| 1. |
- Berglin-Enquist, Ida, et al.
(författare)
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Murine models of acute neuronopathic Gaucher disease
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:44, s. 17483-17488
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Tidskriftsartikel (refereegranskat)abstract
- Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.
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| 2. |
- Földváry Ličina, Veronika, et al.
(författare)
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Development of the ASHRAE Global Thermal Comfort Database II
- 2018
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Ingår i: Building and Environment. - : Elsevier BV. - 0360-1323. ; 142, s. 502-512
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Tidskriftsartikel (refereegranskat)abstract
- Recognizing the value of open-source research databases in advancing the art and science of HVAC, in 2014 the ASHRAE Global Thermal Comfort Database II project was launched under the leadership of University of California at Berkeley's Center for the Built Environment and The University of Sydney's Indoor Environmental Quality (IEQ) Laboratory. The exercise began with a systematic collection and harmonization of raw data from the last two decades of thermal comfort field studies around the world. The ASHRAE Global Thermal Comfort Database II (Comfort Database), now an online, open-source database, includes approximately 81,846 complete sets of objective indoor climatic observations with accompanying “right-here-right-now” subjective evaluations by the building occupants who were exposed to them. The database is intended to support diverse inquiries about thermal comfort in field settings. A simple web-based interface to the database enables filtering on multiple criteria, including building typology, occupancy type, subjects' demographic variables, subjective thermal comfort states, indoor thermal environmental criteria, calculated comfort indices, environmental control criteria and outdoor meteorological information. Furthermore, a web-based interactive thermal comfort visualization tool has been developed that allows end-users to quickly and interactively explore the data.
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| 3. |
- Hamaguchi, Isao, et al.
(författare)
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Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia.
- 2002
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Ingår i: Blood. - 1528-0020. ; 100:8, s. 2724-2731
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Forty percent of the patients are blood transfusion-dependent. Recent reports show that the ribosomal protein S19 (RPS19) gene is mutated in 25% of all patients with DBA. We constructed oncoretroviral vectors containing the RPS19 gene to develop gene therapy for RPS19-deficient DBA. These vectors were used to introduce the RPS19 gene into CD34(+) bone marrow (BM) cells from 4 patients with DBA with RPS19 gene mutations. Overexpression of the RPS19 transgene increased the number of erythroid colonies by almost 3-fold. High expression levels of the RPS19 transgene improved erythroid colony-forming ability substantially whereas low expression levels had no effect. Overexpression of RPS19 had no detrimental effect on granulocyte-macrophage colony formation. Therefore, these findings suggest that gene therapy for RPS19-deficient patients with DBA using viral vectors that express the RPS19 gene is feasible. (Blood. 2002;100:2724-2731)
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| 4. |
- Hamaguchi, Isao, et al.
(författare)
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Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient Diamond-Blackfan anemia improves following RPS19 gene transfer
- 2003
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Ingår i: Molecular Therapy. - 1525-0024. ; 7:5, s. 613-622
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FIL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.
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| 5. |
- Karlsson, Stefan, et al.
(författare)
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Development of gene therapy for blood disorders by gene transfer into haematopoietic stem cells.
- 2002
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 8:3, s. 255-260
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Tidskriftsartikel (refereegranskat)abstract
- Haematopoietic stem cells (HSCs) are important target cells for gene therapy of blood disorders due to their pluripotency and ability to reconstitute haematopoiesis following myeloablation and transplantation. HSCs can 'self-renew' and generate new stem cells. Genetically modified stem cells are therefore expected to last a lifetime in the recipient following blood and marrow transplantation, and can potentially cure haematological disorders. Oncoretroviral vectors have been the main vectors used for HSCs because of their ability to integrate into the chromosomes of their target cells. Because oncoretroviral vectors require dividing target cells for successful localization of the preintegration complex and subsequent chromosomal integration of the provirus, only the dividing fraction of the target cells can be transduced. As only a small fraction of haematopoietic stem cells is dividing at any one time, oncoretroviral vector transduction of human HSCs has been low in clinical trials. However, patients with severe combined immune deficiency-X1 (SCID-X1) have recently been treated successfully by gene therapy of autologous bone marrow cells using oncoretroviral vectors containing the common gamma chain gene. While several additional disorders may potentially be treated successfully using oncoretroviral gene transfer to HSCs, many disorders may require much higher gene transfer efficiency than was achieved in the SCID-X1 study. Therefore, lentiviral vectors have recently emerged as promising vectors for human HSCs because they can transduce dividing and nondividing HSCs efficiently, and may become the vectors of choice in the future for treatment of blood disorders where a large fraction of HSCs has to be corrected.
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| 6. |
- Malm, T M, et al.
(författare)
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Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice
- 2005
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 18:1, s. 134-142
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Tidskriftsartikel (refereegranskat)abstract
- The role of microglia recruited from bone marrow (BM) into the CNS during the progression of Alzheimer's disease (AD) is poorly understood. To investigate whether beta-amyloid (Abeta) associated microglia are derived from blood monocytes, we transplanted BM cells from enhanced green fluorescent protein expressing mice into young or old transgenic AD mice and determined the engraftment of BM-derived cells into the brain and their relative distribution near Abeta deposits. When young transgenic mice were transplanted before the onset of AD-like pathology and the brains analyzed 6.5 months later, the number of engrafted cells was significantly higher than in age-matched wild type mice. Moreover, the number of BM-derived cells associated with Abeta was significantly higher than in old transgenic mice transplanted after the establishment of AD-like pathology. Local inflammation caused by intrahippocampal lipopolysaccharide injection significantly increased the engraftment of BM-derived cells in old AD mice and decreased the hippocampal Abeta burden. These results suggest that infiltration of BM-derived monocytic cells into the brain contributes to the development of microglial reaction in AD.
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| 7. |
- Matsson, Hans, et al.
(författare)
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Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation.
- 2004
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Ingår i: Mol Cell Biol. - 0270-7306. ; 24:9, s. 4032-4037
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Tidskriftsartikel (refereegranskat)abstract
- The ribosomal protein S19 (RPS19) is located in the small (40S) subunit and is one of 79 ribosomal proteins. The gene encoding RPS19 is mutated in approximately 25% of patients with Diamond-Blackfan anemia, which is a rare congenital erythroblastopenia. Affected individuals present with decreased numbers or the absence of erythroid precursors in the bone marrow, and associated malformations of various organs are common. We produced C57BL/6J mice with a targeted disruption of murine Rps19 to study its role in erythropoiesis and development. Mice homozygous for the disrupted Rps19 were not identified as early as the blastocyst stage, indicating a lethal effect. In contrast, mice heterozygous for the disrupted Rps19 allele have normal growth and organ development, including that of the hematopoietic system. Our findings indicate that zygotes which are Rps19(-/-) do not form blastocysts, whereas one normal Rps19 allele in C57BL/6J mice is sufficient to maintain normal ribosomal and possibly extraribosomal functions.
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| 8. |
- Woods, Niels-Bjarne, et al.
(författare)
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Development of Gene Therapy for Hematopoietic Stem Cells using Lentiviral Vectors
- 2002
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Ingår i: Leukemia. - 1476-5551. ; 16:4, s. 563-569
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hematopoietic stem cells are an ideal target for genetic manipulation for the purpose of curing hematological disorders as they have the ability to develop into all blood lineages and to self-renew. In this study we demonstrate that lentiviral vectors, based on HIV-1, can efficiently transfer genes into human hematopoietic progenitor and stem cells as assessed following stem cell transplantation in immune compromised mice. High efficiency transduction of repopulating cells was achieved in both primary (48±23%, n=6) and secondary transplant recipients (64±13%). These results demonstrate the ability of lentiviral vectors to efficiently transduce human pluripotent candidate stem cells. Modifications to the vector design were performed to optimize the vector for high-level transgene expression in the progeny of the repopulating cells. Eight-fold higher expression levels were achieved in mice in both the lymphoid and myeloid progeny cells compared to the original lentiviral vectors. We also analyzed the vector copy number in the bone marrow cells by semi-quantitative PCR. To our surprise we found that on average there were multiple vector copies integrated per transduced cell (5.6±3.3 n=12). While the multiple vector copy integration into stem cells is efficient in terms of transduction and expression, it may increase the risk for insertional mutagenesis. Transduction of murine embryonic stem cells was performed to study transgene expression throughout in vitro differentiation to hematopoietic cells. In addition, we optimized the conditions for gene transfer into murine hematopoietic progenitors in order to be able to test hematopoietic stem cell gene therapy in animal models of human disease. These studies demonstrate the ability of lentiviral vectors to efficiently transduce human hematopoietic stem cells, and advance lentiviral vectors as a tool for the treatment of hematological disorders.
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