Role of intracellular transport, sorting and release of membrane type 1 matrix metalloproteinase (MT1-MMP) in tumor cell invasion and metastatic dissemination

The primary cause of death in cancer patients is the development of metastatic secondary tumours in distal organs. This is a complex process during which metastatic tumour cells need to overcome the natural barriers impeding access to vascular or lymphatic pathways: importantly they also need to alter the extracellular environment to allow ectopic cancer growth in distant locations. These events generally require the direct participation of released and exposed matrix metalloproteinases (MMPs), a family of related zinc-dependent proteases. Regulation of MMP activity is known to occur by modulation of gene expression, via zymogen activation and inhibition by tissue inhibitors of metalloproteinases (TIMPs). It is now evident, however, that modulation of intracellular trafficking, membrane sorting and cell surface release can also regulate MMP activities. These latter topics are still not well understood and, for this reason, represent the main aims of the present study. In particular, it has clearly emerged that MT1-MMP, a membrane-type MMP, is essential for the growth for human cancers, and acts by disrupting the three-dimensional matrix, which would otherwise impede cell proliferation. Ablation of the gene encoding MT1-MMP causes the most significant phenotype among the MMP knockout mice, and suggests that the activity of MT1-MMP cannot be substituted by any of the other members of the family. For this reason, the main focus of my PhD thesis is the regulation of MT1-MMP activity. Here I show that, in a melanoma cell line, the majority (80%) of MT1-MMP is sorted to detergent-resistant membrane fractions; however, it is only the minor (20%) detergent-soluble fraction of MT1-MMP that undergoes intracellular processing to the mature form. Also, this processed MT1-MMP is the sole form responsible for ECM degradation in vitro. Finally, furin-dependent processing of MT1-MMP is shown to occur intracellularly after exit from the Golgi apparatus and prior to arrival at the plasma membrane. It is thus proposed that the association of MT1-MMP with different membrane subdomains might be crucial in the control of its different activities: for instance in cell migration and invasion and other less defined roles such as MTl-MMP-dependent signaling pathways

Attention to the speaker. The conscious assessment of utterance interpretations in working memory

The role of conscious attention in language processing has been scarcely considered, despite the wide-spread assumption that verbal utterances manage to attract and manipulate the addressee’s attention. Here I claim that this assumption is to be understood not as a figure of speech but instead in terms of attentional processes proper. This hypothesis can explain a fact that has been noticed by supporters of Relevance Theory in pragmatics: the special role played by speaker-related information in utterance interpretation. I argue that representation of the speaker in working memory reliably enhances the activation of speaker-related information and, consequently, the role it plays in determining the content of interpretations

Constructing the context through goals and schemata: top-down processes in comprehension and beyond

My main purpose here is to provide an account of context selection in utterance understanding in terms of the role played by schemata and goals in top-down processing. The general idea is that information is organized hierarchically, with items iteratively organized in chunks—here called “schemata”—at multiple levels, so that the activation of any items spreads to schemata that are the most accessible due to previous experience. The activation of a schema, in turn, activates its other components, so as to predict a likely context for the original item. Since each input activates its own schemata, conflicting schemata compete with (and inhibit) each other, while multiple activations of a schema raise its likelihood to win the competition. There is therefore a double movement—with bottom-up activation of schemata enabling top-down prediction of other contextual components—triggered by multiple sources. Another claim of the paper is that goals are represented by schemata placed at the highest-levels of the executive hierarchy, in accordance with Fuster’s model of the brain as a hierarchically organized perception action cycle. This account can be considered, in part at least, a development of ideas contained in Relevance Theory, though it may imply that some other claims of the theory are in need of revision. Therefore, a secondary purpose of the paper is a contribution to the analysis of that theory

Language and action: a common intentional, generative, and inferential process.

The thesis that language is a special case of action is analysed in terms of the following three claims. First, language is presumably just as intentional as action is, in the precise sense that both involve largely automatic processing of goal-directed representations, with conscious attention essentially granting stability to the process. Second, this largely automatic processing of both language and action seems to be based on a shared generative mechanism. Third, this common process can be described as a bidirectional inferential device, which at the same time allows the prediction of goals from means and the retrodiction of means from goals. These considerations converge towards the idea that language processing is based on domain-general processes which are shared with non-linguistic action

The continuum problem: Modified Occam's Razor and conventionalisation of meaning

According to Grice's “Modified Occam's Razor”, in case of uncertainty between the implicature account and the polysemy account of word uses it is parsimonious to opt for the former. However, it is widely agreed that uses can be partially conventionalised by repetition. This fact, I argue, raises a serious problem for MOR as a methodological principle, but also for the substantial notion of implicature in lexical pragmatics. In order to overcome these problems, I propose to reinterpret implicatures in terms of implicature-like effects delivered by non-inferential processes

Are there communicative intentions?

Grice in pragmatics and Levelt in psycholinguistics have proposed models of human communication where the starting point of communicative action is an individual intention. This assumption, though, has to face serious objections with regard to the alleged existence of explicit representations of the communicative goals to be pursued. Here evidence is surveyed which shows that in fact speaking may ordinarily be a quite automatic activity prompted by contextual cues and driven by behavioural schemata abstracted away from social regularities. On the one hand, this means that there could exist no intentions in the sense of explicit representations of communicative goals, following from deliberate reasoning and triggering the communicative action. On the other hand, however, there are reasons to allow for a weaker notion of intention than this, according to which communication is an intentional affair, after all. Communicative action is said to be intentional in this weaker sense to the extent that it is subject to a double mechanism of control, with respect both to present-directed and future-directed intentions

Bringing tabletop technologies to kindergarten children

Taking computer technology away from the desktop and into a more physical, manipulative space, is known that provide many benefits and is generally considered to result in a system that is easier to learn and more natural to use. This paper describes a design solution that allows kindergarten children to take the benefits of the new pedagogical possibilities that tangible interaction and tabletop technologies offer for manipulative learning. After analysis of children's cognitive and psychomotor skills, we have designed and tuned a prototype game that is suitable for children aged 3 to 4 years old. Our prototype uniquely combines low cost tangible interaction and tabletop technology with tutored learning. The design has been based on the observation of children using the technology, letting them freely play with the application during three play sessions. These observational sessions informed the design decisions for the game whilst also confirming the children's enjoyment of the prototype

An associative account of inferences: The development towards the prototype

Abstract: According to a traditional view, inferences are personal-level entities pertaining to the domain of reasons, and therefore they cannot be accounted for in causal terms – specifically, as mere associations. I intend to argue that this is at the very least a drastic simplification, for two reasons. First, the word “association” is polysemous, so we should specify in which of its possible senses an inference is not a mere association. Second, personal-level inferences based on formal rules are only the extreme end of a complex developmental trajectory. As the last decades of research in the field have shown, we should refrain from identifying the entire domain of reasoning with that final stage, which is in fact mostly contingent upon extensive logical training. In this paper, I try to disentangle some major stages in the development of full-fledged (prototypical) inferences, and then to show that all of them – till the final one – can be considered associative in appropriate senses of the word.Keywords: Reasoning; Association; Consciousness; Inference; Development Un approccio associativo alle inferenze: l’evoluzione verso il prototipoRiassunto: Secondo una concezione tradizionale, le inferenze sono entità collocate al livello della persona e appartenenti al dominio delle ragioni, e pertanto non è possibile ridurle a un resoconto causale – più specificamente, a mere associazioni. Intendo sostenere che questa è quanto meno una drastica semplificazione, per due ragioni. Primo, la parola “associazione” è polisemica, quindi dovremmo precisare in quale senso un’inferenza non è una mera associazione. Secondo, inferenze al livello della persona e basate su regole formali sono solo il punto estremo di una complessa traiettoria di sviluppo. Come gli ultimi decenni di ricerca in questo campo hanno mostrato, dovremmo evitare di identificare l’intero dominio del ragionamento con questo stadio finale, che di fatto dipende da un esteso addestramento logico. In questo articolo, provo a discriminare alcuni stadi essenziali nello sviluppo delle inferenze in senso pieno (prototipiche), e quindi a mostrare che ciascuno di essi – incluso quello finale – possono essere considerati associativi in qualche opportuno senso della parola.Parole chiave: Ragionamento; Associazione; Coscienza; Inferenza; Svilupp