The dynamic mitochondria-nuclear redistribution of FKBP51 during the process of adipocyte differentiation is regulated by PKA

Los glucocorticoides tienen un papel central en la adipogénesis, por su unión al receptor RG cito-plasmático formando parte de un heterocomplejo también integrado por una inmunofilina (INM) de alto peso molecular, FKBP51 o FKBP52. Durante la diferenciación adipocítica los niveles de Hsp90, Hsp70 y p23 no se modifican, mientras la expresión de FKBP52 disminuye y la de FKBP51 aumenta progresivamente. FKBP51 sufre una dinámica redistribución mitocondria-núcleo al inicio del proceso de adipogénesis, concentrándose en la lámina nuclear coincidiendo temporalmente con su reorganización. A las 48 h la INM se concentra nuevamente en las mitocondrias. Esta dinámica redistribución mitocondria-núcleo es regulada por glucocorticoides principalmente, por la vía AMPc-PKA ya que la inhibición de PKA por PKI-miristoilado bloquea la traslocación de FKBP51 a núcleo inducida por 3-isobutil-1-metilxantina (IBMX). PKA-c se asocia con RG de manera ligando-dependiente potenciando su actividad transcripcional y ésta disminuye con IBMX, forskolina o dibutiril-AMPc que inducen la traslocación a núcleo de FKBP51 y, por lo tanto, PKA podría ejercer un papel dual en la regulación de dicho factor. En síntesis, la presencia de FKBP51 en el núcleo dependiente de la activación de PKA puede ser crítica para el control de RG y posiblemente para otros factores no pertenecientes a la familia de los receptores nucleares cuya función es regulada también por dicha vía de señalización, evento que tiene lugar en una etapa del proceso de diferenciación con alto nivel de remodelamiento de cromatina, pero donde la transcripción debe estar estrictamente controlada para la adquisición del fenotipo adipocítico.The dynamic mitochondria-nuclear redistribution of FKBP51 during the process of adipo- cyte differentiation is regulated by PKA. Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90-Hsp70 and a high molecular weight im- munophilin FKBP51 or FKBP52. We have found that FKBP51 level of expression progressively increases, FKBP52 decreases, whereas Hsp90, Hsp70, and p23 remain unchanged when 3T3-L1 preadipocytes differentiate. Interest- ingly, FKBP51 translocates from mitochondria to the nucleus at the onset of adipogenesis. FKBP51 transiently concentrates in the nuclear lamina, at a time that this nuclear compartment undergoes its reorganization. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. We found that the dynamic FKBP51 mitochondrial-nuclear shuttling is regulated by glucocorticoids and mainly on cAMP-PKA signaling since PKA inhibition by myristoilated-PKI, abrogated FKBP51 nuclear translocation induced by 3-isobutyl-1-methylxanthine (IBMX). It has been reported that PKA interacts with GR in a ligand dependent manner potentiating its transcrip- tional capacity. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutyryl-cAMP, compounds that induced nuclear translocation of FKBP51, therefore PKA may exert a dual role in the control of GR. In summary, the presence of FKBP51 in the nucleus may be critical for GR transcriptional control, and possibly for the control of other transcription factors that are not members of the nuclear receptor family but are regulated by PKA signaling pathway, when transcription has to be strictly controlled to succeed in the acquisition of the adipocyte phenotype.Fil: Toneatto, Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Charó, Nancy Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Susperreguy, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Piwien Pilipuk, Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Dynamic mitochondrial–nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation

Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90•Hsp70 and one high molecular weight immunophilin FKBP51 or FKBP52. When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 expression progressively increases, whereas FKBP52 decreases, and Hsp90, Hsp70, p23 and Cyp40 remain unchanged. Interestingly, FKBP51 rapidly translocates from mitochondria to the nucleus where it is retained upon its interaction with chromatin and the nuclear matrix. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. Importantly, this dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, since its inhibition by PKI or knock-down of PKA-cα by siRNA, abrogated FKBP51 nuclear translocation induced by IBMX. In addition, FKBP51 electrophoretic pattern of migration is altered by treatment of cells with PKI or knock-down of PKA-cα suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 co-localizes with PKA-cα in mitochondria. When adipogenesis is triggered, PKA-cα also moves to the nucleus co-localizing with FKBP51 mainly in the nuclear lamina. Moreover, FKBP51 and GR interaction increases when preadipocytes are induced to differentiate. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutiryl-cAMP, compounds that induced FKBP51 nuclear translocation, but not by an specific activator of EPAC. FKBP51 knock-down facilitates while ectopic expression of FKBP51 blocks adipogenesis. These findings indicate that the dynamic mitochondrial-nuclear shuttling of FKBP51 regulated by PKA may be key in fine tuning the transcriptional control of GR-target genes required for the acquisition of adipocyte phenotype.Fil: Toneatto, Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Guber, Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Charó, Nancy Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Susperreguy, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Schwartz, Jessica. University Of Michigan; Estados UnidosFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Piwien Pilipuk, Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

Severely Dependent Alcohol Abusers May Be Vulnerable To Alcohol Cues in Television Programs

The self-reported ability of 96 alcohol abusers to resist the urge to drink heavily was assessed after they viewed a videotape of a popular prime time television program complete with advertisements. Different versions of the videotape were used to evaluate the effects of a television program with and without alcohol scenes as crossed with the effects of three different types of commercials (i.e., beer, nonalcoholic beverages, food). Before and after viewing the videotape, subjects, who were led to believe that they were participating in two separate and unrelated sets of experimental procedures, completed several drinking questionnaires. Responses to one of the questionnaires provided an unobtrusive measure of self-reported ability to resist the urge to drink heavily. Results indicated that alcohol cues in a television program affected some alcohol abusers\u27 perceived ability to resist the urge to drink heavily. In particular, those with higher alcohol dependence scores showed a decrease in confidence after viewing a television program with alcohol cues compared to subjects who watched the same program but without the alcohol scenes. The clinical implications of these findings are discussed. Until further research is forthcoming, given the artificial nature of the study setting, the results of this study must be viewed with some caution

Oxidative Stress and Antimicrobial Activity of Chromium(III) and Ruthenium(II) Complexes on Staphylococcus aureus and Escherichia coli

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. The main aim of this work was to establish the potential of the synthetic alfa-diimine chromium(III) and Ruthenium(II) complexes (where the alfa-diimine ligands are bpy = 2,2-bipyridine; phen = 1,10-phenanthroline and dppz = dipyrido[3,2-a:2´,3´-c]-phenazine) like [Cr(phen)3]3+, [Cr(phen)2(dppz)]3+, [Ru(phen)3]2+ and [Ru(bpy)3]2+ as antibacterial agents by generating oxidative stress. The [Cr(phen)3]3+ and [Cr(phen)2(dppz)]3+ complexes showed activity against Gram positive and Gram negative bacteria with minimum inhibitory concentrations (MICs) ranging from 0.125 µg/mL to 1 µg/mL, while [Ru(phen)3]2+ and [Ru(bpy)3]2+ does not exhibit antimicrobial activity against the two bacterial genera studied at the concentration range used. When ciprofloxacin was combined with [Cr(phen)3]3+ for the inhibition of Staphylococcus aureus and Escherichia coli, an important synergistic effect was observed, FIC 0.066 for S. aureus and FIC 0.064 for E. coli. The work described here shows that chromium(III) complexes are bactericidal for S. aureus and E. coli. Our results indicate that alfa-diimine chromium(III) complexes may be interesting to open new paths for metallodrug chemotherapy against different bacterial genera since some of these complexes have been found to exhibit remarkable antibacterial activities.Fil: Paez, Paulina Laura. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas. Departamento de Farmacia; ArgentinaFil: Bazán, Claudia Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones En Fisico- Química de Córdoba. Universidad Nacional de Córdoba. Facultad de Cs.químicas. Instituto de Investigaciones En Fisico- Química de Córdoba; ArgentinaFil: Bongiovanni, Maria Eugenia. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas. Departamento de Farmacia; ArgentinaFil: Toneatto, Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones En Fisico- Química de Córdoba. Universidad Nacional de Córdoba. Facultad de Cs.químicas. Instituto de Investigaciones En Fisico- Química de Córdoba; ArgentinaFil: Albesa, Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Becerra, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Argüello, Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones En Fisico- Química de Córdoba. Universidad Nacional de Córdoba. Facultad de Cs.químicas. Instituto de Investigaciones En Fisico- Química de Córdoba; Argentin

Nicole Bériou – Cécile Caby (éd.), Moines et religieux dans la ville (xiie-xve siècles)

Le colloque de Fanjeaux de 2008 consacré à l’histoire des Moines et religieux dans la ville a réuni un nombre important de spécialistes des ordres religieux, des chanoines et des moines, ainsi que des spécialistes de l’histoire urbaine du Midi. Les régions du Midi ont connu un développement urbain très marqué à partir du xiie siècle et la présence des chanoines, des ordres militaires et mendiants a toujours été très forte, en particulier en Provence et en Languedoc. Jacques Le Goff s’intéress..

Nicole Bériou – Cécile Caby (éd.), Moines et religieux dans la ville (xiie-xve siècles)

Le colloque de Fanjeaux de 2008 consacré à l’histoire des Moines et religieux dans la ville a réuni un nombre important de spécialistes des ordres religieux, des chanoines et des moines, ainsi que des spécialistes de l’histoire urbaine du Midi. Les régions du Midi ont connu un développement urbain très marqué à partir du xiie siècle et la présence des chanoines, des ordres militaires et mendiants a toujours été très forte, en particulier en Provence et en Languedoc. Jacques Le Goff s’intéress..

La richesse des Franciscains. Autour du débat sur les rapports entre économie et religion au Moyen Âge

La littérature historique sur les positions de l’Église vis-à-vis des échanges matériels et de la richesse rencontre souvent l’opinion commune selon laquelle la doctrine morale chrétienne aurait condamné la richesse matérielle et se serait opposée purement et simplement à l’enrichissement et au négoce. De la prédication patristique à la littérature théologique et à l’exégèse médiévale, les sources ecclésiastiques semblent sanctionner inlassablement le profit et la volonté d’acquérir les biens..

A comparison of online versus offline gambling harm in Portuguese pathological gamblers: an empirical study

Over the past decade, gambling has become a very popular activity across Europe including the growth of Internet gambling. Portugal is one of the few European countries where little research has been carried out. Given the lack of studies, a Portuguese sample (N = 1,599) was surveyed concerning their online and offline gambling habits. More specifically, the aim of this study was to identify and compare from the total sample, online pathological gamblers (PGON) (n = 171) and offline pathological gamblers' (PGOF) (n = 171) characteristics, and eventual risk factors for the development of problem gambling. Results demonstrated that PGON had different profiles compared to PGOF, although there were also similarities. Situational characteristics were much more significant for PGON than PGOF (e.g., availability, accessibility, affordability), but PGOF had higher scores than PGON on factors concerning individual characteristics (e.g., intensity of feelings while gambling, depression, suicidal ideation, etc.). Findings also showed differences concerning attitudes toward responsible gambling measures. The fact that situational characteristics are more attractive to online gamblers confirms differences between PGON and PGOF and suggests that this preferred attractiveness may enhance problem gambling potential. Further research is needed to better understand the interaction between Internet situational characteristics and the individual characteristics of gamblers, as well as the profile of the growing population of gamblers that uses both online and offline modes to gamble

Il Porto franco di Trieste ed il suo ruolo nel commercio internazionale

La seguente ricerca analizza del dettaglio il funzionamento del Porto franco di Trieste e, più in generale, il ruolo giocato dallo scalo giuliano nel commercio internazionale e nella global value chain. La ricerca si articola su cinque capitoli. Nel primo capitolo è analizzato nel dettaglio il ruolo economico e logistico di Trieste nel quadro del commercio internazionale, con particolare riferimento al suo inserimento nella rete transeuropea dei trasporti TEN-T e nella Nuova via della seta, anche alla luce degli sviluppi recenti nelle relazioni sino-occidentali. Nel secondo capitolo è fornita una panoramica dell'istituto della zona franca e del porto franco, dalle sue origini nell'antichità sino alle sue più recenti evoluzioni connesse alla globalizzazione ed all'internazionalizzazione delle filiere produttive. Il terzo capitolo illustra i principali istituti del diritto doganale comunitario per l'importazione di merci nel mercato unico, approfondendo in particolare i regimi doganali speciali e la normativa nazionale in materia di contrabbando ed illeciti doganali. Il quarto capitolo espone la genesi storica del Porto franco triestino, dalla sua istituzione tramite la Patente di Carlo VI sino agli sviluppi del secondo dopoguerra, inquadrandola entro una breve trattazione sulla centralità di Trieste nelle relazioni internazionali fra Italia, Austria-Ungheria e Jugoslavia. Il quinto capitolo, infine, scandaglia dettagliatamente la natura giuridica del Porto franco ed i suoi istituti più caratteristici - quali la non onerosità od il credito doganale triestino - letti alla luce di quanto illustrato nei capitoli precedenti.This research assesses in depth the functioning of the Free Port of Trieste and, more in general, the role played by the city in international trade and in the global value chain. The treatise is structured on five chapters. In the first chapter, the economic and logistic role of Trieste in international trade is thoroughly analysed, with particular emphasis on its place within the Trans-European Network of Transports (TEN-T) and the New Silk Road, also in light of the recent developments in Sino-Western relations. In the second chapter, an overview of free zones and free ports is provided, since their origin in the Antiquities until their most recent evolutions related to the spread of globalisation and the internationalisation of supply chains. The third chapter summarises the main elements of EU customs law for the importation of goods in the common market, deepening in particular the special procedures and the Italian national regulation on smuggling and customs offences. The fourth chapter expounds on the historical genesis of the Free Port of Trieste, since its inception with the Patent of Charles VI until the developments of the post-war period, framing it within a short dissertation on the centrality of the city in the international relations amongst Italy, Austria-Hungary, and Jugoslavia. The fifth chapter, finally, explores in detail the legal nature of the Free Port and of the idiosyncratic elements thereof - such as the principle of freedom from charges or the local special customs credit - all seen in light of the content of the previous chapters

Impact of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults. Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination. Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively. Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented