| 1. |
- Bentzer, Peter, et al.
(författare)
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Heparin-binding protein is important for vascular leak in sepsis
- 2016
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBP-induced increases in permeability.METHODS: Association between HBP at admission with clinical signs of increased permeability was investigated in 341 patients with septic shock. Mechanisms of action and potential treatment strategies were investigated in cultured human endothelial cells and in mice.RESULTS: Following adjustment for comorbidities and Acute Physiology and Chronic Health Evaluation (APACHE) II, plasma HBP concentrations were weakly associated with fluid overload during the first 4 days of septic shock and the degree of hypoxemia (PaO2/FiO2) as measures of increased systemic and lung permeability, respectively. In mice, intravenous injection of recombinant human HBP induced a lung injury similar to that observed after lipopolysaccharide injection. HBP increased permeability of vascular endothelial cell monolayers in vitro, and enzymatic removal of luminal cell surface glycosaminoglycans (GAGs) using heparinase III and chondroitinase ABC abolished this effect. Similarly, unfractionated heparins and low molecular weight heparins counteracted permeability increased by HBP in vitro. Intracellular, selective inhibition of protein kinase C (PKC) and Rho-kinase pathways reversed HBP-mediated permeability effects.CONCLUSIONS: HBP is a potential mediator of sepsis-induced acute lung injury through enhanced endothelial permeability. HBP increases permeability through an interaction with luminal GAGs and activation of the PKC and Rho-kinase pathways. Heparins are potential inhibitors of HBP-induced increases in permeability.
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| 2. |
- Fisher, Jane, et al.
(författare)
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Is heparin-binding protein inhibition a mechanism of albumin's efficacy in human septic shock?
- 2018
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Ingår i: Critical Care Medicine. - 0090-3493. ; 46:5, s. 364-374
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Our objectives were to determine first whether albumin prevents heparin-binding protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma heparin-binding protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. Design: In vitro human endothelial and renal cell model and observation cohort of septic shock. Settings: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Patients: Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). Interventions: In vitro: heparin-binding protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Measurements and Main Results: Transendothelial electrical resistance - a marker of permeability - of human endothelial cells was measured using a voltohmmeter. We measured plasma heparin-binding protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an heparin-binding protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited heparin-binding protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher heparin-binding protein-to-albumin ratio (1.6 vs 0.89; p < 0.001) and heparin-binding protein (38.2 vs 20.8 ng/mL; p < 0.001) than patients without acute kidney injury. The highest heparin-binding protein-to-albumin ratio (> 3.05), heparin-binding protein quartiles (> 69.8), and heparin-binding protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-binding protein and heparin-binding protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of heparin-binding protein-to-albumin ratio and heparin-binding protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Conclusions: Albumin inhibits heparin-binding protein-induced increased human endothelial cell permeability and heparin-binding protein greater than 30 ng/mL and heparin-binding protein-to-albumin ratio greater than 3.01 - but not serum albumin - identified patients at increased risk for acute kidney injury in septic shock.
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| 3. |
- Huhn, Evelyn Annegret, et al.
(författare)
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Effectiveness of real-time continuous glucose monitoring to improve glycaemic control and pregnancy outcome in patients with gestational diabetes mellitus : a study protocol for a randomised controlled trial
- 2020
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Real-time continuous glucose monitoring (rt-CGM) informs users about current interstitial glucose levels and allows early detection of glycaemic excursions and timely adaptation by behavioural change or pharmacological intervention. Randomised controlled studies adequately powered to evaluate the impact of long-term application of rt-CGM systems on the reduction of adverse obstetric outcomes in women with gestational diabetes (GDM) are missing. We aim to assess differences in the proportion of large for gestational age newborns in women using rt-CGM as compared with women with self-monitored blood glucose (primary outcome). Rates of neonatal hypoglycaemia, caesarean section and shoulder dystocia are secondary outcomes. A comparison of glucose metabolism and quality of life during and after pregnancy completes the scope of this study.METHODS AND ANALYSIS: Open-label multicentre randomised controlled trial with two parallel groups including 372 female patients with a recent diagnosis of GDM (between 24+0 until 31+6 weeks of gestation): 186 with rt-CGM (Dexcom G6) and 186 with self-monitored blood glucose (SMBG). Women with GDM will be consecutively recruited and randomised to rt-CGM or control (SMBG) group after a run-in period of 6-8 days. The third visit will be scheduled 8-10 days later and then every 2 weeks. At every visit, glucose measurements will be evaluated and all patients will be treated according to the standard care. The control group will receive a blinded CGM for 10 days between the second and third visit and between week 36+0 and 38+6. Cord blood will be sampled immediately after delivery. 48 hours after delivery neonatal biometry and maternal glycosylated haemoglobin A1c (HbA1c) will be assessed, and between weeks 8 and 16 after delivery all patients receive a re-examination of glucose metabolism including blinded CGM for 8-10 days.ETHICS AND DISSEMINATION: This study received ethical approval from the main ethic committee in Vienna. Data will be presented at international conferences and published in peer-reviewed journals.TRIAL REGISTRATION NUMBER: NCT03981328; Pre-results.
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| 4. |
- Kollmer, Marius, et al.
(författare)
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Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits
- 2016
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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. ; 113:20, s. 5604-5609
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Tidskriftsartikel (refereegranskat)abstract
- Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.
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| 5. |
- Lill, Christina M., et al.
(författare)
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The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:12, s. 1407-1416
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Tidskriftsartikel (refereegranskat)abstract
- A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Ab42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 x 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Ab42 suggesting that TREM2's role in AD may involve tau dysfunction. (C) 2015 The Alzheimer's Association.
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| 6. |
- Luize, Bruno Garcia, et al.
(författare)
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Geography and ecology shape the phylogenetic composition of Amazonian tree communities
- 2024
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Ingår i: JOURNAL OF BIOGEOGRAPHY. - 0305-0270 .- 1365-2699. ; 51:7, s. 1163-1184
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Amazonia hosts more tree species from numerous evolutionary lineages, both young and ancient, than any other biogeographic region. Previous studies have shown that tree lineages colonized multiple edaphic environments and dispersed widely across Amazonia, leading to a hypothesis, which we test, that lineages should not be strongly associated with either geographic regions or edaphic forest types. Location: Amazonia. Taxon: Angiosperms (Magnoliids; Monocots; Eudicots). Methods: Data for the abundance of 5082 tree species in 1989 plots were combined with a mega-phylogeny. We applied evolutionary ordination to assess how phylogenetic composition varies across Amazonia. We used variation partitioning and Moran's eigenvector maps (MEM) to test and quantify the separate and joint contributions of spatial and environmental variables to explain the phylogenetic composition of plots. We tested the indicator value of lineages for geographic regions and edaphic forest types and mapped associations onto the phylogeny. Results: In the terra firme and v & aacute;rzea forest types, the phylogenetic composition varies by geographic region, but the igap & oacute; and white-sand forest types retain a unique evolutionary signature regardless of region. Overall, we find that soil chemistry, climate and topography explain 24% of the variation in phylogenetic composition, with 79% of that variation being spatially structured (R-2 = 19% overall for combined spatial/environmental effects). The phylogenetic composition also shows substantial spatial patterns not related to the environmental variables we quantified (R-2 = 28%). A greater number of lineages were significant indicators of geographic regions than forest types. Main Conclusion: Numerous tree lineages, including some ancient ones (>66 Ma), show strong associations with geographic regions and edaphic forest types of Amazonia. This shows that specialization in specific edaphic environments has played a long-standing role in the evolutionary assembly of Amazonian forests. Furthermore, many lineages, even those that have dispersed across Amazonia, dominate within a specific region, likely because of phylogenetically conserved niches for environmental conditions that are prevalent within regions.
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| 7. |
- Selvaraju, Karthik, et al.
(författare)
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Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System
- 2021
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.
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| 8. |
- Snäll, Johanna, et al.
(författare)
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Differential neutrophil responses to bacterial stimuli: Streptococcal strains are potent inducers of heparin-binding protein and resistin-release.
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are critical for the control of bacterial infections, but they may also contribute to disease pathology. Here we explore neutrophil responses, in particular the release of sepsis-associated factors heparin-binding protein (HBP) and resistin in relation to specific bacterial stimuli and sepsis of varying aetiology. Analyses of HBP and resistin in plasma of septic patients revealed elevated levels as compared to non-infected critically ill patients. HBP and resistin correlated significantly in septic patients, with the strongest association seen in group A streptococcal (GAS) cases. In vitro stimulation of human neutrophils revealed that fixed streptococcal strains induced significantly higher release of HBP and resistin, as compared to Staphylococcus aureus or Escherichia coli. Similarly, neutrophils stimulated with the streptococcal M1-protein showed a significant increase in co-localization of HBP and resistin positive granules as well as exocytosis of these factors, as compared to LPS. Using a GAS strain deficient in M1-protein expression had negligible effect on neutrophil activation, while a strain deficient in the stand-alone regulator MsmR was significantly less stimulatory as compared to its wild type strain. Taken together, the findings suggest that the streptococcal activation of neutrophils is multifactorial and involves, but is not limited to, proteins encoded by the FCT-locus.
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| 9. |
- Sohn, Robert A., et al.
(författare)
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Explosive volcanism on the ultraslow-spreading Gakkel ridge, Arctic Ocean
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 453:7199, s. 1236-1238
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Tidskriftsartikel (refereegranskat)abstract
- Roughly 60% of the Earth's outer surface is composed of oceanic crust formed by volcanic processes at mid-ocean ridges. Although only a small fraction of this vast volcanic terrain has been visually surveyed or sampled, the available evidence suggests that explosive eruptions are rare on mid-ocean ridges, particularly at depths below the critical point for seawater (3,000 m)1. A pyroclastic deposit has never been observed on the sea floor below 3,000 m, presumably because the volatile content of mid-ocean-ridge basalts is generally too low to produce the gas fractions required for fragmenting a magma at such high hydrostatic pressure. We employed new deep submergence technologies during an International Polar Year expedition to the Gakkel ridge in the Arctic Basin at 85° E, to acquire photographic and video images of 'zero-age' volcanic terrain on this remote, ice-covered ridge. Here we present images revealing that the axial valley at 4,000 m water depth is blanketed with unconsolidated pyroclastic deposits, including bubble wall fragments (limu o Pele)2, covering a large (>10 km2) area. At least 13.5 wt% CO2 is necessary to fragment magma at these depths3, which is about tenfold the highest values previously measured in a mid-ocean-ridge basalt4. These observations raise important questions about the accumulation and discharge of magmatic volatiles at ultraslow spreading rates on the Gakkel ridge5 and demonstrate that large-scale pyroclastic activity is possible along even the deepest portions of the global mid-ocean ridge volcanic system.
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| 10. |
- ter Steege, Hans, et al.
(författare)
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Mapping density, diversity and species-richness of the Amazon tree flora
- 2023
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Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Using 2.046 botanically-inventoried tree plots across the largest tropical forest on Earth, we mapped tree species-diversity and tree species-richness at 0.1-degree resolution, and investigated drivers for diversity and richness. Using only location, stratified by forest type, as predictor, our spatial model, to the best of our knowledge, provides the most accurate map of tree diversity in Amazonia to date, explaining approximately 70% of the tree diversity and species-richness. Large soil-forest combinations determine a significant percentage of the variation in tree species-richness and tree alpha-diversity in Amazonian forest-plots. We suggest that the size and fragmentation of these systems drive their large-scale diversity patterns and hence local diversity. A model not using location but cumulative water deficit, tree density, and temperature seasonality explains 47% of the tree species-richness in the terra-firme forest in Amazonia. Over large areas across Amazonia, residuals of this relationship are small and poorly spatially structured, suggesting that much of the residual variation may be local. The Guyana Shield area has consistently negative residuals, showing that this area has lower tree species-richness than expected by our models. We provide extensive plot meta-data, including tree density, tree alpha-diversity and tree species-richness results and gridded maps at 0.1-degree resolution. A study mapping the tree species richness in Amazonian forests shows that soil type exerts a strong effect on species richness, probably caused by the areas of these forest types. Cumulative water deficit, tree density and temperature seasonality affect species richness at a regional scale.
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