We have previously shown that a high-protein, carbohydrate-free diet can decrease the production of glycerol-3-phosphate (G3P) from glucose and increase glyceroneogenesis in both brown (BAT) and epididymal (EAT) adipose tissue. Here, we utilized an in-vivo approach to examine the hypothesis that there is reciprocal regulation in the G3P synthesis from glucose (via glycolysis) and glyceroneogenesis in BAT, EAT and liver of fasted rats and cafeteria diet-fed rats. Glyceroneogenesis played a prominent role in the generation of G3P in the liver (similar to 70 %) as well as in BAT and EAT (similar to 80 %) in controls rats. The cafeteria diet induced an increase in the total glyceride-glycerol synthesis and G3P synthesis from glucose and a decrease in glyceroneogenesis in BAT; this diet did not affect either the total glyceride-glycerol synthesis or G3P generation from glyceroneogenesis or glycolysis in the liver or EAT. Fasting induced an increase in total glyceride-glycerol synthesis and glyceroneogenesis and a decrease in G3P synthesis from glucose in the liver but did not affect either the total glyceride-glycerol synthesis or G3P synthesis from glyceroneogenesis in BAT and EAT, despite a reduction in glycolysis in these tissues. These data demonstrate that reciprocal changes in the G3P generation from glucose and from glyceroneogenesis in the rat liver and BAT occur only when the synthesis of glycerides-glycerol is increased. Further...

A síntese de peptídeos em fase sólida passo a passo (SPFS) tem sido aplicada com sucesso na preparação de peptídeos curtos, médios e de determinados sequências contendo mais de 30 resíduos. Entretanto, esta apresenta problemas e limitações que podem ser contornados pela síntese convergente de peptídeos em fase sólida (SCPFS) que se baseia na condensação entre fragmentos peptídicos Nα-acilados protegidos em suas cadeias laterais (doadores de acila) a fragmentos protegidos ligados a um suporte polimérico (receptores de acila). Além de desenvolver outros projetos enfocados na síntese de peptídeos ou no uso de sintéticos para o estudo de peptídeos biologicamente ativos ou proteinas, o nosso grupo de pesquisa tem se dedicado a estudar o emprego de temperaturas altas em SPFS. O objetivo final é propor protocolos ágeis alternativos aos empregados classicamente. Neste trabalho nos propusemos a investigar alguns aspectos da SCPFS e a explorar a possibilidade de agilizá-Ia a 60°C. Para tanto, empregamos como modelos a colecistocinina-33 humana (hCCK-33) não sulfatada e o análogo [Gln1]-gomesina. As seqüências destes peptídeos foram divididas em: doadores de acila (fragmentos central e N-terminal da hCCK-33 não sulfatada de 11 e de 5 resíduos...

No presente trabalho foram desenvolvidas duas rotas sintéticas: uma para a preparação de uma série de seleno-carboidratos quirais, derivados da D-xilose e D-galactose, e outra aplicada à obtenção de glicoconjugados e dissacarídeos, onde as duas unidades básicas encontram-se ligadas por um átomo de selênio. Através de estratégias sintéticas simples e eficientes, obteve-se uma série de compostos heterocíclicos com elevado potencial para aplicação biológica. Para a síntese dos derivados xilofuranosídeos, a D-xilose 1 foi inicialmente convertida no diol 3, passando por um intermediário bis-acetonídeo 2. Tosilação seletiva da hidroxila primária, seguida da reação com nucleófilos de selênio resultou na síntese dos seleno-carboidratos 5a-j. Adicionalmente, o composto 5a foi convertido no derivado metilglicosilado 6, mediante desproteção do acetonídeo e reação com metanol em meio ácido. A reação do tosilato 4 com Li2Se2 e Li2Se resultou na formação do disseleneto 7 e do seleneto 8. Posteriormente, uma série de seleno-carboidratos funcionalizados foi preparada pela clivagem redutiva de 7 e reação do selenolato formado com eletrófilos selecionados. A expansão do escopo do trabalho para síntese de derivados galactopiranosídeos contendo selênio seguiu estratégia à anterior. Assim...

A síntese de nanopartículas com morfologia controlada vem sendo objeto de interesse crescente no campo da Ciência dos Materiais. Devido a essa motivação, o principal objetivo desse trabalho foi a síntese e caracterização de pseudoboemita e boemita apresentando uma ou duas dimensões nanométricas. O método de síntese utilizado para a obtenção de pseudoboemita fibrilar é baseado na reação de um alcóxido de alumínio, em solução aquosa de ácido acético. Para a preparação de boemita, um único método de síntese, a síntese hidrotérmica, foi utilizado, com o emprego de três precursores: uma pseudoboemita, um sal orgânico (o monohidróxido diacetato de alumínio) e o trihidróxido de alumínio gibsita, este último em duas formas: uma gibsita comercial e uma gibsita sintetizada que utiliza iodo como ativador. As pseudoboemitas e as boemitas obtidas foram caracterizadas por difração de raios-X e microscopia eletrônica de varredura. Algumas amostras de pseudoboemita e de boemita foram caracterizadas por análise térmica diferencial e por espectroscopia vibracional na região do infravermelho. Foram obtidas pseudoboemitas com morfologia fibrilar (partículas anisométricas alongadas); no caso das boemitas foram produzidas distintas morfologias (de acordo com o precursor e com as condições de síntese empregadas em sua obtenção): fibrilar (duas dimensões em escala nanométrica)...

Esse trabalho de doutorado visou explorar a reação de Morita-Baylis- Hillman (MBH) nos aspectos relacionados ao seu mecanismo e a utilização de seus adutos, como substratos para síntese de moléculas com propriedades biológicas. Realizamos estudos mecanísticos dessa reação, utilizando ESI-MS, sendo possível, interceptar e caracterizar, em fase gasosa, intermediários dessa reação. Outro estudo nos permitiu re-avaliar o comportamento de (tio)uréias como catalisadores desta reação. Neste trabalho, propomos um mecanismo com a participação de (tio)uréias na reação de MBH. Na segunda parte deste trabalho de tese visamos a utilização de adutos de MBH na síntese de moléculas de interesse biológico. Sendo assim, realizamos a síntese de esqueletos 4-fluoroquinolônicos. Para tal, utilizamos adutos de MBH derivados do o-nitrobenzaldeído. Em particular, estudamos o mecanismo de uma etapa desta síntese, uma ciclização em TFA. Neste estudo, um novo intermediário chave foi caracterizado por ESI-MS. Após 4 etapas sequenciais preparamos a Norfloxacina. Outro alvo foi a síntese enantiosseletiva de um análogo do DFP. Neste trabalho, utilizamos um aduto de MBH que após 3 etapas obtivemos um álcool alílico derivado...

Esta dissertação trata principalmente da pesquisa de métodos matemáticos e algoritmos com a finalidade de gerar e controlar fluxos de som em tempo real dentro do escopo da síntese granular. Inicialmente abordamos os fundamentos matemáticos da Síntese Granular proposta pelo Prêmio Nobel de Física Dennis Gabor. Em seguida apresentamos uma breve revisão histórica do uso desta técnica em composições eletroacústicas e analisamos alguns dos mais conhecidos aplicativos atuais para síntese granular. Com base nestes estudos desenvolvemos um software para síntese granular em tempo real que denominamos EVOGrain. Este aplicativo apresenta uma interface gráfica intuitiva e amigável com a qual o compositor controla a síntese granular desenhando, com uso do mouse, retângulos de diferentes tamanhos e posição. As coordenadas destes retângulos fornecem informação que guia a execução de um algoritmo genético, que por sua vez controla os parâmetros de um módulo de síntese granular em tempo real resultando em sonoridades e texturas que evoluem dinamicamente. Na segunda parte da dissertação apresentamos os resultados da nossa pesquisa realizada no laboratório Input Devices for Music Interaction Lab (IDMIL) da McGill University através de um estágio pelo programa de intercâmbio canadense Emerging Leaders from the Americas Program (ELAP). Nesta pesquisa...

The first total synthesis of the antineoplastic marine natural product metachromin-A (1) was accomplished through a convergent synthetic approach amenable to the preparation of analogues for biological studies. The synthesis involved twelve steps in its longest sequence and sixteen steps overall. The total synthesis of the racemic metachromin-A features: (1) an efficient synthesis of the quinone intermediate 11; (2) efficient protocols for the preparation of the key fragments 5 and 6; (3) a highly regioselective Thiele-Winter acetoxylation step; and (4) a stereoselective Horner-Wadsworth-Emmons coupling reaction employing fragment 6 as a non-stabilized phosphonate as an effective partner. The metachromin-A synthesis was made formally enantioselective by the asymmetric synthesis of fragment 5 employing the methodologies developed by Simpkins (asymmetric deprotonation with a chiral nitrogenated base) and d’Angelo (enantioselective deracemization). This latter protocol furnished fragment 5 with an enantiomeric excess of ~85%, as determined by ¹H-NMR spectroscopy.

Few developments have leapfrogged over predecessor technology as quickly and extensively as synthetic biology. Based on cutting-edge DNA synthesis technology, synthetic biology has already fueled an expansion of opportunities in biological engineering, with advanced capabilities that surpass those provided by traditional recombinant DNA technology. Improvements in synthesis technology are accelerating the pace of innovation in everything from the development of renewable energy to the production of bulk and fine chemicals, from information processing to environmental monitoring, and from agricultural productivity to breakthroughs in human health and medicine. Synthetic biology promises vast improvements to our well-being and our understanding of the living world. Like any powerful technology, DNA synthesis has the potential to be misused. In the wrong hands, the new capabilities enabled by synthetic biology could give rise to both known and unforeseeable threats to our biological safety and security. Current government oversight of the DNA synthesis industry falls short of addressing this unfortunate reality. Here, we introduce and outline a practical plan for developing an effective governance framework for the DNA synthesis industry. A thoughtfully crafted and effectively implemented framework would protect our continued well-being in at least two ways. First...

Growth stimulation of Avena coleoptile tissue by indoleacetic acid (IAA) and fusicoccin (FC) was compared by measuring both their influence on RNA and protein synthesis during IAA or FC stimulated growth. FC stimulated growth more than IAA during the initial four hour exposure, after which the growth rate gradually declined to the control rate. FC, but not IAA, increased the uptake of 3H-Ieucine into tissue and the specific radioactivity of extracted protein. Cycloheximide inhibited the incorporation of 3H-Ieucine into protein by approximately 60% to 70% in all cases. In the presence of cycloheximide 3H-radioactivity accumulated in FC-treated tissue, whereas IAA did not seem to influence 3H-accumulation. These results suggest that FC stimulated leucine uptake into the tissue and that increased specific activity of coleoptile protein is due to increased leucine uptake, not an increased rate of protein synthesis. There was no measurable influence of IAA and/or FC on RNA and protein synthesis during the initial hours of a growth stimulation. Inhibitors of RNA and protein synthesis, actinomycin D and cycloheximide, respectively, severely inhibited IAA enhanced growth but only partially inhibited FC stimulated growth. The data are consistent with suggestions that a rapidly turning over protein participates in IAA stimulated growth...

The toxicology of the cyanobacterial alkaloid cylindrospermopsin (CYN), a potent inhibitor of protein synthesis, appears complex and is not well understood. In exposed mice the liver is the main target for the toxic effects of CYN. In this study primary mouse hepatocyte cultures were used to investigate the mechanisms involved in CYN toxicity. The results show that 1-5 microM CYN caused significant concentration-dependent cytotoxicity (52%-82% cell death) at 18 h. Protein synthesis inhibition was a sensitive, early indicator of cellular responses to CYN. Following removal of the toxin, the inhibition of protein synthesis could not be reversed, showing behavior similar to that of the irreversible inhibitor emetine. In contrast to the LDH leakage, protein synthesis was maximally inhibited by 0.5 microM CYN. No protein synthesis occurred over 4-18 h at or above this concentration. Inhibition of cytochrome P450 (CYP450) activity with 50 microM proadifen or 50 microM ketoconazole diminished the toxicity of CYN but not the effects on protein synthesis. These findings imply a dissociation of the two events and implicate the involvement of CYP450-derived metabolites in the toxicity process, but not in the impairment of protein synthesis. Thus...

1,2-Dioxines, also known as endoperoxides are a specific type of cyclic peroxide, characterised by an unsaturated six-membered peroxide ring. They are abundant in nature and have been isolated from many natural products and have been shown to exhibit a wide spectrum of biological roles. Ozonolysis is a well established method for the oxidative cleavage of alkenes, although examples involving 1,2-dioxines are extremely rare. The furanoid and anhydrofuran linalool oxides have been established as common compounds in wine and as natural products from other sources. Previous methods of synthesis have followed a variety of different routes although many experimental details are unclear and of limited value. It was therefore felt that a gap exists in the literature with regard to an effective synthesis for these compounds and the development of a new synthetic pathway to afford both compounds, and analogues thereof, from a common starting material would be of value. The aim of this project was therefore to combine these areas and utilise 1,2-dioxine chemistry for the synthesis of the furanoid and anhydrofuran linalool oxides, with a key step in the synthesis being the ozonolysis of a bicyclic bridged 1,2-dioxine to yield the necessary keto-aldehyde precursor. Since little attention has been focussed on exploring the ozonolysis reaction of bicyclic alkenes...

Der erste Teil der Dissertation beschreibt die Entwicklung und Validierung von polymergebundener o-Iodoxybenzoesäure (IBX-Harz) als Oxidationsmittel in der polymerunterstützten Lösungssynthese (PASP-Synthese). Es wurden Syntheseprotokolle für substituierte o-Iodoxybenzoesäuren entwickelt, um über eine Linkerfunktion zur Immobilisierung ans Polymer zu verfügen. Es wurde ein Syntheseprotokoll zur Festphasensynthese von IBX-Harz entwickelt und optimiert. Nach Immobilisierung von 5-Hydroxy-2-iodbenzoe-säuremethylester auf Merrifield- und Wang-Brommethyl-Harze verschiedener Ausgangsbeladungen über die Hydroxygruppe und Methylester Verseifung wurde die polymergebundene 2-Iodbenzoesäure zu polymergebundenem IBX oxidiert. Mit einem Derivat der Caro’schen Säure, dem Tetrabutylammoniumpersulfat gelang es, polymergebundenes IBX zu erhalten. Die Oxidation von Piperonylalkohol zu Piperonal wurde als Testsystem zur Bestimmung der Aktivität des IBX-Harzes eingeführt. Die Aktivität des IBX-Harzes lag bei maximal 0,65 mmol/g. Harze mit sehr hohen Beladungen (bis 4,4 mmol/g) zeigten schlechtere Reinheiten der Oxidationsprodukte als Merrifield-Harze mit kleinerer Beladung (1,0 – 1,2 mmol/g). Die hohe Konzentration des Oxidationsmittels erwies sich als entscheidender Faktor...

Die zukünftigen Entwicklungen auf dem Gebiet der Glykobiologie hängen wesentlich von der Verfügbarkeit eindeutig definierter, d.h. synthetisch dargestellter Verbindungen ab. Um Struktur-Wirkungsstudien auch mit Substanzbibliotheken strukturell diverser Oligosaccharide oder Glykokonjugate durchführen zu können, ist daher die Entwicklung effizienter Syntheseprotokolle notwendig, die den einfachen und möglichst automatisierbaren Zugang zu medizinalchemisch relevanten Kohlenhydraten erlauben. Vor diesem Hintergrund beschäftigt sich die vorliegende Dissertation mit der Entwicklung neuer Synthesestrategien für die festphasenunterstützte Kohlenhydratchemie zum parallelisierbaren präparativen Aufbau von Oligosacchariden und Glykokonjugaten. Der erste Teil der Dissertation beschreibt die Entwicklung des TAL-Systemes (Trimellitsäureanhydrid-Linker) als neues Linkersystem der Festphasenchemie in polymeren Gelen. Dieses besteht in der Kombination zweier glykosylierungsbeständiger Schutzgruppen, der Phthalimid- und Benzylgruppe, die sich beide in der Lösungssynthese von Zuckern bewährt haben. Ausgehend von polymerem Phthalanhydrid, dem eigentlichen TAL-Harz, wurden jeweils orthogonale Protokolle zur Immobilisierung und Abspaltung von Aminosubstraten entwickelt und bis zur Anwendbarkeit für die Darstellung von Aminoglykokonjugaten optimiert. Die Produktfreisetzung wurde entweder durch Nukleophile erreicht oder durch eine Zweischrittreaktion von Borhydrid-Reduktion und anschließender Lactonisierung...

Die Dissertation besteht aus zwei Teilen. Der erste Teil beschäftigt sich mit der Synthese von spiroverknüpften Scaffolds. Heterozyklische Spiroverbindungen sind für Medizinische Chemie wegen ihrer potentiellen Mehrzahl durch Derivatisierung und wegen ihrer besonderen Orientierung der Ringe im Raum interessant. Vor kurzem wurde die Ringschluss Metathese Reaktion als direkter Zugang zu den spirozyklischen Systemen anerkannt. Wir fanden heraus, dass die Sequenz der Aminoallylierung von zyklischen Keton mit Carbaminsäureester und Allyltrimethylsilan mit Zugabe von Bortrifluorid-diethylether Komplex und darauf folgender Alkylierung mit -Brommethylacrylsäure Methylester und anschließendem Ringschluss Metathese bietet einen effizienten und innovativen Weg zum stickstoffhaltigen spirozyklischen Scaffolds. Im Gegenzug zu den früher mit ähnlichen Methoden synthetisierten Verbindungen, besitzen unsere Scaffolds eine funktionalisierte Doppelbindung, welche für weitere Derivatisierungen geeignet ist. Mehrere Substanzen, die geschützte Stickstoffatome in verschiedenen Ringpositionen enthalten, wurden in Grammmenge synthetisiert. Um das synthetische Potential von hergestellten ,-ungesättigte Ester darzustellen...

Synthesis is the automatic construction of a system from its specification. In classical synthesis algorithms, it is always assumed that the system is ``constructed from scratch' rather than composed from reusable components. This, of course, rarely happens in real life, where almost every non-trivial commercial software system relies heavily on using libraries of reusable components. Furthermore, other contexts, such as web-service orchestration, can be modeled as synthesis of a system from a library of components. In contrast to classical synthesis, synthesis from components aims to build the desired system using components from a given library. In this dissertation, we consider the problem of control-flow synthesis from libraries of probabilistic components. We develop an automata-theoretic approach to solve the problem, investigate the expressive power of probabilistic control-flow, and examine the close relationship between synthesis from components and games with partial information.

(A) Solid phase synthesis of oligonucleotides are well documented and are extensively studied as the demands continue to rise with the development of antisense, anti-gene, RNA interference, and aptamers. Although synthesis of RNA sequences faces many challenges, most notably the choice of the 2' -hydroxy protecting group, modified 2' -O-Cpep protected ribonucleotides were synthesized as alternitive building blocks. Altering phosphitylation procedures to incorporate 3' -N,N-diethyl phosphoramidites enhanced the overall reactivity, thus, increased the coupling efficiency without loss of integrety. Furthermore, technical optimizations of solid phase synthesis cycles were carried out to allow for successful synthesis of a homo UIO sequences with a stepwise coupling efficiency reaching 99% and a final yield of 91 %. (B) Over the past few decades, dipyrrometheneboron difluoride (BODIPY) has gained recognition as one of the most versatile fluorophores. Currently, BODIPY labeling of oligonucleotides are carried out post-synthetically and to date, there lacks a method that allows for direct incorporation of BODIPY into oligonucleotides during solid phase synthesis. Therefore...

[ES] En el presente trabajo se presentan los resultados obtenidos en el estudio de las reacciones de Síntesis Autopropagada a Alta Temperatura (Self-propagating High-temperature Synthesis, SHS) de Nitruro de Silicio. La síntesis autopropagada a alta temperatura consiste básicamente en la generación de reacciones altamente exotérmicas capaces de automantenerse. Se puede considerar como principal ventaja del método el ahorro energético que supone. La síntesis se realiza sobre una mezcla inicial de silicio metálico sobre la cual se realizan adiciones de diluyente y otros aditivos (sales amónicas) que afectan al desarrollo de la reacción. Se ha estudiado la influencia que en este sistema pueden tener las proporciones de las distintas incorporaciones en la mezcla, tanto en el material resultante como en las condiciones de reacción. Igualmente se ha estudiado la posibilidad de utilización de nuevos aditivos que puedan minimizar el impacto medio ambiental. Se presentan los estudios microestructurales del material obtenido, la identificación cristalográfica de las fases presentes así como los comportamientos de los parámetros que definen la propia reacción. Con la información obtenida se propone el mecanismo predominante de la síntesis del Nitruro de Silicio mediante SHS.; [EN] In the present paper results obtained during synthesis of Silicon Nitride by Self-propagating High-temperature Synthesis (SHS) are shown. Self-propagating High-temperature Synthesis is based on the high enthalpy of certain reactions able to be self-sustained. One of the most important advantages of the method is its very low energy consumption. The synthesis is carried out with a mixture of silicon powder with some additions of diluents and other synthesis aids (ammonium salts). The influence of the mixture composition on reaction parameters and characteristics of the obtained products has been studied. The use of new synthesis aids has been also studied in order to decrease the environmental impact of the process. Microstructural study...

The purpose of this thesis is to study the methodology of behavioral synthesis and evaluate its usefulness compared to Register Transfer Level (RTL) synthesis. Custom IC design uses high-powered synthesis tools. Engineers have traditionally used RTL level descriptions of their circuits as input to these synthesis tools. As new Behavioral Synthesis tools are becoming more powerful, the option to describe their circuitry in a higher and more abstract level is becoming a more feasible option. Describing circuitry at a higher level has many advantages. It is easier to make architecture changes and higher level descriptions generally have significantly less lines of code and faster development times. To study behavioral synthesis a tri-linear interpolation algorithm is used. An RTL style and two different behavioral styles are used. Each are compared for area, power consumption, synthesis time, code length and throughput. The design is simulated before and after synthesis to verify the accuracy of the design using VHDL. Behavioral Compiler from Synopsys will be used to synthesize the design from VHDL to the gate level. It was found that behavioral synthesis can produce results nearly as good as an RTL described circuit. The results were generally 20% - 30% worse for this implementation using behavioral synthesis.

Lauterbach, Jochen A.; Chen, Jingguang G.; Synthesis of supported nanoparticles with consistent particle size is a bridge between what researchers refer to as the “materials gap,” the gap in structure complexity between single crystals and supported catalysts. Controlling particle size during supported catalyst synthesis allows researchers to investigate optimal conditions for desired activity and/or selectivity toward specific chemical reactions. This information can lead to the possibility to tune catalyst synthesis to optimize efficiency and cost while minimizing the waste of precious, nonrenewable resources. This thesis investigates a procedure potentially capable of synthesizing supported catalysts with uniformly-sized nanoparticles. This combines the idealized environment of a model system with the increased complexity associated with nanoparticle size and support effects. To bridge the materials gap, extensive work has been performed to determine how metallic structures affect adsorbate interactions. Chapter 1 discusses density functional theory (DFT) calculations used to predict adsorbate binding energies on metal monolayer bimetallic surfaces and the correlation to single crystal surfaces and polycrystalline foils. Recently...