No description available.

No description available.

No description available.

No description available.

No description available.

[pt] A Síndrome da Imunodeficiência Adquirida (SIDA/AIDS) é causada pelo HIV. De uma forma geral, o HIV é um retrovírus que ataca o sistema imunológico, principalmente os linfócitos T auxiliares (também chamados de linfócitos T4 ou T CD4+), que normalmente se encontram na corrente sanguínea e são responsáveis por toda a coordenação da defesa imunológica do organismo. Muitas estratégias de tratamento estão sendo desenvolvidas e testadas, incluindo o uso de medicamentos que impedem o vírus de entrar na célula (inibidores de fusão). Estes medicamentos representam uma abordagem muito interessante no tratamento do HIV/AIDS, uma vez que os outros tipos de fármacos atacam o vírus somente após a infecção no linfócito. Dentre os promissores candidatos a novos inibidores de fusão, destacam-se o maraviroc, vicriviroc, aplaviroc e o para-biciclo AMD 3100. Foi constatado que os biciclosexibem efeitos biológicos relevantes, toxicidade reduzida e que os substituintes ligados ao anel central interferem na atividade biológica desses compostos. Sendo assim, neste trabalho, o AMD 3100 foi considerado um protótipo para a síntese de diidrazonas, que representam uma classe de compostos orgânicos definidas pela presença do grupo funcional R1R2C=N-NR3R4. Estudos revelam que hidrazonas e várias hidrazonas substituídas estão associadas com uma ampla aplicabilidade biológica. Os espaçadores aromáticos utilizados foram os centros precursores 2,5-dimetoxitereftalaldeído, 2,5-diidroxitereftaladeído e tereftalaldeído, os quais foram modificados em posições relativas para por compostos bioativos como a hidrazida do ácido furânico, hidrazida do ácido tiofênico e hidrazida do ácido isonicotínico através de uma reação de condensação. Dessa forma, nove diidrazonas foram obtidas e caracterizadas por análise elementar, pelas técnicas espectroscópicas IV, Raman e UV-Vis, termogravimetria e RMN de 1H. Um estudo preliminar in silico (computacional) de avaliação farmacológica também foi realizado a fim de avaliar o desempenho relativo a algumas propriedades moleculares relevantes para a farmacocinética de uma droga no corpo humano. A estrutura cristalina foi obtida para apenas uma das di-hidrazonas. Baseando-se na constatação de que íons metálicos em metalofármacos contribuem para o aumento das potencialidades dos mesmos e de que os complexos de zinco com AMD3100 são os que apresentam melhores resultados biológicos, realizaram-se tentativas para obtenção de complexos de zinco para cada di-hidrazona sintetizada. Foram obtidos três complexos binucleares de zinco(II), uma vez que os demais ligantes apresentaram uma solubilidade muito baixa para se realizar as sínteses. Os complexos foram caracterizados por análise elementar, FT-IR, Raman e espectroscopia UV-Vis e termogravimetria. Concluiu-se que as di-hidrazonas relatadas nesse trabalho apresentam bons rendimentos, propriedades farmocinéticas e moleculares importantes e que a estrutura cristalina obtida apresenta duas conformações diferentes. Nos complexos, a coordenação acontece pelo sistema N2O-doador dos braços pendentes e os substituintes do anel aromático central participam da coordenação (no caso dos oxigênios dos grupos metoxila e fenol). / [en] The Acquired Immune Deficiency Syndrome (HIV/AIDS) is caused by HIV. In general, HIV is a retrovirus that attacks the immune system, primarily helper T lymphocytes (also called T4 or CD4 + T lymphocytes) which are normally found in the bloodstream and are responsible for all the coordination of the immune defense body. Several treatment strategies are being developed and tested, including the use of drugs that prevent the virus from entering the cell (entry inhibitor). These drugs represent a very interesting approach in the treatment of HIV/AIDS, since other types of drugs attack the virus only after the infection the lymphocytes. Among the promising candidates for new fusion inhibitors, the highlights are maraviroc, vicriviroc, aplaviroc and para-bicyclo AMD 3100. It was found that the bicyclic exhibit significant biological effects, and reduced toxicity to the central ring substituents attached to interfere in the activity these organic compounds. Thus, in this work, the AMD 3100 was considered a prototype for the synthesis of di-hydrazones, which represent a class of organic compounds defined by the presence of the functional group R1R2C = N-NR3R4. Studies have shown that several hydrazones and substituted hydrazones are associated with a broad biological applicability. The aromatic spacers used were the precursors centers 2,5-dimethoxyterephthalaldehyde, 2,5-dihydroxyterephthalaldehyde and terephthalaldehyde, which were modified in relative positions to a bioactive compounds such as furan acid hydrazide, thiophenic acid hydrazide and isonicotinic acid hydrazide by a condensation reaction. Thus, nine di-hydrazones were obtained and characterized by elemental analysis, by IR spectroscopic techniques, Raman and UV-Vis spectroscopy, thermogravimetric analysis and 1H NMR. A preliminary study in silico (computational) pharmacological evaluation was also conducted to evaluate the relative performance of some relevant molecular properties for the pharmacokinetics of a drug in the human body. The crystal structure was obtained for only one of the di-hydrazone. Based on the fact that metal ions in metallodrugs contribute to increasing the potential of the same and that the zinc complexes with AMD3100 are those with best biological results, there were attempts to obtain zinc complexes for each di-hydrazone synthesized. Three complexes were obtained dinuclear zinc(II), since the other ligands showed very low solubility to carry out the synthesis. The compounds were characterized by elemental analysis, FT-IR, Raman and UV-Vis spectroscopy and thermogravimetric analysis. It was concluded that the di-hydrazone reported in this work have very good yields important farmocinéticas and molecular properties that the obtained crystal structure shows two different conformations. In the complex , the coordination takes place by the arms pending N2O - donor system and the central aromatic ring substituents involved coordination (in the case of the oxygens of methoxyl groups and phenol).

Vision impairment and blindness are in industrialized countries primarily caused by the degeneration of the retina, the light sensing tissue inside the eye. The degeneration, occurring in diseases like age-related macular degeneration (AMD) or retinitis pigmentosa (RP), can be caused by environmental factors as well as genetic defects and thus shows diverse pathologies. In all conditions, the light detecting photoreceptors (rods and/or cones) are dying caused by either direct photoreceptor damage or as a secondary effect following degeneration of supporting cells. Although promising treatment approaches are currently under investigation, up to date it is not possible to cure these diseases. Amongst these therapeutic strategies, pre-clinical studies evaluating the replacement of degenerated cells by transplantation of new photoreceptors demonstrated promising results. First studies conducted the specific enrichment and transplantation of primary photoreceptors derived from postnatal mice and their sufficient integration and differentiation into mature photoreceptors in wild-type as well as degenerated mouse retinae. Recent experiments additionally proved the recovery of some dim-light vision after transplantation in mice lacking night sight. The in vitro differentiation of whole eye cups containing photoreceptors, out of human or mouse ES or iPS cells, peaked in the transplantation of ES-derived photoreceptors into wild-type as well as degenerated mice and the integration and maturation of these cells. These observations are encouraging, but prior to a save implementation of this strategy into a clinical routine, several further hurdles need to be challenged. Collection of photoreceptors out of whole retinal tissues prior to transplantation was shown to be an important step to reach high integration rates. Additionally, transplantation of photoreceptors derived from stem cells comprises the risk of tumor formation after transplantation and thus also requires depletion of inadvertent cells. Therefore, we established the enrichment of photoreceptors using the cell surface marker dependent method magnetic-activated cell sorting (MACS). For identification of suitable target-specific surface markers, we characterized young transplantable mouse photoreceptors using microarray analysis and screened their transcriptome. Amongst others, ecto-5´nucleotidase (Nt5e, termed CD73) was identified being a rod photoreceptor specific cell surface protein. Thus, we enriched young photoreceptors with CD73-dependent MACS with sufficient purity and transplanted these cells into the subretinal space of wild-type mice. In contrast to unsorted retinal cells, enriched photoreceptors integrated in significantly higher number into the host retina, proving that MACS is a suitable alternative for specific photoreceptor enrichment. Testing other proteins, identified as photoreceptor specific, for MACS suitability and the translation of this approach to photoreceptors, derived from mouse as well as human iPS or ES cells, should be the focus of consecutive investigations. The integration of grafted cells into the retina is a complex process dependent on a variety of influencing factors. Transplantation experiments in aging wild-type mice and a rod-depleted mouse model, containing a retina composed of cone and cone-like photoreceptors, indicated that the activation of Müller glia cells facilitates integration of transplanted photoreceptors. Besides that, reduced outer limiting membrane (OLM) integrity, increased subretinal graft distribution or reduced retinal cell density are further suggested as potential cell engraftment enhancers. These factors might open up important possibilities of host retina manipulation to increase cell integration rates. Although retinal transplantation experiments were in addition to mice also performed using pigs or rats as hosts, the transplantation of enriched single photoreceptors, following the protocols successfully established in mice, has not been performed in other species. Nevertheless, transferring this technique is important and would allow better predictions for future application in human patients. Therefore, we transferred our protocol, using CD73 based MACS, to the rat and successfully enriched rat photoreceptors with sufficient purity. We subsequently transplanted these cells into the subretinal space of rats as well as mice and observed limited integration capacity of grafted cells. Only few transplanted rat photoreceptors were localized in the rat retina, lacking proper photoreceptor morphology. Especially regarding a perspective clinical application in humans, these data are remarkable. They imply the question, whether low integration in rat represents a general problem and might thus also be relevant for treatment in humans, or whether the rat retina forms just an exception. Thus, further detailed analysis of the cellular and molecular mechanisms underlying the integration process of transplanted photoreceptors represent an essential prerequisite for the development of a safe and efficient therapy, aiming to treat retinal degenerative diseases characterized by photoreceptor loss. / Degenerationserkrankungen der Netzhaut (Retina) sind in Industrieländern die Hauptursache für verminderte Sehfähigkeit und Blindheit. Sowohl Umweltfaktoren als auch vererbte Mutationen können Defekte wie altersbedingte Makuladegeneration (AMD) oder Retinitis pigmentosa (RP) auslösen und führen zu einem sehr variablen Krankheitsbild. Eine Gemeinsamkeit aller Formen ist das Absterben der lichtdetektierenden Fotorezeptoren (Stäbchen und/oder Zapfen). Dieses kann entweder durch direkte Schädigung, oder als Sekundäreffekt nach Degeneration der unterstützenden Zellen erfolgen. Obwohl im Moment vielversprechende Behandlungsansätze untersucht werden, ist es zurzeit nicht möglich, retinale Degenerationserkrankungen dieser Art zu heilen. Ein erfolgversprechender Ansatz könnte jedoch der Ersatz der degenerierten Zellen durch transplantierte Fotorezeptoren sein. Erste Studien demonstrierten die spezifische Anreicherung von primären Fotorezeptoren aus der Netzhaut neugeborener Mäuse und deren subretinale Transplantation in Wildtyp-Mäuse und Mausmodelle mit retinaler Degeneration. Die transplantierten Zellen integrierten in die Empfängernetzhaut und entwickelten sich in ausgereifte Fotorezeptoren und konnten unter anderem bei nachtblinden Mäusen die Sehfähigkeit bei Dunkelheit verbessern. Die Differenzierung von humanen oder murinen ES- und iPS-Zellen in vitro in vollständige Retinae und die Transplantation daraus gewonnener Fotorezeptoren in Mäuse, bilden vorläufig den Höhepunkt dieser Entwicklung. Obwohl die Fortschritte der jüngsten Vergangenheit beeindruckend sind, sollten vor der sicheren und effektiven Anwendung einer retinalen Zellersatztherapie als therapeutische Maßnahme beim Menschen noch einige wissenschaftliche Fragestellungen beantwortet werden. Studien zeigen, dass Zellpopulationen, die direkt aus der Spendernetzhaut entnommen und transplantiert wurden, auf Grund ihrer Heterogenität in geringeren Zahlen in die Empfängerretina einwandern als angereicherte Fotorezeptoren. Zusätzlich besteht bei unsortierten Zellen, die aus Stammzellpopulationen gewonnen wurden, das Risiko einer Tumorbildung. Daher haben wir die magnetisch-aktivierte Zellsortierung (MACS) zur Anreicherung junger Fotorezeptoren etabliert. Die dabei benötigten, für Fotorezeptoren spezifischen, Oberflächenproteine wurden mit Hilfe von Microarray-Analysen des Transkriptoms junger Stäbchen von Mäusen identifiziert. Dabei wurde unter anderem die 5\'-Nukleotidase (Nt5e, CD73) entdeckt, die uns die erfolgreiche Anreicherung junger Mausfotorezeptoren mit Hilfe von CD73-vermitteltem MACS erlaubte. Die Transplantation dieser angereicherten Zellpopulation in die Netzhaut von Empfängertieren resultierte in einer signifikant erhöhten Integrationsrate im Vergleich zu nicht-angereicherten retinalen Zellen. Die Überprüfung der Nutzbarkeit weiterer identifizierter Oberflächenproteine zur Zellanreicherung bzw. die Übertragung der etablierten Protokolle zur Zellsortierung und Transplantation auf Fotorezeptoren aus ES- und iPS-Zellkulturen, sollten im Fokus nachfolgender Experimente stehen. Die Integration transplantierter Zellen in die Empfängernetzhaut ist ein komplexer Prozess und von unterschiedlichen Einflussfaktoren abhängig. Durch Transplantationsexperimente in alternden Wildtyp-Mäusen und einem Mausmodell, dessen Fotorezeptorschicht keine Stäbchen und stattdessen nur Zapfen und zapfenähnlichen Fotorezeptoren aufweist, konnte gezeigt werden, dass vor allem die Aktivierung von Müllerzellen die Integrationsrate der Fotorezeptoren erhöht. Neben dieser sogenannten Gliose werden weitere Faktoren, wie die reduzierte Stabilität der äußeren Grenzmembran, die flächenmäßig größere Verteilung der transplantierten Zellen im subretinalen Raum oder die reduzierte Dichte der Zellen in der äußeren Körnerschicht, als potentielle integrationsfördernde Komponenten in Betracht gezogen. Diese bilden interessante Schwerpunkte für weitere Forschungen, um eine ausreichende Zellintegration durch Manipulation der Empfängernetzhaut, auch in der klinischen Anwendung, zu erreichen. Obwohl Transplantationsexperimente zusätzlich zur Maus auch in anderen Empfängerspezies, wie Ratten und Schweinen, durchgeführt wurden, liegen bis jetzt keine Studien vor, die die in der Maus erfolgreich etablierten Protokolle der Zellanreicherung und Transplantation von Fotorezeptor-Suspensionen in diesen Spezies reproduzierte. Der Transfer dieser Technik und eine Generalisierung der Anwendbarkeit eines Fotorezeptorersatzes durch Transplantation in verschiedenen Säugetierarten geben jedoch wichtige Hinweise für eine mögliche Translation dieser Technologie für klinische Anwendungen. Deshalb haben wir unser bereits an der Maus getestetes Protokoll auf die Ratte übertragen und erfolgreich Fotorezeptoren der Ratte mit Hilfe von CD73-vermitteltem MACS angereichert. Nach deren Transplantation in die Netzhaut von Ratten und Mäusen zeigten die Rattenfotorezeptoren aber eine stark verminderte Integrationsfähigkeit und das Fehlen einer reifen Fotorezeptormorphologie. Speziell in Hinsicht auf eine zukünftige klinische Anwendung sind diese Ergebnisse relevant, da sie die Frage aufwerfen, ob die mangelnde Integration in der Ratte ein generelles Problem darstellt und daher auch beim Menschen zu erwarten ist, oder ob sie nur eine Ausnahme im Rattenmodell bildet. Aus diesem Grund bildet die weitere Erforschung der zellulären und molekularen Mechanismen der Integration transplantierter Fotorezeptoren eine wichtige Grundlage für die Entwicklung einer sicheren und effizienten Therapie mit dem Ziel, degenerative Netzhauterkrankungen zu heilen.

La présence d'un scotome maculaire oblige les patients à utiliser la vision excentrée ce qui provoque une difficulté à coordonner les systèmes oculomoteur et visuo-attentionnel. La lecture devient alors une des plaintes majeures chez ces patients, et les processus impliqués dans la baisse des performances de lecture restent mal connus. Dans la plupart des cas, le patient développe une ou plusieurs zones de la rétine excentrée dites préférentielles, et dénommées couramment PRLs. Nous nous proposons ici d'utiliser une approche psychophysique afin d'étudier les processus de la lecture en vision excentrée. Nous avons tout d'abord élaboré un test de lecture francophone informatisé suivant les principes des MNRead Acuity Charts afin de pouvoir évaluer la vitesse maximale de lecture chez des patients porteurs de scotomes centraux binoculaires dont l'atteinte avait été mesurée à l'aide d'un micropérimètre MP-1. Deux analyses utilisant des modèles statistiques à effets mixtes nous ont permis de mettre en évidence des prédicteurs efficaces de la vitesse maximale de lecture: 1) l'espace interligne; 2) le type de DMLA ; 3) la surface du scot; 4) la distance entre la PRL de fixation et la fovéa; 5) le statut du cristallin. Puis, nous nous sommes intéressés aux stratégies de lecture déployées par les patients. L'analyse de la distribution verticale des fixations enregistrées pendant la lecture nous a permis de mettre en évidence que dans 97% des cas, les patients utilisent une zone préférentielle de la rétine unique dans le plan vertical.Ces résultats présentent des intérêts théoriques et pratiques dans la création de nouveaux supports visuels et techniques de réadaptation. / Patients with central field loss (CFL) have to use eccentric vision and complain particularly about reading. The purpose of this thesis is to investigate reading processes in those patients using psychophysical tools. First, we investigated predictors of reading performances. We developed a French computerized version of the MNRead Acuity Charts to assess Maximum Reading Speed in patients with binocular scotomas, measured with the microperimeter MP-1. Two distinct analyses using mixed effects models allowed us to estimate the influence of predictors of Maximum Reading Speed: 1) interline spacing; 2) AMD type; 3) scotoma size; 4) distance between fixation PRL and fovea; 5) lens status. Then, we investigated oculomotor patterns of patients during sentence reading. Analysing the vertical distribution of fixations lead us to the conclusion that in most cases (97%), patients use a single eccentric preferred retinal locus (PRL) in the vertical meridian during reading. One potential goal of these studies is to find some ways to enhance text display and improve visual readaptation.

No description available.

Several modern multi-core architectures support the dynamic control of the CPU's clock rate, allowing processor cores to temporarily operate at speeds exceeding the operational base frequency. Conversely, cores can operate at a lower speed or be disabled altogether to save power. Such facilities are notably provided by Intel's Turbo Boost and AMD's Turbo CORE technologies. Frequency control is typically driven by the operating system which requests changes to the performance state of the processor based on the current load of the system. In this paper, we investigate the use of dynamic frequency scaling from user space to speed up multi-threaded applications that must occasionally execute time-critical tasks or to solve problems that have heterogeneous computing requirements. We propose a general-purpose library that allows selective control of the frequency of the cores - subject to the limitations of the target architecture. We analyze the performance trade-offs and illustrate its benefits using several benchmarks and real-world workloads when temporarily boosting selected cores executing time-critical operations. While our study primarily focuses on AMD's architecture, we also provide a comparative evaluation of the features, limitations, and runtime overheads of both Turbo Boost and Turbo CORE technologies. Our results show that we can successful exploit these new hardware facilities to accelerate the execution of key sections of code (critical paths) improving overall performance of some multi-threaded applications. Unlike prior research, we focus on performance instead of power conservation. Our results further can give guidelines for the design of hardware power management facilities and the operating system interfaces to those facilities.