cognition; this is the ability to construct and maintain long-term goal-directed processes having no biological basis. Once...

  2. Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses.

    McConnell, Kevin W; McDunn, Jonathan E; Clark, Andrew T; Dunne, W Michael; Dixon, David J; Turnbull, Isaiah R; Dipasco, Peter J; Osberghaus, William F; Sherman, Benjamin; Martin, James R; Walter, Michael J; Cobb, J Perren; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

    2010-01-01

    Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, then treatment involves only nonspecific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar after disparate infections with similar mortalities. Prospective, randomized controlled study. Animal laboratory in a university medical center. Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple time points. The host response was dependent on the causative organism as well as kinetics of mortality, but the pro-inflammatory and anti-inflammatory responses were independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of five distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary macrophage inflammatory peptide-2 and interleukin-10 with progression of infection, whereas elevated plasma tumor necrosis factor sr2 and macrophage chemotactic peptide-1 were indicative of fulminant disease with >90% mortality within 48 hrs. Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a

  3. Eliciting Autoimmunity to Ovarian Tumors in Mice by Genetic Disruption of T Cell Tolerance Mechanisms

    Nelson, Brad H

    2005-01-01

    Research in the fields of basic immunology and autoimmunity has identified several distinct mechanisms through which immune tolerance is established and maintained in the normal host, and additional...

  4. Quantum mechanics

    Rae, Alastair I M

    2016-01-01

    A Thorough Update of One of the Most Highly Regarded Textbooks on Quantum Mechanics Continuing to offer an exceptionally clear, up-to-date treatment of the subject, Quantum Mechanics, Sixth Edition explains the concepts of quantum mechanics for undergraduate students in physics and related disciplines and provides the foundation necessary for other specialized courses. This sixth edition builds on its highly praised predecessors to make the text even more accessible to a wider audience. It is now divided into five parts that separately cover broad topics suitable for any general course on quantum mechanics. New to the Sixth Edition * Three chapters that review prerequisite physics and mathematics, laying out the notation, formalism, and physical basis necessary for the rest of the book * Short descriptions of numerous applications relevant to the physics discussed, giving students a brief look at what quantum mechanics has made possible industrially and scientifically * Additional end-of-chapter problems with...

  5. Respiratory mechanics

    Wilson, Theodore A

    2016-01-01

    This book thoroughly covers each subfield of respiratory mechanics: pulmonary mechanics, the respiratory pump, and flow. It presents the current understanding of the field and serves as a guide to the scientific literature from the golden age of respiratory mechanics, 1960 - 2010. Specific topics covered include the contributions of surface tension and tissue forces to lung recoil, the gravitational deformation of the lung, and the interdependence forces that act on pulmonary airways and blood vessels. The geometry and kinematics of the ribs is also covered in detail, as well as the respiratory action of the external and internal intercostal muscles, the mechanics of the diaphragm, and the quantitative compartmental models of the chest wall is also described. Additionally, flow in the airways is covered thoroughly, including the wave-speed and viscous expiratory flow-limiting mechanisms; convection, diffusion and the stationary front; and the distribution of ventilation. This is an ideal book for respiratory ...

  6. College mechanics

    Şengül, Caner

    2016-01-01

    College Mechanics QueBank has been designed to be different, enthusiastic, interesting and helpful to you. Therefore, it is not just a test bank about mechanics but also it is like a compass in order to find your way in mechanics Each chapter in this book is put in an order to follow a hierarchy of the mechanics topics; from vectors to simple harmonic motion. Throughout the book there are many multiple choice and long answer questions for you to solve. They have been created for YGS, LYS, SAT, IB or other standardized exams in the world because mechanics has no boundaries and so Physics has no country. Learn the main principle of each chapter and explore the daily life applications. Then you can start to solve the questions by planning a problem solving method carefully. Finally, enjoy solving the questions and discover the meachanics of the universe once more.

  7. Fracture Mechanics

    Zehnder, Alan T

    2012-01-01

    Fracture mechanics is a vast and growing field. This book develops the basic elements needed for both fracture research and engineering practice. The emphasis is on continuum mechanics models for energy flows and crack-tip stress- and deformation fields in elastic and elastic-plastic materials. In addition to a brief discussion of computational fracture methods, the text includes practical sections on fracture criteria, fracture toughness testing, and methods for measuring stress intensity factors and energy release rates. Class-tested at Cornell, this book is designed for students, researchers and practitioners interested in understanding and contributing to a diverse and vital field of knowledge. Alan Zehnder joined the faculty at Cornell University in 1988. Since then he has served in a number of leadership roles including Chair of the Department of Theoretical and Applied Mechanics, and Director of the Sibley School of Mechanical and Aerospace Engineering.  He teaches applied mechanics and his research t...

  8. Number of perceptually distinct surface colors in natural scenes.

    Marín-Franch, Iván; Foster, David H

    2010-09-30

    The ability to perceptually identify distinct surfaces in natural scenes by virtue of their color depends not only on the relative frequency of surface colors but also on the probabilistic nature of observer judgments. Previous methods of estimating the number of discriminable surface colors, whether based on theoretical color gamuts or recorded from real scenes, have taken a deterministic approach. Thus, a three-dimensional representation of the gamut of colors is divided into elementary cells or points which are spaced at one discrimination-threshold unit intervals and which are then counted. In this study, information-theoretic methods were used to take into account both differing surface-color frequencies and observer response uncertainty. Spectral radiances were calculated from 50 hyperspectral images of natural scenes and were represented in a perceptually almost uniform color space. The average number of perceptually distinct surface colors was estimated as 7.3 × 10(3), much smaller than that based on counting methods. This number is also much smaller than the number of distinct points in a scene that are, in principle, available for reliable identification under illuminant changes, suggesting that color constancy, or the lack of it, does not generally determine the limit on the use of color for surface identification.

  9. Mistakes To Avoid In Attacking The Moral/Conventional Distinction

    Alejandro Rosas

    2012-11-01

    Full Text Available In an experimental critique of the moral/conventional (M/C distinction, Kelly et al. (2007 present new experimental data about responses to transgressions involving harm, where the novelty is that transgressors are grown-ups, rather than children. Their data do not support the moral/conventional distinction. The contrast between grown-up and schoolyard transgressions does not seem, however, to explain their results: they also use two schoolyard transgressions with similar negative results for the M/C distinction.I here attempt to explain away their results by calling attention to two mistakes in their experimental design. One refers to the use of questionnaire-items of the type that Turiel and collaborators have called mixed-domain situations, which extend over both a moral and a conventional domain. Participants respond to these cases differently than to prototypical moral situations, because some allow the authority rule to override the moral rule. The second mistake emerges in the grown-up transgressions labeled as Whipping/temporal, Whipping/Authority, Spanking/Authority, Prisoner abuse/Authority. These are not the typical transgressions unambiguously “involving a victim who has been harmed, whose rights have been violated, or who has been subject to an injustice”. The victims are also transgressors and harm is inflicted on them as punishment. Plausibly, rules about corporal punishment depend on authority in a way that rules about harming the innocent do not.

  10. Adaptation of flower and fruit colours to multiple, distinct mutualists.

    Renoult, Julien P; Valido, Alfredo; Jordano, Pedro; Schaefer, H Martin

    2014-01-01

    Communication in plant-animal mutualisms frequently involves multiple perceivers. A fundamental uncertainty is whether and how species adapt to communicate with groups of mutualists having distinct sensory abilities. We quantified the colour conspicuousness of flowers and fruits originating from one European and two South American plant communities, using visual models of pollinators (bee and fly) and seed dispersers (bird, primate and marten). We show that flowers are more conspicuous than fruits to pollinators, and the reverse to seed dispersers. In addition, flowers are more conspicuous to pollinators than to seed dispersers and the reverse for fruits. Thus, despite marked differences in the visual systems of mutualists, flower and fruit colours have evolved to attract multiple, distinct mutualists but not unintended perceivers. We show that this adaptation is facilitated by a limited correlation between flower and fruit colours, and by the fact that colour signals as coded at the photoreceptor level are more similar within than between functional groups (pollinators and seed dispersers). Overall, these results provide the first quantitative demonstration that flower and fruit colours are adaptations allowing plants to communicate simultaneously with distinct groups of mutualists. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

  11. Ataques de nervios: culturally bound and distinct from panic attacks?

    Keough, Meghan E; Timpano, Kiara R; Schmidt, Norman B

    2009-01-01

    The Diagnostic and Statistical Manual of Mental Disorders [DSM-IV-TR; American Psychiatric Association [APA], 2000) has emphasized the importance of understanding psychopathology within a cultural framework by including culture-bound syndromes within its appendices. These syndromes are proposed to be bound to certain cultures and distinct from other psychological disorders. Included among the syndromes are ataques de nervios (ADN), which are reported to be bound to the Hispanic culture and closely resemble panic attacks. However, the cultural distinctiveness and phenomenology of ADN has not been adequately investigated. The current study employed an ethnically diverse study sample (N=342) of undergraduates. Participants completed a number of measures that assessed acculturation, syndrome and anxiety risk factors. In contrast to the DSM-IV's conceptualization of ADN, the rate of ADN did not significantly vary across the three main groups (African American, Caucasian, and Hispanic participants) nor did it vary based on acculturation. More consistent with the DSM-IV, the symptom comparisons indicated some differentiation between ADN and panic attacks. The present report provides data indicating that ADNs, as described by the DSM-IV, are not unique to the Hispanic culture and are experienced by non-Hispanic individuals at similar rates to Hispanic-endorsement. The findings are consistent with the DSM-IV assertion that ADNs and PAs are distinct syndromes. (c) 2008 Wiley-Liss, Inc.

  12. Participation and social participation: are they distinct concepts?

    Piškur, Barbara; Daniëls, Ramon; Jongmans, Marian J; Ketelaar, Marjolijn; Smeets, Rob J E M; Norton, Meghan; Beurskens, Anna J H M

    2014-03-01

    The concept of participation has been extensively used in health and social care literature since the World Health Organization introduced its description in the International Classification of Functioning, Disability and Health (ICF) in 2001. More recently, the concept of social participation is frequently used in research articles and policy reports. However, in the ICF, no specific definition exists for social participation, and an explanation of differences between the concepts is not available. The central question in this discussion article is whether participation, as defined by the ICF, and social participation are distinct concepts. This article illustrates the concepts of participation and social participation, presents a critical discussion of their definitions, followed by implications for rehabilitation and possible future directions. A clear definition for participation or social participation does not yet exist. Definitions for social participation differ from each other and are not sufficiently distinct from the ICF definition of participation. Although the ICF is regarded an important conceptual framework, it is criticised for not being comprehensive. The relevance of societal involvement of clients is evident for rehabilitation, but the current ICF definition of participation does not sufficiently capture societal involvement. Changing the ICF's definition of participation towards social roles would overcome a number of its shortcomings. Societal involvement would then be understood in the light of social roles. Consequently, there would be no need to make a distinction between social participation and participation.

  13. Distinct Evening Fatigue Profiles in Oncology Outpatients Receiving Chemotherapy

    Wright, Fay; Cooper, Bruce A.; Conley, Yvette P.; Hammer, Marilyn J.; Chen, Lee-May; Paul, Steven M.; Levine, Jon D.; Miaskowski, Christine; Kober, Kord M.

    2018-01-01

    Background Fatigue is the most common and debilitating symptom experienced by oncology patients during chemotherapy (CTX). Fatigue severity demonstrates a large amount of inter-individual and diurnal variability. Purpose Study purposes were to evaluate for subgroups of patients with distinct evening fatigue profiles and evaluate how these subgroups differed on demographic, clinical, and symptom characteristics. Methods Outpatients with breast, gastrointestinal, gynecological, or lung cancer (n=1332) completed questionnaires six times over two cycles of CTX. Lee Fatigue Scale (LFS) evaluated evening fatigue severity. Latent profile analysis was used to identify distinct evening fatigue profiles. Results Four distinct evening fatigue classes (i.e., Low (14.0%), Moderate (17.2%), High (36.0%), Very High (32.8%)) were identified. Compared to the Low class, patients in the Very High evening fatigue class were: younger, female, had childcare responsibilities, had more years of education, had a lower functional status, had a higher comorbidity burden, and were diagnosed with breast cancer. Patients in the Very High class reported higher levels of depressive symptoms, sleep disturbance, and evening fatigue at enrollment. Conclusions Findings provide new insights into modifiable risk factors for higher levels of evening fatigue. Clinicians can use this information to identify higher risk patients and plan appropriate interventions. PMID:29725554

  14. Processing vertical size disparities in distinct depth planes.

    Duke, Philip A; Howard, Ian P

    2012-08-17

    A textured surface appears slanted about a vertical axis when the image in one eye is horizontally enlarged relative to the image in the other eye. The surface appears slanted in the opposite direction when the same image is vertically enlarged. Two superimposed textured surfaces with different horizontal size disparities appear as two surfaces that differ in slant. Superimposed textured surfaces with equal and opposite vertical size disparities appear as a single frontal surface. The vertical disparities are averaged. We investigated whether vertical size disparities are averaged across two superimposed textured surfaces in different depth planes or whether they induce distinct slants in the two depth planes. In Experiment 1, two superimposed textured surfaces with different vertical size disparities were presented in two depth planes defined by horizontal disparity. The surfaces induced distinct slants when the horizontal disparity was more than ±5 arcmin. Thus, vertical size disparities are not averaged over surfaces with different horizontal disparities. In Experiment 2 we confirmed that vertical size disparities are processed in surfaces away from the horopter, so the results of Experiment 1 cannot be explained by the processing of vertical size disparities in a fixated surface only. Together, these results show that vertical size disparities are processed separately in distinct depth planes. The results also suggest that vertical size disparities are not used to register slant globally by their effect on the registration of binocular direction of gaze.

  15. Heterogeneity of reward mechanisms.

    Lajtha, A; Sershen, H

    2010-06-01

    The finding that many drugs that have abuse potential and other natural stimuli such as food or sexual activity cause similar chemical changes in the brain, an increase in extracellular dopamine (DA) in the shell of the nucleus accumbens (NAccS), indicated some time ago that the reward mechanism is at least very similar for all stimuli and that the mechanism is relatively simple. The presently available information shows that the mechanisms involved are more complex and have multiple elements. Multiple brain regions, multiple receptors, multiple distinct neurons, multiple transmitters, multiple transporters, circuits, peptides, proteins, metabolism of transmitters, and phosphorylation, all participate in reward mechanisms. The system is variable, is changed during development, is sex-dependent, and is influenced by genetic differences. Not all of the elements participate in the reward of all stimuli. Different set of mechanisms are involved in the reward of different drugs of abuse, yet different mechanisms in the reward of natural stimuli such as food or sexual activity; thus there are different systems that distinguish different stimuli. Separate functions of the reward system such as anticipation, evaluation, consummation and identification; all contain function-specific elements. The level of the stimulus also influences the participation of the elements of the reward system, there are possible reactions to even below threshold stimuli, and excessive stimuli can change reward to aversion involving parts of the system. Learning and memory of past reward is an important integral element of reward and addictive behavior. Many of the reward elements are altered by repeated or chronic stimuli, and chronic exposure to one drug is likely to alter the response to another stimulus. To evaluate and identify the reward stimulus thus requires heterogeneity of the reward components in the brain.

  16. Natural Microbial Assemblages Reflect Distinct Organismal and Functional Partitioning

    Wilmes, P.; Andersson, A.; Kalnejais, L. H.; Verberkmoes, N. C.; Lefsrud, M. G.; Wexler, M.; Singer, S. W.; Shah, M.; Bond, P. L.; Thelen, M. P.; Hettich, R. L.; Banfield, J. F.

    2007-12-01

    The ability to link microbial community structure to function has long been a primary focus of environmental microbiology. With the advent of community genomic and proteomic techniques, along with advances in microscopic imaging techniques, it is now possible to gain insights into the organismal and functional makeup of microbial communities. Biofilms growing within highly acidic solutions inside the Richmond Mine (Iron Mountain, Redding, California) exhibit distinct macro- and microscopic morphologies. They are composed of microorganisms belonging to the three domains of life, including archaea, bacteria and eukarya. The proportion of each organismal type depends on sampling location and developmental stage. For example, mature biofilms floating on top of acid mine drainage (AMD) pools exhibit layers consisting of a densely packed bottom layer of the chemoautolithotroph Leptospirillum group II, a less dense top layer composed mainly of archaea, and fungal filaments spanning across the entire biofilm. The expression of cytochrome 579 (the most highly abundant protein in the biofilm, believed to be central to iron oxidation and encoded by Leptospirillum group II) is localized at the interface of the biofilm with the AMD solution, highlighting that biofilm architecture is reflected at the functional gene expression level. Distinct functional partitioning is also apparent in a biological wastewater treatment system that selects for distinct polyphosphate accumulating organisms. Community genomic data from " Candidatus Accumulibacter phosphatis" dominated activated sludge has enabled high mass-accuracy shotgun proteomics for identification of key metabolic pathways. Comprehensive genome-wide alignment of orthologous proteins suggests distinct partitioning of protein variants involved in both core-metabolism and specific metabolic pathways among the dominant population and closely related species. In addition, strain- resolved proteogenomic analysis of the AMD biofilms

  17. The rodent ultrasound production mechanism.

    Roberts, L H

    1975-03-01

    Rodents produce two types of sounds, audible and ultrasonic, that differ markedly in physical structure. Studies of sound production in light gases show that whereas the audible cries appear to be produced, as in the case of most other mammals, by vibrating structures in the larynx, the ultrasonic cries are produced by a different mechanism, probably a whistle. 'Bird-call' whistles are shown to have all the properties of rodent ultrasonic cries and to mimic them in almost every detail. Thus it is concluded that rodents have two distinct sound production mechanisms, one for audible cries and one for ultrasonic cries.

  18. Quantum mechanics

    Powell, John L

    2015-01-01

    Suitable for advanced undergraduates, this thorough text focuses on the role of symmetry operations and the essentially algebraic structure of quantum-mechanical theory. Based on courses in quantum mechanics taught by the authors, the treatment provides numerous problems that require applications of theory and serve to supplement the textual material.Starting with a historical introduction to the origins of quantum theory, the book advances to discussions of the foundations of wave mechanics, wave packets and the uncertainty principle, and an examination of the Schrödinger equation that includ

  19. Quantum mechanics

    Rae, A.I.M.

    1981-01-01

    This book, based on a thirty lecture course given to students at the beginning of their second year, covers the quantum mechanics required by physics undergraduates. Early chapters deal with wave mechanics, including a discussion of the energy states of the hydrogen atom. These are followed by a more formal development of the theory, leading to a discussion of some advanced applications and an introduction to the conceptual problems associated with quantum measurement theory. Emphasis is placed on the fundamentals of quantum mechanics. Problems are included at the end of each chapter. (U.K.)

  20. Indexing mechanisms

    Wood, A.G.; Parker, G.E.; Berry, R.

    1976-01-01

    It is stated that the indexing mechanism described can be used in a nuclear reactor fuel element inspection rig. It comprises a tubular body adapted to house a canister containing a number of fuel elements located longtitudinally, and has two chucks spaced apart for displacing the fuel elements longitudinally in a stepwise manner, together with a plunger mechanism for displacing them successively into the chucks. A measuring unit is located between the chucks for measuring the diameter of the fuel elements at intervals about their circumferences, and a secondary indexing mechanism is provided for rotating the measuring unit in a stepwise manner. (U.K.)

  1. Robot Mechanisms

    Lenarcic, Jadran; Stanišić, Michael M

    2013-01-01

    This book provides a comprehensive introduction to the area of robot mechanisms, primarily considering industrial manipulators and humanoid arms. The book is intended for both teaching and self-study. Emphasis is given to the fundamentals of kinematic analysis and the design of robot mechanisms. The coverage of topics is untypical. The focus is on robot kinematics. The book creates a balance between theoretical and practical aspects in the development and application of robot mechanisms, and includes the latest achievements and trends in robot science and technology.

  2. Biophysical subsets of embryonic stem cells display distinct phenotypic and morphological signatures.

    Tom Bongiorno

    Full Text Available The highly proliferative and pluripotent characteristics of embryonic stem cells engender great promise for tissue engineering and regenerative medicine, but the rapid identification and isolation of target cell phenotypes remains challenging. Therefore, the objectives of this study were to characterize cell mechanics as a function of differentiation and to employ differences in cell stiffness to select population subsets with distinct mechanical, morphological, and biological properties. Biomechanical analysis with atomic force microscopy revealed that embryonic stem cells stiffened within one day of differentiation induced by leukemia inhibitory factor removal, with a lagging but pronounced change from spherical to spindle-shaped cell morphology. A microfluidic device was then employed to sort a differentially labeled mixture of pluripotent and differentiating cells based on stiffness, resulting in pluripotent cell enrichment in the soft device outlet. Furthermore, sorting an unlabeled population of partially differentiated cells produced a subset of "soft" cells that was enriched for the pluripotent phenotype, as assessed by post-sort characterization of cell mechanics, morphology, and gene expression. The results of this study indicate that intrinsic cell mechanical properties might serve as a basis for efficient, high-throughput, and label-free isolation of pluripotent stem cells, which will facilitate a greater biological understanding of pluripotency and advance the potential of pluripotent stem cell differentiated progeny as cell sources for tissue engineering and regenerative medicine.

  3. Fracture mechanics

    Perez, Nestor

    2017-01-01

    The second edition of this textbook includes a refined presentation of concepts in each chapter, additional examples; new problems and sections, such as conformal mapping and mechanical behavior of wood; while retaining all the features of the original book. The material included in this book is based upon the development of analytical and numerical procedures pertinent to particular fields of linear elastic fracture mechanics (LEFM) and plastic fracture mechanics (PFM), including mixed-mode-loading interaction. The mathematical approach undertaken herein is coupled with a brief review of several fracture theories available in cited references, along with many color images and figures. Dynamic fracture mechanics is included through the field of fatigue and Charpy impact testing. Explains computational and engineering approaches for solving crack-related problems using straightforward mathematics that facilitate comprehension of the physical meaning of crack growth processes; Expands computational understandin...

  4. Analytical mechanics

    Lemos, Nivaldo A

    2018-01-01

    Analytical mechanics is the foundation of many areas of theoretical physics including quantum theory and statistical mechanics, and has wide-ranging applications in engineering and celestial mechanics. This introduction to the basic principles and methods of analytical mechanics covers Lagrangian and Hamiltonian dynamics, rigid bodies, small oscillations, canonical transformations and Hamilton–Jacobi theory. This fully up-to-date textbook includes detailed mathematical appendices and addresses a number of advanced topics, some of them of a geometric or topological character. These include Bertrand's theorem, proof that action is least, spontaneous symmetry breakdown, constrained Hamiltonian systems, non-integrability criteria, KAM theory, classical field theory, Lyapunov functions, geometric phases and Poisson manifolds. Providing worked examples, end-of-chapter problems, and discussion of ongoing research in the field, it is suitable for advanced undergraduate students and graduate students studying analyt...

  5. Engineering mechanics

    Gross, Dietmar; Schröder, Jörg; Wall, Wolfgang A; Rajapakse, Nimal

    Statics is the first volume of a three-volume textbook on Engineering Mechanics. The authors, using a time-honoured straightforward and flexible approach, present the basic concepts and principles of mechanics in the clearest and simplest form possible to advanced undergraduate engineering students of various disciplines and different educational backgrounds. An important objective of this book is to develop problem solving skills in a systematic manner. Another aim of this volume is to provide engineering students as well as practising engineers with a solid foundation to help them bridge the gap between undergraduate studies on the one hand and advanced courses on mechanics and/or practical engineering problems on the other. The book contains numerous examples, along with their complete solutions. Emphasis is placed upon student participation in problem solving. The contents of the book correspond to the topics normally covered in courses on basic engineering mechanics at universities and colleges. Now in i...

  6. Supersymmetric mechanics

    Stelle, Kellogg S

    2007-01-01

    With the development of the electronic archives in high-energy physics, there has been increasing questioning of the role of traditional publishing styles, particularly in the production of conference books. One aspect of traditional publishing that still receives wide appreciation, however, is in the production of well-focussed pedagogical material. The present two-volume edition, 'Supersymmetric Mechanics-Vol 1', edited by S Bellucci and 'Supersymmetric Mechanics-Vol 2', edited by S Bellucci, S Ferrara and A Marrani, is a good example of the kind of well-digested presentation that should still find its way into university libraries. This two-volume set presents the material of a set of pedagogical lectures presented at the INFN National Laboratory in Frascati over a two-year period on the subject of supersymmetric mechanics. The articles include the results of discussions with the attending students after the lectures. Overall, this makes for a useful compilation of material on a subject that underlies much of the current effort in supersymmetric approaches to cosmology and the unification programme. The first volume comprises articles on 'A journey through garden algebras' by S Bellucci, S J Gates Jr and E Orazi on linear supermultiplet realizations in supersymmetric mechanics,'Supersymmetric mechanics in superspace' by S Bellucci and S Krivonos, 'Noncommutative mechanics, Landau levels, twistors and Yang-Mills amplitudes' by V P Nair, 'Elements of (super) Hamiltonian formalism' by A Nersessian and 'Matrix mechanics' by C Sochichiu. The second volume consists entirely of a masterful presentation on 'The attractor mechanism and space time singularities' by S Ferrara. This presents a comprehensive and detailed overview of the structure of supersymmetric black hole solutions in supergravity, critical point structure in the scalar field moduli space and the thermodynamic consequences. This second volume alone makes the set a worthwhile addition to the research

  7. Soil Mechanics

    Verruijt, A.

    2010-01-01

    This book is the text for the introductory course of Soil Mechanics in the Department of Civil Engineering of the Delft University of Technology, as I have given from 1980 until my retirement in 2002. It contains an introduction into the major principles and methods of soil mechanics, such as the analysis of stresses, deformations, and stability. The most important methods of determining soil parameters, in the laboratory and in situ, are also described. Some basic principles of applied mecha...

  8. Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants.

    Dron, Jacqueline S; Hegele, Robert A

    2017-04-01

    There are many reports of human variants in proprotein convertase subtilisin-kexin type 9 (PCSK9) that are either gain-of-function (GOF) or loss-of-function (LOF), with downstream effects on LDL cholesterol and cardiovascular disease (CVD) risk. However, data on particular mechanisms have only been minimally curated. GOF variants are individually ultrarare, affect all domains of the protein, act to reduce LDL receptor expression through several mechanisms, are a minor cause of familial hypercholesterolemia, have been reported mainly within families, have variable LDL cholesterol-raising effects, and are associated with increased CVD risk mainly through observational studies in families and small cohorts. In contrast, LOF variants can be either ultrarare mutations or relatively more common polymorphisms seen in populations, affect all domains of the protein, act to increase LDL receptor expression through several mechanisms, have variable LDL cholesterol-lowering effects, and have been associated with decreased CVD risk mainly through Mendelian randomization studies in epidemiologic populations. There is considerable complexity underlying the clinical concept of both LOF and GOF variants of PCSK9. But despite the underlying mechanistic heterogeneity, altered PCSK9 secretion or function is ultimately correlated with plasma LDL cholesterol level, which is also the driver of CVD outcomes.

  9. Mutant p53 - heat shock response oncogenic cooperation: a new mechanism of cancer cell survival

    Evguenia eAlexandrova

    2015-04-01

    Full Text Available The main tumor suppressor function of p53 as a ‘guardian of the genome’ is to respond to cellular stress by transcriptional activation of apoptosis, growth arrest or senescence in damaged cells. Not surprisingly, mutations in the p53 gene are the most frequent genetic alteration in human cancers. Importantly, mutant p53 (mutp53 proteins not only lose their wild-type tumor suppressor activity, but also can actively promote tumor development. Two main mechanisms accounting for mutp53 proto-oncogenic activity are inhibition of the wild-type p53 in a dominant-negative fashion and gain of additional oncogenic activities known as gain-of-function (GOF. Here we discuss a novel mechanism of mutp53 GOF, which relies on its oncogenic cooperation with the heat shock machinery. This coordinated adaptive mechanism renders cancer cells more resistant to proteotoxic stress and provides both, a strong survival advantage to cancer cells and a promising means for therapeutic intervention.

  10. Leaching mechanisms

    Dougherty, D.R.; Colombo, P.

    1984-01-01

    Sufficient data are lacking to provide a basis for adequately assessing the long term leaching behavior of solidified low level radioactive waste forms in their disposal environment. Although the release of radioactivity from a waste form to an aqueous environment is recognized to be due to one or more mechanisms such as diffusion, dissolution, corrosion or ion exchange, the leaching mechanisms and the factors which control the leaching behavior of waste forms are not fully understood. This study will determine the prevailing mechanisms for a variety of selected LLW solidification agents which are being considered for use by defense and commercial generators and which will cover the broadest possible number of mechanisms. The investigation will proceed by the postulation of mathematical models representative of the prevailing mechanism(s) and the use of statistically designed experiments to test the actual leaching behavior of laborattory samples against the postulated representations. Maximum use of existing leach data in the literature will be made by incorporating literature results into a computerized data base along with the experimental results generated in this task

  11. Relational quantum mechanics

    Rovelli, C.

    1996-01-01

    I suggest that the common unease with taking quantum mechanics as a fundamental description of nature (the open-quotes measurement problemclose quotes) could derive from the use of an incorrect notion, as the unease with the Lorentz transformations before Einstein derived from the notion of observer-independent time. I suggest that this incorrect notion that generates the unease with quantum mechanics is the notion of open-quotes observer-independent stateclose quotes of a system, or open-quotes observer-independent values of physical quantities.close quotes I reformulate the problem of the open-quotes interpretation of quantum mechanicsclose quotes as the problem of deriving the formalism from a set of simple physical postulates. I consider a reformulation of quantum mechanics in terms of information theory. All systems are assumed to be equivalent, there is no observer-observed distinction, and the theory describes only the information that systems have about each other; nevertheless, the theory is complete

  12. STRUCTURAL IDENTIFICATION OF DISTINCT INVERSIONS OF PLANAR KINEMATIC CHAINS

    Dr. Shubhashis Sanyal

    2011-12-01

    Full Text Available 0 0 1 171 979 International Islamic University 8 2 1148 14.0 Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Times New Roman";} Inversions are various structural possibilities of a kinematic chain. The number of inversions depends on the number of links of a kinematic chain. At the stage of structural synthesis, identification of distinct structural inversions of a particular type of kinematic chain is necessary. Various researchers have proposed methods for identification of distinct inversions. Present method based on Link joint connectivity is proposed to identify the distinct inversions of a planar kinematic chain. Method is tested successfully on single degree and multiple degree of freedom planar kinematic chains. ABSTRAK: Penyonsangan merupakan kebarangkalian pelbagai struktur suatu rangkaian kinematik. Jumlah songsangan bergantung kepada jumlah hubungan suatu rangkaian kinematik. Pada peringkat sintesis struktur, pengenalan songsangan struktur yang berbeza untuk suatu jenis rangkaian kinematik adalah perlu. Ramai penyelidik telah mencadangkan pelbagai kaedah pengenalan songsangan yang berbeza. Kaedah terkini berdasarkan hubungan kesambungan bersama telah dicadangkan untuk mengenalpasti songsangan yang berbeza dalam suatu satah rangkaian kinematik.

  13. Genetically Distinct Subsets within ANCA-Associated Vasculitis

    Lyons, Paul A.; Rayner, Tim F.; Trivedi, Sapna; Holle, Julia U.; Watts, Richard A.; Jayne, David R.W.; Baslund, Bo; Brenchley, Paul; Bruchfeld, Annette; Chaudhry, Afzal N.; Tervaert, Jan Willem Cohen; Deloukas, Panos; Feighery, Conleth; Gross, Wolfgang L.; Guillevin, Loic; Gunnarsson, Iva; P, Lorraine Harper M.R.C; Hrušková, Zdenka; Little, Mark A.; Martorana, Davide; Neumann, Thomas; Ohlsson, Sophie; Padmanabhan, Sandosh; Pusey, Charles D.; Salama, Alan D.; Sanders, Jan-Stephan F.; Savage, Caroline O.; Segelmark, Mårten; Stegeman, Coen A.; Tesař, Vladimir; Vaglio, Augusto; Wieczorek, Stefan; Wilde, Benjamin; Zwerina, Jochen; Rees, Andrew J.; Clayton, David G.; Smith, Kenneth G.C.

    2013-01-01

    BACKGROUND Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti–proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2×10−89, P = 5.6×10−12, and P = 2.6×10−7, respectively). Anti–myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1×10−8). CONCLUSIONS This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.) PMID

  14. Rhinovirus infection induces distinct transcriptome profiles in polarized human macrophages.

    Rajput, Charu; Walsh, Megan P; Eder, Breanna N; Metitiri, Ediri E; Popova, Antonia P; Hershenson, Marc B

    2018-05-01

    Infections with rhinovirus (RV) cause asthma exacerbations. Recent studies suggest that macrophages play a role in asthmatic airway inflammation and the innate immune response to RV infection. Macrophages exhibit phenotypes based on surface markers and gene expression. We hypothesized that macrophage polarization state alters gene expression in response to RV infection. Cells were derived from human peripheral blood derived monocytes. M1 and M2 polarization was carried out by using IFN-γ and IL-4, respectively, and RNA was extracted for Affymetrix Human Gene ST2.1 exon arrays. Selected genes were validated by quantitative (q)PCR. Treatment of nonactivated (M0) macrophages with IFN-γ and IL-4 induced the expression of 252 and 153 distinct genes, respectively, including previously-identified M1 and M2 markers. RV infection of M0 macrophages induced upregulation of 232 genes; pathway analysis showed significant overrepresentation of genes involved in IFN-α/β signaling and cytokine signaling in the immune system. RV infection induced differential expression of 195 distinct genes in M1-like macrophages but only seven distinct genes in M2-like-polarized cells. In a secondary analysis, comparison between M0-, RV-infected, and M1-like-polarized, RV-infected macrophages revealed differential expression of 227 genes including those associated with asthma and its exacerbation. qPCR demonstrated increased expression of CCL8, CXCL10, TNFSF10, TNFSF18, IL6, NOD2, and GSDMD and reduced expression of VNN1, AGO1, and AGO2. Together, these data show that, in contrast to M2-like-polarized macrophages, gene expression of M1-like macrophages is highly regulated by RV.

  15. Group Frames With Few Distinct Inner Products and Low Coherence

    Thill, Matthew

    2015-10-01

    Frame theory has been a popular subject in the design of structured signals and codes in recent years, with applications ranging from the design of measurement matrices in compressive sensing, to spherical codes for data compression and data transmission, to spacetime codes for MIMO communications, and to measurement operators in quantum sensing. High-performance codes usually arise from designing frames whose elements have mutually low coherence. Building off the original “group frame” design of Slepian which has since been elaborated in the works of Vale and Waldron, we present several new frame constructions based on cyclic and generalized dihedral groups. Slepian\\'s original construction was based on the premise that group structure allows one to reduce the number of distinct inner pairwise inner products in a frame with n elements from [(n(n-1))/2] to n-1. All of our constructions further utilize the group structure to produce tight frames with even fewer distinct inner product values between the frame elements. When n is prime, for example, we use cyclic groups to construct m-dimensional frame vectors with at most [(n-1)/m] distinct inner products. We use this behavior to bound the coherence of our frames via arguments based on the frame potential, and derive even tighter bounds from combinatorial and algebraic arguments using the group structure alone. In certain cases, we recover well-known Welch bound achieving frames. In cases where the Welch bound has not been achieved, and is not known to be achievable, we obtain frames with close to Welch bound performance.

  16. Puerto Rico and Florida manatees represent genetically distinct groups

    Hunter, Margaret E.; Mignucci-Giannoni, Antonio A.; Tucker, Kimberly Pause; King, Timothy L.; Bonde, Robert K.; Gray, Brian A.; McGuire, Peter M.

    2012-01-01

    The West Indian manatee (Trichechus manatus) populations in Florida (T. m. latirostris) and Puerto Rico (T. m. manatus) are considered distinct subspecies and are listed together as endangered under the United States Endangered Species Act. Sustained management and conservation efforts for the Florida subspecies have led to the suggested reclassification of the species to a threatened or delisted status. However, the two populations are geographically distant, morphologically distinct, and habitat degradation and boat strikes continue to threaten the Puerto Rico population. Here, 15 microsatellite markers and mitochondrial control region sequences were used to determine the relatedness of the two populations and investigate the genetic diversity and phylogeographic organization of the Puerto Rico population. Highly divergent allele frequencies were identified between Florida and Puerto Rico using microsatellite (F ST = 0.16; R ST = 0.12 (P ST = 0.66; Φ ST = 0.50 (P E = 0.45; NA = 3.9), were similar, but lower than those previously identified in Florida (HE = 0.48, NA = 4.8). Within Puerto Rico, the mitochondrial genetic diversity values (π = 0.001; h = 0.49) were slightly lower than those previously reported (π = 0.002; h = 0.54) and strong phylogeographic structure was identified (F ST global = 0.82; Φ ST global = 0.78 (P population size (N = 250), and distinct threats and habitat emphasize the need for separate protections in Puerto Rico. Conservation efforts including threat mitigation, migration corridors, and protection of subpopulations could lead to improved genetic variation in the endangered Puerto Rico manatee population.

  17. Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

    Trikha, Saurabh; Jeremic, Aleksandar M.

    2013-01-01

    Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin’s molecular forms, thereby serving a cyto-protective role in these cells. PMID:24019897

  18. Distinctive Design A Practical Guide to a Useful, Beautiful Web

    Dawson, Alexander

    2011-01-01

    Learn to produce a web site that stands out from the crowd One of the web designer's greatest challenges is to create a site distinctive enough to get noticed among the millions of sites already on the web. This book examines the bond between code, content and visuals to guide you through the factors that increase your design's visibility, usability and beauty. Using this practical advice, even web designers who lack strong artistic skills can develop super sites that strengthen the message and stand out from the crowd.Most books focus primarily on graphic design principles; this one shows you

  19. A microarray analysis of two distinct lymphatic endothelial cell populations

    Bernhard Schweighofer

    2015-06-01

    Full Text Available We have recently identified lymphatic endothelial cells (LECs to form two morphologically different populations, exhibiting significantly different surface protein expression levels of podoplanin, a major surface marker for this cell type. In vitro shockwave treatment (IVSWT of LECs resulted in enrichment of the podoplaninhigh cell population and was accompanied by markedly increased cell proliferation, as well as 2D and 3D migration. Gene expression profiles of these distinct populations were established using Affymetrix microarray analyses. Here we provide additional details about our dataset (NCBI GEO accession number GSE62510 and describe how we analyzed the data to identify differently expressed genes in these two LEC populations.

  20. Distinct termination morphologies for vertically aligned carbon nanotube forests

    Vinten, P; Marshall, P; Lefebvre, J; Finnie, P

    2010-01-01

    Vertically aligned carbon nanotube forests, including single-walled nanotubes, are imaged optically as they grow in situ from cobalt/alumina catalyst using water-assisted acetylene chemical vapor deposition. Three distinct termination morphologies are identified and investigated optically and via scanning electron microscopy. Quantitative growth dynamics are extracted and show gradual deceleration and sudden termination of growth. The termination morphology is discussed in terms of the balance of forces within the forest. We speculate that sudden termination is a collective effect arising from an imbalance in these forces.

  1. Responses of an isolation system with distinct multiple frequencies

    Wu, Ting-shu; Seidensticker, R.W.

    1991-01-01

    Base isolation systems are generally designed with a single natural frequency. A major concern for these isolation systems is that, if the dominant frequency of a future earthquake is equal or close to the system's natural frequency, the ground motion will be greatly amplified because of resonance,and the superstructure would suffer severe damages. This paper present an isolation system designed with two distinct frequencies. Its responses to different ground motions, including a harmonic motion, show that no excessive amplification will occur. Adoption of this isolation system would greatly enhance the safety of an isolated superstructure against future strong earthquakes. 3 refs., 4 figs., 2 tabs

  2. Seismic isolation systems designed with distinct multiple frequencies

    Wu, Ting-shu; Seidensticker, R.W.

    1991-01-01

    Two systems for seismic base isolation are presented. The main feature of these system is that, instead of only one isolation frequency as in conventional isolation systems, they are designed to have two distinct isolation frequencies. When the responses during an earthquake exceed the design value(s), the system will automatically and passively shift to the secondly isolation frequency. Responses of these two systems to different ground motions including a harmonic motion with frequency same as the primary isolation frequency, show that no excessive amplification will occur. Adoption of these new systems certainly will greatly enhance the safety and reliability of an isolated superstructure against future strong earthquakes. 3 refs

  3. Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks

    Ruiz-Rizzo, Adriana L.; Neitzel, Julia; Müller, Hermann J.; Sorg, Christian; Finke, Kathrin

    2018-01-01

    Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's “theory of visual attention” (TVA) allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity) and selectivity functions (i.e., top-down control and spatial laterality). However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower) visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less) efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable visual attention

  4. Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks.

    Ruiz-Rizzo, Adriana L; Neitzel, Julia; Müller, Hermann J; Sorg, Christian; Finke, Kathrin

    2018-01-01

    Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's "theory of visual attention" (TVA) allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity) and selectivity functions (i.e., top-down control and spatial laterality). However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower) visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less) efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable visual attention

  5. Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks

    Adriana L. Ruiz-Rizzo

    2018-03-01

    Full Text Available Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's “theory of visual attention” (TVA allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity and selectivity functions (i.e., top-down control and spatial laterality. However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI. Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable

  6. Distinct Neural Substrates for Maintaining Locations and Spatial Relations in Working Memory

    Kara J Blacker

    2016-11-01

    Full Text Available Previous work has demonstrated a distinction between maintenance of two types of spatial information in working memory (WM: spatial locations and spatial relations. While a body of work has investigated the neural mechanisms of sensory-based information like spatial locations, little is known about how spatial relations are maintained in WM. In two experiments, we used fMRI to investigate the involvement of early visual cortex in the maintenance of spatial relations in WM. In both experiments, we found less quadrant-specific BOLD activity in visual cortex when a single spatial relation, compared to a single spatial location, was held in WM. Also across both experiments, we found a consistent set of brain regions that were differentially activated during maintenance of locations versus relations. Maintaining a location, compared to a relation, was associated with greater activity in typical spatial WM regions like posterior parietal cortex and prefrontal regions. Whereas maintaining a relation, compared to a location, was associated with greater activity in the parahippocampal gyrus and precuneus/retrosplenial cortex. Further, in Experiment 2 we manipulated WM load and included trials where participants had to maintain three spatial locations or relations. Under this high load condition, the regions sensitive to locations versus relations were somewhat different than under low load. We also identified regions that were sensitive to load specifically for location or relation maintenance, as well as overlapping regions sensitive to load more generally. These results suggest that the neural substrates underlying WM maintenance of spatial locations and relations are distinct from one another and that the neural representations of these distinct types of spatial information change with load.

  7. Timing the Generation of Distinct Retinal Cells by Homeobox Proteins

    Decembrini, Sarah; Andreazzoli, Massimiliano; Vignali, Robert; Barsacchi, Giuseppina; Cremisi, Federico

    2006-01-01

    The reason why different types of vertebrate nerve cells are generated in a particular sequence is still poorly understood. In the vertebrate retina, homeobox genes play a crucial role in establishing different cell identities. Here we provide evidence of a cellular clock that sequentially activates distinct homeobox genes in embryonic retinal cells, linking the identity of a retinal cell to its time of generation. By in situ expression analysis, we found that the three Xenopus homeobox genes Xotx5b, Xvsx1, and Xotx2 are initially transcribed but not translated in early retinal progenitors. Their translation requires cell cycle progression and is sequentially activated in photoreceptors (Xotx5b) and bipolar cells (Xvsx1 and Xotx2). Furthermore, by in vivo lipofection of “sensors” in which green fluorescent protein translation is under control of the 3′ untranslated region (UTR), we found that the 3′ UTRs of Xotx5b, Xvsx1, and Xotx2 are sufficient to drive a spatiotemporal pattern of translation matching that of the corresponding proteins and consistent with the time of generation of photoreceptors (Xotx5b) and bipolar cells (Xvsx1 and Xotx2). The block of cell cycle progression of single early retinal progenitors impairs their differentiation as photoreceptors and bipolar cells, but is rescued by the lipofection of Xotx5b and Xvsx1 coding sequences, respectively. This is the first evidence to our knowledge that vertebrate homeobox proteins can work as effectors of a cellular clock to establish distinct cell identities. PMID:16903786

  8. Francis Bacon and the Art-Nature Distinction.

    Weeks, Sophie

    2007-07-01

    Commentators generally expound Bacon's position on the art-nature relationship in terms of how much it retained or departed from traditional conceptions. This paper argues that an appreciation of the Baconian meaning of the terms "art" and "nature" requires a close examination of his wider cosmogonical speculations. Bacon's cosmogonical account moves from a state of unbridled chaos to the relatively stable system for which the term "nature" is normally used. The fundamental principle lying at the heart of Baconian cosmogony is an enriched and appetitive matter: eternal, unchanging, and the plenipotentiary source of all things. Successive limitations of matter's absolute power produced a lazy and habitual nature, which Bacon labelled "nature free." To shift nature from this otiose condition, the Baconian operator recapitulates the original binding of matter. Bacon designated the systematic procedures of binding nature the science of magic. Magic is Bacon's human counterpart to the original cosmogonical process that gave rise to the current system of nature. In Bacon's cosmogony, all possible worlds unfold out of matter: the function of art is to shake out nature's hidden folds. Hence, the distinction between naturalia and artificialia maps on to the distinction between actual and potential. Nature free is without purpose, but art - nature bound - knowingly brings into being an alternative nature designed for human utility.

  9. BARE retrotransposons are translated and replicated via distinct RNA pools.

    Wei Chang

    Full Text Available The replication of Long Terminal Repeat (LTR retrotransposons, which can constitute over 80% of higher plant genomes, resembles that of retroviruses. A major question for retrotransposons and retroviruses is how the two conflicting roles of their transcripts, in translation and reverse transcription, are balanced. Here, we show that the BARE retrotransposon, despite its organization into just one open reading frame, produces three distinct classes of transcripts. One is capped, polyadenylated, and translated, but cannot be copied into cDNA. The second is not capped or polyadenylated, but is destined for packaging and ultimate reverse transcription. The third class is capped, polyadenylated, and spliced to favor production of a subgenomic RNA encoding only Gag, the protein forming virus-like particles. Moreover, the BARE2 subfamily, which cannot synthesize Gag and is parasitic on BARE1, does not produce the spliced sub-genomic RNA for translation but does make the replication competent transcripts, which are packaged into BARE1 particles. To our knowledge, this is first demonstration of distinct RNA pools for translation and transcription for any retrotransposon.

  10. Branchial Cilia and Sperm Flagella Recruit Distinct Axonemal Components

    Konno, Alu; Shiba, Kogiku; Cai, Chunhua; Inaba, Kazuo

    2015-01-01

    Eukaryotic cilia and flagella have highly conserved 9 + 2 structures. They are functionally diverged to play cell-type-specific roles even in a multicellular organism. Although their structural components are therefore believed to be common, few studies have investigated the molecular diversity of the protein components of the cilia and flagella in a single organism. Here we carried out a proteomic analysis and compared protein components between branchial cilia and sperm flagella in a marine invertebrate chordate, Ciona intestinalis. Distinct feature of protein recruitment in branchial cilia and sperm flagella has been clarified; (1) Isoforms of α- and β-tubulins as well as those of actins are distinctly used in branchial cilia or sperm flagella. (2) Structural components, such as dynein docking complex, tektins and an outer dense fiber protein, are used differently by the cilia and flagella. (3) Sperm flagella are specialized for the cAMP- and Ca2+-dependent regulation of outer arm dynein and for energy metabolism by glycolytic enzymes. Our present study clearly demonstrates that flagellar or ciliary proteins are properly recruited according to their function and stability, despite their apparent structural resemblance and conservation. PMID:25962172

  11. Distinctive personality profiles of fibromyalgia and chronic fatigue syndrome patients

    Jacob N. Ablin

    2016-09-01

    Full Text Available Objective The current study is an innovative exploratory investigation, aiming at identifying differences in personality profiles within Fibromyalgia Syndrome (FMS and Chronic Fatigue Syndrome (CFS patients. Method In total, 344 participants (309 female, 35 male reported suffering from FMS and/or CFS and consented to participate in the study. Participants were recruited at an Israeli FM/CFS patient meeting held in May 2013, and through an announcement posted on several social networks. Participants were asked to complete a research questionnaire, which included FMS criteria and severity scales, and measures of personality, emotional functioning, positivity, social support and subjective assessment of general health. In total, 204 participants completed the research questionnaire (40.7% attrition rate. Results A cluster analysis produced two distinct clusters, which differed significantly on psychological variables, but did not differ on demographic variables or illness severity. As compared to cluster number 2 (N = 107, participants classified into cluster number 1 (N = 97 showed a less adaptive pattern, with higher levels of Harm Avoidance and Alexithymia; higher prevalence of Type D personality; and lower levels of Persistence (PS, Reward dependence (RD, Cooperation, Self-directedness (SD, social support and positivity. Conclusion The significant pattern of results indicates at least two distinct personality profiles of FM and CFS patients. Findings from this research may help improve the evaluation and treatment of FM and CFS patients, based on each patient’s unique needs, psychological resources and weaknesses, as proposed by the current trend of personalized medicine.

  12. Temporomandibular joint formation requires two distinct hedgehog-dependent steps.

    Purcell, Patricia; Joo, Brian W; Hu, Jimmy K; Tran, Pamela V; Calicchio, Monica L; O'Connell, Daniel J; Maas, Richard L; Tabin, Clifford J

    2009-10-27

    We conducted a genetic analysis of the developing temporo-mandibular or temporomandi-bular joint (TMJ), a highly specialized synovial joint that permits movement and function of the mammalian jaw. First, we used laser capture microdissection to perform a genome-wide expression analysis of each of its developing components. The expression patterns of genes identified in this screen were examined in the TMJ and compared with those of other synovial joints, including the shoulder and the hip joints. Striking differences were noted, indicating that the TMJ forms via a distinct molecular program. Several components of the hedgehog (Hh) signaling pathway are among the genes identified in the screen, including Gli2, which is expressed specifically in the condyle and in the disk of the developing TMJ. We found that mice deficient in Gli2 display aberrant TMJ development such that the condyle loses its growth-plate-like cellular organization and no disk is formed. In addition, we used a conditional strategy to remove Smo, a positive effector of the Hh signaling pathway, from chondrocyte progenitors. This cell autonomous loss of Hh signaling allows for disk formation, but the resulting structure fails to separate from the condyle. Thus, these experiments establish that Hh signaling acts at two distinct steps in disk morphogenesis, condyle initiation, and disk-condyle separation and provide a molecular framework for future studies of the TMJ.

  13. Timing the generation of distinct retinal cells by homeobox proteins.

    Sarah Decembrini

    2006-09-01

    Full Text Available The reason why different types of vertebrate nerve cells are generated in a particular sequence is still poorly understood. In the vertebrate retina, homeobox genes play a crucial role in establishing different cell identities. Here we provide evidence of a cellular clock that sequentially activates distinct homeobox genes in embryonic retinal cells, linking the identity of a retinal cell to its time of generation. By in situ expression analysis, we found that the three Xenopus homeobox genes Xotx5b, Xvsx1, and Xotx2 are initially transcribed but not translated in early retinal progenitors. Their translation requires cell cycle progression and is sequentially activated in photoreceptors (Xotx5b and bipolar cells (Xvsx1 and Xotx2. Furthermore, by in vivo lipofection of "sensors" in which green fluorescent protein translation is under control of the 3' untranslated region (UTR, we found that the 3' UTRs of Xotx5b, Xvsx1, and Xotx2 are sufficient to drive a spatiotemporal pattern of translation matching that of the corresponding proteins and consistent with the time of generation of photoreceptors (Xotx5b and bipolar cells (Xvsx1 and Xotx2. The block of cell cycle progression of single early retinal progenitors impairs their differentiation as photoreceptors and bipolar cells, but is rescued by the lipofection of Xotx5b and Xvsx1 coding sequences, respectively. This is the first evidence to our knowledge that vertebrate homeobox proteins can work as effectors of a cellular clock to establish distinct cell identities.

  14. Distinct pathways of neural coupling for different basic emotions.

    Tettamanti, Marco; Rognoni, Elena; Cafiero, Riccardo; Costa, Tommaso; Galati, Dario; Perani, Daniela

    2012-01-16

    Emotions are complex events recruiting distributed cortical and subcortical cerebral structures, where the functional integration dynamics within the involved neural circuits in relation to the nature of the different emotions are still unknown. Using fMRI, we measured the neural responses elicited by films representing basic emotions (fear, disgust, sadness, happiness). The amygdala and the associative cortex were conjointly activated by all basic emotions. Furthermore, distinct arrays of cortical and subcortical brain regions were additionally activated by each emotion, with the exception of sadness. Such findings informed the definition of three effective connectivity models, testing for the functional integration of visual cortex and amygdala, as regions processing all emotions, with domain-specific regions, namely: i) for fear, the frontoparietal system involved in preparing adaptive motor responses; ii) for disgust, the somatosensory system, reflecting protective responses against contaminating stimuli; iii) for happiness: medial prefrontal and temporoparietal cortices involved in understanding joyful interactions. Consistently with these domain-specific models, the results of the effective connectivity analysis indicate that the amygdala is involved in distinct functional integration effects with cortical networks processing sensorimotor, somatosensory, or cognitive aspects of basic emotions. The resulting effective connectivity networks may serve to regulate motor and cognitive behavior based on the quality of the induced emotional experience. Copyright © 2011. Published by Elsevier Inc.

  15. Two Distinct Scene-Processing Networks Connecting Vision and Memory.

    Baldassano, Christopher; Esteva, Andre; Fei-Fei, Li; Beck, Diane M

    2016-01-01

    A number of regions in the human brain are known to be involved in processing natural scenes, but the field has lacked a unifying framework for understanding how these different regions are organized and interact. We provide evidence from functional connectivity and meta-analyses for a new organizational principle, in which scene processing relies upon two distinct networks that split the classically defined parahippocampal place area (PPA). The first network of strongly connected regions consists of the occipital place area/transverse occipital sulcus and posterior PPA, which contain retinotopic maps and are not strongly coupled to the hippocampus at rest. The second network consists of the caudal inferior parietal lobule, retrosplenial complex, and anterior PPA, which connect to the hippocampus (especially anterior hippocampus), and are implicated in both visual and nonvisual tasks, including episodic memory and navigation. We propose that these two distinct networks capture the primary functional division among scene-processing regions, between those that process visual features from the current view of a scene and those that connect information from a current scene view with a much broader temporal and spatial context. This new framework for understanding the neural substrates of scene-processing bridges results from many lines of research, and makes specific functional predictions.

  16. The uses and abuses of the coherence – correspondence distinction

    Polonioli, Andrea

    2015-01-01

    Kenneth Hammond introduced a distinction between coherence and correspondence criteria of rationality as a tool in the study of judgment and decision-making. This distinction has been widely used in the field. Yet, as this paper seeks to show, the relevant notions of coherence and correspondence have been progressively considered to be too narrow and have undergone non-trivial conceptual changes since their original introduction. I try to show, first, that the proliferation of conceptualizations of coherence and correspondence has created confusion in the literature and that appealing to such notions has not helped to elucidate discussions over the nature of rational judgment and decision-making. Nevertheless, I also argue for a reframing of the debate. In fact, what seems to underlie several contemporary appeals to the notions of coherence and correspondence is best explained in terms of a contrast between what I call rule-based and goal-based rationality. Whilst these categories do need further refinement, they do seem to be useful for organizing and understanding research on rational judgment and decision-making. PMID:25983700

  17. Vertically distinct microbial communities in the Mariana and Kermadec trenches

    Donaldson, Sierra; Osuntokun, Oladayo; Xia, Qing; Nelson, Alex; Blanton, Jessica; Allen, Eric E.; Church, Matthew J.; Bartlett, Douglas H.

    2018-01-01

    Hadal trenches, oceanic locations deeper than 6,000 m, are thought to have distinct microbial communities compared to those at shallower depths due to high hydrostatic pressures, topographical funneling of organic matter, and biogeographical isolation. Here we evaluate the hypothesis that hadal trenches contain unique microbial biodiversity through analyses of the communities present in the bottom waters of the Kermadec and Mariana trenches. Estimates of microbial protein production indicate active populations under in situ hydrostatic pressures and increasing adaptation to pressure with depth. Depth, trench of collection, and size fraction are important drivers of microbial community structure. Many putative hadal bathytypes, such as members related to the Marinimicrobia, Rhodobacteraceae, Rhodospirilliceae, and Aquibacter, are similar to members identified in other trenches. Most of the differences between the two trench microbiomes consists of taxa belonging to the Gammaproteobacteria whose distributions extend throughout the water column. Growth and survival estimates of representative isolates of these taxa under deep-sea conditions suggest that some members may descend from shallower depths and exist as a potentially inactive fraction of the hadal zone. We conclude that the distinct pelagic communities residing in these two trenches, and perhaps by extension other trenches, reflect both cosmopolitan hadal bathytypes and ubiquitous genera found throughout the water column. PMID:29621268

  18. Distinct functional programming of human fetal and adult monocytes.

    Krow-Lucal, Elisabeth R; Kim, Charles C; Burt, Trevor D; McCune, Joseph M

    2014-03-20

    Preterm birth affects 1 out of 9 infants in the United States and is the leading cause of long-term neurologic handicap and infant mortality, accounting for 35% of all infant deaths in 2008. Although cytokines including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, and IL-1 are produced in response to in utero infection and are strongly associated with preterm labor, little is known about how human fetal immune cells respond to these cytokines. We demonstrate that fetal and adult CD14(+)CD16(-) classical monocytes are distinct in terms of basal transcriptional profiles and in phosphorylation of signal transducers and activators of transcription (STATs) in response to cytokines. Fetal monocytes phosphorylate canonical and noncanonical STATs and respond more strongly to IFN-γ, IL-6, and IL-4 than adult monocytes. We demonstrate a higher ratio of SOCS3 to IL-6 receptor in adult monocytes than in fetal monocytes, potentially explaining differences in STAT phosphorylation. Additionally, IFN-γ signaling results in upregulation of antigen presentation and costimulatory machinery in adult, but not fetal, monocytes. These findings represent the first evidence that primary human fetal and adult monocytes are functionally distinct, potentially explaining how these cells respond differentially to cytokines implicated in development, in utero infections, and the pathogenesis of preterm labor.

  19. Analysis of pharmacogenetic traits in two distinct South African populations

    Ikediobi Ogechi

    2011-05-01

    Full Text Available Abstract Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109 and Cape Mixed Ancestry (CMA (n = 67 groups. The minor allele frequencies (MAFs of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1] were significantly different between the Xhosa and CMA populations (Bonferroni p CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1 between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations.

  20. Quantum mechanics

    Fitzpatrick, Richard

    2015-01-01

    Quantum mechanics was developed during the first few decades of the twentieth century via a series of inspired guesses made by various physicists, including Planck, Einstein, Bohr, Schroedinger, Heisenberg, Pauli, and Dirac. All these scientists were trying to construct a self-consistent theory of microscopic dynamics that was compatible with experimental observations. The purpose of this book is to present quantum mechanics in a clear, concise, and systematic fashion, starting from the fundamental postulates, and developing the theory in as logical manner as possible. Topics covered in the book include the fundamental postulates of quantum mechanics, angular momentum, time-dependent and time-dependent perturbation theory, scattering theory, identical particles, and relativistic electron theory.

  1. Analytical mechanics

    Helrich, Carl S

    2017-01-01

    This advanced undergraduate textbook begins with the Lagrangian formulation of Analytical Mechanics and then passes directly to the Hamiltonian formulation and the canonical equations, with constraints incorporated through Lagrange multipliers. Hamilton's Principle and the canonical equations remain the basis of the remainder of the text. Topics considered for applications include small oscillations, motion in electric and magnetic fields, and rigid body dynamics. The Hamilton-Jacobi approach is developed with special attention to the canonical transformation in order to provide a smooth and logical transition into the study of complex and chaotic systems. Finally the text has a careful treatment of relativistic mechanics and the requirement of Lorentz invariance. The text is enriched with an outline of the history of mechanics, which particularly outlines the importance of the work of Euler, Lagrange, Hamilton and Jacobi. Numerous exercises with solutions support the exceptionally clear and concise treatment...

  2. Quantum mechanics

    Ghosh, P K

    2014-01-01

    Quantum mechanics, designed for advanced undergraduate and graduate students of physics, mathematics and chemistry, provides a concise yet self-contained introduction to the formal framework of quantum mechanics, its application to physical problems and the interpretation of the theory. Starting with a review of some of the necessary mathematics, the basic concepts are carefully developed in the text. After building a general formalism, detailed treatment of the standard material - the harmonic oscillator, the hydrogen atom, angular momentum theory, symmetry transformations, approximation methods, identical particle and many-particle systems, and scattering theory - is presented. The concluding chapter discusses the interpretation of quantum mechanics. Some of the important topics discussed in the book are the rigged Hilbert space, deformation quantization, path integrals, coherent states, geometric phases, decoherene, etc. This book is characterized by clarity and coherence of presentation.

  3. Wave Mechanics or Wave Statistical Mechanics

    Qian Shangwu; Xu Laizi

    2007-01-01

    By comparison between equations of motion of geometrical optics and that of classical statistical mechanics, this paper finds that there should be an analogy between geometrical optics and classical statistical mechanics instead of geometrical mechanics and classical mechanics. Furthermore, by comparison between the classical limit of quantum mechanics and classical statistical mechanics, it finds that classical limit of quantum mechanics is classical statistical mechanics not classical mechanics, hence it demonstrates that quantum mechanics is a natural generalization of classical statistical mechanics instead of classical mechanics. Thence quantum mechanics in its true appearance is a wave statistical mechanics instead of a wave mechanics.

  4. Mechanical seals

    Mayer, E

    1977-01-01

    Mechanical Seals, Third Edition is a source of practical information on the design and use of mechanical seals. Topics range from design fundamentals and test rigs to leakage, wear, friction and power, reliability, and special designs. This text is comprised of nine chapters; the first of which gives a general overview of seals, including various types of seals and their applications. Attention then turns to the fundamentals of seal design, with emphasis on six requirements that must be considered: sealing effectiveness, length of life, reliability, power consumption, space requirements, and c

  5. Statistical mechanics

    Davidson, Norman

    2003-01-01

    Clear and readable, this fine text assists students in achieving a grasp of the techniques and limitations of statistical mechanics. The treatment follows a logical progression from elementary to advanced theories, with careful attention to detail and mathematical development, and is sufficiently rigorous for introductory or intermediate graduate courses.Beginning with a study of the statistical mechanics of ideal gases and other systems of non-interacting particles, the text develops the theory in detail and applies it to the study of chemical equilibrium and the calculation of the thermody

  6. Reliability for systems of degrading components with distinct component shock sets

    Song, Sanling; Coit, David W.; Feng, Qianmei

    2014-01-01

    This paper studies reliability for multi-component systems subject to dependent competing risks of degradation wear and random shocks, with distinct shock sets. In practice, many systems are exposed to distinct and different types of shocks that can be categorized according to their sizes, function, affected components, etc. Previous research primarily focuses on simple systems with independent failure processes, systems with independent component time-to-failure, or components that share the same shock set or type of shocks. In our new model, we classify random shocks into different sets based on their sizes or function. Shocks with specific sizes or function can selectively affect one or more components in the system but not necessarily all components. Additionally the shocks from the different shock sets can arrive at different rates and have different relative magnitudes. Preventive maintenance (PM) optimization is conducted for the system with different component shock sets. Decision variables for two different maintenance scheduling problems, the PM replacement time interval, and the PM inspection time interval, are determined by minimizing a defined system cost rate. Sensitivity analysis is performed to provide insight into the behavior of the proposed maintenance policies. These models can be applied directly or customized for many complex systems that experience dependent competing failure processes with different component shock sets. A MEMS (Micro-electro mechanical systems) oscillator is a typical system subject to dependent and competing failure processes, and it is used as a numerical example to illustrate our new reliability and maintenance models

  7. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling.

    Hoefnagel, Juliette J; Dijkman, Remco; Basso, Katia; Jansen, Patty M; Hallermann, Christian; Willemze, Rein; Tensen, Cornelis P; Vermeer, Maarten H

    2005-05-01

    In the European Organization for Research and Treatment of Cancer (EORTC) classification 2 types of primary cutaneous large B-cell lymphoma (PCLBCL) are distinguished: primary cutaneous follicle center cell lymphomas (PCFCCL) and PCLBCL of the leg (PCLBCL-leg). Distinction between both groups is considered important because of differences in prognosis (5-year survival > 95% and 52%, respectively) and the first choice of treatment (radiotherapy or systemic chemotherapy, respectively), but is not generally accepted. To establish a molecular basis for this subdivision in the EORTC classification, we investigated the gene expression profiles of 21 PCLBCLs by oligonucleotide microarray analysis. Hierarchical clustering based on a B-cell signature (7450 genes) classified PCLBCL into 2 distinct subgroups consisting of, respectively, 8 PCFCCLs and 13 PCLBCLsleg. PCLBCLs-leg showed increased expression of genes associated with cell proliferation; the proto-oncogenes Pim-1, Pim-2, and c-Myc; and the transcription factors Mum1/IRF4 and Oct-2. In the group of PCFCCL high expression of SPINK2 was observed. Further analysis suggested that PCFCCLs and PCLBCLs-leg have expression profiles similar to that of germinal center B-cell-like and activated B-cell-like diffuse large B-cell lymphoma, respectively. The results of this study suggest that different pathogenetic mechanisms are involved in the development of PCFCCLs and PCLBCLs-leg and provide molecular support for the subdivision used in the EORTC classification.

  8. Testing the distinctiveness of visual imagery and motor imagery in a reach paradigm.

    Gabbard, Carl; Ammar, Diala; Cordova, Alberto

    2009-01-01

    We examined the distinctiveness of motor imagery (MI) and visual imagery (VI) in the context of perceived reachability. The aim was to explore the notion that the two visual modes have distinctive processing properties tied to the two-visual-system hypothesis. The experiment included an interference tactic whereby participants completed two tasks at the same time: a visual or motor-interference task combined with a MI or VI-reaching task. We expected increased error would occur when the imaged task and the interference task were matched (e.g., MI with the motor task), suggesting an association based on the assumption that the two tasks were in competition for space on the same processing pathway. Alternatively, if there were no differences, dissociation could be inferred. Significant increases in the number of errors were found when the modalities for the imaged (both MI and VI) task and the interference task were matched. Therefore, it appears that MI and VI in the context of perceived reachability recruit different processing mechanisms.

  9. Allelic recombination between distinct genomic locations generates copy number diversity in human β-defensins

    Bakar, Suhaili Abu; Hollox, Edward J.; Armour, John A. L.

    2009-01-01

    β-Defensins are small secreted antimicrobial and signaling peptides involved in the innate immune response of vertebrates. In humans, a cluster of at least 7 of these genes shows extensive copy number variation, with a diploid copy number commonly ranging between 2 and 7. Using a genetic mapping approach, we show that this cluster is at not 1 but 2 distinct genomic loci ≈5 Mb apart on chromosome band 8p23.1, contradicting the most recent genome assembly. We also demonstrate that the predominant mechanism of change in β-defensin copy number is simple allelic recombination occurring in the interval between the 2 distinct genomic loci for these genes. In 416 meiotic transmissions, we observe 3 events creating a haplotype copy number not found in the parent, equivalent to a germ-line rate of copy number change of ≈0.7% per gamete. This places it among the fastest-changing copy number variants currently known. PMID:19131514

  10. One target, different effects: a comparison of distinct therapeutic antibodies against the same targets.

    Shim, Hyunbo

    2011-10-31

    To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-α, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.

  11. Choosing the rules: distinct and overlapping frontoparietal representations of task rules for perceptual decisions.

    Zhang, Jiaxiang; Kriegeskorte, Nikolaus; Carlin, Johan D; Rowe, James B

    2013-07-17

    Behavior is governed by rules that associate stimuli with responses and outcomes. Human and monkey studies have shown that rule-specific information is widely represented in the frontoparietal cortex. However, it is not known how establishing a rule under different contexts affects its neural representation. Here, we use event-related functional MRI (fMRI) and multivoxel pattern classification methods to investigate the human brain's mechanisms of establishing and maintaining rules for multiple perceptual decision tasks. Rules were either chosen by participants or specifically instructed to them, and the fMRI activation patterns representing rule-specific information were compared between these contexts. We show that frontoparietal regions differ in the properties of their rule representations during active maintenance before execution. First, rule-specific information maintained in the dorsolateral and medial frontal cortex depends on the context in which it was established (chosen vs specified). Second, rule representations maintained in the ventrolateral frontal and parietal cortex are independent of the context in which they were established. Furthermore, we found that the rule-specific coding maintained in anticipation of stimuli may change with execution of the rule: representations in context-independent regions remain invariant from maintenance to execution stages, whereas rule representations in context-dependent regions do not generalize to execution stage. The identification of distinct frontoparietal systems with context-independent and context-dependent task rule representations, and the distinction between anticipatory and executive rule representations, provide new insights into the functional architecture of goal-directed behavior.

  12. Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment.

    An, Yang; Wang, Shuzhen; Li, Songlin; Zhang, Lulu; Wang, Dayong; Wang, Haojie; Zhu, Shibai; Zhu, Wan; Li, Yongqiang; Chen, Wenwu; Ji, Shaoping; Guo, Xiangqian

    2017-09-11

    Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors.

  13. Fluid mechanics

    Granger, R.A.

    1985-01-01

    This text offers the most comprehensive approach available to fluid mechanics. The author takes great care to insure a physical understanding of concepts grounded in applied mathematics. The presentation of theory is followed by engineering applications, helping students develop problem-solving skills from the perspective of a professional engineer. Extensive use of detailed examples reinforces the understanding of theoretical concepts

  14. Fluid Mechanics.

    Drazin, Philip

    1987-01-01

    Outlines the contents of Volume II of "Principia" by Sir Isaac Newton. Reviews the contributions of subsequent scientists to the physics of fluid dynamics. Discusses the treatment of fluid mechanics in physics curricula. Highlights a few of the problems of modern research in fluid dynamics. Shows that problems still remain. (CW)

  15. Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88

    Huajia Zhang

    2016-06-01

    Full Text Available Toll-like receptor 4 (TLR4 plays a central role in host responses to bacterial infection, but the precise mechanism(s by which its downstream signaling components coordinate the bone marrow response to sepsis is poorly understood. Using mice deficient in TLR4 downstream adapters MYD88 or TRIF, we demonstrate that both cell-autonomous and non-cell-autonomous MYD88 activation are major causes of myelosuppression during sepsis, while having a modest impact on hematopoietic stem cell (HSC functions. In contrast, cell-intrinsic TRIF activation severely compromises HSC self-renewal without directly affecting myeloid cells. Lipopolysaccharide-induced activation of MYD88 or TRIF contributes to cell-cycle activation of HSC and induces rapid and permanent changes in transcriptional programs, as indicated by persistent downregulation of Spi1 and CebpA expression after transplantation. Thus, distinct mechanisms downstream of TLR4 signaling mediate myelosuppression and HSC exhaustion during sepsis through unique effects of MyD88 and TRIF.

  16. Salmonella Typhimurium undergoes distinct genetic adaption during chronic infections of mice

    Søndberg, Emilie; Jelsbak, Lotte

    2016-01-01

    Background Typhoid fever caused by Salmonella enterica serovar Typhi (S. Typhi) is a severe systemic human disease and endemic in regions of the world with poor drinking water quality and sewage treatment facilities. A significant number of patients become asymptomatic life-long carriers of S....... Typhi and serve as the reservoir for the disease. The specific mechanisms and adaptive strategies enabling S. Typhi to survive inside the host for extended periods are incompletely understood. Yet, elucidation of these processes is of major importance for improvement of therapeutic strategies...... been transmitted to the other two mice. Re-infection with this clone confirmed that it is superior to the wild type for intestinal colonisation. Conclusions During 4 to 6 weeks of chronic infections, S. Typhimurium acquired distinct SNPs in known regulators of metabolic and virulence genes. One SNP...

  17. Pairing versus phase coherence of doped holes in distinct quantum spin backgrounds

    Zhu, Zheng; Sheng, D. N.; Weng, Zheng-Yu

    2018-03-01

    We examine the pairing structure of holes injected into two distinct spin backgrounds: a short-range antiferromagnetic phase versus a symmetry protected topological phase. Based on density matrix renormalization group (DMRG) simulation, we find that although there is a strong binding between two holes in both phases, phase fluctuations can significantly influence the pair-pair correlation depending on the spin-spin correlation in the background. Here the phase fluctuation is identified as an intrinsic string operator nonlocally controlled by the spins. We show that while the pairing amplitude is generally large, the coherent Cooper pairing can be substantially weakened by the phase fluctuation in the symmetry-protected topological phase, in contrast to the short-range antiferromagnetic phase. It provides an example of a non-BCS mechanism for pairing, in which the paring phase coherence is determined by the underlying spin state self-consistently, bearing an interesting resemblance to the pseudogap physics in the cuprate.

  18. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome

    Morselli, Eugenia; Mariño, Guillermo; Bennetzen, Martin V

    2011-01-01

    Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy...... independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation...... and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate...

  19. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.

    Morselli, Eugenia; Mariño, Guillermo; Bennetzen, Martin V; Eisenberg, Tobias; Megalou, Evgenia; Schroeder, Sabrina; Cabrera, Sandra; Bénit, Paule; Rustin, Pierre; Criollo, Alfredo; Kepp, Oliver; Galluzzi, Lorenzo; Shen, Shensi; Malik, Shoaib Ahmad; Maiuri, Maria Chiara; Horio, Yoshiyuki; López-Otín, Carlos; Andersen, Jens S; Tavernarakis, Nektarios; Madeo, Frank; Kroemer, Guido

    2011-02-21

    Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate the autophagic cascade. At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy. Altogether, these data underscore the importance of an autophagy regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated.

  20. PDB-NMA of a protein homodimer reproduces distinct experimental motility asymmetry

    Tirion, Monique M.; ben-Avraham, Daniel

    2018-03-01

    We have extended our analytically derived PDB-NMA formulation, Atomic Torsional Modal Analysis or ATMAN (Tirion and ben-Avraham 2015 Phys. Rev. E 91 032712), to include protein dimers using mixed internal and Cartesian coordinates. A test case on a 1.3 {\\mathringA} resolution model of a small homodimer, ActVA-ORF6, consisting of two 112-residue subunits identically folded in a compact 50 {\\mathringA} sphere, reproduces the distinct experimental Debye-Waller motility asymmetry for the two chains, demonstrating that structure sensitively selects vibrational signatures. The vibrational analysis of this PDB entry, together with biochemical and crystallographic data, demonstrates the cooperative nature of the dimeric interaction of the two subunits and suggests a mechanical model for subunit interconversion during the catalytic cycle.