Academic literature on the topic 'Compound 1080'

The toxicity of sodium monofluoroacetate (1080) to captive feral pigs was compared in wheat and pellet bait. Mortality following 4.34 mg 1080 kg-1 was significantly higher among pigs receiving 1080 in wheat bait (60%, 24/40) than in pellet bait (28%, 11/40, X*2=7.31, 1 d.f., P<O.05). There were no significant differences between pigs receiving each bait type in terms of time until vomiting began, frequency, mass of vomitus produced, or in time until death. The amount and concentration of 1080 in vomitus and the proportion of 1080 dose ejected were unrelated to bait type. Surviving pigs produced vomitus with a greater 1080 concentration but smaller mass than those that died. Bait type is an important determinant of the toxicity of 1080 to captive feral pigs and should be closely evaluated before specific bait types are used in the field.

Injection and mixing techniques for the preparation of fresh meat baits containing sodium monofluoroacetate (1080) were evaluated. Both techniques produced baits containing variable quantities of 1080. The injection of 1 ml of 6.0-mg ml-1 1080 and 0.5 ml of 13.6-mg ml-1 1080 solution produced baits containing (mean � SD) 2.9 � 0.6 and 3.5 � 0.5 mg of 1080 respectively; the ranges were 1.9-4.1 and 2.1-4.4 mg respectively. Decreasing the injection volume while increasing the 1080 concentration did not increase the percentage of 1080 recovered from baits. Mixed baits prepared by tumbling with 1 ml of 5.7-mg ml-1 1080 and 1 ml of 10-mg ml-1 1080 per bait contained 3.8 � 1.9 and 5.3 � 2.1 mg of 1080 respectively, with respective ranges of 1.2-11.3 and 1.2-13.2 mg per bait. The injection method produced baits more uniform with respect to the amount of 1080 in the bait. A significant fraction of the 1080 added in both methods of preparation was not found. Experiments showed that this loss was due to biochemical reaction rather than physical loss.

Post-mortem investigations of 207 feral pigs poisoned in the field were conducted to assess the influence on 1080 dose of bait type, site, sex, bodyweight and distance from bait stations. The stomachs of most (126/207) pigs contained only bait material., Bait type significantly affected intake and 1080 dose, with pellet intake greater than cereal baits. Sex and bodyweight also influenced intake: females ingested significantly larger 1080 doses than males; and larger pigs tended to consume more bait in absolute terms but lower doses of 1080 (mg kg-1). Average intake of 1080 varied widely at different locations. Pigs that died close to bait stations had higher 1080 doses but smaller proportions of bait in their stomach contents than those that died away from bait stations.

The cytotoxicity of the brown alga Sargassum siliquastrum on human cancer cells (AGS, HT-29, HT-1080, and MCF-7) was investigated. Bioassay-guided fractionation of the crude extracts showed that the 85% aq. methanol (MeOH) fraction was the most toxic. Seven known meroterpenoids (1-7) were isolated from this cytotoxic fraction. Each compound was evaluated for its cytotoxic effect on human cancer cells. Compounds 1, 2, and 4 showed strong cytotoxicity against AGS, HT-29, and HT-1080 cell lines, with IC50 values ranging from 0.5 to 5.7 μg/mL.

The toxicity of sodium monofluoroacetate (1080) to captive feral pigs, Sus scrofa, was assessed over a range of doses (1.50-21.3 mg 1080 kg-1 bodyweight) administered orally in wheat bait to 80 animals. Calculated LD*50 was 4.11 mg 1080 kg-1 (95% fiducial limits: 3.02-5.34 mg kg-1) and LD*9O was 11.25 mg kg-1 (8.05-21.69 mg kg-1). The incidence (98%) and frequency (mean � SD = l3.6 � 6.7 overall) of vomiting were high. Frequency of vomiting was unrelated to log*10 dose (r= -0.015; N= 80; NS), although time until vomiting began (r= -0.558; N=77; P<O.05) and time until death (r= -0.391; N=47; P<0.05) had a significant negative association with log*10 dose. Median latency was 49 min (range 10-350 min; N=77) and median time until death was 244 min (range 131-7200 min; N=47). Sex and bodyweight had no effect on frequency of vomiting, time until death or prognosis. Feral pigs yere much less sensitive to 1080 under these test conditions than those in earlier studies. Because the present experiment seems likely to resemble field situations, these results warrant careful examination of field intake and mortality of feral pigs during 1080 poisoning.

Baiting with sodium monofluoroacetate (1080) to protect lambs (Ovis aries) from red foxes (Vulpes vulpes L.) has become more frequent in NSW and other parts of Australia during the last 10 years despite the lack of reported evidence evaluating the effects of fox baiting on lamb survival. NSW Agriculture has developed fox control recommendations aimed at minimising impact, but these guidelines have not been tested experimentally. Defining the extent of a pest problem and the effectiveness of pest control are key components of a strategic approach to vertebrate pest management as it is the damage of pests that justifies their control. This thesis describes an experimental evaluation of the recommended practice of fox control in NSW. The effects of three levels of fox control were tested in the experiment; no treatment, baiting once a year before lambing (the recommended practice) and baiting three times a year (thought to be the maximum farmers would instigate). Each treatment had two replicates. No previous manipulative experiment using synchronous controls and matched replicates has been undertaken to test the effects. The study quantifies the level of fox predation on healthy lambs and the level of predation on lambs that had other causes including illness and mismothering contributing to this fox predation. It also examines the response of the fox population, lamb predation and lambing outcomes to different levels of fox control. The cost effectiveness of fox control is examined in relation to lamb predation and an investigation of the optimum level of fox control is begun. The experiment also provides the first chance to consider the examination of multiple response variables and the scale of field ecology experiments required to recognise a significant response and avoid a Type II error due to between replicate variability even with tightly controlled site selection criteria to standardise experimental sites, and with the synchrony of experimental control and treatment surveys. The study occurred on five sheep properties near Boorowa (34°28'S, 148°32'E) and Murringo (34°18'S, 148°3 1'E) in south-eastern Australia. The terrain was undulating to hilly with a maximum elevation of 660 m above sea level. The main agricultural enterprises in the district are Merino wool, fat lamb and beef cattle production and winter cereal cropping. The native vegetation of Eucalyptus woodland has been mostly cleared, though remnant patches occur. Most of the area is now sown with pasture of Phalaris tuberosa, Lolium spp. and clover Trifolium spp.. The experimental properties grazed self-replacing Merino flocks, primarily for wool production, so lamb survival was vital to the economic operation of the farm. Over 50 selection criteria including lamb survival rates, ewe fertility and bloodline, sheep management practices, climate and habitat features that affect lamb survival, past fox control practices and prey species were used to select sites Sites were representative of most sheep farming properties in the region, but were also extremely similar in factors that affected fox abundance and ewe and lamb survival, thus minimising variation between replicate sites. The manufactured meat baits used to poison foxes contained 3 mg of sodium monofluoroacetate (compound 1080). A replacement baiting program was carried out in 1995 and 1996. Fox control programs were carried out over the experimental units and adjacent buffer zones covering approximately two fox territories, approximately 6km2, around the lambing paddock under study. The recommended fox control practices described by NSW Agriculture also included neighbouring farmers taking part in an extended group baiting program. In all the area baited at varying intensities totalled 3400 km2. Synchronised lambing with neighbours was a further recommended practice to reduce fox predation and was carried out on these sites. Lambing occurred during a six to eight week period in late winter on all sites, a practice known as 'spring lambing', and on many surrounding properties so a surplus of lambs was available to foxes over a relatively short time. The benefits of fox control were measured directly as enhanced lamb survival derived from differences in lamb marking rates between ultrasounded flocks of approximately 1000 ewes and the predation of lambs was measured from over 2000 lamb carcases post-mortemed in 1994, 1995 and 1996. A mean of 138 lambs were expected at ultrasounding from 100 ewes and 113 lambs per 100 ewes were alive at lamb marking. There was no significant (P>0.05) effect of fox control on lambing performance (the number of lambs per 100 ewes that lambed) Fox predation was inferred as the cause of lamb death in a minimum of 0.8% and a maximum of 5.3% of lamb carcases during 1995 and 1996. There was a significant (P<0 05) effect of fox control on the minimum possible percentage of lamb carcases classified as healthy lambs killed by foxes, with the percentage declining from 1.50% (no fox control), to 0.90% (fox control once per year) to 0.25% (fox control three times per year). There was also a significant (P<0.005) effect of fox control on the maximum possible percentage of lamb carcases classified as healthy lambs killed by foxes with the percentage declining from 10.25% (no fox control), to 6.50% (fox control once per year) to 3.75% (fox control three times per year). The observed results were used to estimate the number of treatment replicates needed to be confident of detecting an effect of predator control on lamb marking performance. The estimated numbers were very high if small effects were to be detected. No significant correlation between the fox density and the minimum and maximum possible number of lambs carcases classified as killed by foxes was found. Bait uptake was monitored as were the costs of fox control.

La primera part d’aquesta tesi aborda el tema de la b-boració d’iminas α,β-insaturades per la síntesi de γ-amino alcohols. Es descriu un nou mètode basat en la organocatàlisi, evitand la ultilizació de metalls de transició com catalizadors. En aquest cas el reactiu bis(pinacolat)diboron s’activa amb una base i MeOH generand in situ un bor nucleòfil que interacciona amb el doble enllaç d’imines α,β-insaturades, com sustrat acceptor. La ultilizació de fosfina és necessaria per activar el sustrat. En el cas de que la fosfina és (S)-MeBoPhoz la β-boración es produeix de forma enantioselectiva amb excessos enantiomèrics fins 70%. Una major diastereoselectividad s’obte despres de la reducció i oxidació per la formació del compost dessitjat γ-amino alcohol. De manera interesant, es pot dir que en pressència de catalitzadors de Cu, la utilización de aquesta mateixa fosfina como lligand, la enenatioselectivitat baixa fins valors moderats. S’ha tractat de utilizar aquesta mateixa via de síntesi per la preparació d’un compost bioactiu como el Tramadol. El capítulo 3, tracta d’aquesta síntesi i a pesar de que molts sistemas catalítics han estat considerats, cap ha donat un producte final òptim. La darrera part d’aquesta tesis tracta de la inserció d’un sistema diazo, tal como (trimetilsilil)diazometà), per generar compostos gem-diborans. El tractament dels compuestos gem-diborans com a bases litiadas, LiTMP, van genrar un carbanió estable el qual pot atacar compostos carbonílics como cetonas per donar lloc a la B-O eliminació via Peterson, i generar olefines gem-sililborans. Posterior funcionalizació, via Suzuki-Miyaura cross-coupling, ha estat demostrada en aquesta tesis. Més innovador ha resultat el process d’iododesililació, que ha permés la síntesi d’olefinas tetrasustituidas despres de dos acoplamients creuats selectius. S’ha pogut concluir la tesis amb la preparació de (E)-Tamoxifen amb elevats valors de selectivitat ( E/Z = 90:10).
La primera parte de esta tesis cubre el tema de la b-boración de iminas α,β-insaturadas para la síntesis de γ-amino alcoholes. Se describe un nuevo método basado en la organocatalisis, evitando la ultilización de metales de transición como catalizadores. En este caso el reactivo bis(pinacolato)diboron se activa con una base y MeOH generando in situ un boro nucleófilo que interacciona con el doble enlace de iminas α,β-insaturadas, como sustrato aceptor. La ultilización de fosfina es necesaria para activar el sustrato. Cuando la fosfina es (S)-MeBoPhoz la β-boración se produce de forma enantioselectiva con excesos enantiomericos hasta 70%. Una mayor diastereoselectividad se obtiene despues de la reducción y oxidación para la formación del compuesto deseado γ-amino alcohol. De manera interesante, se debe decir que en presencia de catalidores de Cu, la utilización de esta misma fosfina como ligando, la enenatioselectividad bajó hasta valores moderados. Se ha tratado de utilizar esta misma via de síntesis para la preparación de un compuesto bioactivo como el Tramadol. El capítulo 3, trata de esta síntesis y a pesar de que muchos sistemas catalíticos se han considerado, ninguno ha dado un producto final deseado. La última parte de esta tesis trata de la inserción de un sistema diazo, tal como (trimetilsilil)diazometano), para generar compuestos gem-diboranos. El tratamiento de los compuestos gem-diboranos con bases litiadas, tales como LiTMP, generaron un carbanion estabilizado el cual puede atacar compuestos carbonílicos como cetonas para dar lugar a la B-O eliminacion via Peterson, y dar lugar a las olefinas gem-sililboranos. Posterior funcionalización, via Suzuki-Miyaura cross-coupling, has sido demostrada en esta tesis. Incluso más innovador ha resultado el proceso de iododesililación, permitiendo la síntesis de olefinas tetrasustituidas despues de dos acoplamientos cruzados selectivos. Se ha podido concluir la tesis con la preparación de (E)-Tamoxifen con elevados valores de selectividad ( E/Z = 90:10).
The first part covered the topic of the β-boration reaction towards the synthesis of γ-amino alcohols. A new metal-free approach to the β-borylation of α,β-unsaturated imines generated in situ has been reported. In this case the diboron compound, bis(pinacolato)diboron, is activated by a base/MeOH system which generates a nucleophilic boron moiety that can interact with a α,β-unsaturated acceptor (imine). This latter is activated by a catalytic amount of phosphine. When a chiral phosphine such as (S)-MeBoPhoz is used, the β-borylation can be performed in an enantioselective manner with ee values up to 70%. After a high diasteroselective protocol of reduction and oxidation we could provide the desired γ-amino alcohol. Interestingly, when a copper salt is modified with the (S)-MeBoPhoz ligand the enantioselectivities dropped showing generally lower values of ee than the organocatalytic approach. It has been tried to apply this chemistry to the synthesis of bioactive compounds such as Tramadol This part of the manuscript covered the attempts that were made to achieve the total synthesis. Many catalytic systems have been tried but unfortunately, none of them had positive results. The last part of the thesis is based on the insertion of a diazocompound, such as (trimethylsilyl)diazomethane), to generate the gem-diboron compound 18. The treatment of compound 18 with a lithiated base, such as LiTMP, generated a stabilized carbanion which can attack carbonyl compounds like ketones to afford, after a Peterson-type B-O elimination, a gem-silylboron olefin. We demonstrated that further functionalizations, suck as Suzuki-Miyaura cross-coupling, could be performed. Even the more challenging iododesilylation was successfully allowing the synthesis of tetrasubstituted olefins after two consecutive cross-couplings. Towards this aim, the synthesis of (E)-Tamoxifen was achieved with high values of selectivity (ratio E/Z = 90:10).

Research for new antivirals to treat Influenza A virus infections has gained importance during this last decade due to the imminent danger of an Influenza pandemic. For some years, several new strains of this virus have appeared worldwide causing small outbreaks with a notable relevance, for example the ‘avian flu’ (H5N1 in 2007; H7N9 in 2012) and ‘swine flu’ (H1N1 in 2009), that have triggered the assumption that a new pandemic is coming. There are several strategies to treat an Influenza A virus infection targeting some of its surface proteins. In this Thesis, several compounds inhibiting the M2 channel of the virus are designed, synthesized and evaluated. Our approach is based on the synthesis of amantadine’s analogues by ring expansion, contraction and rearrangement. Amantadine is a drug already approved by the FDA for the treatment of Influenza A virus and it is known to target the M2 channel. Although it is no longer in use, because the FDA has recommended against its use, due to the appearance of resistance, it possessed good activity and an acceptable pharmacological behaviour. Our main goal was to synthesize an analogue of amantadine that was able to overcome the resistant virus and provide a new therapeutic alternative to the already marketed neuraminidase inhibitors such as Oseltamivir and Zanamivir. Importantly, we took advantage of the wide expertise of our research group in synthesizing polycyclic compounds to start a new research field that was based on the application of these optimized synthetic routes to the Medicinal chemistry. We established some external collaboration in order to set up the milestones and to build the rationale of the current project. These new collaborations are the following: - Prof. Lieve Naesens research group in the Rega Institute for Medical Research in Leuven, Belgium. This group of virologist made the plaque reduction assays and the study of the mutants to establish the mechanism of action of the tested compounds. - Lawrence H. Pinto research group of the Northwestern University, Evanston, Illinois, USA. This group of biochemist made the patch clamp assay to check if our compounds targeted the M2 channel. - Prof. Javier Luque of Universitat de Barcelona, Barcelona, España. This group made the docking and molecular dynamics of our compounds. In the following figures, the general structures of the compounds synthesized in the current Thesis are shown. Several of them showing an outstanding activity that allowed us to publish in the most important journals of the Medicinal Chemistry field: It it worth to mention that, several compounds have shown better activity than the reference compound, Amantadine. The most distinguished compounds are the following: Compound 1, 2 and 3 showed a superior activity against H1N1 strain in the cell culture assay while being almost inactive in the patch clamp assay. Prof. Lieve Naesen’s research group tried to identify the mechanism of action of these compounds selecting the mutants of hemagglutinin under the pressure of our compounds, revealing that this protein was the target of the first cluster of molecules. Compound 4 and 5 showed an outstanding activity against the wild-type and V27A M2 channels of influenza A virus. Taken together, all of these results show that tuning the polycyclic scaffold of amantadine could be the way to overcome the already stated resistance. A second part of this current Thesis consisted in a collection of compounds that have activity against vaccinia virus. These compounds are analogues of Tecovirimat®, a compound that it is currently in phase III clinical trials. When we started this project, we wanted to explore the impact in the EC50 of changing the polycyclic scaffold of the Tecovirimat® molecule, a common tool used in Medicinal Chemistry. We synthesized nearly 40 compounds and we obtained activities similar to Tecovirimat®, although none of our molecules was better than the reference compound.

Systems based on the organic ligand 3-bpp display a wide variety of magnetic behaviour, and have been studied in depth in the field of spin crossover (SCO). However, despite the apparent richness of SCO behaviour observed for 3-bpp systems, at the time of undertaking this thesis there were no published examples of the use of synthetic derivatives of 3-bpp in this field of research. This was remarked upon by Olguín and Brooker, who attributed this lack of 3-bpp analogues not to a lack of interest, but to “synthetic issues”. Therefore, the initial challenge set out was to develop a methodology that would allow the synthesis of functionalised 3-bpp ligands. Once obtained, these ligands would then be used for the generation of mononuclear Fe(II) compounds, with a view to study their macroscopic properties. Provided that this strategy was successful, and depending on the availability of structural data, an attempt would then be made to outline correlations between the observed magnetic properties and the relationship between the lattice entities, both spin-active and –inactive. The development of this work is detailed over the course of the ten Chapters. The first is an Introduction, primarily to the general field of SCO, the theory underlying its occurrence and its potential utility, but also describes the latest advances in the field before focussing on the family of 3-bpp systems. Chapter 2 contains the synthetic procedures and experimental details for the physical characterisation of the compounds obtained. Chapter 3 then describes the development of the novel polypyrazolyl ligands that have been designed for the subsequent investigation of their coordination chemistry. The magneto-structural properties of a new [Fe(3-bpp)2]2+ salt are described, and the compound shown to display a gradual spin crossover. Chapters 4 and 5 provide an in-depth study of a mononuclear compound, [Fe(H4L)2](ClO4)2•H2O•2(CH3)2CO (1), containing one of the polypyrazolyl ligands. A strongly cooperative spin transition is found to be intimately related to the structure and level of disorder within the lattice. This conclusion is supported by a description of the thermally trapped crystal structure. The photo-physical properties of 1 are then described, through the study of its meta-stable HS phase, which is distinct to the thermally trapped meta-stable HS phase. A Raman spectroscopy study of the system is then used to observe photo-switching within the hysteresis loop, and as a means of following the pressure-induced spin switch. Chapters 6 and 7 use compound 1 as the basis of an investigation into the effect of varying the anions and solvents within the lattice on the magnetic properties and crystal packing. A case where the spin crossover becomes more cooperative on ageing the compound is described. Chapter 8 details the compounds obtained using another 3-bpp derivative, which results in the formation of distorted structures that do not display SCO. In Chapter 9, the structural data provided by this thesis is collated with that found in the CSD for mononuclear Fe(II) systems with 3-bpp ligands. The data is then analysed from two points of view: a first, which involves previously defined parameters for the distortion of the cations, both in terms of their shape and in terms of the coordination sphere using Continuous Symmetry Measures. And a second, which uses Hirshfeld surface analysis to look at the bonding motifs and intermolecular interactions that are observed in the novel compounds obtained in this thesis. Chapter 10 offers conclusions based on the results obtained in this thesis.
A pesar de la riqueza de los comportamientos de la transición de espín de los sistemas basados en el ligando 3-bpp, no se ha estudiado ningún derivado del ligando. Así pues, el reto inicial de esta tesis fue el de desarrollar ligandos derivados del 3-bpp. Estos se utilizarían en la síntesis de compuestos mononucleares de Fe(II), para estudiar sus propiedades macroscópicas. Este trabajo se detalla a lo largo de nueve capítulos. El capítulo 2 contiene los procedimientos experimentales para la síntesis y caracterización de los compuestos obtenidos. El capítulo 3 describe el desarrollo de los ligandos que fueron utilizados en la química de coordinación. Se detallan las propiedades magneto-estructurales de una nueva sal [Fe(3-bpp)2](ClO4)2 que presenta una transición de espín gradual. Los capítulos 4 y 5 estudian el compuesto [Fe(H4L)2](ClO4)2•H2O•2(CH3)2CO (1). Se observa que una transición de alta cooperatividad se asocia al desorden cristalográfico. Se procede a describir las propiedades foto-físicas del compuesto, mediante el estudio de su fase meta-estable de espín alto inducido por irradiación. Un estudio de espectroscopia de Raman se llevó a cabo, permitiendo así la observación de un proceso de “photo-switch” dentro del ciclo de histéresis. Los espectros obtenidos sirvieron para seguir la transición al aplicar una presión externa. Los capítulos 6 y 7 investigan el efecto de los aniones y disolventes sobre las propiedades magnéticas y el empaquetamiento estructural del compuesto 1. Se describe un caso dónde un proceso de envejecimiento del compuesto lleva a que se aumente su grado de cooperatividad. En el capítulo 8, se utiliza otro derivado del 3-bpp para preparar unos compuestos mononucleares de Fe(II). Debido a la deformación estructural presentada por estos compuestos, no se observa una transición de espín. En el capítulo 9, se recogen los datos estructurales obtenidos a lo largo de la tesis, y se combinan con los datos disponibles en el CSD para compuestos mononucleares de Fe(II). Se analizan los datos para medir la forma y distorsión de los cationes, y para estudiar los tipos de interacción intermolecular mediante los análisis de superficies de Hirshfeld. El capítulo 10 saca unas conclusiones basadas en los resultados descritos en los capítulos anteriores.

L’objectiu d’aquesta tesis es desenvolupar una nova estratègia preventiva i terapèutica que requereixi les mínimes modificacions dels hàbits dietètics simultàniament efectiva en contra de l’obesitat i les seves malalties associades. Per aquest estudi s’han seleccionat compostos alimentaris presents en una dieta sana on el seus efectes beneficiosos han estat documentats tant en la obesitat com el risc de patir malalties cardiovasculars. S’inclou els polifenols com l’epigallocatechin gallate (EGCG) i les proantocyanidines i també els àcids grassos poliinsaturats omega 3 (PUFAs) o l’àcid docosahexaenoic (DHA). El treball esta enfocat en el funcionament mitocondrial del múscul, el teixit mes important de l’organisme en el control del balanç de nutrients. Els nostres resultats indiquen que hi ha una millora postprandial amb un increment de la capacitat d’oxidació dels àcids grassos millorant el perfil lipídic i la flexibilitat metabòlica.
El objetivo principal de esta tesis es desarrollar una nueva estrategia preventiva y terapéutica que requiera les mínimas modificaciones de los hábitos dietéticos simultáneamente efectiva en contra de la obesidad y sus enfermedades asociadas. Para este estudio se han seleccionado compuestos alimentarios presentes en una dieta sana dónde sus efectos beneficiosos han estado documentados tanto en la obesidad como en el riesgo de desarrollar enfermedades cardiovasculares. Se incluyen los polifenoles como el epigalocatequin galato (EGCG) y las proantocianidinas; también los ácidos grasos poliinsaturados omega 3 (PUFAs) y el acido docosahexaenoico (DHA). El trabajo está enfocado en el funcionamiento mitocondrial de musculo, el tejido más importante del organismo en el control del balance de nutrientes. Nuestros resultados indican que hay una mejora postprandial con un incremento de la capacidad de oxidación de los ácidos grasos mejorando el perfil lipídico y la flexibilidad metabólica.
The global goal of the present thesis is the development of a new preventative and therapeutic strategy that requires only minor modifications of dietary habits and simultaneously effective against obesity and its major associated diseases. For this study, we have selected food ingredients characteristic in healthy diets which has been documented beneficial effects on obesity or cardiovascular disease risk. These include plant polyphenols, epigallocatechin gallate (EGCG) and proanthocyanidins as well as the sea fish omega-3 polyunsaturated fatty acids (PUFAs) and docosahexaenoic acid (DHA). Our work is focused on the mitochondrial function of skeletal muscle, a major player in the body’s overall nutrient balance, and adipose tissue, which is the key regulator of energy homeostasis in the organism affected by obesity and related diseases. Our results indicate a postprandial improvement with an increase of the fatty acid oxidation capacity, improving lipid profile and metabolic flexibility.

La immunoteràpia nutricional es basa en fomentar la salut mitjançant el consum de compostos bioactius presents de manera natural en els aliments, com les procianidines, un tipus de flavonoid, i/o l’àcid docosahexaenoic (DHA), un àcid gras omega-3, optimitzant la funcionalitat del propi sistema immune i millorant així el seu paper com a responsable de la preservació de l’organisme enfront desestabilitzadors de la homeòstasis. La recerca que aquesta tesi abasta es centra en el paper del perfil nutricional en la regulació de la interacció immunitat-metabolisme (immunometabolisme). Amb aquesta finalitat, en la primera part del treball presentat en aquesta tesi, es va determinar si els macròfags, les cèl•lules efectores de la immunitat innata, poden percebre de manera diferencial la composició de la dieta. Hem demostrat que els compostos bioactius dels aliments modulen, a nivell molecular, l’activació dels macròfags. A més, aquest efecte immunomodulador és dependent del compost, on factors intrínsecs com les propietats químiques o nutritives són determinants per la seva bioactivitat. La segona part va tenir com a objectiu determinar el paper primordial del patró nutricional en la regulació de la interacció entre el sistema immune i el metabolisme. Utilitzant un model d’obesitat induïda per la dieta es va inferir que, mentre una dieta hipercalòrica provoca un deteriorament de l’immunometabolisme, el consum de bioactius pot enfortir-ne la relació. A la tercera part, es va analitzar el paper de les interaccions gen-dieta en l’expressió fenotípica dels trets associats amb la obesitat. Per aquest motiu, dos races de rates congènites, fenotípicament diferents, van ser sotmeses a un desequilibri immunometabòlic com a conseqüència de la ingesta d’una dieta hipercalòrica. Es va deduir que les interaccions entre els factors genètics i nutricionals són fonamentals per a la susceptibilitat d’un genotip a l’obesitat induïda per la dieta. Hem establert que el perfil nutricional és una eina poderosa per orientar la funcionalitat de l’eix immunometabòlic. A més, arribem a la conclusió que compostos bioactius presents en els aliments poden millorar-ne l’eficiència d’aquest eix, promovent així un estat saludable.
La immunoterapia nutricional se basa en fomentar la salud mediante el consumo de componentes bioactivos presentes de forma natural en los alimentos, como las procianidinas, un tipo de flavonoides, o el ácido docosahexaenoico (DHA), un ácido graso omega-3, optimizando la funcionalidad del propio sistema inmune y mejorando así su papel como responsable de la preservación del organismo frente a desestabilizadores de la homeostasis. La investigación que engloba esta tesis se centra en el papel del perfil nutricional en la regulación de la interacción inmunidad-metabolismo (immunometabolismo). Con esta finalidad, en la primera parte del trabajo presentado es esta tesis, se determinó si los macrófagos, las células efectoras de la inmunidad innata, pueden percibir de manera diferencial la composición de la dieta. Hemos demostrado que los compuestos bioactivos de los alimentos modulan, a nivel molecular, la activación de los macrófagos. Además, este efecto immunomodulador es dependiente del compuesto, donde factores intrínsecos tales como sus propiedades químicas o nutritivas son determinantes para su bioactividad. La segunda parte tuvo como objetivo determinar el papel primordial del patrón nutricional en la regulación de la interacción entre el sistema inmune y el metabolismo. Utilizando un modelo de obesidad inducida por la dieta se infirió que, mientras una dieta hipercalórica provoca un deterioro del immunometabolismo, el consumo de bioactivos pueden fortalecer su estrecha relación. En la tercera parte, se analizó el papel de las interacciones gen-dieta en la expresión fenotípica de los rasgos asociados con la obesidad. Para ello, dos razas de ratas congénitas, fenotípicamente diferentes, fueron sometidas a un desequilibrio immunometabólico como consecuencia de la ingesta de una dieta hipercalórica. Se dedujo que las interacciones entre los factores genéticos y nutricionales son fundamentales para la susceptibilidad de un genotipo a la obesidad inducida por la dieta. Hemos establecido que el perfil nutricional es una herramienta poderosa para orientar la funcionalidad del eje immunometabólico. Además, llegamos a la conclusión que compuestos bioactivos presentes en los alimentos pueden mejorar la eficiencia de este eje, promoviendo así un estado saludable.
Nutritional immunotherapy is based on promoting health through the dietary intake of natural bioactive compounds found in food, such as the procyanidins and docosahexaenoic n-3 polyunsaturated fatty acid (DHA), optimising the functionality of the host’s own immune system and improving its role in the preservation of the body against destabilisers of homeostasis. The research that this thesis encompasses is focused on the role of the nutritional profile in the regulation of immunometabolism. To accomplish this purpose, in the first part of the work presented in this thesis, we determined whether macrophages, the effector cells of innate immunity, could differentially sense dietary composition. We demonstrated that bioactive food compounds modulate, at the molecular level, the functionality of macrophages by hindering macrophage activation. Furthermore, this immunomodulatory effect is compound-dependent, relying on the intrinsic factors of each compound, such as chemical and nutritional properties, to determine its bioactivity. The second part was aimed at determining the role of the dietary pattern within the complex crosstalk of immunity and metabolism using an in vivo model of diet-induced obesity. We determined that immunometabolic regulation depends on the nutritional profile. While a diet based on foods with a high energy content can weaken immunometabolism, the presence of bioactive foods can strengthen the relationship. Within the third part, we evaluated the role of gene-diet interactions in the phenotypic expression of obesity-related complex traits. Using a diet-induced obesity model, two distinct genetic backgrounds (phenotypically different inbred rat strains) were immunometabolically challenged. Our results revealed that interactions between genetic and dietary factors are fundamental for the susceptibility of a genotype to diet-induced obesity. We established that the nutritional profile is a powerful tool to target the functionality of the immunometabolic axis. We further concluded that bioactive compounds present in food improve the efficiency of this axis, thereby promoting a healthy state.

Els fàrmacs constitueixen un grup gran, important i divers, de compostos químics dissenyats per a causar efectes terapèutics sobre la salut principalment humana, però també animal. Per la seva composició, són bioactius i difícils de degradar encara que presentin una dosi mínima. La seva varietat estructural, de composició i efectes és enorme i mentre que alguns d'ells són eliminats completament a les depuradores, d'altres romanen inalterats o parcialment transformats. A més a més, malgrat ser estrictament regulats per assajos clínics abans de la seva distribució al mercat, no existeixen restriccions específiques per al seu alliberament en el medi ambient, i encara manca un mètode de quantificació estàndard per a detectar-los. Cal implementar tecnologies alternatives en les depuradores per a eliminar aquests principis actius de l'aigua abans de ser abocats al medi ambient. Un possible tractament és l'ús de fongs ligninolítics per a degradar aquests compostos. En relació amb aquest tractament, el fong T. versicolor, membre del grup de fongs de podridura blanca, ha estat àmpliament estudiat en l'eliminació de molts fàrmacs en aigües residuals i condicions no estèrils. Tanmateix, encara hi ha diverses qüestions a resoldre d’entre les quals en destaquen: els compostos recalcitrants, la generació de productes de transformació i colls d'ampolla operacionals. Es consideren recalcitrants aquells fàrmacs que romanen inalterats a causa de la seva estructura estable durant els tractaments d’eliminació. En el cas dels tractaments amb fongs, aquesta estabilitat depèn principalment de factors com el mecanisme de degradació, directament afectat pel metabolisme de les espècies de fong emprades. Per tal de descobrir candidats potencials per a l'eliminació i biodegradació de compostos recalcitrants es va realitzar un experiment de cribatge entre 6 espècies diferents de fongs. Espècies poc estudiades, com ara S. rugosoannulata i G. luteofolius, van permetre obtenir importants eliminacions vinculades amb processos de biodegradació. També es va estudiar l'eliminació de fàrmacs tenint en compte els diferents mecanismes de biodegradació i sorció en cultius submergits. Pel que fa a la sorció, les anàlisis dels fàrmacs presents en la fase líquida i en la biomassa del fong mostren resultats semblants respecte de la sorció estimada a partir de controls amb biomassa de fong inactivats per calor. S'ha demostrat que 6 dies no és temps suficient per al fong per a poder degradar els contaminants adsorbits. Pel que fa a la generació de productes de transformació a partir dels compostos principals, es van identificar o-desmethylvenlafaxine i n-desmethylvenlafaxine com els dos principals productes de transformació biològica generats durant la degradació del compost recalcitrant venlafaxina. D'altra banda, els productes de transformació generats pel fong P. ostreatus en la degradació de diclofenac i ketoprofè coincideixen amb les molècules generades per T. versicolor en el mateix tipus de tractament, segons els seus perfils de ressonància magnètica nuclear. A més a més, estudis sobre dos dels principals mecanismes enzimàtics dels fongs, van demostrar que l'enzim extracel·lular lacasa està implicat en la degradació de compostos recalcitrants com l'atenolol, mentre que el complex enzimàtic intracel·lular citocrom P450 intervé en l’eliminació de diclofenac. Els colls d'ampolla operacionals com la competència de la microbiota nativa pels nutrients en els bioreactors fúngics provoquen diversos problemes en l’aplicació del tractament en continu. Per a prevenir la proliferació de bacteris, es va avaluar la implementació d'un biofiltre de sorra per a la reducció de la càrrega bacteriana en aigües residuals d'hospital. Malgrat aconseguir certa reducció bacteriana, aquest pretractament no va permetre reduir prou la càrrega bacteriana d’entrada del reactor amb el fong. En canvi, la microbiota nativa present en el biofiltre de sorra va ser capaç d’eliminar concentracions de l’antibiòtic ciprofloxacina i l'analgèsic ibuprofè. Això va motivar l’anàlisi molecular mitjançant electroforesi en gel de gradient desnaturalitzant (DGGE) per tal d’analitzar els canvis que es produïen en la microbiota com a conseqüència de l’exposició continuada a fàrmacs i quines poblacions microbianes eren candidats potencials responsables de l’eliminació dels fàrmacs en qüestió. Un altre dels problemes operatius a tractar en reactors amb T. versicolor va ser la necessitat de proveir de carboni el reactor per una banda, i del control del pH per l’altra. En aquesta tesi, P. ostreatus i S. rugosoannulata han demostrat poder-se autoproveir de carboni a partir d'aigües residuals amb alts valors de demanda química d'oxigen (DQO), evitant així la necessitat del seu subministrament. A més a més, S. rugosoannulata també va poder reduir el pH de les aigües residuals hospitalàries al seu nivell òptim i, per tant, va mostrar trets prometedors de cara a la seva futura plena implementació en reactors.
Los fármacos son un grupo grande, importante y diverso, de compuestos químicos diseñados para causar efectos terapéuticos sobre la salud principalmente humana, pero también animal. Por su composición, son bioactivos y difíciles de degradar aunque presenten una dosis mínima. Su variedad estructural, de composición y efectos es enorme y mientras que algunos de ellos son eliminados completamente en las depuradoras, otros permanecen inalterados o parcialmente transformados. Además, a pesar de ser estrictamente regulados por ensayos clínicos antes de su distribución en el mercado, no existen restricciones específicas para su liberación en el medio ambiente, y aún falta un método de cuantificación estándar para detectarlos. Hay que implementar tecnologías alternativas en las depuradoras para eliminar estos principios activos del agua antes de ser vertidos al medio ambiente. Un posible tratamiento es el uso de hongos ligninolíticos. En relación con este tratamiento, el hongo T. versicolor, perteneciente al grupo de hongos de podredura blanca, ha sido ampliamente estudiado en la eliminación de muchos principios activos farmacéuticos en aguas residuales y condiciones no estériles. Sin embargo, aún hay varias cuestiones a resolver entre las cuales destacan: los compuestos recalcitrantes, la generación de productos de transformación y cuellos de botella operacionales. Se consideran recalcitrantes aquellos fármacos que permanecen inalterados debido a su estructura estable durante los tratamientos de eliminación. En el caso de los tratamientos con hongos, esta estabilidad depende principalmente de factores como el mecanismo de degradación, directamente relacionado con el metabolismo de las especies de hongo empleadas. En ese sentido se realizó un experimento de cribado entre 6 especies diferentes de hongos para descubrir candidatos potenciales para tratar compuestos recalcitrantes. Especies hasta ahora poco estudiadas, como S. rugosoannulata y G. luteofolius, proporcionaron importantes eliminaciones, vinculadas a procesos de biodegradación. También se estudió la eliminación de fármacos teniendo en cuenta los diferentes mecanismos de biodegradación y sorción en cultivos sumergidos. En cuanto a la sorción, los análisis de los fármacos presentes en la fase líquida y en la biomasa del hongo muestran resultados similares respecto a la sorción estimada a partir de controles con biomasa de hongo inactivada por el calor. Se ha demostrado que 6 días no es tiempo suficiente para que el hongo pueda degradar los contaminantes adsorbidos. En cuanto a la generación de productos de transformación a partir de compuestos principales, se identificaron o-desmethylvenlafaxine y n-desmethylvenlafaxine como los dos principales productos de transformación biológica generados durante la degradación del compuesto recalcitrante venlafaxina. Por otra parte, los productos de transformación generados por el hongo P. ostreatus en la degradación de diclofenaco y ketoprofeno coinciden con las moléculas generadas por T. versicolor en el mismo tratamiento, según sus perfiles de resonancia magnética nuclear. Además, estudios sobre dos de los principales mecanismos enzimáticos de los hongos, demostraron que enzima extracelular lacasa está implicada en la degradación de compuestos recalcitrantes como el atenolol, mientras que el complejo enzimático intracelular citocromo P450 interviene en la eliminación de diclofenaco. Los cuellos de botella operacionales como la contaminación microbiana y la competencia por los nutrientes en los biorreactores fúngicos provocan varios problemas en el mantenimiento de los mismos. Para prevenir la proliferación de bacterias se evaluó la implementación de un biofiltro de arena para la reducción de la carga bacteriana en aguas residuales de hospital. A pesar de conseguir cierta reducción bacteriana, este pretratamiento no permitió reducir suficientemente la carga bacteriana de entrada del reactor con el hongo. En cambio, la microbiota nativa presente en el biofiltro de arena fue capaz de eliminar concentraciones del antibiótico ciprofloxacina y el analgésico ibuprofeno. Esto motivó el análisis molecular mediante electroforesis en gel de gradiente desnaturalizante (DGGE) para analizar los cambios que se producían en la microbiota como consecuencia de la exposición continuada a fármacos y que poblaciones microbianas eran candidatos potenciales responsables de la elimincación de dichos fármacos. Otro de los problemas operativos a tratar en reactores con T. versicolor es la necesidad de proveer el reactor de carbono por un lado, y del control del pH por el otro. En esta tesis, P. ostreatus y S. rugosoannulata han demostrado poderse autoproveer de carbono a partir de aguas residuales con altos valores de demanda química de oxígeno (DQO), evitando así la necesidad de su suministro. Además, S. rugosoannulata también pudo reducir el pH de las aguas residuales hospitalarias a su nivel óptimo y, por tanto, mostró rasgos prometedores para su futura implementación completa en reactores.
Pharmaceutical active compounds are an important, large and diverse group of chemical compounds designed to cause therapeutic effects on health, mainly human but also animal. Because of their composition, they are bioactive and difficult to be degraded even when present at a minimal dose. Their variety of structure, composition and effects is huge, while some of them are completely removed at wastewater treatment plants, others are only partially or non-removed. Furthermore, despite of being strictly regulated by clinical trials before their market distribution, specific restrictions for their release in the environment are almost non-existent, and there is not a standard quantification method yet. Regarding this situation, there is a need to implement alternative technologies in wastewater treatment plants to remove pharmaceuticals from water before entering the environment. One possible treatment is the use of ligninolytic fungi to degrade these compounds. In relation with this approach, the white-rot fungus T. versicolor has been widely studied in the removal of many pharmaceutical active compounds in wastewater under non-sterile conditions. However, there are still several questions to tackle: recalcitrant compounds unable to be degraded, the generation of transformation products, and operational bottlenecks can be highlighted among many other. Certain pharmaceuticals are considered recalcitrant due to its stable structure when treated for their removal. In fungal treatment, this stability depends mainly on factors such as the degradation mechanism, which is directly affected by the metabolism of the fungal species. A screening experiment among 6 different species of fungi attempted to discover new candidates in the removal and biodegradation of recalcitrant compounds. Scarcely studied species such as S. rugosoannulata and G. luteofolius obtained considerable removals linked to biodegradation processes. The removal of pharmaceutical active compounds has also been studied in terms of biodegradation and sorption mechanisms in submerged cultures. Regarding sorption processes, the analyses of the pharmaceutical active compounds present in liquid phase and in fungal biomass showed similar results respect to the sorption estimated by heat killed control biomass. It has been proven that 6 days is generally insufficient time for fungal biomass to degrade the adsorbed contaminants. Concerning the generation of transformation products from parental compounds, odesmethylvenlafaxine and n-desmethylvenlafaxine were identified as the two main biological transformation products generated during the degradation of the recalcitrant compound venlafaxine. On the other hand, transformation products generated by the fungus P. ostreatus in the degradation of diclofenac and ketoprofen coincide with the molecules generated by T. versicolor in the same treatment according to their nuclear magnetic resonance profiles. Besides, studies on two main fungal enzymatic mechanisms showed that the extracellular enzyme laccase is involved in the degradation of recalcitrant compounds such as atenolol, whereas the intracellular enzymatic complex cytochrome P450 is involved in diclofenac transformation. Operational bottlenecks, such as microbial competition by native microbiota for nutrients in fungal bioreactors, cause several problems in applying continuous treatment. In order to prevent bacteria proliferation, the implementation of a biosand filter for the reduction of a high bacterial load in hospital wastewater was evaluated. This pretreatment was not able to achieve enough reduction in bacterial load of the fungal reactor’s inlet. Instead, the native microbiota present in the biosand filter was able to remove spiked concentrations of the antibiotic ciprofloxacin and the analgesic ibuprofen. This opened the way for a molecular biology study with denaturing gradient gel electrophoresis (DGGE) to analyse which changes in the microbiota could entail the presence of potential candidates for pharmaceutical removal and which could be those microorganisms. Other operational issues to be tackled in T. versicolor reactors were the need for carbon supply and the pH control. In this thesis, P. ostreatus and S. rugosoannulata have proven able to self-obtain its carbon source from wastewaters achieving high chemical oxygen demand (COD) reductions, avoiding the need for carbon supply. Besides, S. rugosoannulata was also able to lower the pH of hospital wastewaters to its optimal, and hence showing promising features to its full implementation in reactors.

En esta Tesis Doctoral se han preparado una serie de ligandos carbeno N-heterocíclico (NHC, por sus siglas en inglés) funcionalizados con sistemas poliaromáticos. En primer lugar se prepararon una serie de ligandos NHC que incorporan fragmentos poliaromáticos basados en pireno, fenantrofenacina y acenaftoquinoxalina. Estos ligandos fueron coordinados a fragmentos metálicos de iridio, rodio, níquel y paladio. Con fines comparativos, se obtuvieron los complejos análogos derivados de los ligandos imidazolilideno y benzoimidazolilideno. Los complejos derivados de iridio y níquel nos permitieron estudiar las propiedades electrónicas de los ligandos. De manera particular, en esta Tesis Doctoral se demostró, mediante cálculos computacionales de DFT, estudios de infrarrojo y electroquímicos, que las propiedades electrónicas de los ligandos poliaromáticos pueden ser moduladas mediante compuestos orgánicos que favorecen el apilamiento-¿ como, por ejemplo, pireno y hexafluorobenceno. Además, mediante técnicas experimentales y teóricas, se determinó de manera inequívoca la constate de asociación y la regioselectividad de la interacción entre los ligandos NHC con sistemas poliaromáticos y reactivos capaces de establecer interacciones de apilamiento-¿. Asimismo, se demostró que la actividad catalítica de algunos de los complejos preparados puede verse afectada por la presencia de un compuesto que favorezca el apilamiento. En segundo lugar, preparamos una serie de complejos di-metálicos y tri-metálicos basados en ligandos NHC, en los que las unidades carbeno se encuentran unidas por sistemas poliaromáticos extendidos. Cabe destacar que en la literatura hay muy pocos ejemplos de este tipo de complejos. Finalmente, se amplió la versatilidad coordinativa de los ligandos bis(NHC) derivados de bis(imidazolilidinas). Para ello hemos utilizado dos estrategias sintéticas: i) la doble activación C-H de un grupo C(sp3)H2 y ii) la activación de la sal de azolio con una base débil.

Bohr, inspired by Fermi’s discovery of slow neutrons, conceived his theory of the compound nucleus by the end of 1935. He went on to speculate that if the energy of a neutron incident on a nucleus were increased to the fantastically high energy of 1000 million electron volts, the compound nucleus would explode. Using small wooden models Otto Robert Frisch had constructed, Bohr lectured widely on his theory on a trip around the world in the first half of 1937. By then, Russian-born theoretical physicist Gregory Breit and Hungarian-born theoretical physicist Eugene Wigner in Princeton had conceived their fundamentally equivalent theory of neutron+nucleus resonances. Together, their theory and Bohr’s transformed the theory of nuclear reactions. Orso Mario Corbino, Fermi’s mentor, friend, and protector, died on January 23, 1937, at age sixty. Ernest Rutherford, the greatest experimental physicist since Michael Faraday, died on October 19, 1937, at age sixty-six.

We use more than 100 000 chemicals in our daily lives to promote health, treat disease, facilitate transportation, use in industrial processes, grow food and access clean water. While these developments have improved human lives, many of these compounds ultimately end up in our seas and oceans where they represent a threat to marine life, ourselves and our continued use of the oceans to treat our waste, provide us with food and offer us recreation. Many of the pollution problems of previous decades seem to have been resolved, in the developed world, or at least managed to minimise their environmental impacts. However, despite treatments being available that reduce their damaging qualities, a potent mixture of toxic compounds enter the marine environment every day along with other potentially harmful additions including heat, noise and light and non-native species. The question thus arises: is pollution a problem that has really been solved? How well are we managing traditional pollutants? What are the challenges we still face today? What are the upcoming marine pollution challenges that face society? This volume describes the different marine pollutants, the science behind measuring their ecological impacts and how they are monitored in the environment, including traditional and new management approaches. This is an up-to-date account of marine pollution within the broad ecological and social context of a growing, technologically advanced, global population.

Beowulf is a foundational work of Western literature that originated in mysterious circumstances. This book addresses philological questions that are fundamental to the study of the poem. Is Beowulf the product of unitary or composite authorship? How substantially did scribes alter the text during its transmission, and how much time elapsed between composition and preservation? The book answers these questions by distinguishing linguistic and metrical regularities, which originate with the Beowulf poet, from patterns of textual corruption, which descend from copyists involved in the poem’s transmission. It argues, on the basis of archaic features that pervade Beowulf and set it apart from other Old English poems, that the text preserved in the sole extant manuscript (ca. 1000) is essentially the work of one poet who composed it ca. 700. Of course, during the poem’s written transmission, several hundred scribal errors crept into its text. These errors are interpreted in the central chapters of the book as valuable evidence for language history, cultural change, and scribal practice. The book reveals that the scribes earnestly attempted to standardize and modernize the text’s orthography, but their unfamiliarity with obsolete words and ancient heroes resulted in frequent errors. The Beowulf manuscript thus emerges from his study as an indispensible witness to processes of linguistic and cultural change that took place in England between the eighth and eleventh centuries.

Based on cross-linguistic data from several children each learning one of eight languages and grounded in the theoretical frameworks of usage-based phonology, exemplar theory, and Dynamic Systems Theory, this book explores the patterns or phonological templates children develop once they are producing 20–50 words or more. The children are found to begin with ‘selected’ words, which match some of the vocal forms they have practised in babbling; this is followed by the production of more challenging adult word forms, adapted—differently by different children and with some shaping by the particular adult language—to fit that child’s existing word forms. Early accuracy is replaced by later recourse to an ‘inner model’ of what a word can sound like; this is a template, or fixed output pattern to which a high proportion of the children’s forms adhere for a short time, before being replaced by ‘ordinary’ (more adult-like) forms with regular substitutions and omissions. The idea of templates developed in adult theorizing about phonology and morphology; in adult language it is most productive in colloquial forms and pet names or hypocoristics, found in informal settings or ‘language at play’. These are illustrated in some detail for over 200 English rhyming compounds, 100 Estonian and 500 French short forms. The issues of emergent systematicity, the roles of articulatory and memory challenges for children, and the similarities and differences in the function of templates for adults as compared with children are central concerns.

Rashi’s Commentary on the Torah explores the reception history of the most important Jewish Bible commentary ever composed, the Commentary on the Torah of Rashi (Shlomo Yitzhaki, 1040–1105). The Commentary has shaped perceptions of the meaning of the Torah, Judaism’s foundation document, among leading scholars, lay readers, and initiates in Jewish learning for more than nine centuries. The Commentary has benefited from enormous scholarly attention but analysis of diverse reactions to this work has been amazingly scant. Viewing the Commentary’s path to preeminence through a wide array of religious, intellectual, and literary lenses, Lawee focuses considerable attention on a hitherto unexamined—and wholly unexpected—feature of the work’s reception: critical, and at times astonishingly harsh, resistance to it. At the same time, he shows how Rashi’s interpretation of the Torah became an exegetical classic, a staple in the curriculum, a source of shared religious vocabulary for Jews across time and place, and a foundational text that shaped the Jewish nation’s collective identity. The book takes as its larger integrating perspective processes of canonicity as they shape how traditions flourish, disintegrate, or evolve. Rashi’s scriptural magnum opus, the foremost work of Franco-German (Ashkenazic) biblical scholarship, faced stiff completion for canonical preeminence in the form of rationalist reconfigurations of Judaism abroad in Mediterranean seats of learning. It nevertheless emerged triumphant in an intense medieval battle for Judaism’s future. Investigation of the reception of Rashi’s Commentary throws light on issues in Jewish scholarship and spirituality that continue to stir reflection, and even passionate debate, in the Jewish world today.

The production of plasminogen activator inhibitor (PAI) by the human cell-lines Hep G2 and HT 1080 have been studied by immunochemical and functional methods. In conditioned medium collected after 2h, the PAI seemed to be almost fully active, but with increasing incubation time the activity was gradually lost, in spite of that the PAI-antigen content increased continously. The active PAI form can be separated from the inactive form by gel-filtration. The inactive form behaves as a low Mr (about 50,000) component in the absence and in the presence of sodium dodecyl-sulphate. In contrast, the active form of PAI behaves as a high Mr (>300,000) compound in the absence of sodium dodecylsulphate but as a low MT compound in its presence. The low M_r inactive PAI has been purified to homogeneity from HT 1080 conditioned medium, collected in the absence of fetal calf serum. This was achieved by chromatography on Concanavalin A-Sepharose, gel-filtration on Sephacryl S-300 and affinity chromatography on insolubilized monoclonal antibodies against PA-inhibitor. On treatment of this form of the inhibitor with 4 mol/L Guanidinium chloride, the activity was regained, but its gel-filtration behaviour was unchanged in the absence of serum/plasma (Mr about 50,000). Addition of plasma or serum prior to the gel-filtration, changed the elution pattern of PAI towards a high Mr form. The reason for this behaviour is not yet fully understood, but the most plausible explanation is the presence of a high Mr PAI-binding protein in plasma/serum. This hypothesis is presently being explored .

For several years it has been known that plasminogen activator inhibitor in plasma behaves as a high molecular weight compound on gelfiltration, in spite of that the molecular weight is only 50,000 in the presence of sodium dodecylsul-phate. The reason for this has so far been unknown. On gelfiltration of plasma, to which purified latent PAI from HT 1080 cells was added, the PAI antigen gel-filtered as a 50,000 Mr protein. However, if the latent form of PAI was reactivated by guanidinium chloride prior to the gel-filtra-tion experiment, an apparent molecular weight of about 250.000 for PAI antigen and activity was observed. If more than 10,000 U of PAI activity was added/mL of normal human plasma, excess PAI occurred at 50,000 Mr on gel-filtration. Human normalplasma was subjected to gel-filtration on sepha-cryl S-300 or Sepharose 6B and the fractions were checked for capacity to transform low Mr functional PAI to high Mr functional PAI. This capacity was only found in the 150 - 200,000 Mr region of the chromatogram. These data suggest that human plasma contains a protein that binds active forms of PAI. The complex of this protein and PAI could be dissociated by gelfiltration in the presence of 3 mol/L guanidinium chloride or 0.1 % (w/v) sodium dodecylsulphate. The physiological or pathophysiological role of the PAI-binding protein is not known. Work with purification of the protein is in progress. Considerable purification have so far been obtained by precipitation with polyethylenglycol 6000 (0-6%), gel-filtration on Sephacry1 S-300, followed by affinity chromatography on heparin-Sepharose.

Abstract Red phosphorous is one of the inorganic phosphorous compounds used as a flame retardant in microelectronic applications. One of the concerns is a red phosphorus induced pin-to-pin short in the molding compound. This paper discusses the red phosphorous-induced shorts in a 100 Lead TQFP (14x20x1.4mm) plastic package. The devices first failed on boards in the field. After de-soldering them from the boards, the devices were tested and found to have resistive pin-to-pin shorts. Common failure analysis techniques, including parallel lapping, cross sectioning, and X-ray, failed to reveal the resistive shorts and the shorting mechanism. Removing the molding compound by means of a wet chemical etching method using sulfuric acid on a hot plate worked very well and enabled to expose particles in three dimensions. It was concluded that the resistive shorts were not necessarily due to a single large phosphorous particle, but due to small and fragmented pieces of phosphorous.

The oxidation studies of a sulfur to a sulfate ion by various oxyhalide oxidants in organic (thiourea, methionine) and inorganic (sulfate, thiophosphate) compounds were carried out in an acidic solution. The optimized result of the oxidation reaction was obtained when a bromate compound (BrO3−) as an oxidant and a 3 M HNO3 solvent. The chemical yield for the oxidation of the organic and inorganic sulfur compounds to a sulfate ion was monitored as 80% for thiophosphate, 87% for methionine, and 100% for thiourea and sulfate within 5% RSD. The oxidation of thiourea required at least 1.6 equivalents of the bromate in an acidic solution. In the case of the oxidation of methionine and thiophosphate, the oxidation yield was above 80% if the bromate was used at 20 times that of the substrates. The chemical yield in the paper sample (WypAll) exceeded 100% because of its background sulfur contents (910 ppm). The sulfate ion was quantitatively measured by using GPC and/or LSC counting of 35S followed by precipitates of BaSO4. The interfering nuclides (14C, 32P) were removed in an acidic condition. The minimum detectable activity (MDA) of 35S was found to be 0.1 Bq/g.

Low molecular weight (LMW) heparin is characterized by a higher affinity to antithrombin HI, less inhibition of thrombin and increased inhibition of factor Xa. The half life of the antifactor Xa activity of LMW heparin is doubled compared to normal heparin. However, these parameters reflect the pharmacodynamics rather than the kinetic of the compound. We, therefore, analyzed the kinetics of LMW heparin after i.v. injection in man using protamine chloride for gravimetric evaluation of LMW heparin in the plasma samples.Six healthy adults received 100 units per kg body weight normal heparin or 100 anti Xa units per kg LMW heparin (Sandoz AG, Niimberg, FRG). To serial samples of venous blood protamine chloride was added in serial dilutions until the thrombin inhibition was antagonized. Since factor Xa inhibition of LMW heparin cannot be abolished completely by protamine chloride, two amounts of protamine chloride were added to the plasma samples ex vivo, until factor Xa was inhibited up to 0,2 and 0,04 units/ml. The following maximal plasma concentrations (C max) and half lives (T/2) were calculated (average values):The pharmacokinetics of normal heparin show no differences on thrombin and factor Xa interaction. LMW heparin, however, interacts to 30 % with thrombin and to 100 % with factor Xa; the half life on factor Xa is twice as long as on thrombin; releases endogenous compounds with antifactor Xa activity, which are neutralized only hardly by protamine chloride;and these endogenous compounds mediate in part the longer half life.

Hanne Darboven’s (1941-2009) Opus 17a is a composition for solo double bass that is rarely performed due to the physical and mental challenges involved in its performance. It is one of four opuses from the composers monumental 1008 page Wünschkonzert (1984), and was composed during her period of making “mathematical music” based on mathematical systems where numbers were assigned to certain notes and translated to musical scores. It can be described as large-scale minimalism and it is highly repetitive, but even though the same notes and intervals keep repeating, the patterns slightly change throughout the piece. This is an attempt to unfold the many challenges of both interpreting, preparing and performing this 70 minute long solo piece for double bass consisting of a continuous stream of eight notes. It is largely based on my own experiences of preparing, rehearsing and performing Opus 17a, but also on interviews I have conducted with fellow bass players Robert Black and Tom Peters, who have both made recordings of this piece as well as having performed it live. One is met with few instrumental technical challenges such as fingering, string crossing and bowing when performing Opus 17a, but because of its long duration what one normally would take for granted could possibly prove to be challenging.

DIPLANOAGAP: Distribution of Plastics in the North Atlantic Garbage Patch Ponta Delgada (Portugal) – Malaga (Spain) 17.08. – 12.09.2019 The expedition POS 536 is part of a multi-disciplinary research initiative of GEOMAR investigating the origin, transport and fate of plastic debris from estuaries to the oceanic garbage patches. The main focus will be on the vertical transfer of plastic debris from the surface and near-surface waters to the deep sea and on the processes that mediate this transport. The obtained data will help to develop quantitative models that provide information about the level of plastic pollution in the different compartments of the open ocean (surface, water column, seafloor). Furthermore, the effects of plastic debris on marine organisms in the open ocean will be assessed. The cruise will provide data about the: (1) abundance of plastic debris with a minimum size of 100 μm as well as the composition of polymer types in the water column at different depths from the sea surface to the seafloor including the sediment, (2) abundance and composition of plastic debris in organic aggregates (“marine snow”), (3) in pelagic and benthic organisms (invertebrates and fish) and in fecal pellets, (4) abundance and the identity of biofoulers (bacteria, protozoans and metazoans) on the surface of plastic debris from different water depths, (5) identification of chemical compounds (“additives”) in the plastic debris and in water samples.