A questão do livre-arbítrio em John R. Searle: uma contraposição do naturalismo biológico ao fisicalismo e ao funcionalismo

This paper compares the theses of physicalism and functionalism – particularly the computacionalist line – with the biological naturalism of John Searle regarding the possibility of free will. In such contrast, each line is decomposed into its statements so that they can be reviewed. It is argued that the searlean biological naturalism can explain more than the other two philosophies on how free action can have the source of its motivation in what is external to the mental state that makes it beperformed. Finally, even if the issue of free will still is open, I shall argue that free will does not find any room in the scenario that the lines of physicalism and functionalism present

To methylate or not to methylate? Study of Mercury Speciation along\ud the Venetian Littoral System (Q-ALiVe project)

The biogeochemical cycle of mercury (Hg) is affected not only by the physical, chemical and hydrological characteristics of the environment, but also by changes in productivity and biodiversity. In waters the complexes of Hg are related to the salinity and to the load of dissolved organic carbon (DOC) in the dissolved and in the particulate phases. Surface and bottom seawater were sampled along the Venetian coast at ten sites with different characteristics. Samples were analyzed employing hyphenated techniques and LOD (limit of detection) and LOQ (limit of quantification) were quantified. Although for some samples both the species were under the LOQ, the presence of methyl mercury (CH3Hg+) and ionic mercury (Hg2+) at the same time in surface and in bottom waters were observed. Variability in CH3Hg+ concentrations may be due to changes in the phytoplankton communities, which in turn may be affected by nutrient loads from the catchment area and port mouths of the Venice Lagoon. Thus, monitoring these nutrient loads may be essential for the health of the Venetian littoral system, since they may affect blooms, methylation and hyper-bioaccumulation along the trophic web, with effects on the environment and on human health

Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

BACKGROUND: Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question. METHODS: Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine data sets. RESULTS: AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCCs) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours. CONCLUSIONS: An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses

Gene profiling of lung toxicity

Bleomycin is a potent anti-tumour compound used in the treatment of squamous cell carcinomas. An unfortunate side effect of this drug is pulmonary toxicity. The onset of this damage manifests as mild oedema and inflammation which eventually develops into pulmonary fibrosis. The ability to correctly identify patients showing early signs of lung injury could significantly reduce the morbidity associated with bleomycin treatment. As such, this study was undertaken to identify genetic markers of early oedema and inflammation. A model of mild pulmonary injury was induced by bleomycin. Conventional quantitative analysis of broncho-alveolar lavage was used to indicate the severity of the oedematous response, whilst morphological changes were identified by histology and electron microscopy. Macroarrays were used to measure the expression of multiple genes during mild, progressive and severe oedema. Following normalisation and statistical analysis, gene expression patterns were compared from saline- and bleomycin-treated rats. A variety of genes were differentially expressed during each model, with the number increasing with the severity of the oedema. A cluster and two individual genes were consistently expressed across two of the models of oedema. The magnitude of the changes in gene expression were quantified and confirmed by quantitative PCR. In summary, complete toxicological and histological characterisation of the bleomycin-induced model of pulmonary injury successfully identified specific endpoints of injury. This model proved to be ideal for studying differential gene expression in response to drug-induced pulmonary oedema. A cluster of ion channels and trafficking genes has the potential to act as a biomarker. Two specific genetic markers (Na+/CI- betaine/GABA transporter, glucocorticoid receptor), and a protein marker (cocoacrisp) have been identified for the oedema. In addition to these genes and protein being potential biomarkers of injury, they are also prospective targets for clinical treatment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Collagen VI sustains cell stemness and chemotherapy resistance in glioblastoma

Microenvironmental factors are known fundamental regulators of the phenotype and aggressiveness of glioblastoma (GBM), the most lethal brain tumor, characterized by fast progression and marked resistance to treatments. In this context, the extracellular matrix (ECM) is known to heavily influence the behavior of cancer cells from several origins, contributing to stem cell niches, influencing tumor invasiveness and response to chemotherapy, mediating survival signaling cascades, and modulating inflammatory cell recruitment. Here, we show that collagen VI (COL6), an ECM protein widely expressed in both normal and pathological tissues, has a distinctive distribution within the GBM mass, strongly correlated with the most aggressive and phenotypically immature cells. Our data demonstrate that COL6 sustains the stem-like properties of GBM cells and supports the maintenance of an aggressive transcriptional program promoting cancer cell proliferation and survival. In particular, we identified a specific subset of COL6-transcriptionally co-regulated genes, required for the response of cells to replicative stress and DNA damage, supporting the concept that COL6 is an essential stimulus for the activation of GBM cell response and resistance to chemotherapy, through the ATM/ATR axis. Altogether, these findings indicate that COL6 plays a pivotal role in GBM tumor biology, exerting a pleiotropic action across different GBM hallmarks, including phenotypic identity and gene transcription, as well as response to treatments, thus providing valuable information for the understanding of the complex microenvironmental cues underlying GBM malignancy

Reduced variability of erector spinae activity in people with chronic low back pain when performing a functional 3D lifting task

BACKGROUND: Chronic low back pain (LBP) is a leading cause of disability, which is exacerbated in some by repeated lifting. Electromyography (EMG) assessments of isolated erector spinae (ES) regions during lifting identified conflicting results. Here, high-density EMG comprehensively assesses the lumbar and thoracolumbar ES activity in people with and without LBP performing a multiplanar lifting task.METHODS: Four high-density EMG grids (two bilaterally) and reflective markers were affixed over the ES and trunk to record muscle activity and trunk kinematics respectively. The task involved cyclical lifting of a 5 kg box for ∼7 min from a central shelf to five peripheral shelves, returning to the first between movements, while monitoring perceived exertion.RESULTS: Fourteen LBP (26.9 ± 11.1 years) and 15 control participants (32.1 ± 14.6 years) completed the study. LBP participants used a strategy characterised by less diffuse and more cranially-focussed ES activity (P &lt; 0.05). LBP participants also exhibited less variation in ES activity distribution between sides during movements distal to the central shelf (P &lt; 0.05). There were few consistent differences in kinematics, but LBP participants reported greater exertion (P &lt; 0.05).CONCLUSION: In the presence of mild LBP, participants used a less variable motor strategy, with less diffuse and more cranially-focussed ES activity; this motor strategy occurred concomitantly with increased exertion while completing this dynamic task.</p

Phage display and experimental brain therapeutics

Phage display, a powerful polypeptide display technology, affords the rapid identification of peptides and proteins that interact with a target of interest The aims of the project were the phage display identification of peptides that interact with a druggable target in a brain disorder (glioblastoma multiforme) and the identification of peptides that serve as targeting vectors for brain delivery. Validation studies were undertaken to qualify the use of a cyclic 7-mer peptide phage library against targets including streptavidin and paracetamol chosen as examples of a large complex and small simple molecule, respectively. With the aim of identifying peptide phages that bind to the luminal surface of brain micro vasculature, a primary in-vitro porcine model of the blood-brain barrier (BBB) comprising primary brain capillary endothelial cells was established and characterised. An in-vivo phage display was undertaken in the rat with the aim of identifying peptide sequences that mediated translocation across the BBB into brain grey matter. A 7-mer cyclic peptide was identified with sequence AC-SYTSSTM-CGGGS that enhanced the uptake of phages into brain grey matter by 4-fold compared to control wild-type phages. This peptide may serve as a novel targeting vector for the delivery of a therapeutic cargo to the brain. Caveolin-1 was identified as a potential new therapeutic target in in-vitro models of grade IV astrocytomas (glioblastoma multiforme), with siRNA knockdown of caveolin-1 associated with reduced glioma cell proliferation and invasiveness. With the caveolin-1 scaffolding domain (aa 81-101 in the caveolin-1 protein) as a target, an in-vitro peptide phage selection was undertaken and identified a series of peptides that bind the scaffolding domain with high affinity. These peptides will serve as a template for the development of low molecular weight peptidomimetics that inhibit caveolin-1 function. In conclusion, the studies in this thesis have demonstrated the utility of phage display in experimental therapeutics of brain disorders.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

To methylate or not to methylate? Study of Mercury Speciation along the Venetian Littoral System (Q-ALiVe project)

The biogeochemical cycle of mercury (Hg) is affected not only by the physical, chemical and hydrological characteristics of the environment, but also by changes in productivity and biodiversity. In waters the complexes of Hg are related to the salinity and to the load of dissolved organic carbon (DOC) in the dissolved and in the particulate phases. Surface and bottom seawater were sampled along the Venetian coast at ten sites with different characteristics. Samples were analyzed employing hyphenated techniques and LOD (limit of detection) and LOQ (limit of quantification) were quantified. Although for some samples both the species were under the LOQ, the presence of methyl mercury (CH3Hg+) and ionic mercury (Hg2+) at the same time in surface and in bottom waters were observed. Variability in CH3Hg+ concentrations may be due to changes in the phytoplankton communities, which in turn may be affected by nutrient loads from the catchment area and port mouths of the Venice Lagoon. Thus, monitoring these nutrient loads may be essential for the health of the Venetian littoral system, since they may affect blooms, methylation and hyper-bioaccumulation along the trophic web, with effects on the environment and on human health