Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

Networking Notch : regulation of Notch traffic and signaling crosstalk

Utvecklingen av flercelliga organismer är en mångfacetterad process som kräver kommunikation celler emellan. Under utvecklingen av en organism måste cellerna göra vissa val, vilket bestämmer riktningen för deras fortsatta utveckling. Utgående från dessa val erhåller cellerna egenskaper som är karaktäristiska för olika celltyper. Notch-signalräckan är en viktig reglerare av valet mellan olika cellöden. Notch-signalräckan aktiveras när Notch-receptorer som uttrycks på ytan av en cell binder till Notch-ligander som uttrycks på ytan av en annan närliggande cell. Denna avhandling belyser mekanismerna som reglerar omsättningen av såväl Notch-receptorer som -ligander till och från cellmembranen, samt ökar förståelsen för hur dessa mekanismer påverkar Notch-medierade cellöden i stamceller. Internalisering av Notch receptorer anses nödvändigt för fullständig aktivering av Notch-signalvägen. De bakomliggande molekylära mekanismerna är dock fortfarande oklara. Vi har upptäckt att atypiskt protein kinas Cζ (aPKCζ) reglerar internaliseringen av Notch-receptorer. aPKCζ fosforylerar Notch, vilket leder till receptorns internalisering, men effekten är beroende av receptorns signaleringsstatus. Vi visar att aPKCζ reglerar Notch-signaleringen och styr både neuroners och muskelcellers differentiering. Ytterligare har vi analyserat samspelet mellan cellskelettet och Notch-signalvägen. Våra resultat visar att intermediärfilamenten, en del av cellskelettet, är viktiga reglerare av Notch-signaleringen både under neuronal och vaskulär utveckling. Intermediärfilamenten vimentin och GFAP reglerar uttrycket av Notch-ligander vid cellmembranen i hjärnans stödceller, astrocyterna, och påverkar därmed neuronala stamcellers cellödesbeslut. Vimentin är även viktigt reglerare av Notch-signalräckan vid angiogenesen. Celler som saknar vimentin uppvisar avvikande Notch-signalering emedan möss som saknar vimentin påvisar en fördröjd utveckling av vaskulaturen under embryonalstadiet. ------------------------------------------------- Monisoluisten organismien kehittyminen on monimutkainen prosessi, joka vaatii viestintää solujen välillä. Kehittymisen aikana solut joutuvat tiettyjen valintojen eteen, mitkä tulevat määrittämään niiden erilaistumisen suunnan. Solut omaksuvat solutyypille ominaisia ominaisuuksia näihin valintoihin perustuen Notch-signalointireitti säätelee solujen erilaistumista eri suuntiin. Notch-signalointireitti aktivoituu, kun Notch-reseptori yhden solun pinnalla sitoo Notch-ligandin toisen, viereisen solun solukalvolla. Tutkimukseni lisää tuntemusta Notch-reseptoreiden ja ligandien solun sisäisestä liikennöinnistä ja sitä säätelevistä mekanismeista, sekä tämän säätelyn vaikutuksista kantasulojen erilaistumiseen. Notch-signalointireitin aktivoituminen vaatii reseptoreiden ja ligandien sisäistämisen solukalvolta, mutta taustalla olevat ja sisäistymistä säätelevät mekanismit ovat vielä epäselviä. Tutkimukseni osoittaa, että atyyppinen proteiinikinaasi Cζ (aPKCζ) säätelee Notch-reseptoreiden endosytoosia. Endosytoosin lopputulos riippuu siitä onko reseptori aktivoitunut ligandin välityksellä vai ei. Tuloksemme osoittavat aPKCζ säätelevän Notch-signalointia ja kontrolloivan sekä hermosolujen, että lihassolujen erilaistumista. Analysoimme myös Notch-signaloinnin ja solun tukirangan vuorovaikutuksia. Välikokoiset filamentit, jotka ovat osa tukirankaa, säätelevät Notch-signalointia neuronaalisen erilaistumisen sekä verisuonten uudismuodostumisen aikana. Vimentiini ja GFAP ovat välikokoisia säikeitä, jotka säätelevät Notch-ligandien ekspressiota astrosyyttien, eli aivojen hermotukisolujen solukalvolla. Vimentiini säätelee myös Notch-signalointireittiä angiogeneesin aikana. Vimentiiniä vailla olevilla soluilla ilmenee heikentynyttä Notch-signalointia, joka voidaan liittää hiirillä ilmenevään vimenttiinin puutteesta johtuvaan viivästyneeseen verisuonien kehitykseen.

Credibility and Signaling in Disinflation- a Cross Country Examination

This paper develops a model of money demand where the opportunity cost of holding money is subject to regime changes. The regimes are fully characterized by the mean and variance of inflation and are assumed to be the result of alternative government policies. Agents are unable to directly observe whether government actions are indeed consistent with the inflation rate targeted as part of a stabilization program but can construct probability inferences on the basis of available observations of inflation and money growth. Government announcements are assumed to provide agents with additional, possibly truthful information regarding the regime. This specification is estimated and tested using data from the Israeli and Argentine high inflation periods. Results indicate the successful stabilization program implemented in Israel in July 1985 was more credible than either the earlier Israeli attempt in November 1984 or the Argentine programs. Government’s signaling might substantially simplify the inference problem and increase the speed of learning on the part of the agents. However, under certain conditions, it might increase the volatility of inflation. After the introduction of an inflation stabilization plan, the welfare gains from a temporary increase in real balances might be high enough to induce agents to raise their real balances in the short-term, even if they are uncertain about the nature of government policy and the eventual outcome of the stabilization attempt. Statistically, the model restrictions cannot be rejected at the 1% significance level.

CB1 receptor allosteric modulators display both agonist and signaling pathway specificity

We have previously identified allosteric modulators of the cannabinoid CB1 receptor (Org 27569, PSNCBAM-1) which display a contradictory pharmacological profile: increasing the specific binding of the CB1 receptor agonist [3H]CP55940 but producing a decrease in CB1 receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signalling endpoints linked to CB1 receptor activation. We assessed the effect of these compounds on CB1 receptor agonist-induced [35S]GTPγS binding, inhibition and stimulation of forskolin stimulated cAMP production, phosphorylation of ERK, and β arrestin recruitment. We also investigated the effect of these allosteric modulators on CB1 agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signalling as compared to WIN55212 and having little effect on [3H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced [35S]GTPγS binding, simulation (Gαs mediated) and inhibition (Gαi mediated) of cAMP production and β arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphoryation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high affinity CB1 agonist binding sites. The receptor conformation stabilised by the allosterics appears to induce signalling and also selectively traffics orthosteric agonist signalling via the ERK phosphorylation pathway.

Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

Contrasting phylogenetic signals and evolutionary rates in floral traits of Neotropical lianas

The diversity of floral forms has long been considered a prime example of radiation through natural selection. However, little is still known about the evolution of floral traits, a critical piece of evidence for the understanding of the processes that may have driven flower evolution. We studied the pattern of evolution of quantitative floral traits in a group of Neotropical lianas (Bignonieae, Bignoniaceae) and used a time-calibrated phylogeny as basis to: (1) test for phylogenetic signal in 16 continuous floral traits; (2) evaluate the rate of evolution in those traits; and (3) reconstruct the ancestral state of the individual traits. Variation in floral traits among extant species of Bignonieae was highly explained by their phylogenetic history. However, opposite signals were found in floral traits associated with the attraction of pollinators (calyx and corolla) and pollen transfer (androecium and gynoecium), suggesting a differential role of selection in different floral whorls. Phylogenetic independent contrasts indicate that traits evolved at different rates, whereas ancestral character state reconstructions indicate that the ancestral size of most flower traits was larger than the mean observed sizes of the same traits in extant species. The implications of these patterns for the reproductive biology of Bignonieae are discussed. (C) 2011 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 102, 378-390.

Bank dividends and signaling to information-sensitive depositors

Esta tese investiga se a composição do endividamento dos bancos afeta sua política de dividendos. Identificou-se que investidores sensíveis a informações (investidores institucionais) são alvos de sinalização através de dividendos por parte dos bancos. Utilizando uma base de dados exclusiva de bancos brasileiros, foi possível identificar vários tipos de credores, especificamente, investidores institucionais, empresas não financeiras e pessoas físicas, que são alvos potenciais de sinalização por dividendos. Adicionalmente, a existência de vários bancos de capital fechado, controlados e geridos por um pequeno grupo de acionistas, em que a sinalização direcionada a acionistas é implausível, permite inferir que bancos que utilizam mais fundos de investidores sensíveis a informações (institucionais) pagam mais dividendos, controlando por diversas características. Durante a crise financeira, este comportamento foi ainda mais pronunciado. Esta relação reforça o papel dos dividendos como uma forma custosa e crível de comunicar sobre a qualidade dos ativos dos bancos. A hipótese de que os dividendos podem ser utilizados como uma forma de expropriação dos depositantes por parte dos acionistas é refutada, uma vez que, se fosse esse o caso, observar-se-ia esse maiores dividendos em bancos com depositantes menos sensíveis a informação. Além disso, foi verificada uma relação negativa entre o pagamento de dividendos e o custo de captação (juros pagos em certificados de depósito bancário) e uma relação positiva de dividendos com o tamanho e com os lucros passados, e que os bancos de capital fechado pagam mais dividendos do que os de capital aberto, uma descoberta que também se alinha com a ideia de que os depositantes seriam os alvos da sinalização por dividendos. Finalmente, encontrou-se também uma relação negativa entre dividendos e adequação de capital do bancos, o que indica que pressões regulatórias podem induzir os bancos a pagar menos dividendos e que o pagamento de dividendos é negativamente relacionado com o crescimento da carteira de crédito, o que é consistente com a ideia de que os bancos com maiores oportunidades de investimento retêm seus lucros para aumentar seu patrimônio líquido e sua capacidade de conceder crédito.

Expression of genes related to apoptosis, cell cycle and signaling pathways are independent of TP53 status in urinary bladder cancer cells

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Remarks on Bessel beams, signals and superluminality

We address the question about the velocity of signals carried by Bessel beams wave packets propagating in vacuum and having well defined wavefronts in time. We find that this problem in analogous to that of propagation of usual plane wave packets within dispersive media and conclude that the signal velocity cannot be superluminal. (C) 2001 Elsevier B.V. B.V. All rights reserved.

Ultrasonic sensor signals and optimum path forest classifier for the microstructural characterization of thermally-aged inconel 625 alloy

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Role of BDNF secretion and signaling in the activity-dependent refinement of synaptic connections

Neuronal networks exhibit diverse types of plasticity, including the activity-dependent regulation of synaptic functions and refinement of synaptic connections. In addition, continuous generation of new neurons in the “adult” brain (adult neurogenesis) represents a powerful form of structural plasticity establishing new connections and possibly implementing pre-existing neuronal circuits (Kempermann et al, 2000; Ming and Song, 2005). Neurotrophins, a family of neuronal growth factors, are crucially involved in the modulation of activity-dependent neuronal plasticity. The first evidence for the physiological importance of this role evolved from the observations that the local administration of neurotrophins has dramatic effects on the activity-dependent refinement of synaptic connections in the visual cortex (McAllister et al, 1999; Berardi et al, 2000; Thoenen, 1995). Moreover, the local availability of critical amounts of neurotrophins appears to be relevant for the ability of hippocampal neurons to undergo long-term potentiation (LTP) of the synaptic transmission (Lu, 2004; Aicardi et al, 2004). To achieve a comprehensive understanding of the modulatory role of neurotrophins in integrated neuronal systems, informations on the mechanisms about local neurotrophins synthesis and secretion as well as ditribution of their cognate receptors are of crucial importance. In the first part of this doctoral thesis I have used electrophysiological approaches and real-time imaging tecniques to investigate additional features about the regulation of neurotrophins secretion, namely the capability of the neurotrophin brain-derived neurotrophic factor (BDNF) to undergo synaptic recycling. In cortical and hippocampal slices as well as in dissociated cell cultures, neuronal activity rapidly enhances the neuronal expression and secretion of BDNF which is subsequently taken up by neurons themselves but also by perineuronal astrocytes, through the selective activation of BDNF receptors. Moreover, internalized BDNF becomes part of the releasable source of the neurotrophin, which is promptly recruited for activity-dependent recycling. Thus, we described for the first time that neurons and astrocytes contain an endocytic compartment competent for BDNF recycling, suggesting a specialized form of bidirectional communication between neurons and glia. The mechanism of BDNF recycling is reminiscent of that for neurotransmitters and identifies BDNF as a new modulator implicated in neuro- and glio-transmission. In the second part of this doctoral thesis I addressed the role of BDNF signaling in adult hippocampal neurogenesis. I have generated a transgenic mouse model to specifically investigate the influence of BDNF signaling on the generation, differentiation, survival and connectivity of newborn neurons into the adult hippocampal network. I demonstrated that the survival of newborn neurons critically depends on the activation of the BDNF receptor TrkB. The TrkB-dependent decision regarding life or death in these newborn neurons takes place right at the transition point of their morphological and functional maturation Before newborn neurons start to die, they exhibit a drastic reduction in dendritic complexity and spine density compared to wild-type newborn neurons, indicating that this receptor is required for the connectivity of newborn neurons. Both the failure to become integrated and subsequent dying lead to impaired LTP. Finally, mice lacking a functional TrkB in the restricted population of newborn neurons show behavioral deficits, namely increased anxiety-like behavior. These data suggest that the integration and establishment of proper connections by newly generated neurons into the pre-existing network are relevant features for regulating the emotional state of the animal.