Pompeu Fabra University

About: Pompeu Fabra University is a education organization based out in Barcelona, Spain. It is known for research contribution in the topics: Population & Context (language use). The organization has 8093 authors who have published 23570 publications receiving 858431 citations. The organization is also known as: Universitat Pompeu Fabra & UPF.

Nucleotide excision repair is impaired by binding of transcription factors to DNA

Abstract: Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

How Local Excitation-Inhibition Ratio Impacts the Whole Brain Dynamics

Abstract: The spontaneous activity of the brain shows different features at different scales. On one hand, neuroimaging studies show that long-range correlations are highly structured in spatiotemporal patterns, known as resting-state networks, on the other hand, neurophysiological reports show that short-range correlations between neighboring neurons are low, despite a large amount of shared presynaptic inputs. Different dynamical mechanisms of local decorrelation have been proposed, among which is feedback inhibition. Here, we investigated the effect of locally regulating the feedback inhibition on the global dynamics of a large-scale brain model, in which the long-range connections are given by diffusion imaging data of human subjects. We used simulations and analytical methods to show that locally constraining the feedback inhibition to compensate for the excess of long-range excitatory connectivity, to preserve the asynchronous state, crucially changes the characteristics of the emergent resting and evoked activity. First, it significantly improves the model's prediction of the empirical human functional connectivity. Second, relaxing this constraint leads to an unrealistic network evoked activity, with systematic coactivation of cortical areas which are components of the default-mode network, whereas regulation of feedback inhibition prevents this. Finally, information theoretic analysis shows that regulation of the local feedback inhibition increases both the entropy and the Fisher information of the network evoked responses. Hence, it enhances the information capacity and the discrimination accuracy of the global network. In conclusion, the local excitation-inhibition ratio impacts the structure of the spontaneous activity and the information transmission at the large-scale brain level.

Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway

Abstract: During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.

An international survey of chronic obstructive pulmonary disease in young adults according to GOLD stages

Abstract: Background: The recently published GOLD guidelines provide a new system for staging chronic obstructive pulmonary disease (COPD) from mild (stage I) to very severe (stage IV) and introduce a stage 0 (chronic cough and phlegm without airflow obstruction) that includes subjects “at risk” of developing the disease. Methods: In order to assess the prevalence of GOLD stages of COPD in high income countries and to evaluate their association with the known risk factors for airflow obstruction, data from the European Community Respiratory Health Survey on more than 18 000 young adults (20–44 years) were analysed. Results: The overall prevalence was 11.8% (95% CI 11.3 to 12.3) for stage 0, 2.5% (95% CI 2.2 to 2.7) for stage I, and 1.1% (95% CI 1.0 to 1.3) for stages II–III. Moderate to heavy smoking (⩾15 pack years) was significantly associated with both stage 0 (relative risk ratio (RRR) = 4.15; 95% CI 3.55 to 4.84) and stages I+ (RRR = 4.09; 95% CI 3.17 to 5.26), while subjects with stages I+ COPD had a higher likelihood of giving up smoking (RRR = 1.39; 95% CI 1.04 to 1.86) than those with GOLD stage 0 (RRR = 1.05; 95% CI 0.86 to 1.27). Environmental tobacco smoke had the same degree of positive association in both groups. Respiratory infections in childhood and low socioeconomic class were significantly and homogeneously associated with both groups, whereas occupational exposure was significantly associated only with stage 0. All the GOLD stages showed a significantly higher percentage of healthcare resource users than healthy subjects (p Conclusions: A considerable percentage of young adults already suffered from COPD. GOLD stage 0 was characterised by the presence of the same risk factors as COPD and by the same high demand for medical assistance.