New Catalytic Methods for the Preparation of Tryptophans and Pyrroloindolines: Total Synthesis of (+)-Naseseazines A and B and (���)-Aspergilazine A

<p>Tryptophan and unnatural tryptophan derivatives are important building blocks for the total synthesis of natural products, as well as the development of new drugs, biological probes, and chiral small molecule catalysts. This thesis describes various catalytic methods for the preparation of tryptophan derivatives as well as their functionalization and use in natural product total synthesis.</p> <p>Herein, the tandem Friedel���Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate to provide enantioenriched trytophans is reported. This method inspired further work in the area of transition metal catalyzed arylation reactions. We report the development of the coppercatalyzed arylation of tryptamine and tryptophan derivatives. The utility of these transformations is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B. Further work on the development of a mild and general Larock indolization protocol to access unnatural tryptophans is also discussed.</p>

Enantioselective Total Synthesis of Diketopiperazinecontaining Natural Products: (���)-Lansai B, (+)-Nocardioazines A and B, and (���)-Acetylapoaranotin

<p>Diketopiperazine (DKP) motif is found in a wide range of biologically active natural products. This work details our efforts toward two classes of DKP-containing natural products.</p> <p>Class one features the pyrroloindoline structure, derived from tryptophans. Our group developed a highly enantioselective (3 + 2) formal cycloaddition between indoles and acrylates to provide pyrroloindoline products possessing three stereocenters. Utilizing this methodology, we accomplished asymmetric total synthesis of three natural products: (���)-lansai B, (+)-nocardioazines A and B. Total synthesis of (���)-lansai B was realized in six steps, and featured an amino acid dimerization strategy. The total synthesis of (+)-nocardioazine B was also successfully completed in ten steps. Challenges were met in approaching (+)-nocardioazine A, where a seemingly easy last-step epoxidization did not prove successful. After re-examining our synthetic strategy, an early-stage epoxidation strategy was pursued, which eventually yielded a nine-step total synthesis of (+)-nocardioazine A.</p> <p>Class two is the epidithiodiketopiperazine (ETP) natural products, which possesses an additional episulfide bridge in the DKP core. With the goal of accessing ETPs with different peripheral structures for structure-activity relationship studies, a highly divergent route was successfully developed, which was showcased in the formal synthesis of (���)-emethallicin E and (���)-haematocin, and the first asymmetric synthesis of (���)-acetylapoaranotin.</p>

Viabilidad econ��mico-financiera del proyecto de negocio de libre elecci��n B

En este TFG trato de ver la viabilidad econ��mico-financiera de un proyecto empresarial de nueva empresa basado en la innovaci��n, las tendencias actuales de compra y la tecnolog��a. Tras el an��lisis de la evoluci��n de los supermercados y la apuesta por la tecnolog��a, de estos, en otros pa��ses, he tratado de buscar la forma de adaptarla a nuestra sociedad, cultura y costumbres. Scanner Market es un nuevo modelo de supermercado supeditado a un gran almac��n de distribuci��n, en este caso El Corte Ingl��s, pero puede ser aplicado para otros muchos. Basa su comercializaci��n en una tienda f��sica en la que existe una gran variedad de productos en un espacio reducido. Se consigue comercializar tal variedad de productos gracias a la exposici��n de uno solo, de forma que act��e como ���muestra��� para los clientes. En la tienda no hay almac��n, sino que se trata de optimizar el espacio para dar cabida a una amplia oferta de productos (en forma de muestras). Los clientes hacen la compra f��sicamente escaneando el producto a trav��s de una app. para Smartphone o unas pistolas de compra con el mismo software y el pedido es enviado a su hogar por la distribuci��n de El corte Ingl��s.

A study of T = 2 states in ^(12)B, ^(12)C, ^(20)F and ^(28)Al

<p>The lowest T = 2 states have been identified and studied in the nuclei ¹²C, ¹²B, ²⁰F and and ²⁸Al. The first two of these were produced in the reactions ¹⁴C(p,t)¹²C and ¹⁴C (p,³He)¹²B, at 50.5 and 63.4 MeV incident proton energy respectively, at the Oak Ridge National Laboratory. The T = 2 states in ²⁰F and ²⁸Al were observed in (³He,p) reactions at 12-MeV incident energy, with the Caltech Tandem accelerator.</p> <p>The results for the four nuclei studied are summarized below:</p> <p>(1) ¹²C: the lowest T = 2 state was located at an excitation energy of 27595 �� 20 keV, and has a width less than 35 keV.</p> <p>(2) ¹²B: the lowest T = 2 state was found at an excitation energy of 12710 �� 20 keV. The width was determined to be less than 54 keV and the spin and parity were confirmed to be 0⁺. A second ¹²B state (or doublet) was observed at an excitation energy of 14860 �� 30 keV with a width (if the group corresponds to a single state) of 226 �� 30 keV.</p> <p>(3) ²⁰F: the lowest T = 2 state was observed at an excitation of 6513 �� 5 keV; the spin and parity were confirmed to be 0⁺. A second state, tentatively identified as T = 2 from the level spacing, was located at 8210 �� 6 keV.</p> <p>(4) ²⁸Al: the lowest T = 2 state was identified at an excitation of 5997 �� 6 keV; the spin and parity were confirmed to be 0⁺. A second state at an excitation energy of 7491 �� 11 keV is tentatively identified as T = 2, with a corresponding (tentative) spin and parity assignment J^�� = 2⁺.</p> <p>The results of the present work and the other known masses of T = 2 states and nuclei for 8 &#8804; A &#8804; 28 are summarized, and massequation coefficients have been extracted for these multiplets. These coefficients were compared with those from T = 1 multiplets, and then used to predict the mass and stability of each of the unobserved members of the T = 2 multiplets.</p>

Comparison of observed and predicted dates of eyeing, hatching and swim-up for brown trout and Atlantic salmon

Scholars recently derived simple models from published data for the prediction from water temperature of hatching times for the eggs of brown trout (Salmo trutta L.) and Atlantic salmon (Salmo salar L.). A similar model to predict eyeing time for salmon eggs was obtained and used in this study, largely by analogy, to develop equations which might be used to obtain very approximate estimates of eyeing and swim-up times for salmon and brown trout. As the models were based on data for constant temperatures and some of them also had a very inadequate data base, it was desirable that they should be tested, as far as possible, against field and hatchery observations. The present report is a brief summary based on such data as have been obtained to date. None of the data sets were ideal for the purpose and the various inadequacies are discussed later in this report.

Progress on the salmon investigation

An article detailing some of the conclusions of the salmon investigation undertaken by the author, on the River Eden and its tributaries, for the previous few years. It is proposed that seasonal changes in young salmon growth are related to water temperature variation. A figure is included showing length of fish compared to the average temperature of water in the River Eden over a two year duration. The article describes comparative work undertaken to date between three streams within the Thurso watershed and the River Eden. A table is included showing the average size of fish in each of the watercourses compared. Laboratory experiments on the effects of temperature on young salmon are outlined, as well as investigative work undertaken into the realtionship between fish scales and fish length.

Experiments on downstream movement of recently emerged trout and salmon parr in Grassholme channels, 1983-1985

A number of authors have described the manner in which young salmonids, soon after emergence from the gravel, set up and defend territories. This leads to mortality or downstream displacement of the individuals which are unable to acquire territories and is widely accepted as the main method of population regulation amongst young salmonids. In some field experiments the fish were constrained in screened reaches and the option of downstream dispersal for the surplus fry was thus excluded. In order to explore some aspects of downstream dispersal more closely under conditions which gave more control than is obtained in a natural stream, four experimental channels were set up at Grassholme reservoir in Teesdale. The report describes the results of investigations on the timing and rate of downstream movement of young brown trout (Salmo trutta L.) and Atlantic salmon (Salmo salar L.) out of experimental channels, with special reference to the effect of water velocity on the rate of ���emigration���.

Desenvolvimento de t��cnica de an��lise de imagens digitais para avalia����o do est��gio da fibrose em bi��psias hep��ticas de pacientes portadores de hepatite cr��nica por v��rus da hepatite B e C

As hepatites cr��nicas por v��rus s��o as mais frequentes, destacando-se os v��rus das hepatites B (VHB) e C (VHC). O estudo anatomopatol��gico da bi��psia hep��tica �� considerado o padr��o ouro para avaliar com precis��o a distor����o arquitetural e o grau de fibrose do par��nquima do f��gado, importantes fatores progn��sticos para os pacientes portadores de hepatites cr��nicas virais. Na avalia����o histopatol��gica atual, em adi����o aos relatos subjetivos das altera����es histol��gicas, escores semiquantitativos que correlacionam achados morfol��gicos com graus num��ricos s��o usados, tais como os reconhecidos escores de Ishak e METAVIR. Entretanto, em todos estes sistemas h�� a desvantagem da subjetividade do examinador e da incorpora����o de altera����es categ��ricas, sem refer��ncias ��s mudan��as quantitativas do col��geno hep��tico. T��cnicas de an��lise de imagens digitais (AID) que fornecem quantifica����o objetiva dos graus de fibrose em amostras histol��gicas t��m sido desenvolvidas. Todavia, o alto custo e dificuldade ao acesso das tecnologias descritas restringem seu uso a poucos centros especializados. Este estudo visa o desenvolvimento de uma t��cnica de custo acess��vel para a an��lise de imagens digitais da fibrose hep��tica em hepatites cr��nicas virais. Foram estudadas 304 bi��psias de pacientes com hepatite cr��nica por v��rus B e C, obtidas atrav��s de agulhas Menghini. Todas as amostras tinham pelo menos 15 mm de comprimento ou cinco espa��os-porta completos e foram coradas pelo m��todo Tricr��mico de Masson. O estadiamento foi feito por um ��nico hepatopatologista experiente, sem o conhecimento dos dados cl��nicos dos pacientes. Os escores de Ishak e METAVIR foram aplicados. As imagens microsc��picas foram digitalizadas. Os ��ndices de fibrose foram determinados de forma automatizada, em t��cnica desenvolvida no programa Adobe Photoshop. Para o escore de Ishak, observamos os seguintes ��ndices de Fibrose (IF) m��dios: 0,8% 0,0 (est��gio 0), 2.4% 0,6 (est��gio 1), 4,7% 1,6 (est��gio 2), 7,4% 1,4 (est��gio 3), 14,9% 3,7 (est��gio 4), 23,4% 2,9 (est��gio 5) e 34,5% 1,5 (est��gio 6). Para a classifica����o METAVIR: 0,8% 0,1 (est��gio F0), 3,8% 1,8 (est��gio F1), 7,4% 1,4 (est��gio F2), 20,4% 5,2 (est��gio F3) e 34,5% 1,5 (est��gio F4). Observamos uma excelente correla����o entre os ��ndices de fibrose da AID e os escores de Ishak (r=0,94; p<0,001) e METAVIR (r=0,92; p<0,001). Em rela����o �� indica����o de tratamento antiviral, foi observado IF m��dio de 16,4%. Em rela����o ao diagn��stico de cirrose, foi observado IF m��dio de 26,9%, para o escore de Ishak, e 34,5% para a classifica����o METAVIR. A reprodutibilidade intra-observador foi excelente. Este novo m��todo de an��lise de imagens digitais para a quantifica����o de fibrose hep��tica tem custo acess��vel e foi desenvolvido com tecnologia que est�� dispon��vel em todo o mundo, permitindo identificar com precis��o todos os est��gios de fibrose, com excelente reprodutibilidade intra-observador.

Carta enviada por W.I.B. Beveridge a Justo Garate en 1955

1 carta (mecanografiada) ; 190x250mm

The production of freshwater fish for food

It has been estimated that in England and Wales fresh water covers some 340 square miles of which about one quarter is inhabited mainly by salmon and trout; in Scotland the lakes cover an area of 340 square miles. The principal object of this publication is to make available in handy form some of the methods, especially those involving the use of manures, by which crops of fish from water can be increased. The cultivation of water which this implies may be compared directly to the cultivation of farm land: the conditions for growth are made as favourable as possible, the seed is sown in the form of young fish, and after one or perhaps two growing seasons the crop is harvested. There are however many waters about the country where marketable fish are already available and can be removed without prejudice to, and indeed to the advantage of, sporting fisheries. In such cases it is necessary only to remove the fish and to rely on the natural processes of reproduction of those which are left to repopulate the water. Farming waters in the true sense is the concern of the greater part of this publication; the removal of crops of otherwise unwanted fish is considered in the last two sections on perch trapping and eel fisheries.

Propiedades catal��ticas de la lipasa B de Candida antarctica inmovilizada en soportes magn��ticos. Actividad hidrol��tica en medios acuosos

Los enzimas son piezas fundamentales en el correcto funcionamiento de cualquier sistema biol��gico. Gracias a su naturaleza proteica y a las estructuras tridimensionales complejas que son capaces de adoptar, estas mol��culas act��an como catalizadores de reacciones qu��micas. L a funci��n de los enz imas es disminuir la energ��a de activaci��n de la reacci��n, aumentando de este modo la velocidad de reacci��n. L o s enzimas no alteran el balance e nerg��tico de las reacciones en que intervienen, ni modifican, por lo tanto, el equilibrio de la reacci��n . Por este motivo, en las reacciones catalizadas por enzimas se observa una mayor rapidez a la hora de alcanzar el equilibrio. La ciencia que estudia l a velocidad de las reacciones qu��micas que son catalizadas por enzimas es la cin��tica enzim��tica , e n la cual , las mol��culas sobre las que act��an los enzimas se denominan sustratos y las mol��culas resultantes de la conversi��n productos. El estudio de la cin ��tica de un enzima permite explicar los detalles de su mecanismo catal��tico, su papel en el metabolismo o incluso c��mo se controla su actividad en la c��lula. Las dos propiedades m��s importantes a la hora de trabajar con enzimas son: el tiempo que tarda en saturarse con un sustrato en particular y la velocidad m��xima de reacci��n que puede alcanzar. Para el estudio de estas propiedades en el laboratorio se realizan los ensayos enzim��ticos. El procedimiento a seguir en estos casos es medir la aparici��n de un producto o la desaparici��n de un sustrato frente al tiempo.

Propiedades catal��ticas de la lipasa B de Candida antarctica inmovilizada en soportes magn��ticos. Actividad sint��tica en disolventes org��nicos

Este trabajo se centra en la inmovilizaci��n de la lipasa B de Candida antarctica en nanopart��culas magn��ticas y la posterior caracterizaci��n cin��tica de su actividad sint��tica en medios org��nicos para la pr oducci��n de biodiesel. La historia del biodiesel comienza en 1893, cuando Rudolph Diesel, el padre del motor di��sel, puso en marcha el primer motor de este tipo. M��s tarde, en 1900, Diesel gan�� el Grand Prix en la Feria Mundial de Par��s con su m otor impulsado por un biodiesel de aceite de cacahuete. En 1903, adem��s, comenz�� la producci��n del Modelo T de Henry Ford, dise��ado para utilizar etanol como combustible. Diesel cre��a que la utilizaci��n de biodiesel era el futuro de la automoci��n: ��� el uso de aceites vegetales como combustibles para motor puede parecer insignificante hoy en d��a, pero estos aceites puede n convertirse, con el transcurso del tiempo, en combustibles tan importantes como el petr��leo y el carb��n lo son hoy en d��a ��� Sin embargo, a p artir de 1920, los fueles basados en petr��leo comenzaron a ganar terreno, debido a su mayor eficiencia, menor precio y mejor disponibilidad. De esta forma, el mercado de los biofueles qued�� relegado hasta que las distintas crisis del petr��leo (1973, 1979, 19 90) unidas a la creciente preocupaci��n por la poluci��n y la c onservaci��n del medio ambiente, adem��s de al aumento de la poblaci��n y por tanto de la demanda de combustibles , llevaron a devolve r la mirada a estos fueles . Fue en esta ��poca cuando comenz��, p rincipalmente en EEUU y Brasil, la producci��n a gran escala de biocombustibles de primera generaci��n, basados en la utilizaci��n de excedentes agr��colas como el ma��z y la ca��a de az��car para la producci��n de bioetanol y aceites de ma��z y grasas animales par a la producci��n de biodiesel .

������������������������B���������������

������������������������������������������,���������������������������������������������������B������������������,������������������B���������������������������������������������,���������������������������B���������������������������������������������������������������������������������������

Progressive Decrease in the Potential Usefulness of Meningococcal Serogroup B Vaccine (4CMenB, Bexsero (R)) in Gipuzkoa, Northern Spain

The effectiveness of a vaccine is determined not only by the immunogenicity of its components, but especially by how widely it covers the disease-causing strains circulating in a given region. Because vaccine coverage varies over time, this study aimed to detect possible changes that could affect vaccine protection during a specific period in a southern European region. The 4CMenB vaccine is licensed for use in Europe, Canada, and Australia and is mainly directed against Neisseria meningitidis serogroup B. This vaccine contains four main immunogenic components: three recombinant proteins, FHbp, Nhba and NadA, and an outer membrane vesicle [PorA P1.4]. The allelic distribution of FHbp, Nhba, NadA, and PorA antigens in 82 invasive isolates (B and non-B serogroups) isolated from January 2008 to December 2013 were analyzed. 4CMenB was likely protective against 61.8% and 50% of serogroup B and non-B meningococci, respectively, in the entire period, but between 2012 and 2013, the predicted protection fell below 45% (42.1% for serogroup B isolates). The observed decreasing trend in the predicted protection during the 6 years of the study (X-2 for trend = 4.68, p=0.03) coincided with a progressive decrease of several clonal complexes (e. g., cc11, cc32 and cc41/44), which had one or more antigens against which the vaccine would offer protection.

Desenvolvimento e manuten����o de mem��ria imunol��gica ap��s imuniza����o contra Neisseria meningitidis B com a vacina VA-MENGOC-BC

Neisseria meningitidis �� uma das principais causas de meningite bacteriana e septicemia em todo o mundo, acometendo principalmente crian��as menores de 4 anos. Atualmente, n��o existe uma vacina universal contra o meningococo B (MenB). A imunidade protetora contra o meningococo caracteriza-se pela presen��a e persist��ncia de anticorpos bactericidas, por��m pouco se sabe sobre os mecanismos de desenvolvimento desta mem��ria sorol��gica. Avaliamos em modelo animal e em humanos, a gera����o e manuten����o das c��lulas secretoras de anticorpos (ASC) e dos linf��citos B de mem��ria (LBm) ap��s vacina����o contra MenB. Utilizamos como refer��ncia a vacina dift��rica (dT ou DTP), considerada ter ��tima efic��cia em humanos. Para o estudo em modelo animal, grupos de 6 a 8 camundongos su����os, f��meas, de 5 a 6 semanas, foram imunizados com 3 doses da vacina VA-MENGOC-BC ou DTP, via intramuscular, com intervalo de 2 semanas entre as doses. Aproximadamente 2, 4 ou 6 meses ap��s a ��ltima dose, os animais receberam a dose refor��o. A vacina anti-MenB induziu uma resposta prim��ria de ASC maior que a resposta �� dose refor��o. Ao contr��rio, a resposta de ASC �� vacina dT foi maior ap��s o booster. A resposta de LBm anti-MenB permaneceu constante (m��dia de 1%) ao longo de todo o estudo, mas a resposta ao tox��ide dift��rico (TD) foi maior ap��s o booster (m��dia de 1,9%) que ap��s a imuniza����o prim��ria. A concentra����o de IgG, anticorpos bactericidas e opsonizantes contra MenB foi dose-dependente e foi reativada ap��s a administra����o das doses refor��os. Esses resultados sugerem que os LBm presentes no ba��o foram respons��veis pela forte resposta de anticorpos observada ap��s a dose refor��o. Para o TD, ambos ASC e LBm foram importantes na manuten����o da mem��ria sorol��gica. Para o estudo em humanos, seis volunt��rios foram imunizados com 3 doses da vacina VA-MENGOC-BC, via intramuscular, com intervalo de 6 a 7 semanas entre as doses. Seis meses ap��s a imuniza����o prim��ria, os indiv��duos receberam uma dose refor��o. Outro grupo de volunt��rios (n = 5) foi imunizado com uma dose refor��o da vacina dT. Somente ap��s a terceira dose da vacina anti-MenB foi poss��vel detectar a presen��a de LBm em todos os indiv��duos. Seis meses ap��s a imuniza����o prim��ria, a frequ��ncia de LBm voltou ao seu n��vel basal e n��o foi reativada ap��s a dose booster. A vacina dT tamb��m induziu uma resposta de LBm heterog��nea, mas esta foi 5 vezes maior que a induzida por VA-MENGOC-BC. A resposta de anticorpos funcionais anti-MenB foi de curta dura����o com pequena reativa����o ap��s a dose refor��o. As duas vacinas induziram diferentes frequ��ncias de LT de mem��ria central (TCM) e de mem��ria efetora (TEM) ap��s a vacina����o prim��ria e ap��s o booster. A resposta �� dose booster foi caracterizada pelo aumento da popula����o de linf��citos TCM e diminui����o de TEM. A popula����o de linf��citos TCM apresentou maior ativa����o (CD69+) que os linf��citos TEM, especialmente ap��s a vacina����o contra MenB. Concluindo, os dados desta tese indicam que a administra����o de 3 doses da vacina VA-MENGOC-BC teve uma efici��ncia limitada em humanos e sugerem que a baixa efic��cia da vacina, quando utilizada na d��cada de 90 em S��o Paulo e no Rio de Janeiro, pode estar relacionada �� defici��ncia na gera����o e manuten����o de LBm espec��ficos.