Sulfanyl Radical Addition to Alkynes: Revisiting an Old Reaction to Enter the Novel Realms of Green Chemistry, Bioconjugation, and Material Chemistry

In the last decade considerable attention has been devoted to the rewarding use of Green Chemistry in various synthetic processes and applications. Green Chemistry is of special interest in the synthesis of expensive pharmaceutical products, where suitable adoption of “green” reagents and conditions is highly desirable. Our project especially focused in a search for new green radical processes which might also find useful applications in the industry. In particular, we have explored the possible adoption of green solvents in radical Thiol-Ene and Thiol-Yne coupling reactions, which to date have been normally performed in “ordinary” organic solvents such as benzene and toluene, with the primary aim of applying those coupling reactions to the construction of biological substrates. We have additionally tuned adequate reaction conditions which might enable achievement of highly functionalised materials and/or complex bioconjugation via homo/heterosequence. Furthermore, we have performed suitable theoretical studies to gain useful chemical information concerning mechanistic implications of the use of green solvents in the radical Thiol-Yne coupling reactions.

Unione Europea e sanità

La tesi di dottorato "Unione Europea e Sanità" è uno studio sistematico del diritto alla salute e della protezione della sanità pubblica nell'ordinamento giuridico dell'Unione Europea. Il primo capitolo analizza le competenze sanitarie dell'Unione Europea, introdotte per la prima volta dal Trattato di Maastricht e definitivamente sistemate all'art. 168 TFUE. La norma identifica alcuni settori specifici nei quali l'Unione può agire e altri, quali l'organizzazione dei sistemi sanitari e la fornitura di cure mediche, che rimangono in capo agli Stati membri. Il secondo capitolo esamina le deroghe e le esigenze imperative connesse alla salvaguardia della salute nel mercato interno ed è suddiviso in tre sezioni dedicate alla libera circolazione delle merci, al diritto di stabilimento e alla libera prestazione dei servizi. Nella prima ci si è occupati dello sviluppo della legislazione farmaceutica. Nella seconda si sono analizzati il mutuo riconoscimento delle qualifiche professionali e le legislazioni statali che restringono il diritto di stabilimento degli operatori sanitari transfrontalieri. Nella terza si è rivolta l'attenzione alla mobilità dei pazienti che, attraverso la giurisprudenza della Corte di Giustizia, è stata trasfusa in un atto di diritto derivato. Il terzo capitolo si concentra sul ruolo del diritto alla salute nell'ordinamento giuridico dell'Unione Europea in considerazione del valore vincolante della Carta dei diritti fondamentali. Coerentemente, si è scelto di mantenere una struttura tripartita. Nella prima sezione, ci si interroga sull'esistenza di tale diritto alla luce dei pochi casi presenti. Nella seconda, lo si analizza per il tramite delle obbligazioni di proteggere, rispettare ed adempiere, enucleate attraverso alcuni strumenti internazionali e si verifica il ruolo del principio di non discriminazione in relazione all'accesso alle cure. Nella terza, infine, si verifica il ruolo del consenso informato rispetto alla sperimentazione clinica ed alla donazione di materiale biologico.

Novel metabolites and roles for α-tocopherol in humans and mice discovered by mass spectrometry-based metabolomics

Contradictory results from clinical trials that examined the role of vitamin E in chronic disease could be a consequence of interindividual variation, caused by factors such as xenobiotic use. Cometabolism of vitamin E with other pharmaceutical products could affect the bioavailability of the drug. Thus, it is necessary to understand fully the metabolic routes and biological endpoints of vitamin E.

DARPins as bispecific receptor antagonists analyzed for immunoglobulin E receptor blockage

The concept of multispecific antibodies is of high therapeutic interest but has failed to produce pharmaceutical products due to the poor biophysical properties of such molecules. Here, we propose an alternative and simple way to generate bispecific binding molecules using designed ankyrin repeat proteins (DARPins). For this purpose, monovalent DARPins with different epitope specificities were selected against the alpha chain of the high-affinity receptor for human immunoglobulin E (IgE) (FcepsilonRIalpha). Two of the isolated binders interfering with IgE binding to the receptor were joined to each other or to themselves via a flexible protein linker. The resulting bivalent and bispecific DARPins were tested for their ability to prevent allergen-induced cell degranulation using rat basophilic leukemia cells stably transfected with human FcepsilonRIalpha. The bispecific DARPin construct was the most potent one, efficiently blocking the IgE-FcepsilonRI interaction and preventing the release of proinflammatory mediators. Noteworthy, the multivalent and multispecific DARPin construct did not show any alteration of the beneficial biophysical properties of the monovalent parental DARPins. Hence, bispecific DARPins may be used to generate receptor antagonists simultaneously targeting different epitopes on the same molecule. Moreover, they easily overcome the limiting immunoglobulin binding paradigm (one binding molecule=one epitope) and thereby represent an alternative to monoclonal antibodies in cases where the immunoglobulin scaffold is unsuitable.

Self medication behaviors of illegal immigrants living along the U.S.-Mexico border

Mexican immigrants make up the largest subgroup of Hispanics living in the United States. The largest percentage of illegal immigrants comes from México. As such they are a subpopulation with limited access to health care and social services; their health seeking behaviors including self-medication behaviors that, aside from the intake of antibiotics, have not been studied in depth. The analysis of the data presented sought to document the medication behaviors of illegal immigrants living in El Paso County along the U.S.-México border. Of the 80 participants, 31 were taking medication on a regular basis. Of these, 28 claimed that at least one of the medications had been prescribed by a physician, 13 people had bought at least one of their medications in México, nine participants claimed that they had not paid for at least one of the medications they were taking, ten participants reported that they had skipped the doses of at least one of their medications due to monetary constraints. Participants were also asked if they had purchased medication in México during the year prior to the study, 68 of the 80 (85%) participants had bought 295 pharmaceutical products across the border themselves or through a third party. The most frequently purchased medications were antibiotics (17%), followed by syrups, pomades, creams, eardrops, and cold medicine as a group (15%), followed by analgesics (13%) and other non steroidal anti-inflammatory drugs (12%) and oral hypoglycemic agents (6%). ^

Uso de técnicas de minería de texto para la identificación de ensayos clínicos en nanomedicina

La nanotecnología es el estudio que la mayoría de veces es tomada como una meta tecnológica que nos ayuda en el área de investigación para tratar con la manipulación y el control en forma precisa de la materia con dimensiones comprendidas entre 1 y 100 nanómetros. Recordando que el prefijo nano proviene del griego vavoc que significa enano y corresponde a un factor de 10^-9, que aplicada a las unidades de longitud corresponde a una mil millonésima parte de un metro. Ahora sabemos que esta ciencia permite trabajar con estructuras moleculares y sus átomos, obteniendo materiales que exhiben fenómenos físicos, químicos y biológicos, muy distintos a los que manifiestan los materiales usados con una longitud mayor. Por ejemplo en medicina, los compuestos manométricos y los materiales nano estructurados muchas veces ofrecen una mayor eficacia con respecto a las formulaciones químicas tradicionales, ya que muchas veces llegan a combinar los antiguos compuestos con estos nuevos para crear nuevas terapias e inclusive han llegado a reemplazarlos, revelando así nuevas propiedades diagnósticas y terapéuticas. A su vez, la complejidad de la información a nivel nano es mucho mayor que en los niveles biológicos convencionales y, por tanto, cualquier flujo de trabajo en nano medicina requiere, de forma inherente, estrategias de gestión de información avanzadas. Muchos investigadores en la nanotecnología están buscando la manera de obtener información acerca de estos materiales nanométricos, para mejorar sus estudios que muchas veces lleva a probar estos métodos o crear nuevos compuestos para ayudar a la medicina actual, contra las enfermedades más poderosas como el cáncer. Pero en estos días es muy difícil encontrar una herramienta que les brinde la información específica que buscan en los miles de ensayos clínicos que se suben diariamente en la web. Actualmente, la informática biomédica trata de proporcionar el marco de trabajo que permita lidiar con estos retos de la información a nivel nano, en este contexto, la nueva área de la nano informática pretende detectar y establecer los vínculos existentes entre la medicina, la nanotecnología y la informática, fomentando así la aplicación de métodos computacionales para resolver las cuestiones y problemas que surgen con la información en la amplia intersección entre la biomedicina y la nanotecnología. Otro caso en la actualidad es que muchos investigadores de biomedicina desean saber y comparar la información dentro de los ensayos clínicos que contiene temas de nanotecnología en las diferentes paginas en la web por todo el mundo, obteniendo en si ensayos clínicos que se han creado en Norte América, y ensayos clínicos que se han creado en Europa, y saber si en este tiempo este campo realmente está siendo explotado en los dos continentes. El problema es que no se ha creado una herramienta que estime un valor aproximado para saber los porcentajes del total de ensayos clínicos que se han creado en estas páginas web. En esta tesis de fin de máster, el autor utiliza un mejorado pre-procesamiento de texto y un algoritmo que fue determinado como el mejor procesamiento de texto en una tesis doctoral, que incluyo algunas pruebas con muchos de estos para obtener una estimación cercana que ayudaba a diferenciar cuando un ensayo clínico contiene información sobre nanotecnología y cuando no. En otras palabras aplicar un análisis de la literatura científica y de los registros de ensayos clínicos disponibles en los dos continentes para extraer información relevante sobre experimentos y resultados en nano medicina (patrones textuales, vocabulario en común, descriptores de experimentos, parámetros de caracterización, etc.), seguido el mecanismo de procesamiento para estructurar y analizar dicha información automáticamente. Este análisis concluye con la estimación antes mencionada necesaria para comparar la cantidad de estudios sobre nanotecnología en estos dos continentes. Obviamente usamos un modelo de datos de referencia (gold standard) —un conjunto de datos de entrenamiento anotados manualmente—, y el conjunto de datos para el test es toda la base de datos de estos registros de ensayos clínicos, permitiendo distinguir automáticamente los estudios centrados en nano drogas, nano dispositivos y nano métodos de aquellos enfocados a testear productos farmacéuticos tradicionales.---ABSTRACT---Nanotechnology is the scientific study that usually is seen as a technological goal that helps us in the investigation field to deal with the manipulation and precise control of the matter with dimensions that range from 1 to 100 nanometers. Remembering that the prefix nano comes from the Greek word νᾶνος, meaning dwarf and denotes a factor of 10^-9, that applyied the longitude units is equal to a billionth of a meter. Now we know that this science allows us to work with molecular structures and their atoms, obtaining material that exhibit physical, chemical and biological phenomena very different to those manifesting in materials with a bigger longitude. As an example in medicine, the nanometric compounds and the materials in nano structures are often offered with more effectiveness regarding to the traditional chemical formulas. This is due to the fact that many occasions combining these old compounds with the new ones, creates new therapies and even replaced them, reveling new diagnostic and therapeutic properties. Even though the complexity of the information at nano level is greater than that in conventional biologic level and, thus, any work flow in nano medicine requires, in an inherent way, advance information management strategies. Many researchers in nanotechnology are looking for a way to obtain information about these nanometric materials to improve their studies that leads in many occasions to prove these methods or to create a new compound that helps modern medicine against powerful diseases, such as cancer. But in these days it is difficult to find a tool that searches and provides a specific information in the thousands of clinic essays that are uploaded daily on the web. Currently, the bio medic informatics tries to provide the work frame that will allow to deal with these information challenge in nano level. In this context, the new area of nano informatics pretends to detect and establish the existing links between medicine, nanotechnology and informatics, encouraging the usage of computational methods to resolve questions and problems that surge with the wide information intersection that is between biomedicine and nanotechnology. Another present case, is that many biomedicine researchers want to know and be able to compare the information inside those clinic essays that contains subjects of nanotechnology on the different webpages across the world, obtaining the clinic essays that has been done in North America and the essays done in Europe, and thus knowing if in this time, this field is really being exploited in both continents. In this master thesis, the author will use an enhanced text pre-processor with an algorithm that was defined as the best text processor in a doctoral thesis, that included many of these tests to obtain a close estimation that helps to differentiate when a clinic essay contains information about nanotechnology and when it does not. In other words, applying an analysis to the scientific literature and clinic essay available in both continents, in order to extract relevant information about experiments and the results in nano-medicine (textual patterns, common vocabulary, experiments descriptors, characterization parameters, etc.), followed by the mechanism process to structure and analyze said information automatically. This analysis concludes with the estimation, mentioned before, needed to compare the quantity of studies about nanotechnology in these two continents. Obviously we use a data reference model (Gold standard) – a set of training data manually annotated –, and the set of data for the test conforms the entire database of these clinic essay registers, allowing to distinguish automatically the studies centered on nano drugs, nano devices and nano methods of those focus on testing traditional pharmaceutical products.

Interactions métaboliques entre le bisphénol A et le naproxène dans un modèle de foie de rat isolé et perfusé

L'exposition aux mélanges de contaminants (environnementaux, alimentaires ou thérapeutiques) soulève de nombreuses interrogations et inquiétudes vis-à-vis des probabilités d'interactions toxicocinétiques et toxicodynamiques. Une telle coexposition peut influencer le mode d’action des composants du cocktail et donc de leur toxicité, suite à un accroissement de leurs concentrations internes. Le bisphénol A (4 dihydroxy-2,2-diphenylpropane) est un contaminant chimique répandu de manière ubiquitaire dans notre environnement, largement utilisé dans la fabrication des plastiques avec l’un des plus grands volumes de production à l’échelle mondiale. Il est un perturbateur endocrinien par excellence de type œstrogèno-mimétique. Cette molécule est biotransformée en métabolites non toxiques par un processus de glucuronidation. L'exposition concomitante à plusieurs xénobiotiques peut induire à la baisse le taux de glucuronidation du polluant chimique d'intérêt, entre autres la co-exposition avec des médicaments. Puisque la consommation de produits thérapeutiques est un phénomène grandissant dans la population, la possibilité d’une exposition simultanée est d’autant plus grande et forte. Sachant que l'inhibition métabolique est le mécanisme d'interaction le plus plausible pouvant aboutir à une hausse des niveaux internes ainsi qu’à une modulation de la toxicité prévue, la présente étude visait d'abord à confirmer et caractériser ce type d'interactions métaboliques entre le bisphénol A et le naproxène, qui est un anti-inflammatoire non stéroïdiennes (AINS), sur l'ensemble d'un organe intact en utilisant le système de foie de rat isolé et perfusé (IPRL). Elle visait ensuite à déterminer la cinétique enzymatique de chacune de ces deux substances, seule puis en mélange binaire. Dans un second temps, nous avons évalué aussi l’influence de la présence d'albumine sur la cinétique métabolique et le comportement de ces deux substances étudiées en suivant le même modèle de perfusion in vivo au niveau du foie de rat. Les constantes métaboliques ont été déterminées par régression non linéaire. Les métabolismes du BPA et du NAP seuls ont montré une cinétique saturable avec une vélocité maximale (Vmax) de 8.9 nmol/min/ mg prot de foie et une constante d'affinité de l'enzyme pour le substrat (Km) de 51.6 μM pour le BPA et de 3 nmol/min/mg prot de foie et 149.2 μM pour le NAP. L'analyse des expositions combinées suggère une inhibition compétitive partielle du métabolisme du BPA par le NAP avec une valeur de Ki estimée à 0.3542 μM. Les résultats obtenus montrent que l’analyse de risque pour les polluants environnementaux doit donc prendre en considération la consommation des produits pharmaceutiques comme facteur pouvant accroitre le niveau interne lors d’une exposition donnée. Ces données in vivo sur les interactions métaboliques pourraient être intégrées dans un modèle pharmacocinétique à base physiologique (PBPK) pour prédire les conséquences toxicococinétique (TK) de l'exposition d'un individu à ces mélanges chimiques.

Interactions métaboliques entre le bisphénol A et le naproxène dans un modèle de foie de rat isolé et perfusé

L'exposition aux mélanges de contaminants (environnementaux, alimentaires ou thérapeutiques) soulève de nombreuses interrogations et inquiétudes vis-à-vis des probabilités d'interactions toxicocinétiques et toxicodynamiques. Une telle coexposition peut influencer le mode d’action des composants du cocktail et donc de leur toxicité, suite à un accroissement de leurs concentrations internes. Le bisphénol A (4 dihydroxy-2,2-diphenylpropane) est un contaminant chimique répandu de manière ubiquitaire dans notre environnement, largement utilisé dans la fabrication des plastiques avec l’un des plus grands volumes de production à l’échelle mondiale. Il est un perturbateur endocrinien par excellence de type œstrogèno-mimétique. Cette molécule est biotransformée en métabolites non toxiques par un processus de glucuronidation. L'exposition concomitante à plusieurs xénobiotiques peut induire à la baisse le taux de glucuronidation du polluant chimique d'intérêt, entre autres la co-exposition avec des médicaments. Puisque la consommation de produits thérapeutiques est un phénomène grandissant dans la population, la possibilité d’une exposition simultanée est d’autant plus grande et forte. Sachant que l'inhibition métabolique est le mécanisme d'interaction le plus plausible pouvant aboutir à une hausse des niveaux internes ainsi qu’à une modulation de la toxicité prévue, la présente étude visait d'abord à confirmer et caractériser ce type d'interactions métaboliques entre le bisphénol A et le naproxène, qui est un anti-inflammatoire non stéroïdiennes (AINS), sur l'ensemble d'un organe intact en utilisant le système de foie de rat isolé et perfusé (IPRL). Elle visait ensuite à déterminer la cinétique enzymatique de chacune de ces deux substances, seule puis en mélange binaire. Dans un second temps, nous avons évalué aussi l’influence de la présence d'albumine sur la cinétique métabolique et le comportement de ces deux substances étudiées en suivant le même modèle de perfusion in vivo au niveau du foie de rat. Les constantes métaboliques ont été déterminées par régression non linéaire. Les métabolismes du BPA et du NAP seuls ont montré une cinétique saturable avec une vélocité maximale (Vmax) de 8.9 nmol/min/ mg prot de foie et une constante d'affinité de l'enzyme pour le substrat (Km) de 51.6 μM pour le BPA et de 3 nmol/min/mg prot de foie et 149.2 μM pour le NAP. L'analyse des expositions combinées suggère une inhibition compétitive partielle du métabolisme du BPA par le NAP avec une valeur de Ki estimée à 0.3542 μM. Les résultats obtenus montrent que l’analyse de risque pour les polluants environnementaux doit donc prendre en considération la consommation des produits pharmaceutiques comme facteur pouvant accroitre le niveau interne lors d’une exposition donnée. Ces données in vivo sur les interactions métaboliques pourraient être intégrées dans un modèle pharmacocinétique à base physiologique (PBPK) pour prédire les conséquences toxicococinétique (TK) de l'exposition d'un individu à ces mélanges chimiques.

A population balance model for high shear granulation

In a previous paper, Hoornaert et al. (Powder Technol. 96 (1998); 116-128) presented data from granulation experiments performed in a 50 L Lodige high shear mixer. In this study that same data was simulated with a population balance model. Based on an analysis of the experimental data, the granulation process was divided into three separate stages: nucleation, induction, and coalescence growth. These three stages were then simulated separately, with promising results. it is possible to derive a kernel that fit both the induction and the coalescence growth stage. Modeling the nucleation stage proved to be more challenging due to the complex mechanism of nucleus formation. From this work some recommendations are made for the improvement of this type of model.

Strength and attrition resistance of agglomerates and particulate coatings

The mechanical properties of a range of agglomerates and particulate coatings have been measured using a nanoindenter. The effect of formulation properties such as powder and binder properties on coating hardness is described. An attempt is also made to measure the fracture hardness with the nanoindenter. The use of indentation technology to measure fundamental agglomerate properties is critically analysed. Based on the indentation measurements and standard attrition test results, the coating hardness is found closely related to the attrition rate under standard conditions and can be used to screen different powder/binder formulations. (C) 2002 Elsevier Science B.V All rights reserved.

Structural and mechanical properties of nanostructured granular alumina catalysts

Granular gamma-Al2O3 support and 8 wt % CuO/gamma-Al2O3 catalyst were synthesized by a sol-gel granulation method. The pore structure, crush strength, hardness, and elasticity of these sol-gel-derived catalysts were studied and compared with similar commercial catalysts prepared by non-sol-gel methods. Alumina and CuO-coated alumina granular particles prepared by different methods have different macro- and microstructure. The sol-gel-derived granular gamma-alumina and CuO-coated gamma-alumina granular particles have a structure defined by compact packing of uniform, nanosized gamma-alumina crystallites. They are characterized by a more uniform pore size distribution and larger surface area as compared to similar commercial samples with a structure defined by packing of aggregates consisting of nonuniform gamma-alumina crystallites. Because of the differences in the macro- and microstructure, the sol-gel-derived granular samples offer higher crush strength and greater hardness than the commercial samples.

Nucleation regime map for liquid bound granules

Nucleation is the first step in granulation where the powder and liquid first contact. Two types of nucleation in wet granulation processes are proposed. Drop controlled nucleation, where one drop forms one nucleus, occurs when drops hitting the powder surface do not overlap (low spray flux Psi(a)) and the drop must wet quickly into the bed (short drop penetration time t(p)). If either criterion is not met, powder mixing characteristics will dominate (mechanical dispersion regime). Granulation experiments were performed with lactose powder, water, PEG200, and 7% HPC solution in a 6 L and a 25 L mixer granulator. Size distributions were measured as the drop penetration time and spray flux were varied. At short penetration times, decreasing Psi(a) caused the nuclei distribution to become narrower. When drop penetration time was high, the nuclei size distribution was broad independent of changes in dimensionless spray flux. Nucleation regime maps were plotted for each set of experiments in each mixer as a function of the dimensionless distribution width delta. The nucleation regime map demonstrates the interaction between drop penetration time and spray flux in nucleation. The narrowest distribution consistently occurred at low spray flux and low penetration time, proving the existence of the drop controlled regime. The nucleation regime map provides a rational basis for design and scale-up of nucleation and wetting in wet granulation.

Flow patterns in granulating systems

Particle flow patterns were investigated for wet granulation and dry powder mixing in ploughshare mixers using Positron Emission Particle Tracking (PEPT). In a 4-1 mixer, calcium carbonate with mean size 45 mum was granulated using a 50 wt.% solution of glycerol and water as binding fluid, and particle movement was followed using a 600-mum calcium hydroxy-phosphate tracer particle. In a 20-1 mixer, dry powder flow was studied using a 600-mum resin bead tracer particle to simulate the bulk polypropylene powder with mean size 600 mum. Important differences were seen between particle flow patterns for wet and dry systems. Particle speed relative to blade speed was lower in the wet system than in the dry system, with the ratios of average particle speed to blade tip speed for all experiments in the range 0.01-015. In the axial plane, the same particle motion was observed around each blade; this provides a significant advance for modelling flow in ploughshare mixers. For the future, a detailed understanding of the local velocity, acceleration and density variations around a plough blade will reveal the effects of flow patterns in granulating systems on the resultant distribution of granular product attributes such as size, density and strength. (C) 2002 Elsevier Science B.V All rights reserved.

Nonprescription medicine purchases in New Zealand

This study aimed to explore purchases of non-prescription medicines in New Zealand. Researchers were stationed for 5 days in 12 pharmacies throughout New Zealand during June and July of 1999. A brief questionnaire was administered, for each medicine purchased, to all available purchasers aged 16 years and over. At least partial data were collected from 2,597 medicine purchases (approximately 71.2% of medicine sales). Respiratory products comprised 42% of sales. Pharmacists were involved in 19.9% of medicine sales. Pharmacy staff featured in 62.2% of 792 influences on first-time purchases. This study tested a viable method for data collection and yielded valuable pharmaceutical marketing data.

Towards definition of the global biotechnology value chain using cases from Australian biotechnology SMEs

The generic pharmaceutical value chain model has been employed to describe both the global pharmaceutical and biotechnology industries till now. This research investigates the organisational value chain in Australian biotechnology companies in order to assess the appropriateness of the pharmaceutical value chain to small-and medium-sized biotechnology companies. The main theme of the research is: Can a generic model of the organisational value chain be defined for the biotechnology industry? Emanating from the literature, two research propositions were developed. RP1: there are eight major definable elements/activities of the organisational value chain for the biotechnology industry. RP2: Coverage of the elements in the biotechnology value chain ranges from focused to broad. A multiple case study methodology was used to explore these propositions. To develop a number of case studies, data was collected from senior managers of small and medium Australian biotechnology companies using an interview instrument, as well as from publicly available documentation and through observation. The results were analysed using cross-case comparisons. The results showed that an aggregation of the value chains of each organisation can be reduced to these eight definable elements that constitute the biotechnology value chain: basic research, applied research, development, verification and validation, prototype development, clinical trials, manufacturing and marketing. However, the findings also indicate that these major elements of the value chain need to be further reduced into sub-activities or sub-tasks to cater for the unique differences between biotechnology companies. Generally, the findings were consistent with the literature. However, a wider sampling, including international biotechnology organisations should be studied. The major contribution of this research is in the development of a value chain model, including general sub-tasks, for the Australian biotechnology industry.