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- Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targetsPublication . Miranda-Goncalves, Vera; Honavar, Mrinalini; Pinheiro, Celine; Martinho, Olga; Pires, Manuel M.; Pinheiro, Celia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Palmeirim, Isabel; Reis, Rui M.; Baltazar, FatimaBackground. Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD 147 and to assess the therapeutic impact of MCT inhibition in gliomas. Methods. MCTs and CD 147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models. Results. MCT1, MCT4, and CD 147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed. Conclusions. This is the most comprehensive study reporting the expression of MCTs and CD 147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment.
- Differential contribution of the guanylyl cyclase-cyclic GMP-protein kinase g pathway to the proliferation of neural stem cells stimulated by nitric oxidePublication . Carreira, Bruno P.; Morte, Maria Inêss; Lourenço, Ana Sofia; Santos, Ana Isabel; Inácio, Ângela; Ambrósio, António F.; Carvalho, Caetana M.; Araújo, InêsNitric oxide (NO) is an important inflammatory mediator involved in the initial boost in the proliferation of neural stem cells following brain injury. However, the mechanisms underlying the proliferative effect of NO are still unclear. The aim of this work was to investigate whether cyclic GMP (cGMP) and the cGMP-dependent kinase (PKG) are involved in the proliferative effect triggered by NO in neural stem cells. For this purpose, cultures of neural stem cells isolated from the mouse subventricular zone (SVZ) were used. We observed that long-term exposure to the NO donor (24 h), NOC-18, increased the proliferation of SVZ cells in a cGMP-dependent manner, since the guanylate cyclase inhibitor, ODQ, prevented cell proliferation. Similarly to NOC-18, the cGMP analogue, 8-Br-cGMP, also increased cell proliferation. Interestingly, shorter exposures to NO (6 h) increased cell proliferation in a cGMP-independent manner via the ERK/MAP kinase pathway. The selective inhibitor of PKG, KT5823, prevented the proliferative effect induced by NO at 24 h but not at 6 h. In conclusion, the proliferative effect of NO is initially mediated by the ERK/MAPK pathway, and at later stages by the GC/cGMP/PKG pathway. Thus, our work shows that NO induces neural stem cell proliferation by targeting these two pathways in a biphasic manner. Copyright (C) 2012 S. Karger AG, Basel
- Identification of Tsunami deposits and their impact on coastal zones : a study case of the Boca do Rio estuary (Algarve , Portugal)Publication . Font, Eric; Veiga-Pires, C.; Pozo, Manuel; Nave, Silvia; Costas, Susana; Muñoz, Francisco Ruiz; Abad, ManuelTsunamis are unforeseeable phenomena and therefore one of the most devastating natural disasters in terms of human and economic losses. Their impact on coastal and nearshore zones is substantial and need to be accurately evaluated to improve their prevention and management. In the last decades, numerous investigations focused on the identification of paleotsunamis in order to evaluate their frequency in the geological record. However, because storm- and tsunami-deposits are generated by similar depositional mechanisms, their discrimination using classic sedimentological methods is an elusive prospect. A promising approach is to couple classic geological criteria with geophysical and geochemical proxies to search for new benchmarks of tsunami deposits and to integrate them into a multi-disciplinary study. To test our method, we investigate the 1755 Lisbon tsunami deposit from the Boca do Rio estuary and other Tsunami-induced deposits from Algarve (Portugal). First results show that, Sr and Ca are enriched in the tsunami layer probably linked to the presence of shelled organism. Contrarily, others marine seawater indicators, such as Ba and Br, which are usually more concentrated in brackish than in fresh water, and heavy minerals, which are generally used as high energy event indicators, are depleted in the Tsunami deposit. Very low magnetic susceptibility values for the Tsunami deposit also indicate a dilution of iron oxides, reworked from the estuarine clays, within the huge volumes of quartz and carbonate (i.e. diamagnetic), issued from the abrasion of the littoral sandy dune and the surrounding carbonated cliffs. Diffusive Reflective Spectrophotometry analyses show changes in the siliclastic fraction on the sediments from above and below the tsunami layer. These apparent colour variations seem linked to the deposition of finer siliclastic particles after the tsunami, rather than to mineralogical composition. These data suggest that the high energy event affected the geomorphology of the estuary in such a way that it could induce a mis-interpretation of the geological record regarding local sea level changes and coastal evolution history.
- Kidney histological alterations and metallothionein and heat shock protein expression in Wistar rats after fungicide thiram exposurePublication . Paiva, F.; Fialho, L.; Rafael, A.; Silverio Cabrita, A.; Pereira, A. M. F.; Capela e Silva, F.The histological alterations and the expression of metallothionein (MTs) and heat shock protein (Hsp70) in the kidney of Wistar rats after thiram fungicide exposure were evaluated. Animals were distributed into three groups: standard diet group, standard diet + corn oil group and thiram group. Significant differences were found (P<0,05) in the evolution of body weight between rats in the thiram group and those in the control and corn oil groups, and no histological lesions were evident in the animals' kidneys. Differences were found among animals in the group exposed to thiram and the control and oil groups regarding histomorphometric characteristics of the renal corpuscle - except for the proportion in the area of Bowman's capsule: glomerulus area - and regarding the height of the epitelium in the distal tubules. In rats exposed to thiram, a positive moderate to strong immunoexpression was observed for MTs, in the cortical convulated tubules decreasing the cortex towards the medulla, and a strong immunoexpression for Hsp70 in the cortex and medulla areas, in the glomerulus and convulated tubules. The results suggest that thiram may have chronic toxicity in mammals affecting their growth, and that the expression of MTs and Hsp70, a probable cellular adaptive response to the oxidative stress caused by thiram, may be used as a biomarker of exposure to this chemical.
- CYP2C8 status of patients with malaria influences selection of Plasmodium falciparum pfmdr1 Alleles after Amodiaquine-Artesunate treatmentPublication . Cavaco, Isa; Martensson, Andreas; Froberg, Gabrielle; Msellem, Mwinyi; Bjorkman, Anders; Gil, José Pedro
- Quinine Treatment Selects the pfnhe-1 ms4760-1 Polymorphism in Malian Patients with Falciparum MalariaPublication . Kone, Aminatou; Mu, Jianbing; Maiga, Hamma; Beavogui, Abdoul H.; Yattara, Omar; Sagara, Issaka; Tekete, Mamadou M.; Traore, Oumar B.; Dara, Antoine; Dama, Souleymane; Diallo, Nouhoum; Kodio, Aly; Traore, Aliou; Bjoerkman, Anders; Gil, José Pedro; Doumbo, Ogobara K.; Wellems, Thomas E.; Djimde, Abdoulaye A.Background. The mechanism of Plasmodium falciparum resistance to quinine is not known. In vitro quantitative trait loci mapping suggests involvement of a predicted P. falciparum sodium-hydrogen exchanger (pfnhe-1) on chromosome 13. Methods. We conducted prospective quinine efficacy studies in 2 villages, Kolle and Faladie, Mali. Cases of clinical malaria requiring intravenous therapy were treated with standard doses of quinine and followed for 28 days. Treatment outcomes were classified using modified World Health Organization protocols. Molecular markers of parasite polymorphisms were used to distinguish recrudescent parasites from new infections. The prevalence of pfnhe-1 ms4760-1 among parasites before versus after quinine treatment was determined by direct sequencing. Results. Overall, 163 patients were enrolled and successfully followed. Without molecular correction, the mean adequate clinical and parasitological response (ACPR) was 50.3% (n = 163). After polymerase chain reaction correction to account for new infections, the corrected ACPR was 100%. The prevalence of ms4760-1 increased significantly, from 26.2% (n = 107) before quinine treatment to 46.3% (n = 54) after therapy (P = .01). In a control sulfadoxine-pyrimethamine study, the prevalence of ms4760-1 was similar before and after treatment. Conclusions. This study supports a role for pfnhe-1 in decreased susceptibility of P. falciparum to quinine in the field.
- As políticas educativas para o sector da educação de adultos em Portugal: As novas instituições e processos educativos emergentes entre 1996-2006Publication . Barros, RosannaA educação de adultos constitui-se como o tema geral da investigação que agora apresentamos neste livro, e que ambiciona contribuir para aprofundar o entendimento deste sector educacional como objeto sociológico, e mais especificamente, como objeto de políticas educativas e sociais a ser estudado sociologicamente. Assim, se um dos objetivos gerais da pesquisa que suporta o livro visa, desde logo, enriquecer o debate científico da sociologia da educação ( e das ciências da educação) que, em contexto português, só recentemente se tem debruçado de forma mais sistemática sobre as especificidades da educação destinada a uma população adulta, há também um segundo objetivo geral. correlacionado com o primeiro, em que se pretende avançar hipóteses para esclarecer o recente volte face ocorrido em Portugal na agenda das políticas educativas, que seria responsável por alterar, em apenas uma década, a tradicional situação de marginalidade do sector, que de área esquecida passa a área protagonista nos discursos políticos sobre educação.
- Assessing the cost-benefit effect of a plasmodium falciparum drug resistance mutation on parasite growth In vitroPublication . Froberg, Gabrielle; PE, Ferreira; Martensson, Andreas; Ali, Abdullah; Bjorkman, Anders; Gil, J. P.Plasmodium falciparum mutations associated with antimalarial resistance may be beneficial for parasites under drug pressure, although they may also cause a fitness cost. We herein present an in vitro model showing how this combined effect on parasite growth varies with the drug concentration and suggest a calculated drug-specific cost-benefit index, indicating the possible advantage for mutated parasites. We specifically studied the D-to-Y change at position 1246 encoded by the pfmdr1 gene (pfmdr1 D1246Y) in relation to amodiaquine resistance. Susceptibilities to amodiaquine, desethylamodiaquine, and chloroquine, as well as relative fitness, were determined for two modified isogenic P. falciparum clones differing only in the pfmdr1 1246 position. Data were used to create a new comparative graph of relative growth in relation to the drug concentration and to calculate the ratio between the benefit of resistance and the fitness cost. Results were related to an in vivo allele selection analysis after amodiaquine or artesunate-amodiaquine treatment. pfmdr1 1246Y was associated with decreased susceptibility to amodiaquine and desethylamodiaquine but at a growth fitness cost of 11%. Mutated parasites grew less in low drug concentrations due to a predominating fitness cost, but beyond a breakpoint concentration they grew more due to a predominating benefit of increased resistance. The cost-benefit indexes indicated that pfmdr1 1246Y was most advantageous for amodiaquine-exposed parasites. In vivo, a first drug selection of mutant parasites followed by a fitness selection of wild-type parasites supported the in vitro data. This cost-benefit model may predict the risk for selection of drug resistance mutations in different malaria transmission settings.
- Annexin A2: The Importance of Being Redox SensitivePublication . Madureira, Patricia; Waisman, David M.Hydrogen peroxide (H2O2) is an important second messenger in cellular signal transduction. H2O2-dependent signalling regulates many cellular processes, such as proliferation, differentiation, migration and apoptosis. Nevertheless, H2O2 is an oxidant and a major contributor to DNA damage, protein oxidation and lipid peroxidation, which can ultimately result in cell death and/or tumourigenesis. For this reason, cells have developed complex antioxidant systems to scavenge ROS. Recently, our laboratory identified the protein, annexin A2, as a novel cellular redox regulatory protein. Annexin A2 possesses a reactive cysteine residue (Cys-8) that is readily oxidized by H2O2 and subsequently reduced by the thioredoxin system, thereby enabling annexin A2 to participate in multiple redox cycles. Thus, a single molecule of annexin A2 can inactivate several molecules of H2O2. In this report, we will review the studies detailing the reactivity of annexin A2 thiols and the importance of these reactive cysteine(s) in regulating annexin A2 structure and function. We will also focus on the recent reports that establish novel functions for annexin A2, namely as a protein reductase and as a cellular redox regulatory protein. We will further discuss the importance of annexin A2 redox regulatory function in disease, with a particular focus on tumour progression.
- Psychopathy and behavior problems: a comparison of incarcerated male and female juvenile delinquentsPublication . Pechorro, Pedro Santos; Vieira, Duarte Nuno; Poiares, Carlos Alberto; Vieira, Rui Xavier; Maroco, Joao; Neves de Jesus, Saul; Nunes, CristinaThe objective of the present study was to compare incarcerated male and female juvenile offenders regarding psychopathic traits, behavior problems, psychopathy taxon, conduct disorder, self-reported delinquent behavior, and crime seriousness. Within a total forensic sample of 261 detainee participants, subdivided in a male group (n = 217) and a female group (n = 44), statistically significant differences were found. Female juvenile offenders show less callous-unemotional traits, more emotional symptoms, more prosocial behaviors, less self-reported delinquent behavior, and lower crime seriousness. Conduct disorder prevalence was very high, but no statistically significant gender differences were found. The predictive importance of psychopathic traits, behavior problems, psychopathy taxon, and conduct disorder for the prediction of group membership (female versus male) was established by binary logistic regression. (C) 2012 Elsevier Ltd. All rights reserved.