How an emerging drug class dampens harmful immune reactions unibasel NatureComms
Protein-ligand complexes for MD simulations were prepared as follows: 1) the crystal structure of C3b with Cp40 was prepared using the Protein Preparation Wizard as implemented in Maestro . Missing residues 76–77 were reconstructed and hydrogen atoms were added, assuming the physiological pH of 7.4. After protein-protein alignment, the binding site waters resolved at chains D and H of the C3c-compstatin complex were added to the model.
The first 24 ns of each simulation were considered an equilibration phase and thus were not included in the subsequent analyses. The binding affinities were calculated using the MMGB/SA analysis based on 50 frames sampled between 24 and 48 ns of the MD simulation. An in-house script was used to evaluate per residue intramolecular as well as intermolecular hydrogen bonding and hydrophobic interactions of compstatin and its analogue with the C3b.
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Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignanciesAbstract. A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow – stroma, lumen-forming sinusoids and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.
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Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice - Nature CommunicationsCurrent vaccines against SARS-CoV-2 reduce mortality but are less effective in preventing infection. Here the authors show that intranasal vaccination with a subunit vaccine including an TLR2-stimulating adjuvant induces strong neutralising antibody and T-cell responses against SARS-CoV-2 in the lungs that protect against infection.
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