18 research outputs found
ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome
Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.
Abstract
INTRODUCTION
RESULTS
DISCUSSION
MATERIALS AND METHODS
Acknowledgments
Supplementary Materials
REFERENCES AND NOTES
0eLetters
Abstract
Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS
The neutron and its role in cosmology and particle physics
Experiments with cold and ultracold neutrons have reached a level of
precision such that problems far beyond the scale of the present Standard Model
of particle physics become accessible to experimental investigation. Due to the
close links between particle physics and cosmology, these studies also permit a
deep look into the very first instances of our universe. First addressed in
this article, both in theory and experiment, is the problem of baryogenesis ...
The question how baryogenesis could have happened is open to experimental
tests, and it turns out that this problem can be curbed by the very stringent
limits on an electric dipole moment of the neutron, a quantity that also has
deep implications for particle physics. Then we discuss the recent spectacular
observation of neutron quantization in the earth's gravitational field and of
resonance transitions between such gravitational energy states. These
measurements, together with new evaluations of neutron scattering data, set new
constraints on deviations from Newton's gravitational law at the picometer
scale. Such deviations are predicted in modern theories with extra-dimensions
that propose unification of the Planck scale with the scale of the Standard
Model ... Another main topic is the weak-interaction parameters in various
fields of physics and astrophysics that must all be derived from measured
neutron decay data. Up to now, about 10 different neutron decay observables
have been measured, much more than needed in the electroweak Standard Model.
This allows various precise tests for new physics beyond the Standard Model,
competing with or surpassing similar tests at high-energy. The review ends with
a discussion of neutron and nuclear data required in the synthesis of the
elements during the "first three minutes" and later on in stellar
nucleosynthesis.Comment: 91 pages, 30 figures, accepted by Reviews of Modern Physic
CryoFold: Determining protein structures and data-guided ensembles from cryo-EM density maps
Cryo-electron microscopy (EM) requires molecular modeling to refine structural details from data. Ensemble models arrive at low free-energy molecular structures, but are computationally expensive and limited to resolving only small proteins that cannot be resolved by cryo-EM. Here, we introduce CryoFold - a pipeline of molecular dynamics simulations that determines ensembles of protein structures directly from sequence by integrating density data of varying sparsity at 3-5 Å resolution with coarse-grained topological knowledge of the protein folds. We present six examples showing its broad applicability for folding proteins between 72 to 2000 residues, including large membrane and multi-domain systems, and results from two EMDB competitions. Driven by data from a single state, CryoFold discovers ensembles of common low-energy models together with rare low-probability structures that capture the equilibrium distribution of proteins constrained by the density maps. Many of these conformations, unseen by traditional methods, are experimentally validated and functionally relevant. We arrive at a set of best practices for data-guided protein folding that are controlled using a Python GUI
Atoms to Phenotypes:Molecular Design Principles of Cellular Energy Metabolism
A full atomic resolution model of an entire organelle, the photosynthetic chromatophore vesicle of a purple bacterium, is constructed and reveals how the photosynthetic apparatus is optimized for ATP production in low-light habitats