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Dynamic whole-body models for infant metabolism

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1 Abstract Comprehensive, sex-specific whole-body models (WBMs) accounting for organ-specific metabolism have been developed to allow for the simulation of adult and infant metabolism. These WBMs are …nfant metabolism. These WBMs are evaluated daily, giving insights into metabolic flux changes that occur in one day of an infant’s or adult’s life. However, for medical applications, such as in metabolic diseases and their treatment, an evaluation and concentration predictions on a shorter time scale would be beneficial. Therefore, we developed a dynamic infant-WBM that couples metabolite dynamics in short time frames through physiology-based pharma-cokinetic models with the existing infant whole-body models. We then tailored the dynamic infant-WBM enabling the prediction of isovalerylcarnitine (C5), a clinical biomarker used for the inherited metabolic disease isovaleric aciduria (IVA). Our results show that, as expected, the predicted C5 concentrations exceeded the newborn screening thresholds during the time (36 - 72 hours) newborn screening blood samples are taken in the IVA models but not in models simulating healthy infants. We also demonstrate how the dynamic infant-WBMs can be used to test the effect changes in dietary intake have on the biomarker. Since the dynamic infant-WBMs were parametrised with literature-derived experimental or estimated values, we show how uncertainty quantification can be applied to quantify the parameter uncertainties. We found that the fractional unbound plasma needed to be estimated correctly, as this parameter strongly impacted C5 concentration predictions of the dynamic infant-WBMs. Overall, the dynamic infant-WBMs hold promise for personalised medicine, as it enables personalised biomarker concentration predictions of healthy and diseased infant metabolism in various time intervals.

Authors: Elaine Zaunseder, Faiz Khan Mohammad, Ulrike Mütze, Stefan Kölker, Vincent Heuveline, Ines Thiele

Date Published: 26th Nov 2024

Publication Type: Journal

S100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models

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BACKGROUND: The EF-hand Ca 2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of …ancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca 2+ ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75–94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts. METHODS: We applied an integrative translational research pipeline ranging from in silico computational molecular modeling and in vitro biochemical molecular assays as well as isolated rodent and human cardiomyocyte performance assessments to in vivo safety and efficacy studies in small and large animal cardiac disease models. RESULTS: We characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in preclinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca 2+ cycling and prevents β-adrenergic receptor–triggered Ca 2+ imbalances by targeting SERCA2a and RyR2 activity. In line with the S100A1ct-mediated enhancement of SERCA2a activity, modeling suggests an interaction of the peptide with the transmembrane segments of the sarcoplasmic Ca 2+ pump. Incorporation of a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo. CONCLUSIONS: S100A1ct is a promising lead for the development of novel peptide-based therapeutics against heart failure with reduced ejection fraction.

Authors: Dorothea Kehr, Julia Ritterhoff, Manuel Glaser, Lukas Jarosch, Rafael E. Salazar, Kristin Spaich, Karl Varadi, Jennifer Birkenstock, Michael Egger, Erhe Gao, Walter J. Koch, Max Sauter, Marc Freichel, Hugo A. Katus, Norbert Frey, Andreas Jungmann, Cornelius Busch, Paul J. Mather, Arjang Ruhparwar, Martin Busch, Mirko Völkers, Rebecca C. Wade, Patrick Most

Date Published: 21st Nov 2024

Publication Type: Journal

KaMPIng: Flexible and (Near) Zero-Overhead C++ Bindings for MPI

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The Message-Passing Interface (MPI) and C++ form the backbone of high-performance computing, but MPI only provides C and Fortran bindings. While this offers great language interoperability, high-level … programming languages like C++ make software development quicker and less error-prone.We propose novel C++language bindings that cover all abstraction levels from low-level MPI calls to convenient STL-style bindings, where most parameters are inferred from a small subset of parameters, by bringing named parameters to C++. This enables rapid prototyping and fine-tuning runtime behavior and memory management. A flexible type system and additional safety guarantees help to prevent programming errors.By exploiting C++’s template metaprogramming capabilities, this has (near) zero overhead, as only required code paths are generated at compile time.We demonstrate that our library is a strong foundation for a future distributed standard library using multiple application benchmarks, ranging from text-book sorting algorithms to phylogenetic interference.

Authors: Tim Niklas Uhl, Matthias Schimek, Lukas Hübner, Demian Hespe, Florian Kurpicz, Daniel Seemaier, Christoph Stelz, Peter Sanders

Date Published: 17th Nov 2024

Publication Type: Proceedings

Efficient Tree-based Parallel Algorithms for N-Body Simulations Using C++ Standard Parallelism

Abstract

Not specified

Authors: Thomas Lane Cassell, Tom Deakin, Aksel Alpay, Vincent Heuveline, Gonzalo Brito Gadeschi

Date Published: 17th Nov 2024

Publication Type: Journal

Singularity-EOS: Performance Portable Equations of State and Mixed Cell Closures

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We present Singularity-EOS, a new performance-portable library for equations of state and related capabilities. Singularity-EOS provides a large set of analytic equations of state, such as the Gruneisen … equation of state, and tabulated equation of state data under a unified interface. It also provides support capabilities around these equations of state, such as Python wrappers, solvers for finding pressure-temperature equilibrium between multiple equations of state, and a unique modifier framework, allowing the user to transform a base equation of state, for example by shifting or scaling the specific internal energy. All capabilities are performance portable, meaning they compile and run on both CPU and GPU for a wide variety of architectures.

Authors: Jonah M. Miller, Daniel A. Holladay, Jeffrey H. Peterson, Christopher M. Mauney, Richard Berger, Anna Pietarila Graham, Karen C. Tsai, Brandon Barker, Alexander Holas, Ann E. Mattsson, Mariam Gogilashvili, Joshua C. Dolence, Chad D. Meyer, Sriram Swaminarayan, Christoph Junghans

Date Published: 1st Nov 2024

Publication Type: Journal

From spherical stars to disk-like structures: 3D common-envelope evolution of massive binaries beyond inspiral

Abstract

Not specified

Authors: Marco Vetter, Friedrich K. Röpke, Fabian R. N. Schneider, Rüdiger Pakmor, Sebastian T. Ohlmann, Mike Y. M. Lau, Robert Andrassy

Date Published: 1st Nov 2024

Publication Type: Journal

Large-scale ordered magnetic fields generated in mergers of helium white dwarfs

Abstract

Not specified

Authors: Rüdiger Pakmor, Ingrid Pelisoli, Stephen Justham, Abinaya S. Rajamuthukumar, Friedrich K. Röpke, Fabian R. N. Schneider, Selma E. de Mink, Sebastian T. Ohlmann, Philipp Podsiadlowski, Javier Morán-Fraile, Marco Vetter, Robert Andrassy

Date Published: 1st Nov 2024

Publication Type: Journal

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