Browsing by Author "Jimenez, Lucia"
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- Confirmatory factor analysis of the antisocial process screening device: self-report among incarcerated male juvenile offendersPublication . Pechorro, Pedro; Hidalgo, Victoria; Nunes, Cristina; Jimenez, LuciaThe main aim of the present study was to examine the factor structure, internal consistency, and some additional psychometric properties of the Antisocial Process Screening Device-Self-Report (APSD-SR) among a large forensic sample of incarcerated male juvenile offenders (N = 438). The results, based on this forensic sample, support the use of the APSD-SR in terms of its factor structure, and internal consistency despite the fact an item had to be removed from the callous-unemotional (CU) dimension. Statistically significant positive associations were found with measures of psychopathic traits, CU traits, narcissism, and aggression, as well as negative associations with a measure of empathy. Findings provide support for the use of the APSD-SR among the incarcerated male juvenile offender population.
- mTORC2 Is the major second layer kinase negatively regulating FOXO3 activityPublication . Jimenez, Lucia; Amenabar, Carlos; Mayoral-Varo, Victor; Mackenzie, Thomas A.; Ramos, Maria C.; Silva, Andreia; Calissi, Giampaolo; Grenho, Inês; Blanco-Aparicio, Carmen; Pastor, Joaquin; Megías, Diego; Ferreira, Bibiana; Link, WolfgangForkhead box O (FOXO) proteins are transcription factors involved in cancer and aging and their pharmacological manipulation could be beneficial for the treatment of cancer and healthy aging. FOXO proteins are mainly regulated by post-translational modifications including phosphorylation, acetylation and ubiquitination. As these modifications are reversible, activation and inactivation of FOXO factors is attainable through pharmacological treatment. One major regulatory input of FOXO signaling is mediated by protein kinases. Here, we use specific inhibitors against different kinases including PI3K, mTOR, MEK and ALK, and other receptor tyrosine kinases (RTKs) to determine their effect on FOXO3 activity. While we show that inhibition of PI3K efficiently drives FOXO3 into the cell nucleus, the dual PI3K/mTOR inhibitors dactolisib and PI-103 induce nuclear FOXO translocation more potently than the PI3Kδ inhibitor idelalisib. Furthermore, specific inhibition of mTOR kinase activity affecting both mTORC1 and mTORC2 potently induced nuclear translocation of FOXO3, while rapamycin, which specifically inhibits the mTORC1, failed to affect FOXO3. Interestingly, inhibition of the MAPK pathway had no effect on the localization of FOXO3 and upstream RTK inhibition only weakly induced nuclear FOXO3. We also measured the effect of the test compounds on the phosphorylation status of AKT, FOXO3 and ERK, on FOXO-dependent transcriptional activity and on the subcellular localization of other FOXO isoforms. We conclude that mTORC2 is the most important second layer kinase negatively regulating FOXO activity.
- Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear exportPublication . Jimenez, Lucia; Mayoral‐Varo, Victor; Amenábar, Carlos; Ortega, Judit; Sequeira, João G. N.; Machuqueiro, Miguel; Mourato, Cristiana; Silvestri, Romano; Angeli, Andrea; Carta, Fabrizio; Supuran, Claudiu T.; Megías, Diego; Ferreira, Bibiana; Link, WolfgangChromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin-1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose-limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein-labeled HIV-1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1-mediated export, can be followed by co-culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110 alpha, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110 alpha partially relies on CRM1-dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1-independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor.
- Prácticas parentales y calidad de vida en adolescentes holandeses y portugueses: un estudio transculturalPublication . Nunes, Cristina; Bodden, Denise; Lemos, Ida; Lorence, Barbara; Jimenez, LuciaThe aim of this study was to examine differences in Quality of life (QoL) and parenting practices, as well as the impact of parenting practices on QoL in Dutch and Portuguese adolescents. A total of 168 Portuguese (44.64% girls, 55.36% boys) and 155 Dutch adolescents (55.68% girls, 44.32% boys) aged 12-17 years old (M = 14.44, SD = 1.65) completed questionnaires about QoL (Kidscreen-27), several dimensions of parental parenting practices, and socio-demographic information. No significant differences were found between countries on general QoL. On the subscale for school environment, scores were higher for Dutch adolescents. Portuguese adolescents reported that their mothers showed more positive parenting, psychological control and behavioral control than did Dutch adolescents. Dutch fathers showed more responsiveness and harsh discipline, whereas Portuguese fathers showed more psychological control. Parenting practices seem to be culturally dependant. Parenting practices, especially positive parenting and behavioral control, influenced adolescents' QoL regardless of nationality.
- Psychometric properties of an adapted version of the parental sense of competence (PSOC) scale for Portuguese at-risk parentsPublication . Nunes, Cristina; Jimenez, Lucia; Menendez, Susana; Ayala-Nunes, Lara; Hidalgo, VictoriaParental sense of competence is one of the central dimensions targeted on psychosocial interventions aimed at supporting at-risk families. Researchers and practitioners need reliable instruments to assess the parental role adapted for these families. Although the parental sense of competence (PSOC) scale has been frequently used to assess this construct, there is still no adapted version for Portuguese parents. In this study, the reliability, validity and factor structure of the PSOC scale is examined with a clinical sample of 146 mothers from at-risk families receiving psychosocial interventions for family preservation from Child Protective Services. Results show that the Portuguese version of the PSOC measures three distinct constructs with acceptable psychometric properties: efficacy, dissatisfaction and controllability. As expected, the obtained factors were significantly and positively related to parenting alliance and family cohesion, and negatively associated with parenting stress. In sum, the proposed Portuguese version shows reliability and validity evidences to measure three relevant dimensions of parental self-evaluation, and it constitutes a cost- and time-effective instrument suited for at-risk mothers.
- Screening health-promoting compounds for their capacity to induce the activity of FOXO3Publication . Jimenez, Lucia; Silva, Andreia; Calissi, Giampaolo; Grenho, Inês; Monteiro, Ana Rita; Mayoral-Varo, Victor; Blanco-Aparicio, Carmen; Pastor, Joaquin; Bustos, Victor; Bracher, Franz; Megías, Diego; Ferreira, Bibiana; Link, WolfgangSeveral chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived beta-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).