The PfEMP1 family of surface proteins is central for Plasmodium falciparum virulence and must retain the ability to bind to host receptors while also diversifying to aid immune evasion. The ...interaction between CIDRα1 domains of PfEMP1 and endothelial protein C receptor (EPCR) is associated with severe childhood malaria. We combine crystal structures of CIDRα1:EPCR complexes with analysis of 885 CIDRα1 sequences, showing that the EPCR-binding surfaces of CIDRα1 domains are conserved in shape and bonding potential, despite dramatic sequence diversity. Additionally, these domains mimic features of the natural EPCR ligand and can block this ligand interaction. Using peptides corresponding to the EPCR-binding region, antibodies can be purified from individuals in malaria-endemic regions that block EPCR binding of diverse CIDRα1 variants. This highlights the extent to which such a surface protein family can diversify while maintaining ligand-binding capacity and identifies features that should be mimicked in immunogens to prevent EPCR binding.
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•EPCR binding is retained by PfEMP1 CIDRα1 domains despite huge sequence variation•Diverse CIDRα1 domains retain structural and chemical features to bind to EPCR•CIDRα1 domains mimic features of a natural ligand of EPCR and block its binding•Patient sera contain neutralizing antibodies that prevent parasite binding to EPCR
PfEMP1 proteins of Plasmodium must retain binding to host receptor EPCR while diversifying for immune evasion. Using structural studies, Lau et al. show that EPCR-binding surfaces of PfEMP1 are conserved in shape and bonding potential, despite sequence diversity, and identify features that should be mimicked in immunogens preventing EPCR binding.
Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one ...million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.
A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite ...targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio aHR:0.63; 95% CI:0.45-0.89; p = 0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p = 0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p = 0.022) epitope types. The association of symptomatic malaria with reduced hazard of homologous reinfection was strongest for rare epitope types. Symptomatic malaria provides more durable protection against reinfection with parasites bearing homologous epitope types. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.
Im unüberschaubaren Schrifttum zu Machiavelli fehlt es erstaunlicherweise an einer Darstellung seiner Gesetzgebungslehre, die nicht nur seinen berühmten 'Fürsten', sondern vor allem sein Hauptwerk, ...die Discorsi, aber auch seine Geschichte von Florenz und die kleineren Schriften berücksichtigt. Das vorliegende Buch füllt diese Lücke und wendet die gewonnenen Einsichten auf die zeitgenössische Gesetzgebung an.
Sickle-trait hemoglobin protects against severe Plasmodium falciparum malaria. Severe malaria is governed in part by the expression of the Plasmodium falciparum Erythrocyte Membrane Protein 1 ...(PfEMP1) that are encoded by var genes, specifically those variants that bind Endothelial Protein C Receptor (EPCR). In this study, we investigate the effect of sickle-trait on parasite var gene expression and function in vitro and in field-collected parasites. We mapped var gene reads generated from RNA sequencing in parasite cultures in normal and sickle-cell trait blood throughout the asexual lifecycle. We investigated sickle-trait effect on PfEMP1 interactions with host receptors CD36 and EPCR using static adhesion assays and flow cytometry. Var expression in vivo was compared by assembling var domains sequenced from total RNA in parasites infecting Malian children with HbAA and HbAS. Sickle-trait did not alter the abundance or type of var gene transcripts in vitro, nor the abundance of overall transcripts or of var functional domains in vivo. In adhesion assays using recombinant host receptors, sickle-trait reduced adhesion by 73-86% to CD36 and 83% to EPCR. Similarly, sickle-trait reduced the surface expression of EPCR-binding PfEMP1. In conclusion, Sickle-cell trait does not directly affect var gene transcription but does reduce the surface expression and function of PfEMP1. This provides a direct mechanism for protection against severe malaria conferred by sickle-trait hemoglobin.
Biomedical imaging is a driver of scientific discovery and a core component of medical care and is being stimulated by the field of deep learning. While semantic segmentation algorithms enable image ...analysis and quantification in many applications, the design of respective specialized solutions is non-trivial and highly dependent on dataset properties and hardware conditions. We developed nnU-Net, a deep learning-based segmentation method that automatically configures itself, including preprocessing, network architecture, training and post-processing for any new task. The key design choices in this process are modeled as a set of fixed parameters, interdependent rules and empirical decisions. Without manual intervention, nnU-Net surpasses most existing approaches, including highly specialized solutions on 23 public datasets used in international biomedical segmentation competitions. We make nnU-Net publicly available as an out-of-the-box tool, rendering state-of-the-art segmentation accessible to a broad audience by requiring neither expert knowledge nor computing resources beyond standard network training.
•The study assesses municipal energy strategies in Denmark on their inclusion of local communities in strategy production.•A relational definition of energy communities is proposed as an analytical ...framework including multiple governance levels and sectoral domains.•Inadequate internal organization, lacking capacity in municipalities, and the complexity of communities led to procedural deficits.•The procedural deficits in strategy production were identified as main reasons that challenged the implementation of energy targets.•Based on the findings a community-oriented taxonomy of implementation challenges is introduced to ensure an early local anchoring of energy strategies in communities.
The implementation of national renewable energy targets requires policies at the local level. Communities are considered as key arenas of transforming policies into actions, where technical configurations intersect with socioeconomic interests. Local governments put great efforts into developing and applying energy strategies. Although many frontrunner projects are well-documented, insufficient attention is paid to the average-performing municipalities that are challenged in linking technical energy scenarios with socioeconomic realities. The following implementation gap between national policy and local practice leads to a non-attainment of national energy targets. This paper analyses the Strategic Energy Plans (SEP) of 17 Danish municipalities based on their development, scope, and inclusion of local communities. As a synopsis, the main technical, physical, organizational and socioeconomic challenges for local energy policy implementation were illustrated. Internal organization, lacking municipal capacities, combined with the complexity of communities leads to procedural deficits in strategy production. The resulting neglect of socioeconomics and other community peculiarities by technology-driven strategies impede strategy implementation. As a consequence, a community-oriented taxonomy of implementation challenges is introduced. This approach might help to improve the scope of SEPs, ensure a local anchoring of energy strategies, and raise awareness for challenges already present during strategy production to facilitate strategy implementation.
Background
Cutaneous nerve blockade may improve analgesia after hip surgery. Anaesthesia after the lateral femoral cutaneous (LFC) nerve block is too distal for complete coverage of most hip surgery ...incisions, which requires additional anaesthesia of the adjacent, proximal area. The transversalis fascia plane (TFP) block potentially anaesthetises the iliohypogastric and subcostal nerves. The primary aim of the present study was to investigate, if the TFP block provides cutaneous anaesthesia adjacent to the LFC nerve block.
Methods
Active vs placebo TFP blocks were compared in a paired randomised controlled trial (RCT) in 20 volunteers, who all had bilateral LFC nerve blocks. The day preceding the RCT, the area anaesthetised by a novel selective ultrasound guided subcostal nerve block was identified bilaterally in order to assess the contribution of the subcostal nerve to the area anaesthesia by the TFP block.
Results
Anaesthesia of the lateral hip region after TFP block was 80%. The cutaneous anaesthesia after active TFP block was in continuity with the LFC nerve block in 65%. Combined TFP and LFC nerve blockade significantly increased the coverage of hip surgery incisions compared to LFC nerve block alone. The success rate of blocking the subcostal nerve was 50% with the TFP block.
Conclusion
The TFP block anaesthetises the skin proximal to the LFC nerve block by anaesthetising the iliohypogastric and subcostal nerves. TFP block as a supplement to LFC nerve block improves the coverage of the proximal surgical incisions used for hip surgery.
The aim of this open access book is to review and analyse the goods and services of bivalve shellfish. How they are defined, what determines the ecological functions that are the basis for the goods ...and services, what controversies in the use of goods and services exist, and what is needed for sustainable exploitation of bivalves from the perspective of the various stakeholders. The book is focused on the goods and services, and not on impacts of shellfish aquaculture on the benthic environment, or on threats like biotoxins; neither is it a shellfish culture handbook although it can be used in evaluating shellfish culture. The reviews and analysis are based on case studies that exemplify the concept, and show the strengths and weaknesses of the current applications. The multi-authored reviews cover ecological, economic and social aspects of bivalve goods and services. The book provides new insights for scientists, students, shellfish producers, policy advisors, nature conservationists and decision makers. This book is open access under the CC BY license.
Indem Montaigne die Jurisprudenz von Grund auf anzweifelte, hat er ihr zugleich die Grundlagen des Rechts in einer spezifisch neuzeitlichen Weise erschlossen. Obwohl er nichts weniger suchte, ...entdeckte Montaigne beiläufig die Grundlagen des Rechts in ihrer Gesamtheit.
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