The implication of glycans on the ACE2: SARS-CoV-2 spike interaction

Since its emergence in 2019 the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continues to a profoundly impact and threaten human health. For the development of novel prophylactic and therapeutic measures a detailed understanding of the virus-host interaction and features that modulate the interaction is of utmost importance. Attachment of the SARS-CoV-2 virus to human host cells predominantly relies on the specific interaction of the viral spike (S) surface glycoprotein with the receptor angiotensin-converting enzyme 2 (ACE-2). Glycans within or surrounding the binding interface have been demonstrated to play an important role in the ACE2:S interaction. The quality of this interaction is multifaceted and affected by several parameters, such as the speed, the number, the strength and duration of bond formation. As mutations within the coding sequences of the interaction partners may affect their binding capacity, they should be thoroughly studied. In this respect, viral evolution and the effect of mutations within the S-protein have received much attention, while human ACE2 polymorphisms naturally occurring throughout the population have so far been largely ignored. Of note, natural ACE2 polymorphisms and viral spike mutants that result in the loss of glycans within the binding interface should receive our particular attention. Please click Download on the upper right corner to see the full abstract

Allergens with Protease Activity from House Dust Mites

Globally, house dust mites (HDM) are one of the main sources of allergens causing Type I allergy, which has a high risk of progressing into a severe disabling disease manifestation such as allergic asthma. The strong protease activities of a number of these allergens are thought to be involved in several steps of the pathophysiology of this allergic disease. It has been a common notion that protease activity may be one of the properties that confers allergenicity to proteins. In this review we summarize and discuss the roles of the different HDM proteases in the development of Type I allergy

International Journal of Molecular Sciences / Allergens with Protease Activity from House Dust Mites

Globally, house dust mites (HDM) are one of the main sources of allergens causing Type I allergy, which has a high risk of progressing into a severe disabling disease manifestation such as allergic asthma. The strong protease activities of a number of these allergens are thought to be involved in several steps of the pathophysiology of this allergic disease. It has been a common notion that protease activity may be one of the properties that confers allergenicity to proteins. In this review we summarize and discuss the roles of the different HDM proteases in the development of Type I allergy.(VLID)486714

Human Embryo Models and Drug Discovery

For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery

Human Embryo Models and Drug Discovery

For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery

A Biomimetic, Silaffin R5-Based Antigen Delivery Platform

Nature offers a wide range of evolutionary optimized materials that combine unique properties with intrinsic biocompatibility and that can be exploited as biomimetic materials. The R5 and RRIL peptides employed here are derived from silaffin proteins that play a crucial role in the biomineralization of marine diatom silica shells and are also able to form silica materials in vitro. Here, we demonstrate the application of biomimetic silica particles as a vaccine delivery and adjuvant platform by linking the precipitating peptides R5 and the RRIL motif to a variety of peptide antigens. The resulting antigen-loaded silica particles combine the advantages of biomaterial-based vaccines with the proven intracellular uptake of silica particles. These particles induce NETosis in human neutrophils as well as IL-6 and TNF-α secretion in murine bone marrow-derived dendritic cells

Adjuvants and Vaccines Used in Allergen-Specific Immunotherapy Induce Neutrophil Extracellular Traps

Aluminum hydroxide (alum) and monophosphoryl-lipid A (MPLA) are conventional adjuvants in vaccines for allergen-specific immunotherapy (AIT). Alum triggers the release of neutrophil extracellular traps (NETs) by neutrophils. NETs contain expelled decondensed chromatin associated with granular material and may act as danger-associated molecular patterns and activate antigen-presenting cells. We investigated whether adjuvant-induced NETs contribute to innate responses to AIT-vaccines. Human neutrophils were incubated with alum, MPLA and adjuvant-containing AIT-vaccine preparations. NETs were verified by time-lapse and confocal fluorescence microscopy and quantitatively assessed by DNA and elastase release and ROS production. In contrast to MPLA, alum represented a potent trigger for NET release. Vaccine formulations containing alum resulted in less NET release than alum alone, whereas the vaccine containing MPLA induced stronger NET responses than MPLA alone. NETs and alum alone and synergistically increased the expression of molecules involved in antigen presentation, i.e., CD80, CD86 and CD83, by peripheral blood monocytes. Monocyte priming with NETs resulted in individually differing IL-1β- and IL-6-responses. Thus, NETs induced by adjuvants in AIT-vaccines can provide autonomous and cooperative effects on early innate responses. The high diversity of individual innate responses to adjuvants and AIT-vaccines may affect their therapeutic efficacy

Applied Design Thinking LAB Vienna: INTERACCT. Interdisciplinary Technology Education in the 21st Century In cooperation with students: Staff involved

Abstract INTERACCT is a project where two universities in Vienna (University of Applied Arts Vienna: Institute of Art Sciences and Art Education, Department of Design, Architecture and Environment for Education; University of Vienna: Faculty of Informatics, Computer Science Didactics and Learning Research, and Research Group Entertainment Computing), CCRI (Childrens´ Cancer Research Institute), children of an Austrian high school (Schulschiff Bertha von Suttner) and Tsystems (a division of Deutsche Telekom, systems integration, computing and network services and e-business) have been involved within the Applied Design Thinking LAB Vienna from 2009 until today. Aim of the project is to enhance interdisciplinary and participatory approaches in design and technology education. Case study is design of an interactive web based communication platform for improving quality of life for the patients of the stemcell-lab department (SCT-INTERACT) and to improve medical communication and education in outpatient care after pediatric hematopoietic stem cell transplantation (SCT). Spin-off is design of a serious game where healthy and malignant children are participatory involved as well as the students of different teaching subjects (informatics, art and design education), the caring medical staff and the industry partner. 31

Visualizing the DNA repair process by a photolyase at atomic resolution

International audiencePhotolyases, a ubiquitous class of flavoproteins, use blue light to repair DNA photolesions. In this work, we determined the structural mechanism of the photolyase-catalyzed repair of a cyclobutane pyrimidine dimer (CPD) lesion using time-resolved serial femtosecond crystallography (TR-SFX). We obtained 18 snapshots that show time-dependent changes in four reaction loci. We used these results to create a movie that depicts the repair of CPD lesions in the picosecond-to-nanosecond range, followed by the recovery of the enzymatic moieties involved in catalysis, completing the formation of the fully reduced enzyme-product complex at 500 nanoseconds. Finally, back-flip intermediates of the thymine bases to reanneal the DNA were captured at 25 to 200 microseconds. Our data cover the complete molecular mechanism of a photolyase and, importantly, its chemistry and enzymatic catalysis at work across a wide timescale and at atomic resolution