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- Abdel-Hamid, Mohammed K, et al.
(author)
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1,8-Naphthalimide derivatives : new leads against dynamin I GTPase activity.
- 2015
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In: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:29
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Journal article (peer-reviewed)abstract
- Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.
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- Agback, Tatiana, et al.
(author)
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Structural and Functional Characterization of Host FHL1 Protein Interaction with Hypervariable Domain of Chikungunya Virus nsP3 Protein
- 2021
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In: Journal of Virology. - 0022-538X .- 1098-5514. ; 95
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Journal article (peer-reviewed)abstract
- Decades of insufficient control have resulted in unprecedented spread of chikungunya virus (CHIKV) around the globe, and millions have suffered from the highly debilitating disease. Nevertheless, the current understanding of CHIKV-host interactions and adaptability of the virus to replication in mosquitoes and mammalian hosts is still elusive. Our new study shows that four-and-a-half LIM domain protein (FHL1) is one of the host factors that interact with the hypervariable domain (HVD) of CHIKV nsP3. Unlike G3BPs, FHL1 is not a prerequisite of CHIKV replication, and many commonly used cell lines do not express FHL1. However, its expression has a detectable stimulatory effect(s) on CHIKV replication, and Fhl1 knockout (KO) cell lines demonstrate slower infection spread. Nuclear magnetic resonance (NMR)-based studies revealed that the binding site of FHL1 in CHIKV nsP3 HVD overlaps that of another proviral host factor, CD2AP. The structural data also demonstrated that FHL1-HVD interaction is mostly determined by the LIM1 domain of FHL1. However, it does not mirror binding of the entire protein, suggesting that other LIM domains are involved. In agreement with previously published data, our biological experiments showed that interactions of CHIKV HVD with CD2AP and FHL1 have additive effects on the efficiency of CHIKV replication. This study shows that CHIKV mutants with extensive modifications of FHL1or both FHL1and CD2AP-binding sites remain viable and develop spreading infection in multiple cell types. Our study also demonstrated that other members of the FHL family can bind to CHIKV HVD and thus may be involved in viral replication.IMPORTANCE Replication of chikungunya virus (CHIKV) is determined by a wide range of host factors. Previously, we have demonstrated that the hypervariable domain (HVD) of CHIKV nsP3 contains linear motifs that recruit defined families of host proteins into formation of functional viral replication complexes. Now, using NMRbased structural and biological approaches, we have characterized the binding site of the cellular FHL1 protein in CHIKV HVD and defined the biological significance of this interaction. In contrast to previously described binding of G3BP to CHIKV HVD, the FHL1-HVD interaction was found to not be a prerequisite of viral replication. However, the presence of FHL1 has a stimulatory effect on CHIKV infectivity and, subsequently, the infection spread. FHL1 and CD2AP proteins were found to have overlapping binding sites in CHIKV HVD and additive proviral functions. Elimination of the FHL1-binding site in the nsP3 HVD can be used for the development of stable, attenuated vaccine candidates.
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- Andersson, Henrik, 1968, et al.
(author)
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Questioning nursing competences in emergency health care.
- 2009
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In: Journal of emergency nursing: JEN : official publication of the Emergency Department Nurses Association. - : Elsevier BV. - 1527-2966 .- 0099-1767. ; 35:4, s. 305-11
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Medical and technologic developments entail new competence demands in emergency health care, and it follows that head nurses must recognize and create prerequisites, as well as evaluate the competence of registered nurses. The aim of this study is to describe head nurses' conceptions of emergency nursing competence needs and their responsibility for creating prerequisites of competence development in emergency nursing. METHODS: A 24-item questionnaire was sent to all the head nurses (N = 79) of all the existing emergency departments in Sweden. The response rate was 73%, and in the analysis of the data, descriptive statistics were used. RESULTS: According to the head nurses, basic nursing education does not provide sufficient emergency nursing competence. Consequently, there is a need for supplementary formal emergency nursing education. Furthermore, most of the head nurses have inadequate strategies for evaluating competence development, and economic and personnel resources are insufficient to meet the educational needs. A minority of the head nurses consider that they have full responsibility for creating the prerequisites of the competence development of nurses. DISCUSSION: To ensure sufficient nursing competence in emergency health care organizations, there is a need to establish competence demands in emergency nursing and evaluate strategies for competence development. The establishment of a Swedish emergency nurses association would be important for the development of national guidelines of emergency nursing as well as to facilitate the interpretation and concretizing of rules and legislation and to promote questions related to research, development, and education in emergency nursing. With national guidelines and recommendations, the head nurses' responsibilities for the development of nurses' skills would be clarified.
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- Andersson, Ida E, 1982-, et al.
(author)
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Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis
- 2011
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 6:3, s. e17881-
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Journal article (peer-reviewed)abstract
- The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.
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- Andersson, Sofia, 1975-
(author)
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Late Holocene humidity variability in central Sweden
- 2010
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Doctoral thesis (other academic/artistic)abstract
- The aim of this thesis was to reconstruct humidity variability in central Sweden during the late Holocene. A multi-proxy approach was used to infer humidity changes as recorded in a lake and a mire. Age-models were constructed based on radiocarbon dating and the Askja-1875 tephra. Stable isotopes (δ18O and δ13C) on Chara spp encrustations and Pisidium spp mollusc shells and carbon content were analysed in the lake record, whereas peat stratigraphy, humification, testate amoebae assemblages, C/N ratio and stable isotopes (δ13C and δ15N) were analysed in the mire record. Stable isotopes (δ2H and δ18O) on lake water showed that Lake Blektjärnen responded to changes in the balance between evaporation and input water (E/I ratio). A high E/I ratio results from a dry and probably warmer climate during which evaporation and atmospheric equilibration likely enrich lake water in 18O and 13C, respectively, and vice versa for a low E/I ratio. The relatively high Chara δ18O and δ13C values between ca 4400 and 4000 cal yr BP thus suggest relatively dry and likely warm conditions, whereas depleted values suggest wetter and probably cooler conditions between ca 4000 and 3000 cal yr BP. Again, drier and probably warmer conditions were inferred from the relatively enriched δ18O values between ca 2500 and 1000 cal yr BP, and depleted δ18O values were recorded between ca 1000 and 50 cal yr BP indicating wetter and likely cooler conditions. The results from the mire mainly indicated vegetation succession, however, the changes inferred at ca 2600 and 1000 cal yr BP could have been triggered by climate change. This study shows that the proxies responded sensitively to humidity changes in the investigated archives allowing for reconstruction of climate change in central Sweden during late Holocene.
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- Astrom, E, et al.
(author)
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Biochemical bone markers in the assessment and pamidronate treatment of children and adolescents with osteogenesis imperfecta
- 2010
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In: ACTA PAEDIATRICA. - : Blackwell Publishing Ltd. - 0803-5253 .- 1651-2227. ; 99:12, s. 1834-1840
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Journal article (peer-reviewed)abstract
- Aim: To assess the role of biochemical bone markers in classification of children with osteogenesis imperfecta (OI), their possible association with vertebral compression fractures in milder forms of OI and their role in monitoring of intravenous pamidronate (APD) treatment. Methods: Serum total alkaline phosphatase (ALP), bone ALP isoforms (in a subgroup), osteocalcin, type I procollagen carboxy-terminal propeptide, carboxy-terminal telopeptide of type I collagen, and urine deoxypyridinoline (DPD) were measured in a cross-sectional study of 130 untreated individuals, 0.25-20.9 years (median 6.7), with OI types I, III and IV. Of those, sixty-nine were also assessed longitudinally during monthly APD treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Results: Significant differences in bone markers, however not sufficient for individual clinical use, were found in the larger untreated group but not between subgroups with or without vertebral compressions. All bone markers decreased during treatment for 1.0-12.5 years, but with different relative amounts. Changes were not correlated to the improvement in BMD, mobility or pain. Conclusion: Bone markers are, despite significant differences, not useful for the classification of OI type in the individual child and are not associated with vertebral compressions. Serum ALP and urinary DPD are sensitive in monitoring bisphosphonate treatment.
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