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Computational Models for Clinical Applications in Personalized Medicine-Guidelines and Recommendations for Data Integration and Model Validation.

Abstract (Expand)

The future development of personalized medicine depends on a vast exchange of data from different sources, as well as harmonized integrative analysis of large-scale clinical health and sample data. … Computational-modelling approaches play a key role in the analysis of the underlying molecular processes and pathways that characterize human biology, but they also lead to a more profound understanding of the mechanisms and factors that drive diseases; hence, they allow personalized treatment strategies that are guided by central clinical questions. However, despite the growing popularity of computational-modelling approaches in different stakeholder communities, there are still many hurdles to overcome for their clinical routine implementation in the future. Especially the integration of heterogeneous data from multiple sources and types are challenging tasks that require clear guidelines that also have to comply with high ethical and legal standards. Here, we discuss the most relevant computational models for personalized medicine in detail that can be considered as best-practice guidelines for application in clinical care. We define specific challenges and provide applicable guidelines and recommendations for study design, data acquisition, and operation as well as for model validation and clinical translation and other research areas.

Authors: C. B. Collin, T. Gebhardt, M. Golebiewski, T. Karaderi, M. Hillemanns, F. M. Khan, A. Salehzadeh-Yazdi, M. Kirschner, S. Krobitsch, C. o. n. s. o. r. t. i. u. m. Eu-Stands Pm, L. Kuepfer

Date Published: 26th Jan 2022

Publication Type: Journal

Phosphorylation tunes elongation propensity and cohesiveness of INCENP's intrinsically disordered region.

Abstract (Expand)

The inner centromere protein, INCENP, is crucial for correct chromosome segregation during mitosis. It connects the kinase Aurora B to the inner centromere allowing this kinase to dynamically access … its kinetochore targets. However, the function of its central, 440-residue long intrinsically disordered region (IDR) and its multiple phosphorylation sites is unclear. Here, we determined the conformational ensemble of INCENP's IDR, systematically varying the level of phosphorylation, using all-atom and coarse-grain molecular dynamics simulations. Our simulations show that phosphorylation expands INCENP's IDR, both locally and globally, mainly by increasing its overall net charge. The disordered region undergoes critical globule-to-coil conformational transitions and the transition temperature non-monotonically depends on the degree of phosphorylation, with a mildly phosphorylated case of neutral net charge featuring the highest collapse propensity. The IDR transitions from a multitude of globular states, accompanied by several specific internal contacts that reduce INCENP length by loop formation, to weakly interacting and highly extended coiled conformations. Phosphorylation critically shifts the population between these two regimes. It thereby influences cohesiveness and phase behavior of INCENP IDR assemblies, a feature presumably relevant for INCENP's function in the chromosomal passenger complex. Overall, we propose the disordered region of INCENP to act as a phosphorylation-regulated and length-variable component, within the previously defined "dog-leash" model, that thereby regulates how Aurora B reaches its targets for proper chromosome segregation.

Authors: Isabel M Martin, Camilo Aponte-Santamaría, Lisa Schmidt, Marius Hedtfeld, Adel Iusupov, Andrea Musacchio, Frauke Gräter

Date Published: 15th Jan 2022

Publication Type: Journal

Characterizing the optimal solutions to the isotonic regression problem for identifiable functionals

Abstract

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Authors: Alexander I. Jordan, Anja Mühlemann, Johanna F. Ziegel

Date Published: 2022

Publication Type: Journal

Machine learning methods for postprocessing ensemble forecasts of wind gusts: A systematic comparison

Abstract

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Authors: Benedikt Schulz, Sebastian Lerch

Date Published: 2022

Publication Type: Journal

SPART: A versatile and standardized data exchange format for species partition information

Abstract

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Authors: Aurélien Miralles, Jacques Ducasse, Sophie Brouillet, Tomas Flouri, Tomochika Fujisawa, Paschalia Kapli, L. Lacey Knowles, Sangeeta Kumari, Alexandros Stamatakis, Jeet Sukumaran, Sarah Lutteropp, Miguel Vences, Nicolas Puillandre

Date Published: 2022

Publication Type: Journal

Molecular Dynamics Simulation of a Mammalian Cytochrome P450 Protein and its Interaction with Substrates and Redox-Partners

Abstract

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Author: Jonathan Teuffel

Date Published: 2022

Publication Type: Master's Thesis

Slow White Dwarf Mergers as a New Galactic Source of Trans-Iron Elements

Abstract

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Authors: Umberto Battino, Claudia Lederer-Woods, Claudia Travaglio, Friedrich Konrad Röpke, Brad Gibson

Date Published: 2022

Publication Type: Journal

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