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| 2. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 3. |
- Abdelhady, Wael Awad
(författare)
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Glypican-1: Structural and functional analysis of the N-glycosylated human protein
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glypicans are multifunctional cell surface heparan sulphate proteoglycans co-regulating numerous signalling pathways, and are thereby involved in the control of cellular division, differentiation, and morphogenesis. The heparan sulphate (HS) chains are responsible for many of those biological functions; nevertheless recent studies suggest functional roles for the glypican core proteins in mediating the signalling of various growth factors. Glypican-1 (GPC1) is the predominant HS proteoglycan in the developing and adult human brain. In addition, GPC1 is involved in Alzheimer’s disease and scrapie, among others. There is a shortage of detailed structural knowledge regarding the GPC1 core protein and accordingly, we proposed in this thesis to structurally and functionally characterize the human GPC1 core protein and to elucidate its overall topology with respect to the membrane. First, we determined the crystal structure of the human N-glycosylated GPC1 core protein by the two-wavelength MAD method on a SeMet-substituted protein crystal. The GPC1 structure revealed a quite rigid, cylindrical single-domain all α-helical fold with three substantial loops. Shortly afterwards, we achieved improvements of GPC1 crystal diffraction properties by controlled crystal dehydration using a humidity control device (HC1b) and generated better electron density for crystals of GPC1, allowing the building of previously disordered parts of the structure. Using small angle X-ray scattering and other biophysical approaches, we found that the GPC1 core protein lies on the membrane in a transverse orientation, directing a surface evolutionarily conserved in GPC1 orthologues towards the membrane, where it can interact with enzymes involved in HS substitution in the Golgi apparatus. Furthermore, the N-linked glycans are shown to extend the protein stability and lifetime by protection against proteolysis and aggregation. The EXTL3 protein, a member of the exostosin family, functions mainly as an initiator for HS assembly on the glypicans. We have investigated the spectroscopic and structural characteristics of the catalytic region of EXTL3, which exhibits a quite stable extended monomeric structure with two functional domains containing a majority of β sheets. Additionally, it was found that catalytic EXTL3 is occupied with N-glycans at least at two sites and these N-glycans seem critical for proper EXTL3 biosynthesis. To precisely determine how the GPC1 core protein regulates HS assembly through interactions with EXTL3, investigations of the GPC1-EXTL3 complexes are ongoing, and some preliminary results are presented here.
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| 4. |
- Abdelhady, Wael Awad, et al.
(författare)
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GPC1 (glypican 1)
- 2014
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Ingår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - : INIST-CNRS. - 1768-3262. ; 18:7, s. 461-464
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Tidskriftsartikel (refereegranskat)abstract
- Review on GPC1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.
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| 5. |
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| 6. |
- Danielsson, Jens, et al.
(författare)
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Global structural motions from the strain of a single hydrogen bond
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:10, s. 3829-3834
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Tidskriftsartikel (refereegranskat)abstract
- The origin and biological role of dynamic motions of folded enzymes is not yet fully understood. In this study, we examine the molecular determinants for the dynamic motions within the beta-barrel of superoxide dismutase 1 (SOD1), which previously were implicated in allosteric regulation of protein maturation and also pathological misfolding in the neurodegenerative disease amyotrophic lateral sclerosis. Relaxation-dispersion NMR, hydrogen/deuterium exchange, and crystallographic data show that the dynamic motions are induced by the buried H43 side chain, which connects the backbones of the Cu ligand H120 and T39 by a hydrogen-bond linkage through the hydrophobic core. The functional role of this highly conserved H120-H43-T39 linkage is to strain H120 into the correct geometry for Cu binding. Upon elimination of the strain by mutation H43F, the apo protein relaxes through hydrogen-bond swapping into a more stable structure and the dynamic motions freeze out completely. At the same time, the holo protein becomes energetically penalized because the twisting back of H120 into Cu-bound geometry leads to burial of an unmatched backbone carbonyl group. The question then is whether this coupling between metal binding and global structural motions in the SOD1 molecule is an adverse side effect of evolving viable Cu coordination or plays a key role in allosteric regulation of biological function, or both?
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| 7. |
- Drake, TM, et al.
(författare)
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Surgical site infection after gastrointestinal surgery in children: an international, multicentre, prospective cohort study
- 2020
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Ingår i: BMJ global health. - : BMJ. - 2059-7908. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings.MethodsA multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI).ResultsOf 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI.ConclusionThe odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.
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