24 research outputs found

    Mapping the interaction of VWF and factor XIIa and its potential as a new anticoagulant target

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    Von Willebrand Factor and Factor XII have well established roles in haemostasis and coagulation. While VWF is a mediator of platelet capture to sites of vascular injury under high shear stress, FXII initiates the intrinsic pathway of coagulation. Interestingly, multiple studies have shown that absence or inhibition of FXII does not impair haemostatic function but has a thrombo-protective effect, rendering it a potentially safe anticoagulant target. In this study, I investigated a novel binding interaction between VWF and FXII. Using substrate based activation assays, I showed that VWF is a potent and previously unrecognised activator of FXII. Additionally, I demonstrated that both inactive FXII and activated FXII bind to VWF but not to VWF lacking the A1 domain suggesting that the FXII binding site lies within the A1 domain. By carrying out further binding studies using static binding assays and surface plasmon resonance with isolated and full-length VWF A1 domain mutants, I identified amino acids E1452 and D1459 on the α-6 helix of the A1 domain as the FXII binding site in VWF. The physiological relevance of the VWF/FXII interaction was examined using plate-based thrombolysis as well as perfusion assays investigating the formation of platelet rich blood clots under conditions of flow. Using adapted thrombolysis assays, I showed that clot lysis times were significantly reduced when either VWF, FXIIa or activity of both proteins was blocked. Furthermore, I demonstrated that the interaction between VWF and FXIIa facilitates VWF mediated platelet capture under conditions of high shear and that interference with FXII/VWF binding has a prohibitive effect on overall thrombus formation. Based on these results, I hypothesise binding of VWF to FXII is an important component of thrombus formation and inhibition of this interaction might be a novel and safe way to prevent thrombosis without increasing the risk of bleeding side effects.Open Acces

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

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    CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors

    1200 years of decadal-scale variability of Mediterranean vegetation and climate at Pantelleria Island, Italy

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    A new sedimentary sequence from Lago di Venere on Pantelleria Island, located in the Strait of Sicily between Tunisia and Sicily was recovered. The lake is located in the coastal infra-Mediterranean vegetation belt at 2 m a.s.l. Pollen, charcoal and sedimentological analyses are used to explore linkages among vegetation, fire and climate at a decadal scale over the past 1200 years. A dry period from ad 800 to 1000 that corresponds to the ‘Medieval Warm Period’ (WMP) is inferred from sedimentological analysis. The high content of carbonate recorded in this period suggests a dry phase, when the ratio of evaporation/precipitation was high. During this period the island was dominated by thermophilous and drought-tolerant taxa, such as Quercus ilex, Olea, Pistacia and Juniperus. A marked shift in the sediment properties is recorded at ad 1000, when carbonate content became very low suggesting wetter conditions until ad 1850–1900. Broadly, this period coincides with the ‘Little Ice Age’ (LIA), which was characterized by wetter and colder conditions in Europe. During this time rather mesic conifers (i.e. Pinus pinaster), shrubs and herbs (e.g. Erica arborea and Selaginella denticulata) expanded, whereas more drought-adapted species (e.g. Q. ilex) declined. Charcoal data suggest enhanced fire activity during the LIA probably as a consequence of anthropogenic burning and/or more flammable fuel (e.g. resinous Pinus biomass). The last century was characterized by a shift to high carbonate content, indicating a change towards drier conditions, and re-expansion of Q. ilex and Olea. The post-LIA warming is in agreement with historical documents and meteorological time series. Vegetation dynamics were co-determined by agricultural activities on the island. Anthropogenic indicators (e.g. Cerealia-type, Sporormiella) reveal the importance of crops and grazing on the island. Our pollen data suggest that extensive logging caused the local extinction of deciduous Quercus pubescens around ad1750

    Pan-Arctic methanesulfonic acid aerosol: source regions, atmospheric drivers, and future projections

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    Natural aerosols are an important, yet understudied, part of the Arctic climate system. Natural marine biogenic aerosol components (e.g., methanesulfonic acid, MSA) are becoming increasingly important due to changing environmental conditions. In this study, we combine in situ aerosol observations with atmospheric transport modeling and meteorological reanalysis data in a data-driven framework with the aim to (1) identify the seasonal cycles and source regions of MSA, (2) elucidate the relationships between MSA and atmospheric variables, and (3) project the response of MSA based on trends extrapolated from reanalysis variables and determine which variables are contributing to these projected changes. We have identified the main source areas of MSA to be the Atlantic and Pacific sectors of the Arctic. Using gradient-boosted trees, we were able to explain 84% of the variance and find that the most important variables for MSA are indirectly related to either the gas- or aqueous-phase oxidation of dimethyl sulfide (DMS): shortwave and longwave downwelling radiation, temperature, and low cloud cover. We project MSA to undergo a seasonal shift, with non-monotonic decreases in April/May and increases in June-September, over the next 50 years. Different variables in different months are driving these changes, highlighting the complexity of influences on this natural aerosol component. Although the response of MSA due to changing oceanic variables (sea surface temperature, DMS emissions, and sea ice) and precipitation remains to be seen, here we are able to show that MSA will likely undergo a seasonal shift solely due to changes in atmospheric variables.</p
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