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1687 Publications visible to you, out of a total of 1687
Easy uncertainty quantification (EasyUQ): Generating predictive distributions from single-valued model output

Abstract

Not specified

Authors: Eva-Maria Walz, Alexander Henzi, Johanna Ziegel, Tilmann Gneiting

Date Published: 8th Feb 2024

Publication Type: Journal

Mechanical control of the adhesion of malaria-infected erythrocytes to the placenta

Abstract (Expand)

Pathogens use sophisticated adhesion mechanisms to remain attached to the host’s surfaces. A key example of this is the adhesion of erythrocytes infected with Plasmodium, the parasite which causes … malaria, to the microvasculature. Remarkably, in the case of pregnancy-associated malaria, the adherence of parasitized erythrocytes to the placenta is enhanced by the shear of the flowing blood, suggesting a catch-bond adhesion mechanism. The adhesion is mediated by a parasite protein called VAR2CSA which anchors such infected erythrocytes to the proteoglycan matrix of the placenta. In this work, by using extensive equilibrium and force-probe molecular dynamics simulations, we elucidate the—so far unknown—molecular mechanism governing the adhesive function of VAR2CSA. We demonstrate that the elongation tension that arises from the shear of the flowing blood opens VAR2CSA into two structurally-intact domains, thereby exposing cryptic sugar binding sites. The orientation of VAR2CSA with respect to the pulling direction as well as strong sugar-protein shearing interactions favor this mode of opening. Accordingly, as the basis for a catch bond, we propose that mechanical forces strengthen the adhesion of infected erythrocytes, by increasing the number of sugar binding sites in VAR2CSA and not the bond lifetime as it would be canonically thought for a catch bond. This constitutes a new intriguing hypothesis which is of high relevance for our understanding of malaria infection and for the design of vaccines. More generally, our results put forward force-induced multivalency of mechano-responsive proteins as a key new concept for pathogen-host interactions.

Authors: Rita Roessner, Nicholas Michelarakis, Frauke Gräter, Camilo Aponte-Santamaría

Date Published: 8th Feb 2024

Publication Type: Journal

T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery

Abstract (Expand)

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA–presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite … to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual’s unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER’s potency and versatility.

Authors: Miray Cetin, Veronica Pinamonti, Theresa Schmid, Tamara Boschert, Ana Mellado Fuentes, Kristina Kromer, Taga Lerner, Jing Zhang, Yonatan Herzig, Christopher Ehlert, Miguel Hernandez-Hernandez, Georgios Samaras, Claudia Maldonado Torres, Laura Fisch, Valeriia Dragan, Arlette Kouwenhoven, Bertrand Van Schoubroeck, Hans Wils, Carl Van Hove, Michael Platten, Edward W. Green, Frederik Stevenaert, Nathan J. Felix, John M. Lindner

Date Published: 2nd Feb 2024

Publication Type: Journal

Learning to forecast: The Probabilistic Time Series Forecasting Challenge

Abstract

Not specified

Authors: Johannes Bracher, Nils Koster, Fabian Krüger, Sebastian Lerch

Date Published: 1st Feb 2024

Publication Type: Journal

Comparative evaluation of point process forecasts

Abstract

Not specified

Authors: Jonas R. Brehmer, Tilmann Gneiting, Marcus Herrmann, Warner Marzocchi, Martin Schlather, Kirstin Strokorb

Date Published: 1st Feb 2024

Publication Type: Journal

Contact tracing of binary stars: Pathways to stellar mergers

Abstract (Expand)

Stellar mergers are responsible for a wide variety of phenomena such as rejuvenated blue stragglers, highly magnetised stars, spectacular transients, iconic nebulae, and stars with peculiar surface … chemical abundances and rotation rates. Before stars merge, they enter a contact phase. Here, we investigate which initial binary-star configurations lead to contact and classical common-envelope (CE) phases and assess the likelihood of a subsequent merger. To this end, we computed a grid of about 6000 detailed 1D binary evolution models with initial component masses of 0.5 − 20.0 M⊙ at solar metallicity. Both components were evolved, and rotation and tides were taken into account. We identified five mechanisms that lead to contact and mergers: runaway mass transfer, mass loss through the outer Lagrange point L2, expansion of the accretor, orbital decay because of tides, and non-conservative mass transfer. At least 40% of mass-transferring binaries with initial primary-star masses of 5 − 20 M⊙ evolve into a contact phase; > 12% and > 19% likely merge and evolve into a CE phase, respectively. Because of the non-conservative mass transfer in our models, classical CE evolution from late Case-B and Case-C binaries is only found for initial mass ratios qi < 0.15 − 0.35. For larger mass ratios, we find stable mass transfer. In early Case-B binaries, contact occurs for initial mass ratios qi < 0.15 − 0.35, while in Case-A mass transfer, this is the case for all qi in binaries with the initially closest orbits and qi < 0.35 for initially wider binaries. Our models predict that most Case-A binaries with mass ratios of q < 0.5 upon contact mainly get into contact because of runaway mass transfer and accretor expansion on a thermal timescale, with subsequent L2-overflow in more than half of the cases. Thus, these binaries likely merge quickly after establishing contact or remain in contact only for a thermal timescale. On the contrary, Case-A contact binaries with higher mass ratios form through accretor expansion on a nuclear timescale and can thus give rise to long-lived contact phases before a possible merger. Observationally, massive contact binaries are almost exclusively found with mass ratios q > 0.5, confirming our model expectations. Because of non-conservative mass transfer with mass transfer efficiencies of 15 − 65%, 5 − 25%, and 25 − 50% in Case-A, -B, and -C mass transfer, respectively (for primary-star masses above 3 M⊙), our contact, merger, and classical CE incidence rates are conservative lower limits. With more conservative mass transfer, these incidences would increase. Moreover, in most binaries, the non-accreted mass cannot be ejected, raising the question of the further evolution of such systems. The non-accreted mass may settle into circumstellar and circumbinary disks, but could also lead to further contact systems and mergers. Overall, contact binaries are a frequent and fascinating result of binary mass transfer of which the exact outcomes still remain to be understood and explored further.

Authors: J. Henneco, F. R. N. Schneider, E. Laplace

Date Published: 1st Feb 2024

Publication Type: Journal

The role of heparin in spike SARS-CoV-2 infection: From a model for heparan sulfates to a starting structure for antivirals

Abstract

Not specified

Authors: Giulia Paiardi, Maria Milanesi, Matheus Ferraz, Liv Zimmermann, Chiara Urbinati, Pasqua Oreste, Francesca Caccuri, Petr Chlanda, Marco Rusnati, Rebecca C. Wade

Date Published: 1st Feb 2024

Publication Type: Journal

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