| 1. |
- Bergemalm, Daniel, 1977-, et al.
(författare)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 2. |
- Hagberg, Carolina E, et al.
(författare)
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Vascular endothelial growth factor B controls endothelial fatty acid uptake.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 464:7290, s. 917-21
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Tidskriftsartikel (refereegranskat)abstract
- The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.
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| 3. |
- Hedström, Brita, et al.
(författare)
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Visby Innerstad : En användningsplan
- 1973
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Rapport (populärvet., debatt m.m.)abstract
- Sedan lång tid föreligger i stort sett enighet om att bevara innerstadens bebyggelse och att anpassa eventuella nytillskott till det redan bestående. Med den inställningen har förändringsprocessen både dämpats och mildrats men ändå inte bragts att avstanna. Förändringar sker ständigt om det också huvudsakligen i smått: de många synbart så anspråkslösa byggnadsåtgärderna adderar efterhand ihop sig till något större och mer genomgripande. Långsamt, nästan omärkligt, ändrar innerstaden sitt ansikte.Ändå är det inte själva husen som förändrats mest utan användningen av dem. Ur funktionell synpunkt har 1950 - och 60-talen har varit något av en omstörtning i innerstadens historia: den har förlorat nästan hälften av de boende, en stor del av detaljhandeln och praktiskt taget helt sin gamla roll som skolcentrum. I gengäld har ytterstaden vuxit ut till ett sammanhängande kilometerbrett bälte. Till stor del av denna funktionella förändring en följd av beslutet att bevara innerstadens bebyggelse. Vad som inte fått plats inom den gamla ramen har etablerats utandör den.Föreliggande arbete vill ge en översiktlig bild av förändringsförloppen, sedda i ett långt tidsperspektiv men med tonvikt på dagsläget. Bebyggelsen tas upp till utförlig granskning men också användningen av den. Det är just samspelet mellan husen och de funtkioner, de fyller, som kan sägas utgöra bokens huvudtema. I de flesta fall är detta sammanhang hus-användning alldeles konfliktfritt och föranleder därför inte heller någon diskussion. Vad som behandlas är de relativt få problematiska fallen, hus som borde rustas upp för att fylla sin uppgift, hus som är olämpligt nyttjade eller inte använda alls. En serie sådana fall tas upp till systematisk genomgång; samtidigt berörs också de trafik - och miljömässiga konsekvenserna. Bokens syfte är alltså klart: den ger ett underlag av fakta för arbetet med att jämka samman byggnader och användningsformer. I den meningen kan skriften kallas en anvädningsplan för Visby innanför murarna.Arkitekturskolanas arbete har bedrivitis parallellt med den kommunala Innerstadskommitténs verksamhet. Något organiserat samarbete har inte förekommit med de informella kontakterna har varit både täta och goda. Att likheterna mellan Innerstadskommittén och Arkitekturskolans slutsatser blivit så pass stora, kan tillskrivas en gemensam helhetssyn.En av Arkitekturskolans elever, arkitekt Lars-Ingvar Larsson, har tidigare självständigt genomfört en undersökning av förändringar i innerstaden 1945-70- Denna studie publicerats separat och bör uppfattas som ett komplement till den hör föreliggande.Förutom de i innehållsförteckningen nämnda har ytterligare några aktivt medverkat i arbetet. Studiet av trafikfrågorna i innerstaden, i hamnen och öster om ringmuren leddes av Åke Claesson, I fältstudier och diskussioner medverkande Göran Månsson.Arkitekturskolan har fått god hjälp av ett antal initierade personer i Visby. Särskild tacksamhet är vi skyldiga byggnadsnämnden ordförande Henning Jacobson, kommunalrådet C B Stenström, stadsarkitekten Måns Hagbergm f. länsbostadsdorektören Åke Malmberg och landsantikvarien Gunnar Svahnström. I boken publiceringskostnaderna har ekonomiskt bidrag lämnats av Gotlands kommun och Riksantikvarieämbetet.Boken har redigerats av Sture Balgård och Ann Mari Westerlind med hjälp av Henrik O Andersson, Bo Ek, Göran Lindahl, Fredrik von Platen, John Sjöström Gunnar Westerlind och Hans Wetterfors.Skeppsholmen, Stockholm, sommaren 1973.Arkitekturskolans lärare och elever.
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| 4. |
- Henriksson, Roger, et al.
(författare)
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Boron neutron capture therapy (BNCT) for glioblastoma multiforme : a phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA)
- 2008
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 88:2, s. 183-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: To evaluate the efficacy and safety of boron neutron capture therapy (BNCT) for glioblastoma multiforme (GBM) using a novel protocol for the boronophenylalanine-fructose (BPA-F) infusion. PATIENT AND METHODS: This phase II study included 30 patients, 26-69 years old, with a good performance status of which 27 have undergone debulking surgery. BPA-F (900 mg BPA/kg body weight) was given i.v. over 6h. Neutron irradiation started 2h after the completion of the infusion. Follow-up reports were monitored by an independent clinical research institute. RESULTS: The boron-blood concentration during irradiation was 15.2-33.7 microg/g. The average weighted absorbed dose to normal brain was 3.2-6.1 Gy (W). The minimum dose to the tumour volume ranged from 15.4 to 54.3 Gy (W). Seven patients suffered from seizures, 8 from skin/mucous problem, 5 patients were stricken by thromboembolism and 4 from abdominal disturbances in close relation to BNCT. Four patients displayed 9 episodes of grade 3-4 events (WHO). At the time for follow-up, minimum ten months, 23 out of the 29 evaluable patients were dead. The median time from BNCT treatment to tumour progression was 5.8 months and the median survival time after BNCT was 14.2 months. Following progression, 13 patients were given temozolomide, two patients were re-irradiated, and two were re-operated. Patients treated with temozolomide lived considerably longer (17.7 vs. 11.6 months). The quality of life analysis demonstrated a progressive deterioration after BNCT. CONCLUSION: Although, the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy and the treatment time is shorter, the observed side effects and the requirement of complex infrastructure and higher resources emphasize the need of further phase I and II studies, especially directed to improve the accumulation of (10)B in tumour cells.
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| 5. |
- Lindahl, Erik, et al.
(författare)
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Trans vs Cis : A Computational Study of Enasidenib Resistance due to IDH2 Mutations
- 2024
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 26:27, s. 18989-18996
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Tidskriftsartikel (refereegranskat)abstract
- Isocitrate dehydrogenase 2 (IDH2) is a homodimeric enzyme that plays an important role in energy production. A mutation R140Q in one monomer makes the enzyme tumourigenic. Enasidenib is an effective inhibitor of IDH2/R140Q. A secondary mutation Q316E leads to enasidenib resistance. This mutation was hitherto only found in trans, i.e. where one monomer has the R140Q mutation and the other carries the Q316E mutation. It is not clear if the mutation only leads to resistance when in trans or if it has been discovered in {\em trans} only by chance, since it was only reported in two patients. Using molecular dynamics (MD) simulations we show that the binding of enasidenib to IDH2 is indeed much weaker when the Q316E mutation takes place in trans not in cis, which provides a molecular explanation for the clinical finding. This is corroborated by non-covalent interaction (NCI) analysis and DFT calculations. Whereas the MD simulations show a loss of one hydrogen bond upon the resistance mutation, NCI and energy decomposition analysis (EDA) reveal that a multitude of interactions are weakened.
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| 6. |
- Lindahl, Erik, et al.
(författare)
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Trans vs. cis: a computational study of enasidenib resistance due to IDH2 mutations
- 2024
-
Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : ROYAL SOC CHEMISTRY. - 1463-9076 .- 1463-9084. ; 26:27, s. 18989-18996
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Tidskriftsartikel (refereegranskat)abstract
- Isocitrate dehydrogenase 2 (IDH2) is a homodimeric enzyme that plays an important role in energy production. A mutation R140Q in one monomer makes the enzyme tumourigenic. Enasidenib is an effective inhibitor of IDH2/R140Q. A secondary mutation Q316E leads to enasidenib resistance. This mutation was hitherto only found in trans, i.e. where one monomer has the R140Q mutation and the other carries the Q316E mutation. It is not clear if the mutation only leads to resistance when in trans or if it has been discovered in trans only by chance, since it was only reported in two patients. Using molecular dynamics (MD) simulations we show that the binding of enasidenib to IDH2 is indeed much weaker when the Q316E mutation takes place in trans not in cis, which provides a molecular explanation for the clinical finding. This is corroborated by non-covalent interaction (NCI) analysis and DFT calculations. Whereas the MD simulations show a loss of one hydrogen bond upon the resistance mutation, NCI and energy decomposition analysis (EDA) reveal that a multitude of interactions are weakened.
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| 7. |
- Lundblad, Mattias, et al.
(författare)
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Sveriges klimatrapportering - markanvändning och skogsbruk
- 2022
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Ingår i: Fakta. Skog. - 1400-7789.
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Annan publikation (populärvet., debatt m.m.)abstract
- SLU sammanställer Sveriges rapportering av utsläpp och upptag av växthusgaserfrån markanvändning och skogsbruk.Om man undantar markanvändning och skogsbruk var Sveriges utsläpp avväxthusgaser under 2020 46 miljoner ton CO2-ekvivalenter.Markanvändning och skogsbruk bidrog samma år till ett nettoupptag på40 miljoner ton CO2-ekvivalenter, varav skogsmark stod för 96 %.Det största nettoupptaget av kol i levande biomassa sker i produktionsskog,men upptaget per arealenhet är något större i skog som skogsägarnafrivilligt undantagit från skogsbruk
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| 8. |
- Ma, Jianhui, et al.
(författare)
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Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair
- 2019
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 35:3, s. 504-518.e7
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Tidskriftsartikel (refereegranskat)abstract
- Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.
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| 9. |
- Nelander, Sven, 1974, et al.
(författare)
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Predictive screening for regulators of conserved functional gene modules (gene batteries) in mammals
- 2005
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Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The expression of gene batteries, genomic units of functionally linked genes which are activated by similar sets of cis- and trans-acting regulators, has been proposed as a major determinant of cell specialization in metazoans. We developed a predictive procedure to screen the mouse and human genomes and transcriptomes for cases of gene-battery-like regulation. RESULTS: In a screen that covered approximately 40 percent of all annotated protein-coding genes, we identified 21 co-expressed gene clusters with statistically supported sharing of cis-regulatory sequence elements. 66 predicted cases of over-represented transcription factor binding motifs were validated against the literature and fell into three categories: (i) previously described cases of gene battery-like regulation, (ii) previously unreported cases of gene battery-like regulation with some support in a limited number of genes, and (iii) predicted cases that currently lack experimental support. The novel predictions include for example Sox 17 and RFX transcription factor binding sites that were detected in approximately 10% of all testis specific genes, and HNF-1 and 4 binding sites that were detected in approximately 30% of all kidney specific genes respectively. The results are publicly available at http://www.wlab.gu.se/lindahl/genebatteries. CONCLUSION: 21 co-expressed gene clusters were enriched for a total of 66 shared cis-regulatory sequence elements. A majority of these predictions represent novel cases of potential co-regulation of functionally coupled proteins. Critical technical parameters were evaluated, and the results and the methods provide a valuable resource for future experimental design.
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| 10. |
- van Sorge, Nina M., et al.
(författare)
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Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors
- 2021
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Ingår i: EMBO Journal. - : Wiley-VCH Verlagsgesellschaft. - 0261-4189 .- 1460-2075. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed β protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that an IgSF domain in β represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessment revealed that this newly identified IgI3 fold is not exclusively present in GBS but is predicted to be present in adhesins from other clinically important human pathogens. In agreement with this prediction, we found that CEACAM1 binds to an IgI3 domain found in an adhesin from a different streptococcal species. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.
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| 11. |
- Viveca, Lindahl, 1986-
(författare)
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Optimizing sampling of important events in complex biomolecular systems
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proteins and DNA are large, complex molecules that carry out biological functions essential to all life. Their successful operation relies on adopting specific structures, stabilized by intra-molecular interactions between atoms. The spatial and temporal resolution required to study the mechanics of these molecules in full detail can only be obtained using computer simulations of molecular models. In a molecular dynamics simulation, a trajectory of the system is generated, which allows mapping out the states and dynamics of the molecule. However, the time and length scales characteristic of biological events are many orders of magnitude larger than the resolution needed to accurately describe the microscopic processes of the atoms. To overcome this problem, sampling methods have been developed that enhance the occurrence of rare but important events, which improves the statistics of simulation data.This thesis summarizes my work on developing the AWH method, an algorithm that adaptively optimizes sampling toward a target function and simultaneously finds and assigns probabilities to states of the simulated system. I have adapted AWH for use in molecular dynamics simulations. In doing so, I investigated the convergence of the method as a function of its input parameters and improved the robustness of the method. I have also worked on a generally applicable approach for calculating the target function in an automatic and non-arbitrary way. Traditionally, the target is set in an ad hoc way, while now sampling can be improved by 50% or more without extra effort. I have also used AWH to improve sampling in two biologically relevant applications. In one paper, we study the opening of a DNA base pair, which due to the stability of the DNA double helix only very rarely occurs spontaneously. We show that the probability of opening depends on both nearest-neighbor and longer-range sequence effect and furthermore structurally characterize the open states. In the second application the permeability and ammonia selectivity of the membrane protein aquaporin is investigated and we show that these functions are sensitive to specific mutations.
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| 12. |
- Abarenkov, Kessy, et al.
(författare)
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The UNITE database for molecular identification and taxonomic communication of fungi and other eukaryotes: sequences, taxa and classifications reconsidered
- 2024
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Ingår i: Nucleic Acids Research. - 0305-1048 .- 1362-4962. ; 52:D1, s. D791-D797
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Tidskriftsartikel (refereegranskat)abstract
- UNITE (https://unite.ut.ee) is a web-based database and sequence management environment for molecular identification of eukaryotes. It targets the nuclear ribosomal internal transcribed spacer (ITS) region and offers nearly 10 million such sequences for reference. These are clustered into similar to 2.4M species hypotheses (SHs), each assigned a unique digital object identifier (DOI) to promote unambiguous referencing across studies. UNITE users have contributed over 600 000 third-party sequence annotations, which are shared with a range of databases and other community resources. Recent improvements facilitate the detection of cross-kingdom biological associations and the integration of undescribed groups of organisms into everyday biological pursuits. Serving as a digital twin for eukaryotic biodiversity and communities worldwide, the latest release of UNITE offers improved avenues for biodiversity discovery, precise taxonomic communication and integration of biological knowledge across platforms. Graphical Abstract
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| 13. |
- Abraham, Mark James, 1977-, et al.
(författare)
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GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
- 2015
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Ingår i: SoftwareX. - : Elsevier. - 2352-7110. ; 1-2, s. 19-25
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Tidskriftsartikel (refereegranskat)abstract
- GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules. It provides a rich set of calculation types, preparation and analysis tools. Several advanced techniques for free-energy calculations are supported. In version 5, it reaches new performance heights, through several new and enhanced parallelization algorithms. These work on every level; SIMD registers inside cores, multithreading, heterogeneous CPU–GPU acceleration, state-of-the-art 3D domain decomposition, and ensemble-level parallelization through built-in replica exchange and the separate Copernicus framework. The latest best-in-class compressed trajectory storage format is supported.
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| 14. |
- Abraham, Mark James, et al.
(författare)
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Sharing Data from Molecular Simulations
- 2019
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 59:10, s. 4093-4099
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Tidskriftsartikel (refereegranskat)abstract
- Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 (https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.
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| 15. |
- Abrahamsson, B., et al.
(författare)
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Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247
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Tidskriftsartikel (refereegranskat)abstract
- OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
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| 16. |
- Adam, Abderisak, 1988, et al.
(författare)
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Aggregation of factors causing cost overruns and time delays in large public construction projects: Trends and implications
- 2017
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Ingår i: Engineering, Construction and Architectural Management. - 1365-232X .- 0969-9988. ; 24:3, s. 393-406
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThe purpose of this paper is to explore the impact that cost overruns and time delays exert on large public construction projects to clarify how past and current research regard factors causing cost overruns and time delays in large public construction projects.Design/methodology/approachThis paper, which is based on an analysis of a literature selection consisting of 40 journal articles, investigates and ranks the occurrence of and the explanations for cost overruns and time delays in large public construction projects. The study makes use of a kiviat diagram/radar chart in order to visualize multivariate data.FindingsAggregated rankings of important causes of cost overruns and time delays are reported. These show a strong emphasis on the management aspect as a primary cause of cost overruns and delays. Additionally, there seems to be a trend toward deemphasizing the role of financial considerations in explaining cost overruns and delays. It is argued that there needs to be a more rigorous assessment of the impact that each factor has on cost increases and delays based on factual observed data as opposed to retrospective accounts from questionnaire respondents.Research limitations/implicationsOnly public construction projects have been considered. The results will not be directly applicable to privately funded construction projects and/or projects of a smaller size.Originality/valueThe use of trend data, as illustrated in a kiviat diagram, showing how different ranking factors causing cost overruns and time delays has changed in importance over time.
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| 17. |
- Adam, Abderisak, 1988, et al.
(författare)
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Developing Capabilities for Public Construction Clients
- 2014
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Ingår i: Proceedings of the 19th International Symposium on the Advancement of Construction Management and Real Estate, 7-9 Nov 2014, Chongqing.
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Konferensbidrag (refereegranskat)abstract
- Clients in the public sector face a large number of challenges in designing, procur-ing and managing major construction projects in a manner that is conducive to the organization’s overall goals. The role of the client in bringing about successful project completion has more recently been emphasized with a growing number of studies focusing on developing dynamic client capabilities that facilitate the han-dling of a project through all of its different phases. Though the capabilities of the client carries immense importance in all con-struction projects, the importance is further exacerbated by the sheer scale of the projects involved in major construction projects, a development which has prompted governmental agencies to inquire into ways to improve processes in the client organization. To address such inquiries, this paper which is based on a literature review, ex-plores the types of dynamic capabilities that emerge with respect to public con-struction clients and in particular, if and how a specific client capability influences a specific project outcome. The mapping of capabilities constitutes a theoretical foundation for a forthcoming empirical study on the same topic.
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| 18. |
- Adam, Abderisak, 1988, et al.
(författare)
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Implications of cost overruns and time delays on major public construction projects
- 2014
-
Ingår i: Proceedings of the 19th International Symposium on the Advancement of Construction Management and Real Estate, 7-9 Nov 2014, Chongqing.
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Konferensbidrag (refereegranskat)abstract
- For decades, the construction industry has been characterized by costs exceeding budgetary limits and completion times reaching further than what was set out ini-tially. This has been particularly noticeable for large public construction projects where cost overruns and time delays have long been regarded a common occur-rence. Due to the magnitude and frequency of these overruns, they have come to pose a significant financial risk to both clients and contractors, in addition to the impact exerted on the sustainability of the project. In dealing with this, researchers, auditors and practitioners have suggested a broad range of solutions, ranging from technical and economical to psychological and political approaches. In doing so, the contractor’s role has been emphasized whereas the role of the client organization has often been overlooked. This paper which is based on a literature review investigates the occurrence of and the expla-nations for cost overruns and time delays in major construction projects from the public client’s perspective. It also explores the implications of cost overruns and time delays; the purpose of which is to offer an extended understanding of the re-lationship between the client’s actions and effects on cost, time and sustainability parameters.
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| 19. |
- Alekseenko, Andrey, et al.
(författare)
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Experiences with Adding SYCL Support to GROMACS
- 2021
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Ingår i: IWOCL'21. - New York, NY, USA : Association for Computing Machinery (ACM).
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Konferensbidrag (refereegranskat)abstract
- GROMACS is an open-source, high-performance molecular dynamics (MD) package primarily used for biomolecular simulations, accounting for 5% of HPC utilization worldwide. Due to the extreme computing needs of MD, significant efforts are invested in improving the performance and scalability of simulations. Target hardware ranges from supercomputers to laptops of individual researchers and volunteers of distributed computing projects such as Folding@Home. The code has been designed both for portability and performance by explicitly adapting algorithms to SIMD and data-parallel processors. A SIMD intrinsic abstraction layer provides high CPU performance. Explicit GPU acceleration has long used CUDA to target NVIDIA devices and OpenCL for AMD/Intel devices. In this talk, we discuss the experiences and challenges of adding support for the SYCL platform into the established GROMACS codebase and share experiences and considerations in porting and optimization. While OpenCL offers the benefits of using the same code to target different hardware, it suffers from several drawbacks that add significant development friction. Its separate-source model leads to code duplication and makes changes complicated. The need to use C99 for kernels, while the rest of the codebase uses C++17, exacerbates these issues. Another problem is that OpenCL, while supported by most GPU vendors, is never the main framework and thus is not getting the primary support or tuning efforts. SYCL alleviates many of these issues, employing a single-source model based on the modern C++ standard. In addition to being the primary platform for Intel GPUs, the possibility to target AMD and NVIDIA GPUs through other implementations (e.g., hipSYCL) might make it possible to reduce the number of separate GPU ports that have to be maintained. Some design differences from OpenCL, such as flow directed acyclic graphs (DAGs) instead of in-order queues, made it necessary to reconsider the GROMACS's task scheduling approach and architectural choices in the GPU backend. Additionally, supporting multiple GPU platforms presents a challenge of balancing performance (low-level and hardware-specific code) and maintainability (more generalization and code-reuse). We will discuss the limitations of the existing codebase and interoperability layers with regards to adding the new platform; the compute performance and latency comparisons; code quality considerations; and the issues we encountered with SYCL implementations tested. Finally, we will discuss our goals for the next release cycle for the SYCL backend and the overall architecture of GPU acceleration code in GROMACS.
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| 20. |
- Alekseenko, Andrey, 1990-, et al.
(författare)
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GROMACS on AMD GPU-Based HPC Platforms : Using SYCL for Performance and Portability
- 2024
-
Ingår i: CUG2024 Proceedings.
-
Konferensbidrag (refereegranskat)abstract
- GROMACS is a widely-used molecular dynamics software package with a focus on performance, portability, and maintainability across a broad range of platforms. Thanks to its early algorithmic redesign and flexible heterogeneous parallelization, GROMACS has successfully harnessed GPU accelerators for more than a decade.With the diversification of accelerator platforms in HPC and no obvious choice for a well-suited multi-vendor programming model, the GROMACS project found itself at a crossroads. The performance and portability requirements, as well as a strong preference for a standards-based programming model, motivated our choice to use SYCL for production on both new HPC GPU platforms: AMD and Intel.Since the GROMACS 2022 release, the SYCL backend has been the primary means to target AMD GPUs in preparation for exascale HPC architectures like LUMI and Frontier.SYCL is a cross-platform, royalty-free, C++17-based standard for programming hardware accelerators, from embedded to HPC.It allows using the same code to target GPUs from all three major vendors with minimal specialization, which offers major portability benefits.While SYCL implementations build on native compilers and runtimes, whether such an approach is performant is not immediately evident.Biomolecular simulations have challenging performance characteristics: latency sensitivity, the need for strong scaling, and typical iteration times as short as hundreds of microseconds. Hence, obtaining good performance across the range of problem sizes and scaling regimes is particularly challenging.Here, we share the results of our work on readying GROMACS for AMD GPU platforms using SYCL,and demonstrate performance on Cray EX235a machines with MI250X accelerators. Our findings illustrate that portability is possible without major performance compromises.We provide a detailed analysis of node-level kernel and runtime performance with the aim of sharing best practices with the HPC community on using SYCL as a performance-portable GPU framework.
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| 21. |
- Allander, Erik, et al.
(författare)
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Why is Prevention So Difficult and Slow?
- 1997
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Ingår i: Scandinavian Journal of Social Medicine. ; 25:3, s. 145-148
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The abundance of perceived 'possibilities' for prevention contrasts sharply with the difficulties that face preventive programmes. We argue that this situation has emerged from an incomplete understanding of the process of prevention, involving a mixture of biological factors, human decision making and time perspectives. Based on examples, an analysis of the factors in the prevention process is presented.
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| 22. |
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| 23. |
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| 24. |
- Andersson, Magnus, et al.
(författare)
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Transport Pathway in Cu+ P-Type ATPases
- 2014
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 106:2, s. 427A-427A
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 25. |
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| 26. |
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| 27. |
- Apostolov, Rossen, et al.
(författare)
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Scalable Software Services for Life Science
- 2011
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Ingår i: Proceedings of 9th HealthGrid conference.
-
Konferensbidrag (refereegranskat)abstract
- Life Science is developing into one of the largest e- Infrastructure users in Europe, in part due to the ever-growing amount of biological data. Modern drug design typically includes both sequence bioinformatics, in silico virtual screening, and free energy calculations, e.g. of drug binding. This development will accelerate tremendously, and puts high demands on simulation software and support services. e-Infrastructure projects such as PRACE/DEISA have made important advances on hardware and scalability, but have largely been focused on theoretical scalability for large systems, while typical life science applications rather concern small-to-medium size molecules. Here, we propose to address this with by implementing new techniques for efficient small-system parallelization combined with throughput and ensemble computing to enable the life science community to exploit the largest next-generation e-Infrastructures. We will also build a new cross-disciplinary Competence Network for all of life science, to position Europe as the world-leading community for development and maintenance of this software e-Infrastructure. Specifically, we will (1) develop new hierarchical parallelization approaches explicitly based on ensemble and high-throughput computing for new multi-core and streaming/GPU architectures, and establish open software standards for data storage and exchange, (2) implement, document, and maintain such techniques in pilot European open-source codes such as the widely used GROMACS & DALTON, a new application for ensemble simulation (DISCRETE), and large-scale bioinformatics protein annotation, (3) create a Competence Centre for scalable life science software to strengthen Europe as a major software provider and to enable the community to exploit e-Infrastructures to their full extent. This Competence Network will provide training and support infrastructure, and establish a long-term framework for maintenance and optimization of life science codes.
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| 28. |
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| 29. |
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| 30. |
- Beland Lindahl, Karin, et al.
(författare)
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Future forests: Perceptions and strategies of key actors
- 2012
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Ingår i: Scandinavian Journal of Forest Research. - : Informa UK Limited. - 0282-7581 .- 1651-1891. ; 27, s. 154-163
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract This paper investigates how key actors perceive the future of the forest sector: how they position themselves in relation to climate, energy and demography related trends. Actors’ perceptions of future challenges and opportunities influence their choice of strategy and action. Actors’ relative capacity to realise their visions, in turn, shape future forest use. Frame analysis is used to explore selected actor’s perceptions and strategies and the existence of major divisions, i.e. frame conflicts. Empirically, the study is based on the case of Sweden as a typical boreal forest producing region. Actors’ perceptions of the challenges facing the forest sector diverge widely. Yet, most actors see the future of the forest sector as linked to broader issues of climate mitigation and energy transition. These issues trigger fundamental discussions about social change and the role of forests in future society. A major division separates actors who perceive biomass supply as unlimited, or at least not constraining, and those who stress scarcity and re-distribution of resources. This difference, or frame conflict, is reflected in actors’ forest related strategies and may fuel future forest debates and conflicts
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| 31. |
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| 32. |
- Benrick, Anna, 1979, et al.
(författare)
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Interleukin-6 gene knockout influences energy balance regulating peptides in the hypothalamic paraventricular and supraoptic nuclei.
- 2009
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Ingår i: Journal of neuroendocrinology. - : Wiley. - 1365-2826 .- 0953-8194. ; 21:7, s. 620-8
-
Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-6 is a pro-inflammatory cytokine that also affects metabolic function because IL-6 depleted (IL-6(-/-)) mice develop late-onset obesity. IL-6 appears to act in the central nervous system, presumably in the hypothalamus, to increase energy expenditure that appears to involve stimulation of the sympathetic nervous system. In the present study, we explored possible central mechanisms for the effects exerted by IL-6 on body fat. Therefore, we measured the effects of IL-6 depletion in IL-6(-/-) mice on expression of key hypothalamic peptide genes involved in energy balance by the real time polymerase chain reaction. Additionally, co-localisation between such peptides and IL-6 receptor alpha was investigated by immunohistochemistry. IL-6 deficiency decreased the expression of several peptides found in the paraventricular nucleus (PVN), which is a nucleus that has been attributed an adipostatic function. For example, corticotrophin-releasing hormone (CRH), which is reported to stimulate the sympathetic nervous system, was decreased by 40% in older IL-6(-/-) mice. Oxytocin, which is reported to prevent obesity, was also decreased in older IL-6(-/-) animals, as was arginine vasopressin (AVP). The IL-6 receptor alpha was abundantly expressed in the PVN, but also in the supraoptic nucleus, and was shown to be co-expressed to a high extent with CRH, AVP, oxytocin and thyrotrophin-releasing hormone. These data indicate that depletion of endogenous IL-6, a body fat suppressing cytokine, is associated with the decreased expression of CRH and oxytocin (i.e. energy balance regulating peptides) as well as AVP in the PVN. Because IL-6 receptor alpha is co-expressed with CRH, oxytocin and AVP, IL-6 could stimulate the expression of these peptides directly.
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| 33. |
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| 34. |
- Bergh, Cathrine, et al.
(författare)
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Discovery of lipid binding sites in a ligand-gated ion channel by integrating simulations and cryo-EM
- 2024
-
Ingår i: eLife. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 12, s. 2023-01
-
Tidskriftsartikel (refereegranskat)abstract
- Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside fromcanonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ionchannels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution ofthese regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLICby integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipidsin the GLIC closed state, a conformation where none, to our knowledge, were previously known. Three lipidswere associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutantsimulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, whilea putative intersubunit site was preferred in open-state simulations. This work offers molecular details ofGLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependentbinding, and a multidisciplinary strategy for modeling protein-lipid interactions.
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| 35. |
- Bergh, Cathrine, et al.
(författare)
-
Discovery of lipid binding sites in a ligand-gated ion channel by integrating simulations and cryo-EM
- 2024
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside from canonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ion channels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution of these regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLIC by integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipids in the GLIC closed state, a conformation where none, to our knowledge, were previously known.Three lipids were associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutant simulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, while a putative intersubunit site was preferred in open-state simulations. This work offers molecular details of GLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependent binding, and a multidisciplinary strategy for modeling protein-lipid interactions.
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| 36. |
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| 37. |
- Bergh, Cathrine
(författare)
-
From Static Structures to Free Energy Landscapes: Characterizing Conformational Transitions in Biological Macromolecules
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To be alive means to temporarily counteract the fundamental dispersive driving force described by the second law of thermodynamics, eventually leading all systems to decay and disorder. In cells, this task is partly carried out by proteins - small specialized molecular machines that utilize free energy to maintain the proper functioning of the cell. Malfunction of a protein, often caused by genetic mutations, can lead to death and disease, underscoring the importance of understanding their function in order to develop new drugs and therapies. The function of a protein can in principle be fully described by its free energy landscape, a probability distribution that maps the relationship between protein structure and function through motion. However, constructing such free energy landscapes through experimental techniques alone is close to impossible. Some techniques can generate static snapshots of protein structures but do not yield direct information about the function, while other methods capture functional aspects but do not have the resolution to uncover the structural changes involved. Computer simulations in the form of molecular dynamics simulations can bridge this gap but are associated with limitations in the form of sampling relevant timescales and distilling high-dimensional data into a form that properly describes protein function. The aim of this thesis is to develop and apply methods that can overcome the sampling and analysis problems associated with molecular dynamics simulations, assess their predictive power through experimental validation, and explore how such models can be effectively combined with various experimental techniques, such as SANS, cryo-EM, and electrophysiology. Finally, these methods are applied to reveal multiple new structural and functional aspects of pentameric ligand-gated ion channels (pLGICs), which are of great importance to synaptic signal transmission between nerve cells. The work presented in this thesis can be characterized according to three different themes. First, I describe the development of a coarse-grained simulation method that generates an approximate pathway between two known states, and how this can be used to achieve better sampling in molecular dynamics simulation. Then, I investigate how enhanced sampling and Markov state modeling can be used to estimate free energy landscapes of pLGICs, and how such methods can work alongside and inform experimental methods to reveal many new aspects of pLGIC structure and function. Finally, I explore the use of Markov state modeling in the drug discovery field. This thesis thus contributes to computational method development and the understanding of pLGIC function - two different aspects with potential to contribute to the development of new drugs.
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| 38. |
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| 39. |
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| 40. |
- Bergh, Cathrine, et al.
(författare)
-
Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel
- 2021
-
Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.
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| 41. |
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| 42. |
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| 43. |
- Bergqvist, Matilda, et al.
(författare)
-
Dynamic and static quadriceps muscle endurance in people with COPD and healthy age and gender-matched controls
- 2019
-
Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 54:suppl 63
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: It is commonly known that quadriceps muscle endurance is decreased among people with COPD, however, whether static and dynamic quadriceps muscle endurance is affected to the same extent, remains to be determined. The latter of importance for the design of exercise modalities targeting quadriceps endurance in COPD.Methods: Static (isometric) and dynamic (isokinetic, isotonic) measurements of quadriceps muscle endurance was performed using a computerized dynamometer on 30 of individuals with COPD (FEV1 63% predicted) and 30 healthy age and gender-matched controls. Test order was randomized, separated by 30 min of rest. Comparisons between groups included both relative (seconds/repetitions) and absolute (total work [Nm]) measures of quadriceps endurance. Between-group results are presented as percentage difference (%) and effect sizes (ES).Results: When compared to healthy age and gender matched controls, people with COPD had significantly lower absolute measures of quadriceps endurance (isometric -32%, ES 0.66 [moderate]; isokinetic -29%, ES 0.94 [large], isotonic -38%, ES 0.89 [large], all p <0.05) as well as lower relative measures of dynamic quadriceps endurance (isotonic [repetitions] -20%, ES 0.50 [moderate], p = 0.02) while static quadriceps endurance did not differ between groups (isometric [seconds] -3%, ES 0.06 [trivial], p = 0.617).Conclusion: As evident by larger ES, dynamic quadriceps endurance seems to be reduced to a larger extent than static quadriceps endurance in people with COPD. Thus, exercise modalities that aim to improve quadriceps endurance should preferably be designed to increase dynamic quadriceps muscle enduranceFootnotesCite this article as: European Respiratory Journal 2019; 54: Suppl. 63, OA3814.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
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| 44. |
- Bergström, Petra, et al.
(författare)
-
Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by A beta 1-40/42, is associated with mature neuronal phenotypes.
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| 45. |
- Bernsel, Andreas, et al.
(författare)
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Prediction of membrane-protein topology from first principles
- 2008
-
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. ; 105:20, s. 7177-7181
-
Tidskriftsartikel (refereegranskat)abstract
- The current best membrane-protein topology-prediction methods are typically based on sequence statistics and contain hundreds of parameters that are optimized on known topologies of membrane proteins. However, because the insertion of transmembrane helices into the membrane is the outcome of molecular interactions among protein, lipids and water, it should be possible to predict topology by methods based directly on physical data, as proposed >20 years ago by Kyte and Doolittle. Here, we present two simple topology-prediction methods using a recently published experimental scale of position-specific amino acid contributions to the free energy of membrane insertion that perform on a par with the current best statistics-based topology predictors. This result suggests that prediction of membrane-protein topology and structure directly from first principles is an attainable goal, given the recently improved understanding of peptide recognition by the translocon.
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| 46. |
- Bertaccini, Edward, et al.
(författare)
-
A Model of Putative Anesthetic Binding Sites within the Glycine Alpha One Receptor Based on Two New Prokaryotic Ion Channel Templates in the Open State
- 2009
-
Konferensbidrag (refereegranskat)abstract
- INTRODUCTION: Ligand-gated ion channels (LGICs) are thought to mediate a significant proportion of anesthetic effects. We have used molecular modeling to build atomic level models of the glycine alpha one receptor (GlyRa1) to examine its interactions with anesthetics. We have previously built models of a GlyRa1 based on a prokaryotic pentameric ion channel in the closed state from Erwinia Chrysanthemi (ELIC) and demonstrated a possible intersubunit binding site for anesthetics.(1-3) Here, we further validate such a model in the similar construction of a GlyRa1 model based on the open state structures of two new ion channels from the prokaryote Gloebacter violaceus (GLIC).(4-5) These new open state templates have become extremely relevant since anesthetics are thought to bind to and stabilize the open state of the GlyRa1. METHODS: The amino acid sequences and 3D coordinates of the torpedofish nicotinic acetylcholine receptor alpha 1 subunit (nAChRa1 from 2BG9.pdb) and two forms of GLIC (3EHZ.pdb and 3EAM.pdb) were obtained from the RCSB database. The sequence of the human GlyRa1 was obtained from the NCBI database. An initial BLAST sequence search was performed at the NCBI using the GLIC sequences. Among the best scored homologous human sequences were those of the GlyRa1. The three known structures underwent structural alignment for optimum coordinate overlap within Discovery Studio 2.0.1 (Accelrys, San Diego, CA). The amino acid sequence of each structural subunit was then aligned with the sequence of the GlyRa1 using the Align123 algorithm (a derivative of ClustalW). The Modeler module was used for assignment of coordinates for aligned amino acids, the construction of possible loops, and the initial refinement of amino acid sidechains using the averaged coordinates of 3EAM and 3EHZ. Five GlyRa1 subunits were merged to form the final homomeric pentamer. RESULTS: The BLAST derived scores suggest a close homology between the LGICs, GLIC and ELIC. Subsequent CLUSTALW alignment of the GLIC and GlyRa1 sequences demonstrates reasonable sequence similarity. The model of the GlyRa1 is a homomer with pentameric symmetry about a central ion pore and shows significant transmembrane alpha helical and extracellular beta sheet content. Unlike our previous model based on the ELIC template, the current model based on the GLIC templates shows a continuously open pore with a partial restriction within the transmembrane region. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3) (ILE229, SER 267, ALA 288). They now line the intersubunit interface, in contrast to our previous models. However, residues from TM4 that are known to modulate a variety of anesthetic effects on this or homologous LGICs are present but could only indirectly influence an intersubunit anesthetic binding site. CONCLUSIONS: A reasonable model of the GlyRa1 was constructed using homology modeling based on the GLIC templates. This model posits an intersubunit site for anesthetic binding that may communicate with the intrasubunit region of each TMD. However, distinct questions remain regarding an explanation for the effects of TM4 mutations on anesthetic modulation of these channels. 1. Trudell JR, Bertaccini E: Comparative modeling of a GABAA alpha1 receptor using three crystal structures as templates. J Mol Graph Model 2004; 23: 39-49 2. Bertaccini EJ, Shapiro J, Brutlag DL, Trudell JR: Homology modeling of a human glycine alpha 1 receptor reveals a plausible anesthetic binding site. J Chem Inf Model 2005; 45: 128-35 3. Bertaccini E, Trudell JR: Putative Anesthetic Binding Sites within a GlyR alpha 1 Receptor Model Based on a Prokaryotic Template. Anesthesiology 2008: A644 4. Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP, Delarue M, Corringer PJ: X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 2009; 457: 111-4 5. Hilf RJ, Dutzler R: Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 2009; 457: 115-8
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| 47. |
- Bertaccini, Edward J., et al.
(författare)
-
Anesthetic Binding Sites in a GlyRa1 Model Based on Open State Prokaryotic Ion Channel Templates
- 2009
-
Ingår i: Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists.
-
Konferensbidrag (refereegranskat)abstract
- Introduction : Ligand-gated ion channels (LGICs) are thought to mediate a significant proportion of anesthetic effects. We built atomic level models of the glycine alpha one receptor (GlyRa1) to examine its interactions with anesthetics. We previously built models of a GlyRa1 based on a prokaryotic pentameric ion channel in the closed state from Erwinia Chrysanthemi (ELIC) (1-3). Here, we built a GlyRa1 model based on the open state structures of two new ion channels from the prokaryote Gloebacter violaceus (GLIC).(4-5) These new templates are relevant since anesthetics are thought to bind to and stabilize the open state of the GlyRa1. Methods : The 3D coordinates of two forms of GLIC (3EHZ.pdb and 3EAM.pdb) were obtained from the RCSB database. The sequence of the human GlyRa1 was obtained from the NCBI database. A BLAST sequence search was performed using the GLIC sequences. Among the best scored homologous human sequences were those of the GlyRa1. The template structures and the sequence of GlyRa1 were aligned with Discovery Studio 2.0.1 (Accelrys, San Diego, CA) and the Modeler module was used for assignment of coordinates for aligned amino acids, the construction of possible loops, and the initial refinement of amino acid sidechains. Results : The BLAST derived scores suggest a close homology between the LGICs, GLIC and ELIC. Subsequent CLUSTALW alignment of the GLIC and GlyRa1 sequences demonstrates reasonable sequence similarity. The model of the GlyRa1 is a homomer with pentameric symmetry about a central ion pore and shows significant transmembrane alpha helical and extracellular beta sheet content. Unlike our previous model based on the ELIC template, the current model based on the GLIC templates shows a continuously open pore with a partial restriction within the transmembrane region. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3) (ILE229, SER 267, ALA 288). They now line the intersubunit interface, in contrast to our previous models. However, residues from TM4 that are known to modulate a variety of anesthetic effects on this or homologous LGICs are present but could only indirectly influence an intersubunit anesthetic binding site. Normal mode analyses show an iris-like motion similar to previous results.Conclusions : A model of the GlyRa1 was constructed using homology modeling based on the GLIC templates. This model posits an intersubunit site for anesthetic binding that may communicate with the intrasubunit region of each TMD.
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| 48. |
- Bertaccini, E. J., et al.
(författare)
-
Assessment of homology templates and an anesthetic binding site within the ?-aminobutyric acid receptor
- 2013
-
Ingår i: Anesthesiology. - 0003-3022 .- 1528-1175. ; 119:5, s. 1087-1095
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Anesthetics mediate portions of their activity via modulation of the ?-aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling. Methods: The structure of the torpedo acetylcholine receptor (nAChR?), the structures of the ?4 and ?2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50s. Results: Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between ? and ? subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50. Conclusion: Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.
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| 49. |
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| 50. |
- Bertaccini, Edward J, et al.
(författare)
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Modeling Anesthetic Binding Sites within the Glycine Alpha One Receptor Based on Prokaryotic Ion Channel Templates : The Problem with TM4
- 2010
-
Ingår i: Journal of chemical information and modeling. - : American Chemical Society (ACS). - 1549-960X .- 1549-9596. ; 50:12, s. 2248-2255
-
Tidskriftsartikel (refereegranskat)abstract
- Ligand-gated ion channels (LGICs) significantly modulate anesthetic effects. Their exact molecular structure remains unknown. This has led to ambiguity regarding the proper amino acid alignment within their 3D structure and, in turn, the location of any anesthetic binding sites. Current controversies suggest that such a site could be located in either an intra- or intersubunit locale within the transmembrane domain of the protein. Here, we built a model of the glycine alpha one receptor (GlyRa1) based on the open-state structures of two new high-resolution ion channel templates from the prokaryote, Gloebacter violaceus (GLIC). Sequence scoring suggests reasonable homology between GlyRa1 and GLIC. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3): (ILE229, SER 267, and ALA 288). They line an intersubunit interface, in contrast to previous models. However, residues from the fourth transmembrane domain (TM4) that are known to modulate a variety of anesthetic effects are quite distant from this putative anesthetic binding site. While this model can account for a large proportion of the physicochemical data regarding such proteins, it cannot readily account for the alterations on anesthetic effects that are due to mutations within TM4.
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