Targeting the hematopoietic stem cell to correct osteopetrosis

This thesis focuses on developing stem cell targeted gene therapy for the severe hereditary disorder Infantile Malignant Osteopetrosis (IMO) as well as increasing the understanding of how the genetic defect present in IMO affects the hematopoietic stem cells and hematopoiesis in general. IMO is a rare congenital disorder associated with an increased number of non-functional osteoclasts and the absence of bone resorption results in accumulation of sclerotic bone leading to abnormal bone marrow cavity formation insufficient to support hematopoiesis. The most common mutation is in the TCIRG1 gene seen in over 50% of the patients. The children suffer from bone marrow failure, anemia, thrombocytopenia, hepatosplenomegaly, immune dysfunction and recurrent infections. Furthermore, the impaired remodeling of the developing bone results in compression of cranial nerves which leads to neurological impairment, affecting especially vision and hearing which may progress to blindness and deafness. The only curative treatment available today for IMO is bone marrow transplantation. However, this can only be performed if the patient has a suitable stem cell donor. If untreated, the children die around the age of five. Currently no alternative treatment exists, thus IMO is a candidate disease for development of gene therapy. The first two papers are based on studies conducted with the oc/oc mouse model that has a mutation in the homologous gene and shares the same osteopetrotic phenotype as seen in humans. Paper one focuses on developing a clinically relevant model for cell therapy in the oc/oc mouse by replacing radiation conditioning with low-dose busulfan conditioning prior to neonatal bone marrow transplantation and optimizing the administration procedure. In paper two, neonatal oc/oc mice were treated with bone marrow transplantation without any prior conditioning, which showed a rapid reversal of the severe osteopetrotic phenotype despite low level of engraftment and lack of selective expansion of the osteoclastic lineage. In manuscript three human stem cells from patients with IMO were studied and the paper provides the first proof-of-principle of lentiviral-mediated correction restoring the resorptive function of osteoclasts derived from peripheral blood CD34+ cells of IMO patients. In manuscript four the osteoclast significance in hematopoietic stem cell maintenance was studied by generating two adult osteopetrotic mouse models and subsequently analyzing the hematopoiesis of the mice. The results from this study indicate that osteoclast function is not essential for hematopoietic stem cell maintenance in adult mice. Results obtained from the oc/oc mouse model and from IMO patient cells are encouraging for further development of hematopoietic stem cell targeted gene therapy, and will serve as basis for upcoming development of clinical gene therapy of osteopetrosis

The issue of putting a price on trees with high conservation values : a critical review of two monetary valuation tools for trees

I takt med att skyddsvärda träd i städer minskar har flera värderingsverktyg skapats för att skydda dessa genom att ge träd ett ekonomiskt värde. Många av dessa har fått kritik för att inte spegla trädens fulla värde. Uppsatsens syfte är att kritiskt diskutera monetär värdering av naturskyddsvärden, för att belysa problematiken i att använda ekonomiska värderingsverktyg på träd med naturskyddsvärde. Detta görs genom Alnarpsmodellen, ett strukturellt värderingsverktyg, och MyTree, ett instrumentellt värderingsverktyg. Respektive verktygs parametrar undersöks först enskilt för att studera hur de påverkar värderingen. Därefter används verktygen för att värdera nio fiktiva träd, med olika grad av skyddsvärde utifrån egenskaperna storlek och skick. Detta för att undersöka hur verktygen värderar träd med olika grad av skyddsvärde. Studien visar att de båda verktygen ger ett högre värde för ökad trädstorlek vilket speglar ett träds naturskyddsvärde. Vad det gäller skick ger de båda verktygen högst värde till träd utan håligheter, lägre eller lika högt värde för träd med håligheter, och lägst värde för döda träd, vilket inte speglar ett träds naturskyddsvärde. Verktygens problem diskuteras genom tidigare kvantifieringskritik. Det synliggörs då att verktygen bland annat förenklar verkligheten, endast tar hänsyn till generaliserade objektiva värden och är baserat på vad grundarna bakom verktygen anser vara mest värdefullt. Detta kan leda till att felaktiga beslut fattas kring det som har värderats. Däremot finns det en nytta med värderingsverktyg och en styrka med att kombinera ekonomiska värden med subjektiv bedömning eftersom ekonomi har en central roll i beslutsfattande. Detta exemplifieras med fall där värderingsverktyg har använts och gynnat urbana träd och ekologiska funktioner. Slutsatsen från detta arbete är att värderingsverktyg bör användas medvetet då de inte alltid samspelar med naturskyddsvärden. Vi kan konstatera att argumentationen för att bevara urbana träd bör grunda sig i trädets mjuka värden, anpassat efter situation, där stöd i siffror från värderingsverktyg är ett värdefullt tillägg.As trees with high conservation values in cities decrease, several valuation tools have been created to protect trees by giving them economic value. Many of these have been criticized for not reflecting the full value of trees. This work aims to critically discuss the monetary valuation of nature conservation values and to highlight the problems of using economic valuation tools on trees with high nature conservation values. This is done through the Alnarp model, a structural valuation tool, and MyTree, an instrumental valuation tool. Each tool's parameters are first studied individually to analyze how they affect the valuation. Then, the tools are used to monetize nine fictitious trees with varying degrees of conservation value based on size and condition. This provides insight into how the tools value trees with different degrees of conservation value. The study shows that both tools give a higher value for increased tree size, which reflects a tree's nature conservation value. Regarding condition, both tools give the highest value to trees without cavities, lower or equally high value for trees with cavities, and the lowest value for dead trees, which does not reflect a tree's nature conservation value. The problems with the tools are discussed through previous criticism of quantification. It is then revealed that the tools simplify reality, only consider generalized objective values, and are based on what the founders of the tools consider to be most valuable. This can lead to incorrect decisions being made about what has been valued. However, there is a benefit with valuation tools and a strength in combining economic values with subjective assessment, as economics plays a central role in decision-making. This is exemplified by cases where valuation tools have been used and benefited urban trees and ecological functions. The conclusion of this study is that valuation tools should be used consciously as they do not always reflect nature conservation values. We can conclude that the argument for preserving urban trees should be based on the tree's soft values, adapted to the situation, where support in numbers from valuation tools is a valuable addition

The Role of Timing in the Business Model Evolution of Spinoffs

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives license (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits noncommercialre-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.The view of time that dominates conventional management thinking, including the Lean Startup movement’s “fail fast and pivot” approach, often leads to failure in the business model evolution of new ventures spinning off from established firms. Timing is critical for spinoffs because it is a key element of the balance between minimizing risk and maximizing opportunity. In the literature on business model evolution and lean startups, however, the issue of timing is given limited consideration. To address this issue, we present and analyze the role of timing in the business model evolution of C3 Technologies, a spinoff from Saab. The results offer insight regarding the use of managed timing to allow evolutionary processes to let the right moment present itself—and enable the organization to move quickly to seize the moment. This approach allows managers to control the evolutionary process despite the high uncertainty associated with exploring new business models.publishedVersio

Decision-making under uncertainty: A Brehmerian approach

This article discusses the contributions of the late Professor Berndt Brehmer with an emphasis on dynamic decision making under uncertainty. This concept has a long history as ambiguity implied in selective attention, later emphasised by prospect theory, which incorporates a time dimension. Time may be a solution to problems of uncertainty, not least the timing of decisions with each other and with environmental developments. This approach sees  decision making, from a process perspective, ultimately asking whether it makes sense to frame decisions as specific events or as an expression of an ongoing design process where the possibility spaces are expanded rather than limited to decision making among pre-existing alternatives. A dynamic view of the time dimension also encourages decision making as learning through probing actions and negotiation and collaboration, as well as with the environment. As much as this may sound like a recipe for managing second-track processes, it is also a recipe for managing through direct interaction, albeit a less-than-objective one understood through the biased perception of boundedly rational actors

Making sense of complexity in governance: the case of local public management in the City of Stockholm

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.This study found that the problem-solving capacity of a public organization can be understood in terms of the legitimacy of the formulated problems and solutions. Increasing the problemsolving capacity depends on not only the acceptance of problems and how to solve them but also on formal structures and processes. Sensemaking and framing are important keys to unlocking how legitimacy is built, and consequently, how problem-solving capacity is built in a complex organization. We contend that although governance theory recognizes complexity through concepts such as networks and multi-levelness, empirical research tends to downplay what complexity can entail, thus limiting the theoretical development and practical usability of governance theory. Using complexity as a sensemaking framework, we analyze how the top-tier managers of a capital understand the challenges and solutions of coping with rapid growth. We argue that although complexity theory is no panacea to unlocking the difficulties of public sector challenges, it can be a valuable guide to future research on governance.publishedVersio

Barriers and Enablers to Organizational Integration in Cross-border Mergers & Acquisitions

One way to achieve economies of scale and scope, and other potential advantages of firm size, is through mergers and acquisitions (M&As). Being spectacular business events, and very frequent in the eco-system of firms, it has attracted much interest from both researchers and practitioners. However, empirical reviews do not support the popularity of M&A. It seems that the potential synergies are difficult to realize. A key process and major challenge for success, especially for cross-border M&As, is organizational integration. In this work, we have studied organizational integration in cross-border M&As primarily through a qualitative re-investigation of three case studies with the intent to understand what barriers and enablers could explain different outcomes. Through the use of an established coding scheme for variables related to synergy realization, and a database containing a number of coded case studies, we have also been able to make quantitative comparisons, which contributed to our analysis. The outcome is a proposal on how an existing model of synergy realization can be refined for cross-border M&As. It includes the addition of state involvement, legal obstacles, national culture, integration management and union power as factors influencing organizational integration

Public E-Services in Sweden: Old Wine in New Bottles?

This paper describes and analyses the political discourse regarding e-government (including terms earlier used) in Sweden in the period from the 1960s until today, drawing on a review of policy documents. It is found that even though both the meanings ascribed to computers, the political visions, and the main arguments have changed considerably over time, the major plans for action have always remained the same. While goals related to democracy, increased service level, and decentralisation have at different times been at the focus of the debate, increased internal efficiency has always been the target for actions

Carl Gustav Bjurström traducteur de Claude Simon

Le 9 novembre 1985, lors des deuxièmes Assises de la traduction littéraire à Arles, une table ronde en présence de Claude Simon et sous la présidence de Lucien Dällenbach a réuni un certain nombre de traducteurs européens de l’œuvre de Simon : John Fletcher, Uffe Harder, Jukka Mannerkorpi, Guido Neri, Helmut Scheffel et Carl Gustav Bjurström. En hommage au grand traducteur suédois et avec l’aimable autorisation de Madame Inger Bjurström et de l’éditeur des actes des Assises, nous reproduisons..