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Sökning: AMNE:(MEDICAL AND HEALTH SCIENCES Medical Biotechnology) > Licentiatavhandling

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1.
  • Blissing, Annica (författare)
  • Thiopurine S-methyltransferase - characterization of variants and ligand binding
  • 2017
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Thiopurine S-methyltransferase (TPMT) belongs to the Class I S-adenosylmethionine-dependent methyltransferase (SAM-MT) super family of structurally related proteins. Common to the members of this large protein family is the catalysis of methylation reactions using S-adenosylmethionine (SAM) as a methyl group donor, although SAM-MTs act on a wide range of different substrates and carry out numerous biologically important functions. While the natural function of TPMT is unknown, this enzyme is involved in the metabolism of thiopurines, a class of pharmaceutical substances administered in treatment of immune-related disorders. Specifically, methylation by TPMT inactivates thiopurines and their metabolic intermediates, which reduces the efficacy of clinical treatment and increases the risk of adverse side effects. To further complicate matters, TPMT is a polymorphic enzyme with over 40 naturally occurring variants known to date, most of which exhibit lowered methylation activity towards thiopurines. Consequently, there are individual variations in TPMTmediated thiopurine inactivation, and the administered dose has to be adjusted prior to clinical treatment to avoid harmful side effects.Although the clinical relevance of TPMT is well established, few studies have investigated the molecular causes of the reduced methylation activity of variant proteins. In this thesis, the results of biophysical characterization of two variant proteins, TPMT*6 (Y180F) and TPMT*8 (R215H), are presented. While the properties of TPMT*8 were indistinguishable from those of the wild-type protein, TPMT*6 was found to be somewhat destabilized. Interestingly, the TPMT*6 amino acid substitution did not affect the functionality or folding pattern of the variant protein. Therefore, the decreased in vivo functionality reported for TPMT*6 is probably caused by increased proteolytic degradation in response to the reduced stability of this protein variant, rather than loss of function.Also presented herein are novel methodological approaches for studies of TPMT and its variants. Firstly, the advantages of using 8-anilinonaphthalene-1-sulfonic acid (ANS) to probe TPMT tertiary structure and active site integrity are presented. ANS binds exclusively to the native state of TPMT with high affinity (KD ~ 0.2 μm) and a 1:1 ratio. The stability of TPMT was dramatically increased by binding of ANS, which was shown to co-localize with the structurally similar adenine moiety of the cofactor SAM. Secondly, an enzyme activity assay based on isothermal titration calorimetry (ITC) is presented. Using this approach, the kinetics of 6-MP and 6-TG methylation by TPMT has been characterized.
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2.
  • Gund, Anna, 1980 (författare)
  • Design of an Internet-Based Disease Management System for Chronic Heart Failure
  • 2008
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Chronic diseases are one of the most challenging health problems in the world, and their burden on society is increasing. Managing these diseases using eHealth solutions could prove very beneficial, both in terms of economic costs and quality of life for patients. However, reaching these goals require knowledge in how to create distributed disease management systems for chronic diseases.In the project Care@Distance the aim is to acquire knowledge on how to use eHealth in order to improve treatment compliance in chronic diseases, improve possibilities for personalized care, alert about deteriorating health on an individual patient level, obtain acceptance among users (both care providers and patients), and finally introduce eHealth-based disease management systems into standard treatment procedures. This thesis covers one of these aims; designing for acceptance among users, mainly patients, but also care personnel. As a first step, the user group has been limited to only include patients with chronic heart failure, and the nurses connected to them. However, expanding general findings and experiences to other disorders should not cause any difficulties.Both the design process and the evaluation of two prototype systems will be covered in this thesis. The intention of the prototype systems was not to create a technically advanced and innovative system, but to produce a tool for attaining new knowledge about the issues related to introduction of eHealth-based disease management systems in Swedish health care. Both systems are described, the evaluations of the first prototype system are presented, and the results are discussed.Two patient related evaluations and one nurse survey have been performed, and the results indicate that the simple prototype system could be possible to transform into a solution suitable for use in the home of patients. Both the patient evaluations and the nurse survey also give insight into important issues to consider when designing an eHealth-based disease management system for chronic diseases. Especially important is the knowledge that one of the largest challenges will be handling of the information overflow related to regular collection of patient data.Future work includes evaluation and development of the second prototype system. The development of the prototype includes decision support for managing large amounts of patient data, and also increasing mobility of the system. Furthermore, additional measurement methods could be included in the prototype system in order to include special cases of patients, or other disorders.
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3.
  • Wallin, Patric, 1985 (författare)
  • Creating cell microenvironments in vitro
  • 2012
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Stem cells have a great potential to bring about advancements in fields like developmental biology, drug discovery, cancer biology and tissue engineering. In order to be able to use stem cells to their full potential, it is important to have control over their behavior. In vivo cellular fate processes are controlled by the microenvironment around them and the many different factors in it. Cells communicate with their surrounding environment and shape it actively via cell-cell, cell-matrix and cell-liquid interactions. These interactions often happen on the cellular and subcellular length scale in defined time dependent sequences. Consequently, it is important to have systems that can provide different molecular cues with a high spatial and temporal resolution, in order to mimic cell microenvironments in vitro and study cells under controlled conditions. This thesis focuses on cell-matrix and cell-liquid interactions and different ways to create cell niches in cell culture systems. The focus is on designing and characterizing microfluidic cell culture platforms and, in particular, systems that are capable of forming molecular gradients. Flow-based and diffusion-based microfluidic gradient generators were combined with substrates coated with biofunctionalized gold nano dots, chemical active molecules, or electrospun microfibers. Thus, it was possible to provide cells with topographical cues and a defined surface chemistry, as well as soluble molecular cues in a gradient manner, simultaneously. COMSOL Multiphysics simulations were used to assist the design process and characterization of the microfluidic systems, and also to study cell receptor binding interactions in great detail. The developed toolbox of COMSOL modeling, a liquid handling system, a variety of microfluidic networks, surface modification techniques and molecular gradients allows the formation of multifactorial microenvironments to now study induction of cellular fate process of different cell types in vitro.
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4.
  • Norling, Karin, 1988 (författare)
  • Studying the influence of the physicochemical properties of lipid nanoparticles for mucosal vaccine delivery
  • 2017
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Lipid-based nanoparticles have attracted attention as promising pharmaceutical carriers. Reports of them having inherent adjuvant properties make them particularly interesting as vaccine vectors; however, the physicochemical profile of an ideal nanoparticle for mucosal vaccine delivery remains unknown. The aim of this thesis work is to contribute a better understanding of the connection between physicochemical properties of lipid nanoparticles used as vaccine carriers and the activation of the immune response at several different levels of complexity. As combined antigen and adjuvant, we used a novel fusion protein comprising the Cholera toxin A1 subunit, combined with either the M2e or Ealpha peptide and a dimer of the D subunit of Staphylococcus aureus protein A. This fusion protein was coupled to liposomes and lipodisks with systematically varied poly(ethylene glycol) (PEG) content, protein load, rigidity and size/shape. Firstly, a detailed characterization of the biological response in vitro and in vivo, in a mouse model, to two types of fusion protein-carrying lipid particles was performed. Compared with the free fusion protein, which is in itself already an effective vaccination compound, the result showed that the non-PEGylated liposomes more efficiently induce both cell- and antibody-mediated immune responses as well as protection against a lethal virus challenge than both free fusion protein and the PEGylated liposomes. Secondly, an in vitro study was performed, focusing on elucidating the effect of the physicochemical properties of the carrier particle on processing, in particular the antigen presentation in major histocompatibility complex class II (MHC II), by dendritic cells. Out of 6 different formulations, which varied with respect to PEGylation, fusion protein load, membrane rigidity, size and shape it was found that only the DSPC-based liposome formulation, the only liposome formulation in gel phase, was able to increase antigen presentation compared to free fusion protein. Additionally, this formulation lead to an increased amount of surface-bound MHC II, indicating that the liposomes themselves might have an immunostimulatory effect, making them a promising candidate for further evaluation as a vaccine carrier with inherent adjuvant properties.
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5.
  • Gullfot, Fredrika, 1967- (författare)
  • Synthesis of xyloglucan oligo- and polysaccharides with glycosynthase technology
  • 2009
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Xyloglucans are polysaccharides found as storage polymers in seeds and tubers, and as cross-linking glycans in the cell wall of plants. Their structure is complex with intricate branching patterns, which contribute to the physical properties of the polysaccharide including its binding to and interaction with other glycans such as cellulose. Xyloglucan is widely used in bulk quantities in the food, textile and paper making industries. With an increasing interest in technically more advanced applications of xyloglucan, such as novel biocomposites, there is a need to understand and control the properties and interactions of xyloglucan with other compounds, to decipher the relationship between xyloglucan structure and function, and in particular the effect of different branching patterns. However, due to the structural heterogeneity of the polysaccharide as obtained from natural sources, relevant studies have not been possible to perform in practise. This fact has stimulated an interest in synthetic methods to obtain xyloglucan mimics and analogs with well-defined structure and decoration patterns. Glycosynthases are hydrolytically inactive mutant glycosidases that catalyse the formation of glycosidic linkages between glycosyl fluoride donors and glycoside acceptors. Since its first conception in 1998, the technology is emerging as a useful tool in the synthesis of large, complex polysaccharides. This thesis presents the generation and characterisation of glycosynthases based on xyloglucanase scaffolds for the synthesis of well-defined homogenous xyloglucan oligo- and polysaccharides with regular substitution patterns.
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6.
  • Kashfi, Pariya, 1980 (författare)
  • Towards Usable openEHR-aware Clinical Decision Support: A User-centered Design Approach
  • 2011
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Nowadays, the use of computerized approaches to support health care processesin order to improve quality of health care is widespread in the clinical domain.Electronic health records (EHR) and clinical decision support (CDS) are consideredto be two complementary approaches to improve quality of health care.It is shown that EHRs are not able to improve quality of health care withoutbeing supported by other features such as CDS. On the other hand, one of thesuccess factors of CDS is its integration into EHR, and since there are variousinternational EHR standards (such as openEHR) being developed, it is crucialto take these standards into consideration while developing CDS.Various clinical decision support systems (CDSS) are developed but unfortunatelyonly a few of them are being used routinely. Two of the reasons for unacceptability of CDSSs among their users, i.e. clinicians, are shown to be their separation from EHRs and poor usability of the user interfaces. Besides integration into underlying information framework, i.e. EHR systems, consideration of human-computer interaction (HCI) in designing and evaluating CDS isone of the success factors that developers of these systems should keep in mind.This thesis addresses the question of how usable openEHR-aware clinical decision support can be designed and developed in order to improve the quality of health care. To answer this research question, several sub-questions were identified and investigated. This included analyzing \state of the art" in two different aspects of design and development and evaluation of CDS and also investigating application of a customized user-centered design (UCD) process in developing openEHR-based clinical applications.Analysis of state of the art in interplay between HCI and CDS and also the intersection between CDS and EHR revealed that consideration of both HCI and integration of CDS into EHR is more appreciated in theory than in practice and there is still a long way to go before reaching an acceptable level in these two success factors of CDS.Moreover, the experience in designing an openEHR-based clinical application revealed that apart from benefits offered by openEHR approach, such as specifying different roles and involvement of domain experts in defining domain concepts, there are various shortcomings that need to be improved, for instance the limited support for openEHR application developers. Additionally, this study revealed that there are characteristics of the domain, tasks and users in the domain that developers should be informed about while applying UCD methods.
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7.
  • Björkqvist, Susan, 1967 (författare)
  • Source-specific volatile organic compounds in human breath, wood smoke and biogas
  • 1997
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Volatile biogenic compounds are often overlooked in air quality studies. This work deals with the analysis of specific organic compounds of biogenic origin and with their sources. General aspects of indoor air chemistry and measurements of volatile organic compounds in indoor air are also discussed. The determinations were based mainly on adsorbent sampling followed by gas chromatographic separations on different types of suitable columns. Identifications were made by mass spectrometry.
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8.
  • Eriksson, Gustav, 1994 (författare)
  • Atom Probe Tomography Investigations of Biologically Relevant Nanoparticles
  • 2022
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The study of materials at the nanoscale is essential in many scientific disciplines. For example, in materials science the size of the building blocks of a material is directly linked to its properties. New materials are constantly being developed having features at the nanoscale, for example nanoparticles that are used in fields such as catalysis, electronics, and medicine. In biology, many features exist which have nanosized structures including proteins. The 3D secondary structure of proteins is directly linked to their functions; hence structure determination of proteins is of high interest to gain information of biological processes that serves the development of future medicines. Due to the importance of nanostructures, many methods for their investigation have been developed such as X-ray diffraction, electron microscopy, and atom probe tomography. These methods rely on different probes and are thus often considered complementary as they provide different information. For the same reason, they put different constraints or limitations on the materials studied. In this work, two novel methods for studying nanoparticles of biological relevance, gold nanoparticles and hydroxyapatite nanoparticles, have been developed for analysis using atom probe tomography. Gold nanoparticles are popularly used as markers for biomolecules and to immobilize biomolecules on surfaces with retained function and activity. Several methods have been developed in the last decade to study nanoparticles using atom probe tomography, generally involving forming a metal matrix embedding the particles in a material from which a specimen can be made. In this thesis, an alternative approach utilizing a silica matrix made by a sol-gel method used to embed a gold nanoparticle covered surface is presented. This silica-based method provides an environment for the particles that is similar to an aqueous environment. Nanoparticles of hydroxyapatite, a mineral that is found in bone and teeth, are commonly used as biomaterials, for example as coatings to improve the performance of surgical implants. In this thesis, hydroxyapatite nanoparticles immobilized onto titanium are examined. The analysed surfaces were sputter coated with chromium, forming a matrix that allows for correlative transmission electron microscopy and atom probe tomography analysis. It is shown that calcium and phosphorous integrated into the surface oxide of the titanium, revealing detailed insights on immobilization of the nanoparticles on the surface. This integration resembles the osseointegration of bone when compared to similar titanium implants being introduced to the human body.
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9.
  • Olsson, Thomas, 1977 (författare)
  • Characterization of artificial and biological lipid vesicles using TIRF and SPR
  • 2018
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Synthetic lipid vesicles serve as important mimics of cells and the natural membranes that they are enclosed by. As such they are frequently used as simplified models of the highly complex cell membrane to aid in-depth physicochemical and biological characterization of this essential biological structure. Lipid vesicles also fulfill fundamental biological functions, for example in intercellular signaling via extracellular vesicles and also as signal-substance containing intercellular secretory vesicles in the synapses of neurons and in secretory cells of the endocrine glands, which release their cargo to the extracellular space in response to external cues. Lipid-based nanoparticles are also of increasing importance as drug carriers, both for targeted release at specific tissues and for improved cellular uptake. There are today many techniques available to probe a multitude of lipid vesicle properties, including size, structure, content, molecular composition etc. In this thesis work, we have contributed improved means to quantify vesicle size using fluorescence microscopy by using total internal reflection fluorescence (TIRF) microscopy to correlate the measured distribution in fluorescence intensity of individual vesicles to their size, as measured by nanoparticle particle tracking analysis (NTA). A similar approach has been used before by others, but the formalism used that have won prevalence contains a mathematical error, which motivated the introduction of an improved expression for converting total vesicle intensity to vesicle size. We present  the difference between the former and the latter formalism, as well as the possible negative impact of the former when used to draw conclusions for larger sized vesicles in a number of studies. One example when this type of analysis is crucial, is in studies were a certain vesicle property is correlated with vesicle size. One such example is studies of membrane protein function, which is often dependent of membrane curvature. In the second work, we used surface plasmon resonance (SPR) and amperometry as quantitative methods to investigate whether secretory dense core vesicles, isolated from bovine chromaffin cells from the medulla of adrenal glands, are able to maintain their high loading of catecholamine molecules after vesicle isolation and purification and how the vesicle catecholamine content is affected by vesicle exposure to osmotic stress. We found, as also previously reported by intracellular amperometry measurements in live cells, that dense core vesicles release part of the vesicle catecholamine content when exerted to a hyperosmotic shock, and also that this release occurs very rapidly in response to the applied osmotic stress. This work demonstrates the strength of using different complementary label-free measurements to account for the total number of catecholamine molecules in such vesicles and for monitoring molecule release from vesicle compartments in real-time. Further, by using knowledge gained about chromaffin vesicle size from TEM together with changes in refractive index as probed with SPR using suspensions based on ordinary and heavy water, we could estimate the hydration level of the dense protein core of the chromaffin vesicles.
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10.
  • Ponnandai Schanmugavel, Kumaravel, 1991 (författare)
  • Development of a Yeast Model for Functional Analysis of Human Copper Transport Proteins
  • 2018
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • ABSTRACT Copper (Cu) is an important trace element that plays a vital role in several biological processes. It mediates numerous biochemical functions to maintain cellular homeostasis making it an essential metal for sustaining life. Many proteins or enzymes that are involved in various biochemical pathways require copper as a cofactor (also a regulator). In human cells, the Cu uptake is mediated by high-affinity copper uptake protein (Ctr1), followed by cytoplasmic chaperone Atox1 that shuttles Cu from the plasma membrane to Wilson’s disease protein ATP7B (P-type ATPase), a membrane-bound protein located at the Golgi apparatus. ATP7B incorporates Cu to various Cu-dependent enzymes in the secretory pathway. The main biological role of ATP7B (or Wilson Disease Protein) is to maintain the copper balance inside the human cell. Genetic defects in ATP7B often leads to a nonfunctional protein where copper balance is impaired and this condition results in Wilson’s disease (WD).  ATP7B is a large multi-domain membrane transport protein that shows typical characteristics of a P1b type ATPase. In contrast to its bacterial (CopA) or yeast (Ccc2) counterparts which have one or two metal binding domains (MBD) respectively, the human ATP7B has six cytosolic MBDs in the N-terminal region. The reason for the presence of these six MBDs in ATP7B is not completely understood, and neither is the ATP7B mediated copper release in the Golgi. In this thesis, the development of a novel yeast model system for investigating the functional role of ATP7B in copper transport is described. The system probes shuttling of copper via human Atox1 to ATP7B proteins when expressed in a yeast humanized model. Using this system, we investigated the roles of six metal binding domains (MBDs) in ATP7B (Paper 1) and examined the Cu release (paper II). The results address the importance of the yeast model for studying human Cu transport proteins, the role of MBDs in ATP7B mediated Cu transport, the role of Atox1 in shuttling Cu and the significance of the luminal loop in ATP7B for Cu release function. Overall, the yeast model system developed in this thesis has great future potential for studying human copper transport proteins, which are involved in genetic diseases such as WD. The designed system can be expanded by using system biology approaches, to gain further understanding on human copper transport as well as copper transport related disorders.
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