| 1. |
- Raghavan, Maanasa, et al.
(författare)
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Genomic evidence for the Pleistocene and recent population history of Native Americans
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 349:6250
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Tidskriftsartikel (refereegranskat)abstract
- Howand when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
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| 2. |
- Allemani, Claudia, et al.
(författare)
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Breast cancer survival in the US and Europe: a CONCORD high-resolution study
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 132:5, s. 1170-1181
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.
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| 3. |
- Hjorth, Maria, 1978-
(författare)
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Immunological profile and aspects of immunotherapy in type 1 diabetes
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is a chronic, autoimmune disease caused by a T cell mediated attack on the insulin producing pancreatic ß-cells. Even though reasonable quality of life can be acquired with modern insulin therapy, prevention of acute and late serious complications is facilitated by preservation of residual insulin secretion. Preventing β-cell destruction is therefore an important goal of T1D therapy. Characterisation of immunological changes in the course of T1D is essential for understanding the underlying pathogenic mechanisms and for evaluating the efficacy of therapeutic intervention. This thesis aimed to study the immune profile in individuals at increased risk of T1D and in patients diagnosed with the disease. In addition, the immunological effects of treatment with the B vitamin, Nicotinamide, and by antigen-specific immunotherapy using GAD65, have been studied in high-risk individuals and in T1D patients, respectively.We have found that individuals at high risk of T1D had an increased T helper (Th) 1 like immune profile, defined by high secretion of interferon (IFN) -γ. At the time of clinical onset of T1D, the Th1 dominance was diminished. We further demonstrate that children with newly diagnosed T1D had a suppressed Th1 like profile, detected by chemokine and chemokine receptor profile. This was accompanied by an induced population of CCR7+ and CD45RA+ naïve, CD8+cytotoxic T (Tc) cells and a reduced CD45RO+ memory Tc cell pool. It has previously been shown that oral Nicotinamide had no clinical effect in prevention of T1D. However, we found that the treatment was associated with a decreased secretion of IFN-γ. We have previously shown that subcutaneous injections with GAD-alum in T1D children induced a better preservation of endogenous insulin secretion compared with placebo. Here, we demonstrate that the treatment induced an early antigen-specific Th2 and regulatory immune profile. After a few months, and still after more than two years, the recall response to GAD65 was characterised by a broader range of cytokines. GAD-alum treatment also induced a GAD65-specific CD4+CD25highFOXP3+ cell population and reduced the levels of CD4+CD25+ cells. In conclusion, a Th1 like immune profile in pre-diabetic individuals indicates an imbalance of the immune system. At time of clinical onset, and in the period afterwards, reduction of the Th1 associated immune response could be an effect of a suppressed destructive process, selective recruitment of effector T cells to the pancreas or a defective immune regulation. The protective effect of GAD-alum in T1D children seems to be mediated by an early skewing of GAD65-induced responses towards a Th2 phenotype. Further, induction of GAD65-specific T cells with regulatory characteristics might be able to suppress autoreactive responses and inflammation in the pancreas.
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| 4. |
- Izadi, Arman, et al.
(författare)
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The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pyogenes can cause invasive disease with high mortality despite adequate antibiotic treatments. To address this unmet need, we have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the bacterial M protein. Here, we engineer the IgG2-4 subclasses of Ab25. Despite having reduced binding, the IgG3 version promotes stronger phagocytosis of bacteria. Using atomic simulations, we show that IgG3’s Fc tail has extensive movement in 3D space due to its extended hinge region, possibly facilitating interactions with immune cells. We replaced the hinge of IgG1 with four different IgG3-hinge segment subclasses, IgGhxx. Hinge-engineering does not diminish binding as with IgG3 but enhances opsonic function, where a 47 amino acid hinge is comparable to IgG3 in function. IgGh47 shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh47 has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh47 is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh47 versions of anti-SARS-CoV-2 mAbs to broaden the biological applicability, and these also exhibit strongly enhanced opsonic function compared to the IgG1 subclass. The improved function of the IgGh47 subclass in two distant biological systems provides new insights into antibody function.
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| 5. |
- Malmström, Erik, et al.
(författare)
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The importance of fibroblasts in remodelling of the human uterine cervix during pregnancy and parturition.
- 2007
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Ingår i: Molecular Human Reproduction. - : Oxford University Press (OUP). - 1460-2407. ; 13, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that fibroblasts play a crucial role in pathophysiological extracellular matrix remodelling. The aim of this project is to elucidate their role in normal physiological remodelling. Specifically, the remodelling of the human cervix during pregnancy, resulting in an enabled passage of the child, is used as the model system. Fibroblast cultures were established from cervices of non-pregnant women, women after 36 weeks of pregnancy and women directly after partus. The cells were immunostained and quantified by western blots for differentiation markers. The cultures were screened for cytokine and metalloproteinase production and characterized by global proteome analysis. The cell cultures established from partal donors differ significantly from those from non-pregnant donors, which is in accordance with in vivo findings. A decrease in alpha-smooth actin and prolyl-4hydroxylase and an increase in interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMP)-1 and MMP-3 were observed in cultures from partal donors. 2D-gel electrophoresis followed by mass spectrometry showed that the expression of 59 proteins was changed significantly in cultures of partal donors. The regulated proteins are involved in protein kinase C signalling, Ca2+ binding, cytoskeletal organization, angiogenesis and degradation. Our data suggest that remodelling of the human cervix is orchestrated by fibroblasts, which are activated or recruited by the inflammatory processes occurring during the ripening cascade.
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| 6. |
- Wisniewska, Magdalena, et al.
(författare)
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Functional and Structural Properties of a Novel Protein and Virulence Factor (sHIP) in Streptococcus pyogenes.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:26, s. 18175-18188
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pyogenes is a significant bacterial pathogen in the human population. The importance of virulence factors for the survival and colonization of S. pyogenes is well established, and many of these factors are exposed to the extracellular environment enabling bacterial interactions with the host. In the present study we quantitatively analyzed and compared S. pyogenes proteins in the growth medium of a strain that is virulent to mice, with a non-virulent strain. Particularly one of these proteins was present at significantly higher levels in stationary growth medium from the virulent strain. We determined the three-dimensional structure of the protein that showed a unique tetrameric organization composed of four helix-loop-helix motifs. Affinity pull-down mass spectrometry analysis in human plasma demonstrated that the protein interacts with histidine-rich glycoprotein (HRG), and the name sHIP (streptococcal Histidine-rich glycoprotein Interacting Protein) is therefore proposed. HRG has antibacterial activity, and when challenged by HRG, sHIP was found to rescue S. pyogenes bacteria. This and the finding that patients with invasive S. pyogenes infection respond with antibody production against sHIP, suggest a role for the protein in S. pyogenes pathogenesis.
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| 7. |
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| 8. |
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| 9. |
- Aid, Graham, 1980-
(författare)
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Industrial Ecology Methods within Engagement Processes for Industrial Resource Management
- 2013
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The global use of resources such as materials, energy, and water has surpassed sustainable levels by many accounts. The research presented here was explicitly normative in its aim to improve the understanding of, and make sustainable change toward highly systemic issues of resource management. The core methods chosen to work toward this aim were bottom up action research procedures (including stakeholder engagement processes) and industrial ecology analysis tools. These methods were employed and tested in pragmatic combination through two of the author’s case study projects. The first case study, performed between 2009 and 2012, employed a multi-stakeholder process aimed at improving the cycling of construction and demolition waste in the Stockholm region. The second case study produced a strategic tool (Looplocal) built for facilitating more efficient regional industrial resource networks. While the highly participative aim of the cases required a larger contribution of resources than that of more closed studies, it is arguable that the efficacy of approaching the project aims is improved through their employment.
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| 10. |
- Aid, Graham, 1980-
(författare)
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Operationalizing Industrial Ecology in the Waste Sector : Roles and tactics for circular value innovation
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The take-make-waste approach to resource management in human production and consumption systems is contributing to a variety of environmental and social problems worldwide. Additionally, as the world’s population and affluence increase, so do the negative impacts of poor resource management. Lifting the waste management (WM) sector into a new phase of development, which takes its lead from the ideals of Industrial Ecology and circular economy, is seen by many scholars and practitioners as one potential to assist in alleviating these impacts. While there are many studies on how more efficient inter-organizational resource management is (or could be) constructed, there are relatively few business development studies which have explored novel approaches (from roles to tactics) that WM organizations might operationalize toward more efficient resource management.The aim of this thesis is to contribute to the development of knowledge and understanding of how the waste management sector can operationalize more effective and efficient resource management. In approaching this aim, two research questions guided the exploration of: 1) novel roles for WM and 2) support tactics for such roles. Grounded in the broader context of Industrial Ecology (IE) and Business Development, five studies were performed. Two studies, focused on the novel roles of inter-organizational resource management and high value secondary resource extraction, were performed through literature review and interviews, and market driver analysis respectively. In exploring support tactics, two design and proof of concept studies were carried out to investigate data analysis tools for inter-organizational resource management, and one long-term action research engagement project was coordinated to study hands-on inter-organizational collaboration tactics.The studies highlighted that the Swedish WM sector holds some key capacities for operationalizing (and in some cases, is already developing) the novel resource management roles identified: industrial symbiosis facilitator, eco-industrial park manager, holistic facility management, and high value resource extractor. However, depending on the portfolio of services to be performed in such roles, several capacities may need to be developed or strengthened. Main opportunities seen for these roles were – staying ahead of market developments, and aligning activities with organizational goals. The main general risk related to these roles was insufficient returns on investment. Looking forward, the main enablers identified were policy leadership for more balanced market mechanisms, increasing use of external knowledge, developing long term partnerships, lobbying, stockpiling resources, and carefully crafting new business models.The tools developed for strategically applying external information toward the identification of opportunities within new roles showed tactical potential. However, their implementation in broader development processes has yet to be fully validated. The hands-on exploration of change oriented collaboration, highlighted collective system framing and goal setting and face-to-face interaction as key activities for inter-organizational approaches within roles such as industrial symbiosis facilitator.Throughout the studies, several novel roles were investigated. Each of these roles will need to be individually evaluated by directing bodies of WM organizations, and evaluated from the organization’s vision and strategy. If certain roles are chosen to be explored in more detail, they will need to be developed within full business models - addressing issues such as income structure, internal processes and capacities to be developed, and key customers. Through applying IE and business development concepts and findings, WM organizations have possibilities to translate ambitious visions into novel offerings.
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