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- Bestas, Burcu, et al.
(författare)
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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:9, s. 4067-4081
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Tidskriftsartikel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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- Coren, Esther, et al.
(författare)
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Parent training support for intellectually disabled parents
- 2010
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Ingår i: Cochrane Database of Systematic Reviews. - 1469-493X .- 1469-493X. ; :6, s. CD007987-
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Intellectual disability may impact on an individual's capacity to parent a child effectively. Research suggests that the number of intellectually disabled people with children is increasing. Children of parents with intellectual disabilities may be at increased risk of neglectful care which could lead to health, developmental and behavioural problems, or increased risk of intellectual disability.However, there is some indication that some parents with intellectual disabilities are able to provide adequate child care if they are given appropriate training and support to do so. OBJECTIVES: To assess the effectiveness of parent training interventions to support the parenting of parents with intellectual disabilities SEARCH STRATEGY: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO, ASSIA, Sociological Abstracts, Dissertation Abstracts International, MetaRegister of Controlled Trials, and ZETOC. SELECTION CRITERIA: Randomised controlled trials comparing parent training interventions for parents with intellectual disabilities with usual care or with a control group. Outcomes of interest were: the attainment of parenting skills specific to the intervention, safe home practices and the understanding of child health. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and undertook data extraction. MAIN RESULTS: Three trials met the inclusion criteria for this review but no meta-analysis was possible. One study reported improved maternal-child interaction following group parent training compared with the control group. The second study reported some improvements in parents knowledge of life threatening emergencies, ability to recognise dangers and identify precautions and smaller improvements in their ability to implement precautions, use medicines safely and recognise child illness and symptoms. The third study reported improvement in child care and safety skills following the intervention. AUTHORS' CONCLUSIONS: There is some risk of bias in the included studies, with limited information available to assess possible bias and to fully assess the findings of one included study. Whilst the evidence presented here does seem promising with regard to the ability of such interventions to improve parenting knowledge and skill in this population, there is a need for larger RCTs of interventions before conclusions can be drawn about the effectiveness of parent training for this group of parents.
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- Fehr, Manuela A., et al.
(författare)
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Iron enrichments and Fe isotopic compositions of surface sediments from the Gotland Deep, Baltic Sea
- 2010
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Ingår i: Chemical Geology. - : Elsevier BV. - 0009-2541 .- 1872-6836. ; 277:3-4, s. 310-322
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Tidskriftsartikel (refereegranskat)abstract
- Recent sediments from the Gotland Deep display enrichments in reactive Fe, associated with elevated Fe/Al ratios and light Fe isotopic signatures of the bulk sediments that are indicative of euxinic (anoxic and sulfidic) conditions. These enrichments can be explained by the Fe shuttle model where benthic Fe is transported from the shelf to the euxinic basin and transferred to the sediments by pyrite precipitation in the sulfidic water. The data provide evidence that the Fe shuttle at present results in accumulations of Fe that are larger compared to Fe enrichments during the Litorina Sea stage in the Gotland Deep probably caused by an increase of the benthic Fe flux from the shelf to the basin. The derived Fe enrichments are also larger compared to those in recent Black Sea sediments, which likely reflects the larger shelf to basin ratio of the Gotland Deep compare to the Black Sea. The Fe isotope data show no correlation with the organic C content of the samples indicating that the negative Fe isotope signatures are not associated with organic materials, as was suggested as an alternative explanation for the origin of the isotopically light Fe in sediments from the Litorina Sea stage. Conversely, pyrites carry the negative Fe isotopic signature of the sediments, which supports the Fe shuttle model. Variations in the abundance and Fe isotopic signature of reactive Fe and pyrite with depth suggest that syngenetically formed pyrite in the sulfidic water column has a less negative Fe isotopic composition compared to diagenetically produced pyrite.
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- Gupta, Dhanu, et al.
(författare)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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- Gustafsson, Susanne, et al.
(författare)
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Tailored implementation of evidence-based practice in the community care for the aged - initial experiences in a collaborative project in the city of Gothenburg, Sweden
- 2015
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Ingår i: Nordic Conference on implementation of Evidence-Based Practice 20150203-20150204 Bergen, Norge.
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Konferensbidrag (refereegranskat)abstract
- Background: Evidence-based practice (EBP) appears promising in order to strengthen both interprofessional team work and the client´s involvement in his/her care processes. It is therefore of interest to implement EBP in the community care for the aged. But implementation is not always a simple and straightforward process; it may face resistance or difficulties. Factors such as usability, adaptations, barriers, fidelity, and anticipated impact need to be studied when implementing EBP in a new context. Aim: To evaluate the implementation of EBP in community health and social care for the aged in a Swedish setting. This includes the study of the implementation process as well as the impact of EBP on interprofessional teamwork and the care receivers' experiences of care quality. Methods: An explanatory case study in two urban districts in the city of Gothenburg, Sweden, where the implementation of EBP is delivered as a collaborative project with a tailored multifaceted implementation strategy. Data will be collected through documentary information, observations, focus groups, interviews, and a survey, and analyzed using both qualitative and quantitative methods. Results: The collaborative project is on-going with three facilitators using a multifaceted implementation strategy including cooperation between researchers and users, education/learning, and facilitation. Data collection has commenced. Initial experiences reveal that the introductory phase, containing time for persons involved in the collaborative project to get to know each other, each other's areas of expertise and respective organizations, took longer than expected. Also, different care-professions have experienced thus far conducted educational activities in different ways, and some express limited ability to prioritize project activities. Conclusion: The future results of this explanatory case study may be useful for gaining knowledge of and understanding the implementation of EBP in community care for the aged, and to improve the quality of care, support and rehabilitation of older persons.
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- Gustafsson Sfetcovici, Manuela O
(författare)
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Characterization of ankyrin repeat domain 54 (ANKRD54) and its role on the regulation and subcellular localization of Bruton’s tyrosine kinase (BTK)
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bruton's tyrosine kinase (BTK) is an important cytoplasmic signaling protein, where the kinase activity plays a pivotal role in the development, proliferation and differentiation of B-cell lineages. Ankyrin repeat domain 54 (ANKRD54) is a nuclear-resident adaptor protein, where the ankyrin domain repeats are critical for specific protein-protein interaction, while the NLS and NES motifs control the nucleo-cytoplasmic shuttling ability. We have identified and characterized ANKRD54 as a novel functional (paper I), interaction-partner for BTK using proteomics analysis. ANKRD54 is the first protein identified that specially influences the nuclear export of both BTK and TXK/RLK, in a Crm-1 dependent manner. Further, we mapped the interaction site to the C -terminus of BTK-SH3 domain, by using a synthetic peptide of BTK, covering the following region: C- ARDKNGQEEGYIPSNYVTEAEDS. In addition, tyrosine phosphorylation of BTK was investigated in the presence of increased amount of ANKRD54 and selectively the phosphorylation of BTK was down regulated. We have presented a second novel interaction-partner and regulator of BTK (paper II), the 14-3-3 ζ protein, which is also identified by proteomics strategy. In this work, we have mapped the interaction sites on BTK to phospho-serine pS51 in the (RGRRGpS)-motif in the PH-domain and phospho-threonine pT495 in the (RHRFQpT)-motif in the kinase domain. Additionally, a newly characterized 14-3-3 inhibitor (BV02) interfered binding with BTK and siRNA knockdown of 14-3-3ζ increased the nuclear translocation of BTK, while overexpression of 14-3-3ζ resulted in accumulation of BTK in the perinuclear region. We have generated single ankryin domain deletions of ANKRD54 and subsequently characterized their binding capacity and also their influence on the sub-cellular localization of BTK (paper III). In this work, we report that three out of four ankyrin repeats are required for the interaction and nucleo-cytoplasmic shuttling of BTK. Inhibition of Crm-1 nuclear export pathway influences differently the nuclear shuttling; rapid-ANKRD54 versus slow-BTK nuclear accumulation. Furthermore, we have determined that the interaction between BTK and ANKRD54 establishes in the nuclear compartment. We have classified ANKRD54 as a prime interactor to the SH3-domain of BTK (paper IV). In this study, we utilized a screening strategy based on phage display libraries of the complete human “SH3-domainome” as a possible binding-target for ANKRD54. The aim is to identify the target spectrum and specificity of ANKRD54 for SH3 domain library, containing all the 296 human SH3 domains. The novel finding is that BTK is not only binding to ANKRD54, but also stands out as the preferred interactor, being highly dominant over all other human SH3 domains. However, other lower colony-score candidates for SH3-domain interactions were found, but without any further in vivo/in vitro validation.
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