Traumatic brain injury (TBI) is a serious health concern, causing cognitive, motor, and sensory deficits, including olfactory dysfunction. This dissertation explores the effects of TBI on synaptic plasticity within the olfactory system, seeking to define mechanisms guiding postinjury sensory reinnervation. Physical forces induced by TBI can axotomize olfactory receptor neurons (ORNs), which innervate olfactory bulb (OB). These axons regenerate OB projections after injury, a process involving growth through a complex extracellular matrix (ECM). As such, we investigated a potential molecular mechanism capable of modifying local OB ECM to support postinjury synaptogenesis. Since matrix metalloproteinases (MMPs) and their ECM substrates are recognized for TBI therapeutic potential, we explored the role of MMP9 and its substrate osteopontin (OPN) in promoting ORN reinnervation of the OB after mild fluid percussion injury (FPI). First, we confirmed that FPI deafferented the mouse OB. In Chapter 2, we showed concurrent activation of neuroglia, elevated spectrin proteolysis and reduction in ORN-specific olfactory marker protein (OMP). As OMP normalized during regeneration, growth associated protein-43kD (GAP-43) peaked, marking OB entry of ORN growth cones. Ultrastructural analysis revealed ongoing ORN axon shrinkage and degeneration, glial phagocytosis of cellular debris, and a reorganization of synaptic structure. To explore ECM role in mediating postinjury OB reinnervation, we defined the time course of MMP9 activity and several downstream targets. Chapter 3 reports biphasic MMP9 activity increase during acute/subacute degeneration, accompanied by robust generation of 48kD OPN cell signaling peptide. OPN receptor CD44 also increased during the acute/subacute interval, suggesting potential interaction of the two proteins. Finally, we utilized MMP9 knockout (MMP9KO) mice to confirm MMP9 role in OB synaptogenesis. In Chapter 4, MMP9KO reversed FPI-induced lysis of 49kD OPN and altered postinjury expression of ORN axon degeneration marker OMP. Additional ultrastructural analysis verified delayed recovery of OB synaptic features within the injured MMP9KO. Overall, we demonstrated that mild FPI elicits ORN axotomy to induce OB reactive synaptogenesis, and that MMP9 supports reinnervation by processing OPN for activation of local glia, cells which reorganize the ECM for synapse regeneration.

Esta dissertação é um estudo comparativo teórico-prático que lança a hipótese de uma outra categoria de experiência reticular possível no campo contemporâneo das narrativas transmídias, embasada a partir do eixo teórico dos conceitos de \"Experiência\" (Erfahrung) e \"vivência\" (Erlebnis), inicialmente formulados pelo filósofo Walter Benjamin num contexto marcado por convulsões e transformações socioeconômicas e políticas do entreguerras no século XX. Em busca de um rigor metodológico que reflita uma tentativa de superação de um viés tão somente reificador da narrativa transmídia, conscientemente compreeendida enquanto uma mercadoria do capitalismo neoliberal reproduzida tecnicamente, em favor de uma abordagem filosófica sobre a demanda de seu caráter potencialmente colaborativo que produziria um tipo de experiência-em-rede, por nós tomada como hipótese, cujas sutilezas nos propomos investigar, procuramos situar o contexto em que os conceitos benjaminianos foram formulados, para então justificar o seu deslocamento à análise do novo contexto em que surge a transmedia storytelling. Com este arcabouço espera-se compreender como as narrativas transmídia abririam caminhos à compreensão de uma nova experiência hipoteticamente permeada pelo ciberespaço, simultaneamente relacionada ao aspecto fragmentado e individual da Erlebnis, de um lado, e relativamente compatível ao caráter de um saber compartilhado pela coletividade inerente à Erfahrung, de outro: não exclusivamente definida pelos conceitos, mas entendida dialeticamente como uma terceira categoria de experiência mediada por uma inteligência coletiva que parte da síntese de ambos. Investigamos as possibilidades de entendimento desta experiência enquanto resultante de transversalidades dialógicas entre diversos nichos de público relativos aos diferentes fragmentos narrativos que, singulares esteticamente, auto?nomos de sentido e complementares diegeticamente entre si, ao serem dispersos em múltiplos meios sob a forma de diferentes linguagens, levam em conta o caráter potencialmente colaborativo oferecido pelas redes digitais contemporâneas à interação, à participação e às trocas simbólicas: o meio virtual seria, portanto, fundamental à formulação das geometrias de uma experiência reticular compartilhada. Por fim, pelo procedimento da análise textual qualitativa-quantitativa sobre um corpus, com de potencial dialógico entre amostras de 46 unidades de fragmentos narrativos do universo Matrix (das irmãs Wachowski), sob os temas: a) potência de relação transmidiática diegética entre fragmentos e b) convite à participação colaborativa entre nichos; no estudo de caso deste cânone, surgido na virada do século XX ao XXI, buscamos indícios à confrontação da nova categoria propositiva de experiência-em-rede hipotética, ao transbordar-se no desenvolvimento prático de um vídeo enquanto ferramenta inspiradora à análise de outros universos em transmedia storytelling já existentes ou ainda por vir. Em busca de ampliar os horizontes de compreensão deste fenômeno narrativo-midiático, as análises da pesquisa não se fecham sobre seus próprios resultados, mas abrem-se para novas problematizações aos campos afins. / This dissertation is a comparative theoretical-practical study that launches the hypothesis of another category of possible reticular experience in the contemporary field of transmedia storytelling, based on the theoretical axis of the concepts of \"Experience\" (Erfahrung) and \"lived experience\" (Erlebnis), initially formulated by the philosopher Walter Benjamin in a context marked by characteristic socioeconomic and political convulsions and transformations of the interwar period in the 20th century. In search of a methodological rigor that reflects an attempt to overcome a bias that is only reifying the transmedia storytelling, consciously understood as a cultural merchandise of neoliberal capitalism reproduced technically, in favor of a philosophical approach on the demand for its potentially collaborative character that would produce a type of experience-in-network, taken by us as a hypothesis, whose subtleties we propose to investigate, we try to situate the context in which the Benjaminian concepts were formulated, to justify its displacement to the analysis of the new context in which transmedia storytelling arises. With this framework we hope to understand how the transmedia storytelling would open a way to the understanding of a new experience hypothetically permeated by cyberspace, simultaneously related to the fragmented and individual aspect of Erlebnis, on the one hand, and relatively compatible to the character of a knowledge shared by the inherent collectivity of Erfahrung, on the other: not exclusively defined by those concepts, but understood dialectically as a third category of experience mediated by a collective intelligence that starts from the synthesis of both. We investigate the possibilities of understanding this experience as a result of dialogical transversalities between different niche audiences related to the different narrative fragments that, aesthetically singular, autonomous of sense and diegetically complementary to each other, being dispersed in multiple media in the form of different languages, taking into account the potentially collaborative character offered by contemporary digital networks to interaction, participation and symbolic exchanges: the virtual medium would therefore be fundamental to the formulation of the geometries of a shared reticular experience. Finally, by the procedure of qualitative-quantitative textual analysis on a corpus, with a dialogical potential between samples of 46 units of narrative fragments of the Matrix universe (of the Wachowski sisters), under the themes: a) Potential of diegetically transmedia relations between fragments; and b) Invitation for collaborative participation between niches; in the case study of this canon that emerged at the transition from 20th to the 21th century, we looked for clues to the confrontation of the new propositional category of hypothetical experience-in-network, overflowing in the practical development of a video as an inspiring tool for the analysis of other universes in transmedia storytelling already existing or yet to come. In order to broaden the understanding horizons of this media narrative phenomenon, the analysis of the research does not close on its own results, but opens up for new problematizations to the related fields.

La trachée est une structure très complexe des voies respiratoires, qui est composée d'anneaux cartilagineux, fait de cartilage hyalin, et de bandes musculaires, formées de cellules musculaires lisses, dont l'architecture confère à la fois rigidité et souplesse au canal trachéen. Contrairement à d'autres cartilages, tels que ceux trouvés dans la plaque de croissance en développement et dans les articulations adultes, ou aux cellules musculaires lisses des vaisseaux, très peu d'informations sont disponibles sur le développement du cartilage et du tissu musculaire trachéal et sur leur capacité à se minéraliser, bien que la calcification de la trachée soit un événement commun dans la population âgée et plus rare dans certaines pathologies. Dans ce contexte, ce travail de thèse a cherché dans le modèle souris à mieux caractériser le cartilage et le tissu musculaire lisse de la trachée et également comprendre les mécanismes moléculaires jusqu'alors inexplorés, régulant la minéralisation de la trachée. Grâce à une nouvelle technique de culture de cellules provenant de la trachée, nous avons démontré que les chondrocytes et les cellules musculaires lisses trachéaux sont tous deux capables de minéraliser lorsqu'ils sont traités avec un haut niveau de Pi, mais via des mécanismes moléculaires différents. En parallèle, une étude in vivo nous a permis de démontrer que la minéralisation de la trachée se produit uniquement dans les anneaux cartilagineux dès 30 jours après la naissance. Des analyses histologiques et moléculaires ont permis d'affiner ces résultats et de proposer un modèle de minéralisation de la trachée via une progression rostro-caudale dépendante de BMP2 / The trachea is a very complex structure of the respiratory tract, composed of C-shaped cartilaginous rings, made of hyaline cartilage, and muscular bands, made of smooth muscle cells, conferring rigidity and compliance to the windpipe, respectively. In contrast to other intensely studied cartilages such as the ones found in the developing growth plate and in the adult joints or smooth muscle cells from the vasculature, very little information is available on the development of the tracheal cartilage and smooth muscle tissues and on their innate propensity to mineralize, although calcification of the trachea is a common finding in the elderly population and also a rare manifestation of pathologic conditions. In this context, this PhD work sought to better characterized the poorly studied tracheal cartilage and smooth muscle tissue and understand the molecular mechanisms regulating tracheal mineralization that has been unexplored so far. We tackle these questions in the mouse model. Setting up a novel in-vitro culture of tracheal cells, we demonstrated that tracheal chondrocytes and smooth muscles cells are prone to mineralize when treated with high level of Pi, through different molecular mechanisms. In parallel, we found that in vivo mineralization of the trachea only happens in the cartilaginous rings, as early as 30 days after birth. Histological and molecular evidence suggest that tracheal mineralization occurs through a BMP-dependent rostro-caudal progression

This thesis provides novel methodology for statistical analysis of paired high-dimensional genomic data, with the aimto identify gene interactions specific to each group of samples as well as the gene connections that change between the two classes of observations. An example of such groups can be patients under two medical conditions, in which the estimation of gene interaction networks is relevant to biologists as part of discerning gene regulatory mechanisms that control a disease process like, for instance, cancer. We construct these interaction networks fromdata by considering the non-zero structure of correlationmatrices, which measure linear dependence between random variables, and their inversematrices, which are commonly known as precision matrices and determine linear conditional dependence instead. In this regard, we study three statistical problems related to the testing, single estimation and joint estimation of (conditional) dependence structures. Firstly, we develop hypothesis testingmethods to assess the equality of two correlation matrices, and also two correlation sub-matrices, corresponding to two classes of samples, and hence the equality of the underlying gene interaction networks. We consider statistics based on the average of squares, maximum and sum of exceedances of sample correlations, which are suitable for both independent and paired observations. We derive the limiting distributions for the test statistics where possible and, for practical needs, we present a permuted samples based approach to find their corresponding non-parametric distributions. Cases where such hypothesis testing presents enough evidence against the null hypothesis of equality of two correlation matrices give rise to the problem of estimating two correlation (or precision) matrices. However, before that we address the statistical problem of estimating conditional dependence between random variables in a single class of samples when data are high-dimensional, which is the second topic of the thesis. We study the graphical lasso method which employs an L1 penalized likelihood expression to estimate the precision matrix and its underlying non-zero graph structure. The lasso penalization termis given by the L1 normof the precisionmatrix elements scaled by a regularization parameter, which determines the trade-off between sparsity of the graph and fit to the data, and its selection is our main focus of investigation. We propose several procedures to select the regularization parameter in the graphical lasso optimization problem that rely on network characteristics such as clustering or connectivity of the graph. Thirdly, we address the more general problem of estimating two precision matrices that are expected to be similar, when datasets are dependent, focusing on the particular case of paired observations. We propose a new method to estimate these precision matrices simultaneously, a weighted fused graphical lasso estimator. The analogous joint estimation method concerning two regression coefficient matrices, which we call weighted fused regression lasso, is also developed in this thesis under the same paired and high-dimensional setting. The two joint estimators maximize penalized marginal log likelihood functions, which encourage both sparsity and similarity in the estimated matrices, and that are solved using an alternating direction method of multipliers (ADMM) algorithm. Sparsity and similarity of thematrices are determined by two tuning parameters and we propose to choose them by controlling the corresponding average error rates related to the expected number of false positive edges in the estimated conditional dependence networks. These testing and estimation methods are implemented within the R package ldstatsHD, and are applied to a comprehensive range of simulated data sets as well as to high-dimensional real case studies of genomic data. We employ testing approaches with the purpose of discovering pathway lists of genes that present significantly different correlation matrices on healthy and unhealthy (e.g., tumor) samples. Besides, we use hypothesis testing problems on correlation sub-matrices to reduce the number of genes for estimation. The proposed joint estimation methods are then considered to find gene interactions that are common between medical conditions as well as interactions that vary in the presence of unhealthy tissues.

"The goal of this thesis is to extend the theory and practice of matrix completion algorithms, and how they can be utilized, improved, and scaled up to handle large data sets. Matrix completion involves predicting missing entries in real-world data matrices using the modeling assumption that the fully observed matrix is low-rank. Low-rank matrices appear across a broad selection of domains, and such a modeling assumption is similar in spirit to Principal Component Analysis. Our focus is on large scale problems, where the matrices have millions of rows and columns. In this thesis we provide new analysis for the convergence rates of matrix completion techniques using convex nuclear norm relaxation. In addition, we validate these results on both synthetic data and data from two real-world domains (recommender systems and Internet tomography). The results we obtain show that with an empirical, data-inspired understanding of various parameters in the algorithm, this matrix completion problem can be solved more efficiently than some previous theory suggests, and therefore can be extended to much larger problems with greater ease. "

A competição atual exige que cada vez mais as empresas possuam sistemáticas de gerenciamento que possibilitem atuar no controle e na redução dos desperdícios. Este trabalho avalia ferramentas de melhoria do resultado econômico, com foco particular no Gerenciamento Matricial de Despesas (GMD). Considerando que o GMD ainda é muito pouco explorado na literatura específica sobre melhoria do resultado econômico, o principal objetivo do trabalho é contribuir para a consolidação da base conceitual dessa ferramenta. Para isso, primeiramente foi realizada uma pesquisa teórica procurando avaliar o GMD relativamente ao Orçamento Base-Zero (OBZ) e ao Custeio-Alvo/Custeio Kaizen, de forma a entender suas características diferenciais em termos de melhoria do resultado econômico. Fez-se, também, a contextualização do GMD como uma das ferramentas de operacionalização do Orçamento Matricial (OM), juntamente com o Diagnóstico de Desempenho Operacional (DDO) e o Gerenciamento Matricial de Receitas (GMR). Em seguida, buscou-se identificar na literatura as principais etapas de implantação do GMD, as quais foram ajustadas a partir de uma pesquisa exploratória realizada em quatro empresas da região Sul do Brasil. A modelagem final proposta foi, então, aplicada parcialmente numa instituição da área da saúde. Começando pela avaliação dos ambientes interno e externo da empresa, preparou-se a base de dados contábil necessária à implantação do GMD, detalhando-a e analisando que tipo de indicador e de ação seria mais adequado para orientar a redução de custos. Todos estas etapas da aplicação parcial foram analisadas criticamente. / More and more current competition demands that companies have management systems which allow them to act in the control and waste reduction. This work evaluates enhancement tools of economic outcome with a particular focus on the Matrix Management of Expenses (MME). Considering that MME is still a little explored in the specific literature about enhancement tools of economic outcome, the main objective of this work is to contribute to the consolidation of the conceptual base of that tool. For this, a theoretical research was primarily done trying to evaluate the MME related to the Zero-Base Budget (ZBB) and to the Target Costing/ Kaizen Costing, in order to understand their differential characteristics in terms of the enhancement of the economic result. The MME contextualization was also done as one of the operationalization tools of the Matrix Budget (MB), together with the Diagnosis of Operational Performance (DOP) and the Matrix management of Revenues (MMR). Subsequently, it was attempted to identify in the literature the principal stages of MME implementation, which were adjusted from an exploratory research performed in four companies in the southern region of Brazil. Then the final modeling proposed was then partially applied, in a health unit institution. Beginning by the evaluation of the internal and external environments of the institution, a necessary accounting database was prepared for the implantation of the MME, detailing and analyzing what kind of indicator and of action would be more appropriate to guide cost reduction. All the stages of the partial application were analyzed critically.

Physical factors in the environment of a cell affect its function and behavior in a variety of ways. There is increasing evidence that, among these factors, the geometric arrangement of receptor ligands plays an important role in setting the conditions for critical cellular processes. The goal of this thesis is to develop new techniques for probing the role of extracellular ligand geometry, with a focus on T cell activation. In this work, top-down molecular-scale nanofabrication and bottom-up selective self-assembly were combined in order to present functional nanomaterials (primarily biomolecules) on a surface with precise spatial control and single-molecule resolution. Such biomolecule nanoarrays are becoming an increasingly important tool in surface-based in vitro assays for biosensing, molecular and cellular studies. The nanoarrays consist of metallic nanodots patterned on glass coverslips using electron beam and nanoimprint lithography, combined with self-aligned pattern transfer. The nanodots were then used as anchors for the immobilization of biological ligands, and backfilled with a protein-repellent passivation layer of polyethylene glycol. The passivation efficiency was improved to minimize nonspecific adsorption. In order to ensure true single-molecule control, we developed an on-chip protocol to measure the molecular occupancy of nanodot arrays based on fluorescence photobleaching, while accounting for quenching effects by plasmonic absorption. We found that the molecular occupancy can be interpreted as a packing problem, with the solution depending on the nanodot size and the concentration of self-assembly reagents, where the latter can be easily adjusted to control the molecular occupancy according to the dot size. The optimized nanoarrays were used as biomimetic architectures for the study of T cell activation with single-molecule control. T cell activation involves an elaborate arrangement of signaling, adhesion, and costimulatory molecules organized into a stereotypic geometric structure, known as the immunological synapse, between T cell and antigen-presenting cell. Novel bifunctionalization schemes were developed to better mimic the antigen-presenting surfaces. Nanoarrays were functionalized by single molecules of UCHT1 Fab', and served as individual T cell receptor binding sites. The adhesion molecule ICAM-1 was bound to either static PEG background, or a mobile supported lipid bilayer. The minimum geometric requirements (receptor clustering, spacing and stoichiometry) for T cell activation was probed by systematic variation of the nanoarray spacing and cluster size. Out-of-plane spatial control of the two key molecules by way of nanopillar arrays was used to adjust the membrane bending and steric effects, which were essential for the investigation of molecular segregation in T cell activation. The results provide insights into the complicated T cell activation mechanism, with translational implications toward adoptive immunotherapies for cancer and other diseases. This single-molecule platform serves as a novel and powerful tool for molecular and cellular biology, e.g., receptor-mediated signaling/adhesion, especially when multiple ligands or membrane deformation are involved.

O presente trabalho apresenta uma análise da aplicação da ferramenta DSM Design Structure Matrix ao planejamento do processo de projeto de edificações. O objetivo principal desta pesquisa é a análise dos Manuais de Escopo de Projetos e Serviços para a Indústria Imobiliária do ponto de vista do planejamento do processo de projeto, utilizando a ferramenta DSM. Para desenvolvimento da pesquisa primeiramente foi feita uma revisão bibliográfica, onde selecionou-se a metodologia ADePT para o desenvolvimento do planejamento do processo de projeto. Em seguida foram aplicadas as duas primeiras etapas da metodologia ADePT definição do processo e otimização do processo, que forneceram material para uma análise da aplicação da ferramenta DSM ao planejamento do processo de projeto e uma análise crítica sobre os Manuais de Escopo de Projetos e Serviços para a Indústria Imobiliária. O cumprimento das duas primeiras etapas da metodologia ADePT forneceu material com informações que permitiram a observação de algumas incoerências e permitiu a apresentação de críticas e sugestões de alterações em seu conteúdo, como proposta de melhoria à ferramenta-guia que estes se propõem a ser. Por fim, a partir da validação da DSM como ferramenta para o desenvolvimento do planejamento do processo de projeto e com base nas alterações sugeridas para os manuais, foi proposto um novo modelo de processo de projeto. / This study presents an analysis of application of DSM Design Structure Matrix to the planning process of building design. The main objective this study is the analysis of manuals Scope of Projects and Services for the Real State Industry in terms of planning the design process, using the DSM. For development of the study was first done a literature review, where we selected the ADEPT methodology to development planning this process. When we applied the first two stages of ADEPT methodology process definition and optimization of the process, which provided material for an analysis of the implementation of DSM planning in the design process and a critical analysis of the Manuals Scope of Projects and Services for Real State Industry. Compliance with the first two stages of ADEPT methodology provided material with information that allowed the observation of some inconsistencies and allowed the presentation of comments and suggestions for changes in content, as proposed improvements to the tool guide that they purport to be. Finally, from the validation of the DSM as a tool for development planning and design process based on the suggested changes to the manuals, we proposed a new model of the design process.

L’étude des réaction (a,g) d’intérêt astrophysique est vaste. Ces réactions ont un rôle important dans la phase de fusion d’hélium des étoiles, dans la nucléosynthèse au moment du big bang ainsi que dans une grande partie des scénarios d'explosions stellaires. L’étude des réactions (a,g) impliquant des faisceaux stables peut être réalisée de diverse façon. Je me suis concentrée sur deux d'entre elles. La première est l’étude en cinématique directe en détectant les rayons gamma produits. C'est ce que j'ai fait durant ma thèse pour mesurer la section efficace de 7Li(a,g)11B. Cette réaction a été étudiée au cours des années pour différentes raisons en astrophysique nucléaire. Par exemple, il a été postule que cette réaction pourrait résoudre, au moment de la nucléosynthèse du big bang, le problème du Lithium. Il est clair, aujourd'hui, que ce n'est pas la solution, cependant, elle a un rôle dans la production de boron lors des supernovae de type Ic. Une autre façon d’étudier les réactions (a,g) est d'utiliser la cinématique inverse. L’idée est d'envoyer un faisceau d'ions lourd sur une cible d’hélium. Ce type de cinématique permet de détecter, avec une bonne efficacité, le noyau lourd de recul produit si le faisceau qui n'a pas interagit avec la cible, en est correctement séparé. Les séparateurs de masses, comme St. George, sont construit dans ce but. St. George sera impliquer dans la mesure de sections efficaces de réaction d’importance pour le processus s comme 16O(a,g)20Ne. / The study of (a,g) reactions of astrophysical interest is quite vast. These reactions play an important role in the quiescent Helium burning phase of stars, in big bang nucleosynthesis and in most explosive stellar scenarios. The studies of (a,g) reactions involving stable beams are performed in various ways. I have been concentrating on two of them. The first one is studying these reactions in direct kinematics by detecting the produced gamma rays. This is what I did during my thesis to measure the cross section of 7Li(a,g)11B. It has been studied throughout the years for several purposes in nuclear astrophysics. For example, it was postulated it could solve the big bang nucleosynthesis Lithium problem. Nowadays, it is clear it does not.However, this reaction plays a role in the production of Boron during type Ic Supernovae. Another way to study (a,g) reactions is to use inverse kinematics. The idea is to send a heavy element beam on a Helium target. This kind of kinematics allows for the detection, with good efficiency, of the heavy recoil product if the beam that did not interact in the target is properly separated. Recoil mass separators, like St. George, are built for this purpose. St. George will be involved in measuring cross sections of reaction important for the s-process like 16O(a,g)20Ne.

Diabetic symmetrical polyneuropathy is the most common secondary complication of diabetes, with no effective treatment, apart from maintaining tight glycemic control. It is therefore essential to understand the mechanisms underlying the pathogenesis of the disease in order to develop new therapeutic strategies. Biochemical and structural changes are observed in the extracellular matrix (ECM) of the peripheral nerve in diabetes: including increased endoneurial collagen; reduplication of basement membranes around endoneurial capillaries; a thickening of basal lamina; and accumulation of advanced glycation end-products (AGEs). In normal nerves, ischaemic or other damage to distal axons provokes a regenerative response; in diabetes this is abortive and failure of axonal regeneration is a hallmark of clinical and experimental diabetic neuropathy. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes that cleave the protein components of the ECM. MMP-2 and MMP-9 play a central role in Wallerian degeneration and regeneration following nerve injury. This thesis investigates whether MMP-2 and -9 expression and/or activity were altered in the peripheral nerve in diabetes, and could contribute to regenerative failure in diabetic neuropathy. Using an experimental model of diabetes, we have demonstrated that MMP-2, but not MMP-9, is upregulated at gene, protein and activity levels in the rat sciatic nerve 8 weeks post-streptozotocin (STZ). This upregulation was not maintained at later time-points of diabetes. In vitro sciatic nerve cryoculture studies showed that peripheral nerve from STZ-diabetic rats was less supportive for neurite outgrowth from dissociated adult rat sensory neurons than nerve obtained from age-matched control rats. Cyrocultures were pre-treated with either MMP-2 or chondroitinase ABC, remodelling the peripheral nerve ECM, via the removal of inhibitory chondroitin sulfate proteoglycans from the sciatic nerve, and significantly enhanced its ability to support axonal regeneration, and partially restored the diabetes-associated regenerative deficit. However, exogenous MMP-2 or MMP-9 did not directly affect neurite outgrowth of dissociated adult rat sensory neurons. Finally, we assessed the neuroprotective effects of the AGE inhibitors LR90 and pyridoxamine in experimental diabetes, using a number of electrophysiological, behavioural and biochemical endpoints. These inhibitors were effective at preventing the development of some of the functional deficits observed in STZ-diabetes. Sensory nerve conduction velocity deficits and lipid peroxidation in the sciatic nerve were prevented by both LR90 and pyridoxamine. These agents have potential for the treatment of diabetic neuropathy.