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Pereira V.H.,University of Minho | Pereira V.H.,ICVS 3BsPT Government Associate Laboratory | Campos I.,University of Minho | Campos I.,ICVS 3BsPT Government Associate Laboratory | And 3 more authors.
Current Opinion in Behavioral Sciences | Year: 2017

Chronic stress increases the risk of neuropsychiatric, cardiovascular and endocrine diseases. Interestingly, the susceptibility to stress among individuals is variable and only some experience stress-related diseases. The determinants of resilience (the concept of resistance to chronic stress) are still not well understood. Their knowledge may contribute to the development of strategies to tackle stress-related disorders from a preventive perspective. Recent evidences show that the autonomic nervous system may play a role in the susceptibility to stress and may be used as a marker of resilience. Departing from that point, this short review will provide a perspective of the role of the autonomic nervous system in the susceptibility to the stress response. © 2017 Elsevier Ltd


Sampaio-Marques B.,University of Minho | Sampaio-Marques B.,Icvs 3Bspt Government Associate Laboratory | Ludovico P.,University of Minho | Ludovico P.,Icvs 3Bspt Government Associate Laboratory
Biomolecules | Year: 2015

Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. α-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for α-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins’s role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from α-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of α-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies. © 2015 by the authors; licensee MDPI, Basel, Switzerland.


Silva-Gomes R.,University of Minho | Silva-Gomes R.,Icvs 3Bspt Government Associate Laboratory | Marcq E.,University of Minho | Marcq E.,Icvs 3Bspt Government Associate Laboratory | And 16 more authors.
PLoS Neglected Tropical Diseases | Year: 2015

Buruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans infection. BU is characterized by a wide range of clinical forms, including non-ulcerative cutaneous lesions that can evolve into severe ulcers if left untreated. Nevertheless, spontaneous healing has been reported to occur, although knowledge on this process is scarce both in naturally infected humans and experimental models of infection. Animal models are useful since they mimic different spectrums of human BU disease and have the potential to elucidate the pathogenic/protective pathway(s) involved in disease/healing. In this time-lapsed study, we characterized the guinea pig, an animal model of resistance to M. ulcerans, focusing on the macroscopic, microbiological and histological evolution throughout the entire experimental infectious process. Subcutaneous infection of guinea pigs with a virulent strain of M. ulcerans led to early localized swelling, which evolved into small well defined ulcers. These macroscopic observations correlated with the presence of necrosis, acute inflammatory infiltrate and an abundant bacterial load. By the end of the infectious process when ulcerative lesions healed, M. ulcerans viability decreased and the subcutaneous tissue organization returned to its normal state after a process of continuous healing characterized by tissue granulation and reepethelialization. In conclusion, we show that the experimental M. ulcerans infection of the guinea pig mimics the process of spontaneous healing described in BU patients, displaying the potential to uncover correlates of protection against BU, which can ultimately contribute to the development of new prophylactic and therapeutic strategies. © 2015 Silva-Gomes et al.


Pertega-Gomes N.,University of Minho | Pertega-Gomes N.,Icvs 3Bspt Government Associate Laboratory | Baltazar F.,University of Minho | Baltazar F.,Icvs 3Bspt Government Associate Laboratory
International Journal of Molecular Sciences | Year: 2014

Metabolic changes during malignant transformation have been noted for many years in tumours. Otto Warburg first reported that cancer cells preferentially rely on glycolysis for energy production, even in the presence of oxygen, leading to the production of high levels of lactate. The crucial role of lactate efflux and exchange within the tumour microenvironment drew attention to monocarboxylate transporters (MCTs). MCTs have been recognized as promising targets in cancer therapy, and their expression was described in a large variety of tumours; however, studies showing how these isoforms contribute to the acquisition of the malignant phenotype are scarce and still unclear regarding prostate cancer. In this review, we focus on the role for MCTs in cell metabolism, supporting the development and progression of prostate cancer, and discuss the exploitation of the metabolic nature of prostate cancer for therapeutic and diagnostic purposes. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Bessa J.M.,University of Minho | Bessa J.M.,ICVS 3BsPT Government Associate Laboratory | Morais M.,University of Minho | Morais M.,ICVS 3BsPT Government Associate Laboratory | And 9 more authors.
Translational Psychiatry | Year: 2013

There is accumulating evidence that the nucleus accumbens (NAc) has an important role in the pathophysiology of depression. As the NAc is a key component in the neural circuitry of reward, it has been hypothesized that anhedonia, a core symptom of depression, might be related to dysfunction of this brain region. Neuronal morphology and expression of plasticity-related molecules were examined in the NAc of rats displaying anhedonic behavior (measured in the sucrose-consumption test) in response to chronic mild stress. To demonstrate the relevance of our measurements to depression, we tested whether the observed changes were sensitive to reversal with antidepressants (imipramine and fluoxetine). Data show that animals displaying anhedonic behavior display an hypertrophy of medium spiny neurons in the NAc and, in parallel, have increased expression of the genes encoding for brain-derived neurotrophic factor, neural cell adhesion molecule and synaptic protein synapsin 1. Importantly, the reversal of stress-induced anhedonia by antidepressants is linked to a restoration of geneexpression patterns and dendritic morphology in the NAc. Using an animal model of depression, we show that stress induces anhedonic behavior that is associated with specific changes in the neuronal morphology and in the gene-expression profile of the NAc that are effectively reversed after treatment with antidepressants. © 2013 Macmillan Publishers Limited All rights reserved.


Chatterjee A.,University of Texas Medical Branch | Saha S.,University of Texas Medical Branch | Chakraborty A.,University of Texas Medical Branch | Silva-Fernandes A.,University of Minho | And 20 more authors.
PLoS Genetics | Year: 2015

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3’-P and 5’-OH, are processed by mammalian polynucleotide kinase 3’-phosphatase (PNKP), a bifunctional enzyme with 3’-phosphatase and 5’-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14–41 to 55–82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP’s 3’ phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3’-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients’ brain. Finally, long amplicon quantitative PCR analysis of human MJD patients’ brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD. © 2015, Public Library of Science. All Rights Reserved.


Carpenter S.M.,University of Massachusetts Medical School | Carpenter S.M.,Brigham And Womens Hospital | Nunes-Alves C.,University of Massachusetts Medical School | Nunes-Alves C.,University of Minho | And 5 more authors.
PLoS Pathogens | Year: 2016

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection. © 2016 Carpenter et al.


Freitas-Rosa M.,University of Minho | Goncalves S.,University of Minho | Antunes H.,Hepatology and Nutrition Unit of Braga s Hospital | Antunes H.,University of Minho | Antunes H.,Icvs 3Bspt Government Associate Laboratory
Eating and Weight Disorders | Year: 2016

Introduction: The purpose of this study was to examine the prevalence of non-suicidal self-injurious behaviours (NSSI) among healthy weight and overweight adolescents and to examine the role of age, gender, weight status, treatment condition for weight control, and psychological variables (psychopathological symptoms and emotional skills) in the prediction of NSSI. Methods: The study had a cross-sectional design, and participants (n = 370) were aged 14–19 years and were divided in three groups: 205 adolescents with normal weight, 82 adolescents from the community with overweight/obesity, and 83 adolescents with overweight/obesity and in outpatient treatment for weight control. Results: The prevalence of these behaviours in the overweight community group (25.6 %) and in the overweight clinical group (14.5 %) was similar to their healthy weight peers (19 %). Not attending an outpatient treatment for weight control, higher psychopathology and less ability to regulate emotions predict the presence of NSSI. Conclusion: Being overweight is not associated with NSSI, but psychosocial variables such as psychopathology, emotional deregulation and the absence of medical care predict these behaviours. © 2016, Springer International Publishing Switzerland.


Nunes-Alves C.,University of Massachusetts Medical School | Nunes-Alves C.,University of Minho | Nunes-Alves C.,Icvs 3Bspt Government Associate Laboratory | Booty M.G.,University of Massachusetts Medical School | And 18 more authors.
PLoS Pathogens | Year: 2015

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRβ bias. Using a retrogenic model of TB10.44-11-specific CD8+ T cells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-γ production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity. © 2015 Nunes-Alves et al.


Pereira H.,European Institute of Excellence on Tissue Engineering and Regenerative Medicine | Pereira H.,ICVS 3BsPT Government Associate Laboratory | Pereira H.,University of Minho | Pereira H.,Centro Hospitalar Povoa Of Varzim | And 9 more authors.
Arthroscopy - Journal of Arthroscopic and Related Surgery | Year: 2011

Purpose: The aim of this systematic review was to address tissue engineering and regenerative medicine (TERM) strategies applied to the meniscus, specifically (1) clinical applications, indications, results, and pitfalls and (2) the main trends in research assessed by evaluation of preclinical (in vivo) studies. Methods: Three independent reviewers performed a search on PubMed, from 2006 to March 31, 2011, using the term "meniscus" with all of the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were English languagewritten, original clinical research (Level of Evidence I to IV) and preclinical studies of TERM application in knee meniscal lesions. Reference lists and related articles on journal Web sites of selected articles were checked until prepublication for potential studies that could not be identified eventually by our original search. The modified Coleman Methodology score was used for study quality analysis of clinical trials. Results: The PubMed search identified 286 articles (a similar search from 2000 to 2005 identified 161 articles). NonEnglish-language articles (n = 9), Level V publications (n = 19), in vitro studies (n = 118), and 102 studies not related to the topic were excluded. One reference was identified outside of PubMed. Thirty-eight references that met the inclusion criteria were identified from the original search. On the basis of our prepublication search, 2 other references were included. A total of 9 clinical and 31 preclinical studies were selected for further analysis. Of the clinical trials, 1 was classified as Level I, 2 as Level II, and 6 as Level IV. Eight referred to acellular scaffold implantation for partial meniscal replacement, and one comprised fibrin clot application. The mean modified Coleman Methodology score was 48.0 (SD, 15.7). Of the preclinical studies, 11 original works reported on studies using large animal models whereas 20 research studies used small animals. In these studies the experimental design favored cell-seeded scaffolds or scaffolds enhanced with growth factors (GFs) in attempts to improve tissue healing, as opposed to the plain acellular scaffolds that were predominant in clinical trials. Injection of mesenchymal stem cells and gene therapy are also presented as alternative strategies. Conclusions: Partial meniscal substitution using acellular scaffolds in selected patients with irreparable loss of tissue may be a safe and promising procedure. However, there is only 1 randomized controlled study supporting its application, and globally, many methodologic issues of published trials limit further conclusions. We registered a different trend in preclinical trials, with most considering augmentation of scaffolds by cells and/or GFs, as opposed to the predominantly acellular approach in clinical trials. Different TERM approaches to enhance meniscal repair or regeneration are in preclinical analysis, such as the use of mesenchymal stem cells, gene therapy, and GFs alone or in combination, and thus could be considered in the design of subsequent trials. Level of Evidence: Level IV, systematic review of Level I to IV studies. © 2011 Arthroscopy Association of North America.

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