Extra-telomeric functions of telomerase in the pathogenesis of Epstein-Barr virus-driven B-cell malignancies and potential therapeutic implications

Abstract The Epstein-Barr virus (EBV) is a ubiquitous human \u3b3-herpesvirus causally linked to a broad spectrum of both lymphoid and epithelial malignancies. In order to maintain its persistence in host cells and promote tumorigenesis, EBV must restrict its lytic cycle, which would ultimately lead to cell death, selectively express latent viral proteins, and establish an unlimited proliferative potential. The latter step depends on the maintenance of telomere length provided by telomerase. The viral oncoprotein LMP-1 activates TERT, the catalytic component of telomerase. In addition to its canonical role in stabilizing telomeres, TERT may promote EBV-driven tumorigenesis through extra-telomeric functions. TERT contributes toward preserving EBV latency; in fact, through the NOTCH2/BATF pathway, TERT negatively affects the expression of BZLF1, the master regulator of the EBV lytic cycle. In contrast, TERT inhibition triggers a complete EBV lytic cycle, leading to the death of EBV-infected cells. Interestingly, short-term TERT inhibition causes cell cycle arrest and apoptosis, partly by inducing telomere-independent activation of the ATM/ATR/TP53 pathway. Importantly, TERT inhibition also sensitizes EBV-positive tumor cells to antiviral therapy and enhances the pro-apoptotic effects of chemotherapeutic agents. We provide here an overview on how the extra-telomeric functions of TERT contribute to EBV-driven tumorigenesis. We also discuss the potential therapeutic approach of TERT inhibition in EBV-driven malignancies

The hypothalamic-pituitary-adrenal axis in anxiety and panic

This review article focuses on the differential activation of the hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety and panic. The results of experimental studies that assayed adrenocorticotropic hormone, cortisol and prolactin show that real-life panic attacks as well as those induced by selective panicogenic agents, such as lactate and carbon dioxide, do not activate the HPA axis. Accordingly, experiments carried out in two animal models of panic, namely electrical stimulation of the dorsal periaqueductal gray matter of the rat and the escape from the open arm of the elevated T maze, have shown that in neither case stress hormones are increased in the plasma. Also in humans, reported results have shown that neither cortisol nor prolactin levels were increased following simulated public speaking, an experimental task that has been related to panic, in either healthy volunteers or patients with panic disorder diagnosis. Therefore, although the panic attack causes a major sympathetic stimulation, it has little effect on the HPA axis. In contrast, anticipatory or generalized anxiety activates both the HPA and the sympatho-adrenal axes.CNPqFMRPUSP - FAEPA - Hospital das Clínica

Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

open7siBesides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumorigenesis through extra-telomeric functions. The possible therapeutic effects of BIBR1532 (BIBR), a powerful TERT inhibitor, have been evaluated in different cellular backgrounds, but no data are currently available regarding Epstein-Barr virus (EBV)-driven B-cell malignancies. Our aim was to characterize the biological effects of TERT inhibition by BIBR on EBV-immortalized lymphoblastoid cell lines (LCLs) and fully transformed Burkitt's lymphoma (BL) cell lines. We found that BIBR selectively inhibits telomerase activity in TERT-positive 4134/Late and 4134/TERT+ LCLs and EBV-negative BL41 and EBV-positive BL41/B95.8 BL cell lines. TERT inhibition led to decreased cell proliferation, accumulation of cells in the S-phase and ultimately to increased apoptosis, compared with mock-treated control cells. All these effects occurred within 72 h and were not observed in BIBR-treated TERT-negative 4134/TERT- and U2OS cells. The cell cycle arrest and apoptosis, consequent upon short-term TERT inhibition, were associated with and likely dependent on the activation of the DNA damage response (DDR), highlighted by the increased levels of γH2AX and activation of ATM and ATR pathways. Analyses of the mean and range of telomere lengths and telomere dysfunction-induced foci indicated that DDR after short-term TERT inhibition was not related to telomere dysfunction, thus suggesting that TERT, besides stabilizing telomere, may protect DNA via telomere-independent mechanisms. Notably, TERT-positive LCLs treated with BIBR in combination with fludarabine or cyclophosphamide showed a significant increase in the number of apoptotic cells with respect to those treated with chemotherapeutic agents alone. In conclusion, TERT inhibition impairs cell cycle progression and enhances the pro-apoptotic effects of chemotherapeutic agents in TERT-positive cells. These results support new therapeutic applications of TERT inhibitors in EBV-driven B-cell malignancies.openCeleghin, Andrea; Giunco, Silvia; Freguja, Riccardo; Zangrossi, Manuela; Nalio, Silvia; Dolcetti, Riccardo; De Rossi, AnitaCeleghin, Andrea; Giunco, Silvia; Freguja, Riccardo; Zangrossi, Manuela; Nalio, Silvia; Dolcetti, Riccardo; DE ROSSI, Anit

Me, myself and you: How self-consciousness influences time perception

Several investigations have shown that the processing of self-relevant information differs from processing objective information. The present study aimed to investigate the effect of social stimuli on subjective time processing. Here, social stimuli are images of an unknown male and female person and an image of participants' self. Forty university students were tested with a time reproduction task in which they were asked to reproduce the duration of the stimulus previously presented. Images of others or themselves were used to mark the temporal intervals. Participants also performed questionnaires to evaluate the level of anxiety and depression as well as self-consciousness. A generalised linear mixed-effects model approach was adopted. Results showed that male participants with higher Private Self-Consciousness scores showed higher time perception accuracy than females. Also, female participants reported higher scores for the Public Self-Consciousness subscale than male participants. The findings are discussed in terms of social context models of how attention is solicited and arousal is generated by social stimuli, highlighting the effect of social context on subjective perception of time

Effects of reversible inactivation of the dorsomedial hypothalamus on panic- and anxiety-related responses in rats

The medial hypothalamus is part of a neurobiological substrate controlling defensive behavior. It has been shown that a hypothalamic nucleus, the dorsomedial hypothalamus (DMH), is involved in the regulation of escape, a defensive behavior related to panic attacks. The role played by the DMH in the organization of conditioned fear responses, however, is less clear. In the present study, we investigated the effects of reversible inactivation of the DMH with the GABA A agonist muscimol on inhibitory avoidance acquisition and escape expression by male Wistar rats (approximately 280 g in weight) tested in the elevated T-maze (ETM). In the ETM, inhibitory avoidance, a conditioned defensive response, has been associated with generalized anxiety disorder. Results showed that intra-DMH administration of the GABA A receptor agonist muscimol inhibited escape performance, suggesting an antipanic-like effect (P < 0.05), without changing inhibitory avoidance acquisition. Although a higher dose of muscimol (1.0 nmol/0.2 µL; N = 7) also altered locomotor activity in an open field when compared to control animals (0.2 µL saline; N = 13) (P < 0.05), the lower dose (0.5 nmol/0.2 µL; N = 12) of muscimol did not cause any motor impairment. These data corroborate previous evidence suggesting that the DMH is specifically involved in the modulation of escape. Dysfunction of this regulatory mechanism may be relevant in the genesis/maintenance of panic disorder

R&D of carbon nanotubes based nanocomposites for self-heating and de-icing applications

Icing is a problem that aerospace environment has to face. Ice accretion on aircraft surfaces can cause serious problems on flight safety, performances and efficiency. Several ice protection strategies have been developed to overcome the icing hazards in the aerospace industry. The electro-thermal method is one of the popular approaches to prevent ice accretion and accumulation on aircraft surfaces. Given the increasing requirement of composites on aircraft structures, metal frameworks/fibre reinforced composites have been developed as a de-icing solution for the new generation aircraft. Next-generation aircraft structures require increased strength and lightweight composite materials, which pushes a high interest in nanomaterial based composite. In this project it was proposed to fabricate self-heating nanocomposites from carbon nanotubes, as an effective de-icing approach in aerospace. Due to the natural advances of nanomaterials, the nanocomposite electro-thermal structures are also expected to offer enhanced mechanical properties. Carbon nanotubes have been used to fabricate carbon nanotube films (carbon nanotube buckypaper, CNP) that have been integrated into composite structures. The novelties of the project were the chemicals treatments used to improve the electrical conductivity of the carbon nanotubes buckypaper and the mechanical tests used to analyse the mechanical behaviour of the nanocomposites. Due to static and dynamic loads during the flight conditions, it is essential to understand the mechanical characteristics of the CNP-based composites. This work was focused, in accordance with the industrial partner, on improving the electrical characteristics of the nanocomposite without compromising the mechanical properties. Once the optimal electrical characteristics will be reach, the future work should be focused on improving the thermal properties of the nanocomposite to further increase the ice protection efficiency. The results showed that acid treatments of CNTs with nitric acid lead to an electrical conductivity improvement of CNT papers. The CNP showed promising electrical characteristics and heating performances for possible application in self-heating composites. Carbon nanotubes buckypapers embedded in fibre reinforced polymer composites have been fabricated by different processing approaches. Mechanical tests and the study of heating performance demonstrated that the CNP-based composite is a promising self-heating material candidate for ice protection of the aircraft surfaces

Cognitive reserve in dementia: Implications for cognitive training

open9noCognitive reserve (CR) is a potential mechanism to cope with brain damage. The aim of this study was to evaluate the effect of CR on a cognitive training (CT) in a group of patients with dementia. Eighty six participants with mild to moderate dementia were identified by their level of CR quantified by the CR Index questionnaire (CRIq) and underwent a cycle of CT. A global measure of cognition mini mental state examination (MMSE) was obtained before (T0) and after (T1) the training. Multiple linear regression analyses highlighted CR as a significant factor able to predict changes in cognitive performance after the CT. In particular, patients with lower CR benefited from a CT program more than those with high CR. These data show that CR can modulate the outcome of a CT program and that it should be considered as a predictive factor of neuropsychological rehabilitation training efficacy in people with dementia.openMondini, Sara; Madella, Ileana; Zangrossi, Andrea; Bigolin, Angela; Tomasi, Claudia; Michieletto, Marta; Villani, Daniele; Di Giovanni, Giuseppina; Mapelli, DanielaMondini, Sara; Madella, Ileana; Zangrossi, Andrea; Bigolin, Angela; Tomasi, Claudia; Michieletto, Marta; Villani, Daniele; Di Giovanni, Giuseppina; Mapelli, Daniel

Detecting cognitive states from the analysis of structural and functional images of the brain: two applications of Multi-Voxel Pattern Analysis on MRI and fMRI data

In recent years, the efficacy and accuracy of multivariate analysis techniques on neuroimaging data has been tested on different topics. These methods have shown the ability to decode mental states from the analysis of brain scans, for this reason it has been called “brain reading”. The predictions can be applied to general mental states, referring to stable conditions not related to a contingent task (e.g., a neurological diagnosis), or specific mental states, referring to task-related cognitive processes (e.g., the perception of a category of stimuli). According to several neuroscientists, brain reading approach can potentially be useful for applications in both clinical and forensic neuroscience in the future. In the present dissertation, two applications of the brain reading approach are presented on two relevant topics for clinical and forensic neuroscience that have not been extensively investigated with these methods. In Section A, this approach is tested on decoding different levels of Cognitive Reserve from the pattern of grey matter volume, in two MRI studies. In Section B two fMRI studies investigate the possibility of decoding real autobiographical memories from brain activity. The aim of this thesis is to contribute to the amount of studies showing the usefulness of multivariate techniques in decoding “mental states” starting from the analysis of structural and functional brain imaging data, as well as the potential uses in clinical and forensic settings

R&D of carbon nanotubes based nanocomposites for self-heating and de-icing applications

Icing is a problem that aerospace environment has to face. Ice accretion on aircraft surfaces can cause serious problems on flight safety, performances and efficiency. Several ice protection strategies have been developed to overcome the icing hazards in the aerospace industry. The electro-thermal method is one of the popular approaches to prevent ice accretion and accumulation on aircraft surfaces. Given the increasing requirement of composites on aircraft structures, metal frameworks/fibre reinforced composites have been developed as a de-icing solution for the new generation aircraft. Next-generation aircraft structures require increased strength and lightweight composite materials, which pushes a high interest in nanomaterial based composite. In this project it was proposed to fabricate self-heating nanocomposites from carbon nanotubes, as an effective de-icing approach in aerospace. Due to the natural advances of nanomaterials, the nanocomposite electro-thermal structures are also expected to offer enhanced mechanical properties. Carbon nanotubes have been used to fabricate carbon nanotube films (carbon nanotube buckypaper, CNP) that have been integrated into composite structures. The novelties of the project were the chemicals treatments used to improve the electrical conductivity of the carbon nanotubes buckypaper and the mechanical tests used to analyse the mechanical behaviour of the nanocomposites. Due to static and dynamic loads during the flight conditions, it is essential to understand the mechanical characteristics of the CNP-based composites. This work was focused, in accordance with the industrial partner, on improving the electrical characteristics of the nanocomposite without compromising the mechanical properties. Once the optimal electrical characteristics will be reach, the future work should be focused on improving the thermal properties of the nanocomposite to further increase the ice protection efficiency. The results showed that acid treatments of CNTs with nitric acid lead to an electrical conductivity improvement of CNT papers. The CNP showed promising electrical characteristics and heating performances for possible application in self-heating composites. Carbon nanotubes buckypapers embedded in fibre reinforced polymer composites have been fabricated by different processing approaches. Mechanical tests and the study of heating performance demonstrated that the CNP-based composite is a promising self-heating material candidate for ice protection of the aircraft surfaces

Perfil de los ingresantes a las carreras del Área de Ciencias de la Comunicación de la Facultad de Informática, Ciencias de la Comunicación y Técnicas Especiales de la Universidad de Morón : Representaciones, imaginarios y expectativas

La ponencia presenta un avance de la investigación que se lleva a cabo en la Facultad de Informática, Cs. de la comunicación y Técnicas Especiales de la Universidad de Morón durante el año 2018, cuyo objetivo es la elaboración de un perfil de los alumnos que ingresan a 3 carreras del área de Ciencias de la Comunicación de dicha Facultad: Licenciaturas en Publicidad, en Periodismo y en Diseño y Producción en Comunicación Multimedial. El Proyecto releva por un lado la información sociodemográfica, y por otro las representaciones, imaginarios, expectativas, trayectorias familiares y laborales, modalidades del consumo de medios y bienes culturales, de los ingresantes. A la fecha de presentación de la ponencia, el proyecto se encuentra en la etapa de análisis de los datos recolectados.Facultad de Humanidades y Ciencias de la Educació