| 1. |
- Larsson, Lisa, 1980-
(author)
-
Characteristics of Production Innovation
- 2017
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Licentiate thesis (other academic/artistic)abstract
- Today firms must maintain high levels of efficiency, quality control, customer responsiveness and speed, but even the full set of these attributes is not sufficient for sustainable competitive advantage. A further challenging requirement is to innovate successfully, not only in product development but also in production. Traditionally, innovation is regarded as successful product development, and delivering innovative products of sufficient quality at a reasonable price is seen as the primary means of acquiring and maintaining competitiveness. In this context, the role of production development is simply to provide production solutions required for the realization of new products. However, production development (sometimes called ‘production improvement’ or ‘process innovation in production’) may also involve continuous incremental or radical improvement of current production processes or systems in terms of productivity, cost, speed, quality, and/or flexibility.Previous research provides a rather narrow view of production development, largely ignoring value creation, which obscures its importance for organizations. Due to the lack of attention to innovativeness in production development, limited effort is also made to understand how to manage production development projects as innovation processes, where the emphasis is on obtaining value. This retards progress and restrains organizations’ competitiveness, and to some extent the potential social benefits (such as increases in sustainability) of new production technologies. Thus, the primary objective of the research this thesis is based upon was to increase understanding of distinguishing features and valuable outcomes of production innovation, together with challenges in managing production innovation processes. Data underlying this research were collected through case studies of development projects in firms operating in several industries.The research findings show that the pursued outcomes of production innovation are mainly cost reductions and increases in quality. Nevertheless, production innovation also contributes with expansion of product design space, and strengthening innovation capabilities, which in themselves provide sustainable competitive advantage. Further, production innovation is highly dependent on successful implementation – a complex endeavour involving internal organization, external customers and other actors contributing to the production system. Organizations lack support for capturing, prioritization, decision making and resource allocation in production innovation processes, a topic that warrants further research.
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| 2. |
- Mohammadi, Mohammad
(author)
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Risk Management in Tunneling Projects : Estimation and Planning
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Cost overruns and schedule delays are frequently observed occurrences in the construction of transport infrastructure projects. Such phenomena lead to the mismanagement of significant amounts of both public and private resources.An examination of the literature reveals that uncertainty stands out as one of the potential primary causes of cost overruns and schedule delays. To address the impact of uncertainty on time and cost estimations in transport infrastructure projects, probabilistic approaches can be employed. In this doctoral thesis, first a conceptual risk model has been formulated specifically for the purpose of enhancing time and cost estimations in tunneling projects. This risk model serves as a tool to scrutinize and contrast existing probabilistic time and cost estimation models for tunnel projects, aiming to identify potential areas for improvement. Furthermore, the conceptual model is utilized to delve into the factors influencing the accuracy of subjective assessments regarding the input parameters in time estimation models. It also explores methods for incorporating the role of tunneling phases into the subjective assessment of these input parameters.Then, enhancements and updates are introduced to the existingKTH model for time and cost estimation in tunneling projects. This model primarily targets three main sources of uncertainty: variability in construction performance, geological uncertainties, and the potential incidence of disruptive events. The analysis and improvements related to modelling of construction performance involve three sequential steps. In the first step, the construction process is modeled using the work breakdown structure (WBS), enabling a more realistic assessment of tunneling time. Subsequently, in the second step, PERT distributions are employed to model the uncertainty in the duration of unit activities, compared to the commonly used triangular distributions. The third step involves a detailed examination of a real tunnelling project's data to identify components contributing to construction performance variability for unit activities. This analysis pinpoints three main components: typical performance variability, minor performance delays, and minor machinery delays. These components are integrated into the KTH model, resulting in its further update concerning construction performance variability. A novel approach is introduced into the KTH model by leveraging the Metropolis-Hastings (MH) algorithm within the framework of Markov Chain Monte Carlo (MCMC) simulation to address geological uncertainties along the tunnel route. This method facilitates round-by-round simulation of the tunneling process and allows the model to accommodate uncertainty in the critical path for tunneling projects involving multiple headings. These enhancements aim to improve decision-making processes and mitigate risks associated with schedule delays and cost overruns. Additionally, the magnitude of disruptive events are now modeled as stochastic variables, an improvement on the original version of the KTH model.
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| 3. |
- Andersson, Anna-Maria, 1990-
(author)
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Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Tuberculosis (TB) still remains a big threat today, being the leading cause of death by a single infectious agent. The TB epidemic is fueled by HIV along with the increasing drug-resistance which prolongs the already long treatment duration and decreases the success rate for curing TB. In most cases an infection results in latency but HIV patients have a 20-30 times higher risk of developing active TB. There are around 36.9 million people living with HIV globally, with the highest burden in Africa. Although there are effective treatments against the disease, there is no cure for AIDS and the availability of the lifelong treatment is limited in low-income countries were the burden is highest. HIV infection causes an immunodeficiency characterized by the progressive loss of CD4 T cells which increases the risk of opportunistic infections, and infection by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb spreads through aerosols from one person with active tuberculosis to a healthy person. Upon inhalation the bacteria are phagocytosed by alveolar macrophages that secrete cytokines and chemokines to recruit more cells, such as dendritic cells, macrophages and lymphocytes, leading to the formation of a granuloma. During a single TB infection the bacteria are usually contained within the granuloma, but HIV can disrupt the stable granuloma, causing a rupture and dissemination of Mtb. This inflammatory site is also beneficial to HIV since it promotes replication of the virus within infected cells. HIV and Mtb are two successful intracellular pathogens able to avoid immune defense mechanisms both of the innate and adaptive immunity in order to persist and replicate. Their virulence factors can manipulate or inhibit cell signaling, phagosome maturation, autophagy, ROS production, apoptosis and antigen presentation, to promote survival. Boosting of immune defenses with host-directed therapies (HDT) has been proposed as a treatment strategy against TB, either alone or adjunctive to the current regimen.In this thesis, ways to boost the innate immune responses in Mtb and HIV coinfected macrophages were investigated, along with studies of the effect of HIV on Mtb antigen presentation in coinfected dendritic cells. The initial hypothesis was that autophagy induction through inhibition of mammalian target of rapamycin (mTOR) could suppress Mtb growth in HIV coinfected macrophages. However, during a low grade infection, autophagy induction increased Mtb replication due to a decreased autophagic flux and acidification of Mtb phagosomes. A general autophagic flux was induced, although not localized to the Mtb phagosomes, thus not inducing a xenophagy (autophagy of intracellular pathogens). Other ways of inducing autophagy or boosting the response in coinfected macrophages might be more beneficial and therefore the effect of efferocytosis was investigated. Uptake of apoptotic neutrophils by coinfected macrophages did not induce autophagy but enhanced the control of Mtb by other means. Upon efferocytosis, the macrophages acquired active myeloperoxidase (MPO) from the neutrophils that suppressed Mtb growth. The coinfected macrophages also produced more ROS after efferocytosis. The inhibition of Mtb growth could thus be mediated by MPO and the increased ROS production either directly or indirectly.The possibility to boost the innate immunity could prove to be important during an HIV coinfection, when the adaptive immunity is deficient. In addition to the well-known decline in CD4 T cells during the course of HIV progression, we found that HIV infection of dendritic cells inhibited antigen presentation by suppressing the expression of HLA-DR and co-stimulatory molecules on coinfected dendritic cells. Furthermore, HIV reduced secretion of pro-inflammatory cytokines and suppressed antigen processing through inhibition of autophagy. This impaired antigen presentation in coinfected dendritic cells resulted in a decreased activation and response of Mtb-specific CD4 T cells.In conclusion, this thesis shows how HIV can manipulate antigen presentation in Mtb coinfected dendritic cells and subsequently inhibit the adaptive immune response. It also contributes to insights on how efferocytosis of apoptotic neutrophils can boost the innate immune responses during coinfection. Lastly, autophagy induction through mTOR inhibition does not enhance protection against TB. Induction of autophagy should therefore be handled with care, particularly during HIV coinfection.
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| 4. |
- Borgenvik, Anna, 1987-
(author)
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MYC-driven Medulloblastoma : New Targeted Therapies and Mechanisms of Recurrence
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Medulloblastoma is the most common malignant brain tumor of childhood. It arises in the posterior fossa but presents with distinct histological and molecular features. Hence, medulloblastoma is divided into four molecular subgroups, WNT, SHH, Group 3, and Group 4. The overall 5-year survival is ~70% across subgroups but varies with high- and low-risk disease. Standard treatment of medulloblastoma consists of maximal safe tumor resection, radiotherapy, and adjuvant chemotherapy. Despite the rather high success rate of treatment for many patients it also comes with severe long-term debilitating side effects. MYC proteins are master regulators of gene expression often deregulated in cancer. MYC family members MYC and MYCN share similar roles and are found overexpressed or amplified in most medulloblastoma subgroups and correlate with a poor prognosis. Medulloblastoma dissemination and recurrence patterns differ between subgroups but are always associated with a poor prognosis. Recurrent medulloblastoma is not yet curable and will lead to death. In this thesis, we present the first transgenic mouse model of medulloblastoma recurrence and highlight the role of the transcription factor SOX9 in MYC-driven relapse mechanisms. By studying this recurrence model and matched primary-recurrent patient samples we propose a mechanism in which treatment-refractory and quiescent SOX9-positive cells in Group 3 medulloblastoma are necessary for tumor relapse, and how the recurrent tumors can be specifically treated with MGMT inhibitors and doxorubicin.In addition, we address efficient treatment options of primary MYC-driven medulloblastoma where BET bromodomain inhibition (JQ1) in combination with CDK2 inhibition (milciclib) of human Group 3 medulloblastoma will lead to apoptosis and prolonged survival of xenografted mice. This is explained by a dual hit on MYC transcriptional output and MYC protein stability exerted by JQ1 and milciclib respectively. Finally, in a different novel transgenic model of MYC-driven medulloblastoma, we show how temporal Cdk2 knock-out has no effect on MYC protein stability but slows down proliferation and prolongs survival of allografted mice. The need for better treatments and increased understanding of recurrent medulloblastoma is huge. To that end, this thesis focuses on and addresses novel treatments, the role of the cell cycle protein CDK2 as well as relapse mechanisms depending on dormant SOX9-positive cells in highly aggressive MYC-driven medulloblastoma.
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| 5. |
- Henriksson, Catrin, 1961-
(author)
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Coronary Heart Disease and Early Decision Making, from Symptoms to Seeking Care : Studies with Focus on Pre-hospital Delay in Acute Myocardial Infarction Patients
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Despite several investigations and interventions aimed at decreasing the time from symptom onset to medical care seeking in acute myocardial infarction patients, the delay time is still too long for best treatment outcomes. In this thesis, investigations aimed at improving our understanding of the factors influencing delay time are evaluated, as well as attitudes to medical care seeking in patients, relatives and the general public. Additionally, an evaluation was performed to examine whether health-related quality of life had any influence on delay time and re-admissions. Participating patients, relatives and representatives of the general public were generally knowledgeable about acute myocardial infarction (AMI) and its symptomatology. The majority of participants knew about the importance of receiving fast treatment when an AMI occurs. Despite people’s knowledge, several patients and relatives felt uncertain of symptom origin and how to act at symptom onset. Patients commonly consulted an additional person when symptoms did not disappear. However, people appeared to act more appropriately if someone else had chest pain compared to self-experienced symptoms. In patients who had suffered from more than one AMI, poor total health status increased the risk of delaying for more than two hours, but no independent association was found between total health status and re-admissions within the first year post-AMI.
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| 6. |
- Höglund, Anna, 1970-
(author)
-
Vampyrer : En kulturkritisk studie av den västerländska vampyrberättelsen från 1700-talet till 2000-talet
- 2009
-
Doctoral thesis (other academic/artistic)abstract
- Vampires haunt our culture. They live amongst us, they live with us, and very likely, they live for us. Considering the never fading popularity of vampires, it is obvious that these beings satisfy some kind of basic human need. Why are vampires so popular? What kinds of specific characteristics do vampires possess that lead to our never-ending fascination with them? These are questions that are answered in this dissertation, which deals with the vampire narrative’s most significant transformations during the period 1700-2000. This study reveals that the vampire is a monster that allows both identification and distance, which makes it into an appropriate character for people to use when they tell stories about themselves and the surrounding world. This is reflected in vampire narratives. The nature of vampires and the material of vampire narratives are not something that has undergone random changes in the course of history. These transformations have their origins in various societal and cultural processes. Through studying the historical and cultural contexts that have produced vampire narratives, one can understand why vampires have been portrayed in different ways at different times and places. Similarly, studying the vampire narrative can also be used to understand the history and culture in which the narrative was created. An examination of the vampire narrative’s history from a cultural criticism perspective reveals a distinct pattern. The vampire narrative has always attracted most attention in times of social and cultural unrest. In all of the varying contexts where vampire characters appear throughout a story, a power game is occurring – a game where the vampire’s character is strategically used to express political opinions and strengthen ideological beliefs. The constant appearance of vampires in such power games is a distinctive feature within the history of vampire narratives, and the societal turbulence leaves its impression on the vampire narrative. These impressions are analyzed and interpreted in this dissertation in order to reveal the power and the strategies of power within the discourse in which the narrative has been produced. In order to describe how the vampire character has functioned and continues to function in what the study calls conflicts of power relations, the term and phenomena power improvisation is used. In the description of the history of the vampire narrative, one can discern two important sub-processes. The first describes how the vampire character and narrative have been fashioned into what they are today. During the period of interest, the vampire is transformed from the un-dead of folklore to an attractive nobleman and further into to a Count Dracula, in order to simultaneously be portrayed as what this study terms a human vampire. The second sub-process explains why the vampire character and narrative have been fashioned into what they are today. It describes the political and ideological beliefs which exist in the society where the vampire form is created and which give birth to different kinds of vampires. If, in the past, the vampire was a monster that was used to portray that which humans are afraid of, today it is a monster with which humans identify. This, claims the author, is due to the fact that the age in which we live is to a great extent imbued with the logic of consumer culture. People in a consumer culture live lives filled with demands which influence their self-image. Feelings of inadequacy and isolation are typical. For people of today, the vampire is an ally that offers an alternative and meets those needs that are neglected in a consumer society.
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| 7. |
- Karlsson, Elin, 1984-
(author)
-
Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer
- 2014
-
Doctoral thesis (other academic/artistic)abstract
- The prognosis of patients diagnosed with breast cancer has been considerably improved in the latest 25 years, as a result of continuous development of diagnostics and treatment regimens. Though, tumour diseases, for woman mainly lung cancer and breast cancer, still constitute of the most common causes of death in developed countries, following heart diseases. A future utopia is to develop more individualised therapy strategies, to further increase breast cancer survival, but also to decrease the risk of severe side-effects of unnecessary treatments.Normal mammary gland development is regulated by a complex interplay between growth factors and hormones, mainly oestrogen and progesterone, in different cell types. Breast cancer origin and progression is assumed to result from an imbalance in this interplay, leading to the so called “Hallmarks of cancer”, including unlimited cellular proliferation. A central hub in the regulation of proliferation is the intracellular mTOR signalling pathway. Antioestrogen therapy is widely used in breast cancer clinics, however resistance towards this treatment is a remaining problem, and overactivation of mTOR may be one reason behind. A new treatment regimen constituting a combination of mTOR inhibitors with endocrine therapy was recently clinically approved for advanced breast cancers. Although significant benefit for this combination treatment is evident for some patients, counteracting feedback mechanisms are assumed to diminish the effects.The work presented in this thesis focuses on the genes S6K1, S6K2 and 4EBP1 which are main effectors of the intracellular mTOR signalling pathway and thereby secondary targets of the mTOR inhibitors. Our results suggests that the gene amplification status, expression levels of the corresponding mRNA and protein of S6K1, S6K2 and 4EBP1 as well as their cellular localisation may be used to predict breast cancer outcome and the benefit from antioestrogen treatments. These factors are indicated to play separate roles in different subtypes of breast cancer, and specific targeting of S6K1 and S6K2 may be valuable in different tumour subtypes, and in comparison to present day’s mTOR inhibitors, further promote individualised therapies, and thereby increase breast cancer survival.
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| 8. |
- Knutsson, Sofie, 1983-
(author)
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Towards Mosquitocides for Prevention of Vector-Borne Infectious Diseases : discovery and Development of Acetylcholinesterase 1 Inhibitors
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Diseases such as malaria and dengue impose great economic burdens and are a serious threat to public health, with young children being among the worst affected. These diseases are transmitted by mosquitoes, also called disease vectors, which are able to transmit both parasitic and viral infections. One of the most important strategies in the battle against mosquito-borne diseases is vector control by insecticides and the goal is to prevent people from being bitten by mosquitoes. Today’s vector control methods are seriously threatened by the development and spread of insecticide-resistant mosquitos warranting the search for new insecticides. This thesis has investigated the possibilities of vector control using non-covalent inhibitors targeting acetylcholinesterase (AChE); an essential enzyme present in mosquitoes as well as in humans and other mammals. A key requirement for such compounds to be considered safe and suitable for development into new public health insecticides is selectivity towards the mosquito enzyme AChE1. The work presented here is focused on AChE1 from the disease transmitting mosquitoes Anopheles gambiae (AgAChE1) and Aedes aegypti (AaAChE1), and their human (hAChE) and mouse (mAChE) counterparts. By taking a medicinal chemistry approach and utilizing high throughput screening (HTS), new chemical starting points have been identified. Analysis of the combined results of three different HTS campaigns targeting AgAChE1, AaAChE1, and hAChE allowed the identification of several mosquito-selective inhibitors and a number of compound classes were selected for further development. These compounds are non-covalent inhibitors of AChE1 and thereby work via a different mechanism compared to current anti-cholinergic insecticides, whose activity is the result of a covalent modification of the enzyme. The potency and selectivity of two compound classes have been explored in depth using a combination of different tools including design, organic synthesis, biochemical assays, protein X-ray crystallography and homology modeling. Several potent inhibitors with promising selectivity for the mosquito enzymes have been identified and the insecticidal activity of one new compound has been confirmed by in vivo experiments on mosquitoes. The results presented here contribute to the field of public health insecticide discovery by demonstrating the potential of selectively targeting mosquito AChE1 using non-covalent inhibitors. Further, the presented compounds can be used as tools to study mechanisms important in insecticide development, such as exoskeleton penetration and other ADME processes in mosquitoes.
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| 9. |
- Larsson, Carina, 1969-
(author)
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Communicating performance measures : Supporting continuous improvement in manufacturing companies
- 2017
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Licentiate thesis (other academic/artistic)abstract
- Manufacturing enterprises are a key driver of economic growth (Eurostat, 2016). Implementing continuous improvement (CI) is commonly used to increase competitiveness (Hyland et al., 2007), but despite the well-known theory of CI, many manufacturing companies fail in implementing it (Bhasin, 2012; Nordin et al., 2012; Tiwari et al., 2007).An identified critical success factor in CI implementation is the evaluation of performance, including the performance evaluation system itself, the linkage between targets at different company levels, and continual evaluation of performance (Bakås et al., 2011; Scherrer-Rathje et al., 2009; Ukko et al., 2009). Another critical success factor in CI implementation is the communication of performance measures (Bakås et al., 2011; Ukko et al., 2009).This research explores the communication of performance measures. The aim is to support CI by improving the communication of performance measures, and to this end, this thesis concentrates on identifying the main challenges in the communication of performance measures supporting CI. The research scope is manufacturing companies in general, and manufacturing SMEs in particular. The relevant literature concerning the communication of performance measures in manufacturing companies is identified and summarized. Also, current practice is explored, focusing on how performance measures are communicated in manufacturing companies, and whether and how the communication supports CI. This has been done to identify divergences between current practice and theory. Finally, theory and empirical findings are synthesized to identify some of the main challenges to be addressed in order to succeed in CI.The main task is to support CI efforts in manufacturing SMEs, eliminating the identified divergences in the communication of performance measures by adapting these measures to these manufacturing SMEs. These challenges can be summarized as follows: - using both financial performance measures as well as objective and subjective, non-financial performance measures - aligning performance measures with strategy and targets - integrating all performance measure communication, as related to both daily performance and CI, in the same communication loop. - forming two-way communication channels between managers and operators - aligning oral and written communication channels - exploring how information systems can facilitate the communication of performance measures - using and optimizing the visual communication of performance measures
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| 10. |
- Larsson, Jakob C.
(author)
-
Laboratory x-ray fluorescence tomography
- 2018
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Doctoral thesis (other academic/artistic)abstract
- X-ray fluorescence (XRF) tomography is an emerging bio-imaging modality with potential for high-resolution molecular imaging in 3D. In this technique the fluorescence signal from targeted nanoparticles (NPs) is measured, providing information about the spatial distribution and concentration of the NPs inside the object. However, present laboratory XRF tomographysystems typically have limited spatial resolution (>1 mm) and suffer from long scan times and high radiation dose even at high NP concentrations, mainly due to low efficiency and poor signal-to-noise ratio (SNR). Other macroscopic biomedical imaging methods provide either structural information with high spatial resolution (e.g., CT) or functional/molecularinformation with lower resolution (e.g., PET).In this Thesis we present a laboratory XRF tomography system with high spatial resolution (sub-200 μm), low NP concentration and vastly reduced scan times and dose, opening up the possibilities for in vivo small-animal imaging research. The system consists of a high-brightness liquid-metal-jet microfocus x-ray source, x-ray focusing optics and two photon counting detectors. By using the source’s characteristic 24 keV line emission together with spectrally matched molybdenum NPs the Compton background is greatly reduced, increasing the SNR. Each measurement provides information about the spatial distribution and concentration of the NPs, as well as the absorption of the object. An iterative method is used to get aquantitative reconstruction of the XRF image. The reconstructed absorption and XRF images are finally combined into a single 3D overlay image.Using this system we have demonstrated high-resolution dual CT and XRF imaging of both phantoms and mice at radiation doses compatible with in vivo small-animal imaging.
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