La thématique principale de nos travaux est l'étude de l'intégration du mouvement au niveau de la population du cortex visuel primaire du singe éveillé : de l'identification des circuits corticaux impliqués dans le traitement du mouvement,jusqu'à l'identification et l'émergence d'un signal de mouvement. Nous avons ainsi principalement utilisé deux protocoles (mouvement réel ou apparent).La réponse neuronale de population à l'entrée du système (V1) a été comparée à une réponse comportementale en sortie, la réponse de suivi oculaire réflexe (OFR).L'activité de population dans le cortex visuel primaire est enregistrée par imagerie optique de composés sensible au potentiel.Nous avons alors montré que la réponse au contraste dans V1 est contrôlée par un bassin de normalisation dynamique qui évolue lentement via un recrutement progressif et polysynaptique des circuits récurrents locaux. Ce bassin reçoit des afférents horizontaux liés au contraste qui suppriment graduellement le gain au contraste et à la réponse neuronale.Ensuite, en comparant l'activité de population de V1 avec la réponse de suivi oculaire réflexe avec un stimulus dont l'échelle intermédiaire active à la fois l'entrée et la sortie du système, nous avons identifié deux mécanismes distincts, impliqués dans les interactions contextuelles étudiées : un mécanisme précoce et rapide agissant sur les entrées fortes provenant majoritairement de MT et un mécanisme lent et soutenu plus visible sur les entrées faibles provenant majoritairement de V1.Finalement, en étudiant l'intégration et la représentation du mouvement apparent à la surface de V1, nous avons observé que la dynamique de l'activité corticale générée par des stimuli de mouvement apparent induit une suppression non-linéaire à la surface du cortex qui permet à la population de V1 de ne représenter qu'un seul stimulus à la fois, et ferait donc émerger un signal de mouvement non-ambigu.Pour conclure, nos expériences montrent que les interactions non-linéaires entre et parmi les aires corticales entraînent la normalisation, la modulation et l'émergence de différents signaux de mouvement. / Our goal is to study motion integration at population level in V1 in the awake behaving onkey. We compare V1population recorded with optical imaging of voltage sensitive dyes with ocular following response.We have shown that contrast response function in V1 is controlled by a dynamic normalization pool. Then we identified two distinct mechanisms involved in contextual modulations: a fast transient one originating from MT and a show and sustained one, originating from V1. Finally, we have observed that cortical activity dynamics in presponse to apparent motion can induce a suppression wave at acortical surface.

This article reviews the academic literature (1996-2016) that emerged under value sensitive design (VSD). It investigates those VSD projects that employed the tripartite methodology, examining the use of VSD methodological elements, and illustrating common practices and identifying shortcomings. The article provides advice for VSD researchers on how to complete and enhance their methodological approach as the research community moves forward.

Background: Post-myocardial infarction (MI) ventricular septal defects (PIVSD) are an uncommon but life-threatening complication of acute MI. Although surgical closure has been the standard of care, mortality, and recurrence of VSD remain high even after emergent surgery. Transcatheter VSD closure (TCC) devices have become an alternative or adjunct to surgical closure. Methods: Online database search was performed for studies that included adults with PIVSD who underwent medical treatment (MT) alone, surgical closure (SC) (early or late), and TCC (early, late, or for post-surgical residual VSD). Results: Twenty-six studies were included with a total of 737 patients who underwent either MT (N = 100), SC (early (n = 167), late (n = 100)), and TCC (early (n = 176), late (n = 115), or post-surgical residual VSD (n = 79)). The 30-day mortality among MT group was 92 ± 6.3%, among SC was 61 ± 22.5% (early 56 ± 23%, late 41 ± 30%), and for all TCC patients was 33 ± 24% (early 54 ± 32.7%, late 16 ± 26%), and TCC for post-surgical residual VSD 11 ± 34.9%. The mortality among overall SC, overall TCC and early TCC groups was significantly lower as compared with the MT (P < 0.001 for all comparisons). The overall mortality among all TCC, and late TCC groups was significantly lower when compared with the late SC (P < 0.0001, P < 0.0001, respectively). Conclusion: Closure of PIVSD decreases mortality as compared with MT alone and should be attempted as early as possible after diagnosis. Selection of TCC versus SC should be based on factors including complexity of the defect, availability of closure devices, expertise of the operator, and clinical condition of patient.

L'imagerie optique extrinsèque basée sur l'utilisation de colorants sensibles aux potentiels (VSD) est actuellement la seule technique de neuroimagerie offrant la possibilité d'observer l'activité d'une large population de neurones avec une forte résolution spatiale et temporelle. Dans cette thèse, notre but est d'étudier les origines biologiques du signal d'imagerie optique (signal VSD), étant donné que cette question reste sans réponse claire dans la littérature. Identifier l'origine du signal VSD est difficile au niveau physiologique car les molécules de colorant reflètent la dynamique du potentiel de membrane de toutes les membranes du tissu cortical, incluant toutes les couches corticales, tous les types de cellules (excitatrices, inhibitrices, gliales) et tous les compartiments neuronaux (somas, axons, dendrites). Pour répondre à cette question, nous proposons dans cette thèse d'utiliser un modèle biophysique de colonne corticale, à une echelle mésoscopique, prenant en compte les paramètres neuronaux biologiques connus de la structure corticale. Le modèle est basé sur un microcircuit cortical à six populations de neurones interconnectés: une population excitatrice et une population inhibitrice dans chacune des trois principales couches du cortex. Chaque neurone est représenté par une structure morphologique réduite à compartiments avec une dynamique de type Hodgkin-Huxley. Le modèle est alimenté par une activité spontanée, des connexions latérales et une entrée thalamique d'intensité croissante. Les neurones isolés et le comportement en réseau ont été ajustés pour correspondre à des données publiées dans la littérature. Le modèle ainsi ajusté offre ainsi la possibilité de calculer le signal VSD avec une formule linéaire. Nous avons validé le modèle en comparant le signal VSD simulé et le signal VSD mesuré expérimentalement. Grâce à la construction compartimentale de ce modèle, nous confirmons et quantifions le fait que le signal VSD est le résultat d'une moyenne de plusieurs composantes, avec comme contribution majeure, l'activité dendritique des neurones excitateurs des couches superficielles du cortex. Le modèle suggère également que les neurones inhibiteurs, l'activité supraliminaire et les couches profondes participent également au signal, et ce de manière dépendante du temps et de la force de la réponse. Nous arrivons à la conclusion que le signal VSD possède une origine multicomposante dynamique et proposons un nouveau formalisme pour l'interpréter.

This study aims to investigate how to work with sustainability in e-commerce, with a focus on making information available to the consumer as well as how this could be conceptualized. This requires a multidisciplinary approach, with domain knowledge based on environmental science and additional knowledge in information and computer science. In the time we live in now, we see an increased need to think sustainably and act for it in society. Consumption of products or services has a great impact on this and to a large extent via e-commerce today where consumers often find themselves confused in how to make a sustainable choice. We must work towards a more sustainable society and living. If we continue to utilize our planet's resources and assets without letting nature recover, we will probably end up in an unsustainable situation. Previous research shows the complexity in terms of sustainability, the definition as such but also how to assess it, a lack of regulated standards complicates the unified picture of what is actually sustainable. Creating an index or some form of standard for sustainability is not possible for us in relation to the time frame and scope of this study. An attempt to clarify what one can do with a focus on the consumer and how he or she can access information that is available or could be, is for us interesting to investigate. What made this possible was an extensive literature study to acquire the domain knowledge required to be able to understand what we needed to focus on, the literature study itself provided good insights and a good foundation as a starting point. By following a work process based on Design Science Research Methodology and with the opportunity to collaborate with an established company that works to guide consumers in e-commerce, we have been able to work in a concrete and relevant context and thus had the opportunity to test our concepts based on a literature study and data collection methods, consisting of questionnaires and interviews. Key findings from the study were that consumers wanted to know more about sustainability as well as the importance of involving the consumer in the process. Based on a literature study and the data collections, a basic data model for sustainability was developed. Companies in e-commerce should take the initiative to support sustainable online consumption. The task is difficult, but doing so could provide a competetive advantage among the companies and at the same time it contributes to a good cause.

Voltage-gated ion channels play fundamental roles in neural excitability, they are for instance responsible for every single heart beat in our bodies, and dysfunctional channels cause disease that can be even lethal. Understanding how the voltage sensor of these channels function is critical for drug design of compounds targeting neuronal excitability. The opening and closing of the pore in voltage-gated potassium (Kv) channels is caused by the arginine-rich S4 helix of the voltage sensor domain (VSD) moving in response to an external potential. In fact, VSDs are remarkably efficient at turning membrane potential into conformational changes, which likely makes them the smallest existing biological engines. Exactly how this is accomplished is not yet fully known and an area of hot debate, especially due to the lack of structures of the resting and intermediate states along the activation pathway. In this thesis I study how the VSD activation works and show how toxic compounds modulate channel gating through direct interaction with these quite unexplored drug targets. First, I show that a secondary structure transition from alpha- to 3(10)-helix in the S4 helix is an important part of the gating as this helix type is significantly more favorable compared to the -helix in terms of a lower free energy barrier. Second, I present new models for intermediate states along the whole voltage sensor cycle from closed to open and suggest a new gating model for S4, where it moves as a sliding 3(10)-helix. Interestingly, this 3(10)-helix is formed in the region of the single most conserved residue in Kv channels, the phenylalanine F233. Located in the hydrophobic core, it directly faces S4 and creates a structural barrier for the gating charges. Substituting this residue alters the deactivation free energy barrier and can either facilitate the relaxation of the voltage sensor or increase the free energy barrier, depending on the size of the mutant. These results are confirmed by new experimental data that supports that a rigid ring at the phenylalanine position is the rate-limiting factor for the deactivation gating process, while the activation is unaffected. Finally, we study how the activation can be modulated for pharmaceutical reasons. Neurotoxins such as hanatoxin and stromatoxin push S3b towards S4 helix limiting S4's flexibility. This makes it harder for the VSD to activate and might explain the stronger binding affinities in resting state. All these results are highly important both for the general topic of biological macromolecules undergoing functionally critical conformational transitions, as well as the particular case of voltage-gated ion channels where understanding of the gating process is probably the key step to explain the effects of mutations or drug interactions. / <p>QC 20121115</p>

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-07-06T20:38:09Z No. of bitstreams: 1 TiagoSiebertAltavini_TESE.pdf: 2131166 bytes, checksum: e6857312ffe2ac0d8a4cdc18238707e4 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-07-08T17:47:44Z (GMT) No. of bitstreams: 1 TiagoSiebertAltavini_TESE.pdf: 2131166 bytes, checksum: e6857312ffe2ac0d8a4cdc18238707e4 (MD5) / Made available in DSpace on 2016-07-08T17:47:44Z (GMT). No. of bitstreams: 1 TiagoSiebertAltavini_TESE.pdf: 2131166 bytes, checksum: e6857312ffe2ac0d8a4cdc18238707e4 (MD5) Previous issue date: 2016-01-29 / A atividade cerebral espont?nea exibe padr?es que lembram o de coativa??o de conjuntos neuronais em resposta a est?mulos ou tarefas. Estes padr?es tem sido atribu?dos a arquitetura funcional do c?rebro, e.g. conex?es de longo alcance em patches (manchas, fragmentos). N?s investigamos diretamente a contribui??o destas conex?es em patches entre hemisf?rios para mapas espont?neos e evocados na ?rea 18 pr?xima a borda 17/18 de gatos. Registramos mapas com imageamento por votage-sensitive dye (VSD) e atividade despiking enquanto manipulamos o input interhemisf?rico pela desativa??o revers?vel das ?reas correspondentes contralaterais. Durante a desativa??o os mapas espont?neos continuaram sendo gerados com frequ?ncia e qualidade semelhante ao da rede intacta, mas um vi?s de orienta??es cardinais desapareceu. Neur?nios com prefer?ncia por orienta??es horizontais (HN) ou verticais (VN), ao contr?rio dos de prefer?ncia obl?qua, diminuiram sua atividade de repouso, no entanto, HN tiveram a atividade diminu?da mesmo quando estimulados visualmente. Conclu?mos que mapas espont?neos estruturados s?o primariamente gerados por conex?es t?lamo- e/ou intracorticais. Entretanto, conex?es de longo alcance pelo corpo caloso - como um prolongamento da rede de longo alcance intracortical - contribui para um vi?s cardinal, possivelmente porque estas conex?es s?o mais fortes ou mais frequentes entre neur?nios preferindo orienta??es horizontais e/ou cardinais. Estes contornos s?o mais f?ceis de perceber e aparecem com mais frequ?ncia no ambiente natural, cone x?es de longo alcance podem prover o c?rtex visual com um grid de opera??es probabil?sticas de agrupamento em uma cena visual maior. / In the primary visual cortex, neurons with similar physiological features are clustered together in columns extending through all six cortical layers. These columns form modular orientation preference maps. Long-range lateral fibers are associated to the structure of orientation maps since they do not connect columns randomly; they rather cluster in regular intervals and interconnect predominantly columns of neurons responding to similar stimulus features. Single orientation preference maps ? the joint activation of domains preferring the same orientation - were observed to emerge spontaneously and it was speculated whether this structured ongoing activation could be caused by the underlying patchy lateral connectivity. Since long-range lateral connections share many features, i.e. clustering, orientation selectivity, with visual inter-hemispheric connections (VIC) through the corpus callosum we used the latter as a model for long-range lateral connectivity. In order to address the question of how the lateral connectivity contributes to spontaneously generated maps of one hemisphere we investigated how these maps react to the deactivation of VICs originating from the contralateral hemisphere. To this end, we performed experiments in eight adult cats. We recorded voltage-sensitive dye (VSD) imaging and electrophysiological spiking activity in one brain hemisphere while reversible deactivating the other hemisphere with a cooling technique. In order to compare ongoing activity with evoked activity patterns we first presented oriented gratings as visual stimuli. Gratings had 8 different orientations distributed equally between 0? and 180?. VSD imaged frames obtained during ongoing activity conditions were then compared to the averaged evoked single orientation maps in three different states: baseline, cooling and recovery. Kohonen self-organizing maps were also used as a means of analysis without prior assumption (like the averaged single condition maps) on ongoing activity. We also evaluated if cooling had a differential effect on evoked and ongoing spiking activity of single units. We found that deactivating VICs caused no spatial disruption on the structure of either evoked or ongoing activity maps. The frequency with which a cardinally preferring (0? or 90?) map would emerge, however, decreased significantly for ongoing but not for evoked activity. The same result was found by training self-organizing maps with recorded data as input. Spiking activity of cardinally preferring units also decreased significantly for ongoing when compared to evoked activity. Based on our results we came to the following conclusions: 1) VICs are not a determinant factor of ongoing map structure. Maps continued to be spontaneously generated with the same quality, probably by a combination of ongoing activity from local recurrent connections, thalamocortical loop and feedback connections. 2) VICs account for a cardinal bias in the temporal sequence of ongoing activity patterns, i.e. deactivating VIC decreases the probability of cardinal maps to emerge spontaneously. 3) Inter- and intrahemispheric long-range connections might serve as a grid preparing primary visual cortex for likely junctions in a larger visual environment encompassing the two hemifields.

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One of the most common risk factors for stroke is diabetes. Diabetics are 2 to 4 times more likely to have a stroke and are also significantly more likely to show poor functional recovery. In order to determine why diabetes is associated with poor stroke recovery, we tested the hypotheses that diabetes either exacerbates initial stroke damage, or inhibits neuronal circuit plasticity in surviving brain regions that is crucial for successful recovery. Type 1 diabetes was chemically induced in mice four weeks before receiving a targeted photothrombotic stroke in the right forelimb somatosensory cortex to model a chronic diabetic condition. Following stroke, a subset of diabetic mice were treated with insulin to determine if controlling blood glucose levels could improve stroke recovery. Consistent with previous studies, one behavioural test revealed a progressive improvement in sensory function of the forepaw in non-diabetic mice after stroke. By contrast, diabetic mice treated with and without insulin showed persistent deficits in sensori-motor forepaw function. To determine whether these different patterns of stroke recovery correlated with changes in functional brain activation, forepaw evoked responses in the somatosensory cortex were imaged using voltage sensitive dyes at 1 and 14 weeks after stroke. In both diabetic and non-diabetic mice that did not have a stroke, brief mechanical stimulation of the forepaw evoked a robust and near simultaneous depolarization in the primary (FLS1) and secondary somatosensory (FLS2) cortex. One week after stroke, forepaw-evoked responses had not been remapped in the peri-infarct cortex in both diabetic and non-diabetic mice. Fourteen weeks after stroke, forepaw evoked responses in non-diabetic mice re-emerged in the peri-infarct cortex whereas diabetic mice showed very little activation, reminiscent of the 1 week recovery group. Moreover, controlling hyperglycemia using insulin therapy failed to restore sensory evoked responses in the peri-infarct cortex. In addition to these differences in peri-infarct responsiveness, we discovered that stroke was associated with increased responsiveness in FLS2 of non-diabetic, but not diabetic or insulin treated mice. To determine the importance of FLS2 in stroke recovery, we silenced the FLS2 cortex and found that it re-instated behavioural impairments in stroke recovered mice, significantly more so than naïve mice that still had a functioning FLS1. Collectively, these results indicate that both diabetes and the secondary somatosensory cortex play an important role in determining the extent of functional recovery after ischemic cortical stroke. Furthermore, the fact that insulin therapy after stroke did not normalize functional recovery, suggests that prolonged hyperglycemia (before stroke) may induce pathological changes in the brain’s circulation or nervous system that cannot be easily reversed. / Graduate