Molecular characterization of signalling complexes involved in G-protein coupled receptor-induced cardiac hypertrophy

In response to pathological stresses, the heart undergoes a remodelling process associated with cardiac hypertrophy. Since sustained hypertrophy can progress to heart failure, there is an intense investigation about the intracellular signalling pathways that control cardiomyocyte growth. Accumulating evidence has demonstrated that most stimuli known to initiate pathological changes associated with the development of cardiac hypertrophy activate G protein-coupled receptors (GPCRs) including the αl-adrenergic- (αl-AR), Angiotensin II- (AT-R) and endothelin-1- (ET-R) receptors. In this context, we have previously identified a cardiac scaffolding protein, called AKAP-Lbc (Α-kinase anchoring protein), with an intrinsic Rho specific guanine nucleotide exchange factor activity, that plays a key role in integrating and transducing hypertrophic signals initiated by these GPCRs (Appert-Collin, Cotecchia et al. 2007). Activated RhoA controls the transcriptional activation of genes involved in cardiomyocyte hypertrophy through signalling pathways that remain to be characterized. Here, we identified the nuclear factor-Kappa Β (NF-κΒ) activating kinase ΙΚΚβ as a novel AKAP-Lbc interacting protein. This raises the hypothesis that AKAP-Lbc might promote cardiomyocyte growth by maintaining a signalling complex that promotes the activation of the pro-hypertrophic transcription factor NF-κΒ. In fact, the activation of NF- κΒ-dependent transcription has been detected in numerous disease contexts, including hypertrophy, ischemia/reperfusion injury, myocardial infarction, allograft rejection, myocarditis, apoptosis, and more (Hall, Hasday et al. 2006). While it is known by more than a decade that NF-κΒ is a critical mediator of cardiac hypertrophy, it is currently poorly understood how pro-hypertrophic signals controlling NF-κΒ transcriptional activity are integrated and coordinated within cardiomyocytes. In this study, we show that AKAP-Lbc and ΙΚΚβ form a transduction complex in cardiomyocytes that couples activation of αl-ARs to NF-κB-mediated transcriptional reprogramming events associated with cardiomyocyte hypertrophy. In particular, we can show that activation of ΙΚΚβ within the AKAP-Lbc complex promotes NF-κB-dependent production of interleukine-6 (IL-6), which, in turn, enhances foetal gene expression. These findings indicate that the AKAP-Lbc/ΙΚΚβ complex is critical for selectively directing catecholamine signals to the induction of cardiomyocyte hypertrophy.

Blockade of both alpha1A- and alpha1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery.

Attenuation of early restenosis after percutaneous coronary intervention (PCI) is important for the successful treatment of coronary artery disease. Some clinical studies have shown that hypertension is a risk factor for early restenosis after PCI. These findings suggest that alpha(1)-adrenergic receptors (alpha(1)-ARs) may facilitate restenosis after PCI because of alpha(1)-AR's remarkable contribution to the onset of hypertension. In this study, we examined the neointimal formation after vascular injury in the femoral artery of alpha(1A)-knockout (alpha(1A)-KO), alpha(1B)-KO, alpha(1D)-KO, alpha(1A)-/alpha(1B)-AR double-KO (alpha(1AB)-KO), and wild-type mice to investigate the functional role of each alpha(1)-AR subtype in neointimal formation, which is known to promote restenosis. Neointimal formation 4 wk after wire injury was significantly (P < 0.05) smaller in alpha(1AB)-KO mice than in any other group of mice, while blood pressures were not altered in any of the groups of mice after wire injury compared with those before it. These results suggest that lack of both alpha(1A)- and alpha(1B)-ARs could be necessary to inhibit neointimal formation in the mouse femoral artery.

Paraula i poètiques del desig. Tres itineraris del subjecte líric postmodern: alteritat, identitat i escriptura al l’obra de Gabriel Ferrater, Maria-Mercé Marçal i Enric Casasses

La present investigació parteix de la urgència de revisar la poesia catalana contemporània des dels paràmetres de la teoria literària que abracen l’àmbit de la representació del desig. Sota aquest paraigües teòric i la seva estricta vinculació amb les noves formulacions del subjecte líric postmodern, he proposat un estudi comparatiu entre tres grans poètiques que han marcat, cada una d’elles en el seu context socioliterari, un punt d’inflexió: Gabriel Ferrater, Maria-Mercè Marçal i Enric Casasses. Més enllà de la ruptura moderna entre escriptura i exaltació d’una subjectivitat única i monolítica, he investigat i esclarit les variables retòriques (teoria literària ) i ontològiques (discursos filosòfics) que coparticipen en la instal•lació d’un subjecte líric i un quefer poètic postmoderns. Un nou posicionament de la veu lírica que transforma la identitat textural en un procés, en una recerca. Així és que l’alteritat amorosa s’evidencia com el centre de representació i experimentació dels límits del jo líric. A partir de les aproximacions teòriques sobre la representació del desig –que des del postestructuralisme han arribat, mitjançant la crítica literària feminista, fins als nostres dies -, he establert les coordenades metodològiques que justifiquen el triangle comparatiu i m’han permès mostrar com la poesia eròticoamorosa és epicentre de la poesia i la poètica dels tres autors. L’exègesi de les seves obres ha guiat la investigació cap a l’abordatge de les construccions dels “jo” lírics, tot prenent com a centre: a) l’escriptura, obertura cap a l’Altre, b) el subjecte de l’enunciació com a subjecte desitjant, c) les representacions de l’altre/a amorós, d) les retòriques del desig, e) la recerca del plaer textual, i f)moral i poètiques. L’objectiu final ha estat dibuixar un mapa de carreteres per guiar els itineraris de l’escriptura del desig en la nostra poesia i, palesar, a mode de síntesi i d’obertura, com l’obra d’Enric Casasses recull la retòrica de l’alteritat amorosa i funda, des d’ella, la necessitat de la paraula oral i l’acció poètiques.

Comparativa de dues eines de software pel desenvolupament de classificadors d'espectroscòpia de ressonància magnètica nuclear de tumors cerebrals humans

En aquest treball s’ha fet una avaluació comparativa dels resultats que es poden obtenir amb el software SpectraClassifier 1.0 (SC) desenvolupat al nostre grup de recerca, comparant‐lo amb l’SPSS, un programa estadístic informàtic estàndard, en un problema de classificació de tumors cerebrals humans amb dades d’espectroscopia de ressonància magnètica de protó (1H‐ERM). El interès d’aquesta avaluació comparativa radica en la documentació dels resultats obtinguts amb els dos sistemes quan en la correcció dels resultats obtinguts, així com ponderar la versatilitat i usabilitat dels dos paquets de software per a una aplicació concreta d’interès al treball del GABRMN. Per a aquest treball s’han utilitzat dades provinents de dos projecte europeus multicèntrics (INTERPRET i eTumour) en els quals vam participar. Les classes tumorals utilitzades (d’un total de 217 pacients) han sigut les majoritàries des del punt de vista epidemiològic: glioblastoma multiforme, metàstasi, astrocitomes de grau II, ligodendrogliomes de grau II, oligoastrocitomes de grau II i meningiomes de baix grau. Amb les dades d’aquests pacients s’han dissenyat classificadors basats en l’anàlisi discriminant lineal (LDA), s’han avaluat amb diferents mètodes matemàtics i s’han testat amb dades independents. Els resultats han estat satisfactoris, obtenint amb l’SC resultats més robusts amb dades independents respecte la classificació realitzada per l’SPSS.

Latin 15141

Contient : I Sophistica edita a magistro ; II Ciceronis rethorica ars de inventione (105) ; Ciceronis rethorica ad Herennium (142)

Sistema de informação em AIDS: limites e possibilidades

O artigo faz uma análise do atual Sistema de Informação (SI) em AIDS, apontando as dificuldades com que se defrontou ao buscar caracterizar o modo como ocorria e evoluía em 1995 a epidemia da AIDS na Administração Regional de Saúde de Pirituba-Perus (ARS-8) do município de São Paulo. São enumeradas algumas críticas que a Vigilância Epidemiológica e o SI vêm sofrendo nos últimos anos, tais como a centralização e a desagregação das informações; dados que contemplam aspectos eminentemente biológico e a utilização de formulários complexos. Estas questões somadas às dificuldades que se impuseram ao se buscar caracterizar a epidemia na região, revelou que o sistema, tal como se encontrava estruturado, dificultava a caracterização da epidemia e o acompanhamento sistemático pelos níveis locais de saúde. Chama-se a atenção para a necessidade de revisão da finalidade do SI em AIDS, da natureza e da qualidade dos dados coletados. Reitera-se a importância da integração dos diversos bancos de dados sócio-demográficos e do enfoque microlocalizado do Sl para o Distrito de Saúde.

Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models.

Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology. Recent Advances: Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. Critical Issues: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication. Future Directions: These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds. Antioxid. Redox Signal. 18, 1428-1443.

Tunable reporter signal production in feedback-uncoupled arsenic bioreporters.

Escherichia coli-based bioreporters for arsenic detection are typically based on the natural feedback loop that controls ars operon transcription. Feedback loops are known to show a wide range linear response to the detriment of the overall amplification of the incoming signal. While being a favourable feature in controlling arsenic detoxification for the cell, a feedback loop is not necessarily the most optimal for obtaining highest sensitivity and response in a designed cellular reporter for arsenic detection. Here we systematically explore the effects of uncoupling the topology of arsenic sensing circuitry on the developed reporter signal as a function of arsenite concentration input. A model was developed to describe relative ArsR and GFP levels in feedback and uncoupled circuitry, which was used to explore new ArsR-based synthetic circuits. The expression of arsR was then placed under the control of a series of constitutive promoters, which differed in promoter strength, and which could be further modulated by TetR repression. Expression of the reporter gene was maintained under the ArsR-controlled Pars promoter. ArsR expression in the systems was measured by using ArsR-mCherry fusion proteins. We find that stronger constitutive ArsR production decreases arsenite-dependent EGFP output from Pars and vice versa. This leads to a tunable series of arsenite-dependent EGFP outputs in a variety of systematically characterized circuitries. The higher expression levels and sensitivities of the response curves in the uncoupled circuits may be useful for improving field-test assays using arsenic bioreporters.