arXiv subjects

Yougan Cheng

Publications and source records attributed to Yougan Cheng.

3 recordsLinked to original sources

arXiv2026

Best Practices on QSP Model Reporting for Regulatory Use: perspectives from ISoP QSP SIG Working Group

Quantitative systems pharmacology (QSP) models are increasingly applied to inform decision making across drug development and to support regulatory interactions within model informed drug development (MIDD). QSP supports a broad range of applications across drug development and can be tailored to specific therapeutic areas, mechanisms of action, and contexts of use (CoU). While this diversity is a core strength of QSP, it also presents challenges for reporting for regulatory use. Despite the growing impact of QSP models, there is currently no established guidance on how QSP analyses should be documented and reported for regulatory purposes. This white paper, developed by the International Society of Pharmacometrics (ISoP) QSP Special Interest Group Working Group on Credibility Assessment of QSP for Regulatory Use, seeks to address this gap by proposing best practices for QSP model reporting in regulatory settings. The recommendations are grounded in collective real world experience from regulatory interactions and are aligned with reporting guidance established for physiologically based pharmacokinetic (PBPK) modeling and reporting principles outlined in ICH M15. Rather than prescribing a rigid, one size fits all template, this work proposes a flexible, tiered reporting framework that accounts for development phase and model impact. The proposed framework is intended to facilitate regulatory review and enhance transparency while accommodating the inherent diversity of QSP modeling.

math.DS↗

arXiv2015

A Model for Direction Sensing in Dictyostelium Discoideum: Ras Activity and Symmetry Breaking Driven by a Gbetagamma- Mediated, Galpha2-Ric8 -- Dependent Signal Transduction Network

Many eukaryotic cells, including Dictyostelium discoideum (Dicty), neutrophils and other cells of the immune system, can detect and reliably orient themselves in chemoattractant gradients. In Dicty, signal detection and transduction involves a G-protein-coupled receptor (GPCR) through which extracellular cAMP signals are transduced into Ras activation via an intermediate heterotrimeric G-protein (G2). Ras activation is the first polarized response to cAMP gradients in Dicty. Recent work has revealed mutiple new characteristics of Ras activation in Dicty, thereby providing new insights into direction sensing mechanisms and pointing to the need for new models of chemotaxis. Here we propose a novel reaction-diffusion model of Ras activation based on three major components: one involving the GPCR, one centered on G2, and one involving the monomeric G protein Ras. In contrast to existing local excitation, global inhibition (LEGI) models of direction sensing, in which a fast-responding but slowly-diffusing activator and a slow-acting rapidly diffusing inhibitor set up an internal gradient of activity, our model is based on equal diffusion coefficients for all cytosolic species, and the unbalanced local sequestration of some species leads to gradient sensing and amplification. We show that Ric8-modulated G2 cycling between the cytosol and membrane can account for many of the observed responses in Dicty. including imperfect adaptation, multiple phases of Ras activity in a cAMP gradient, rectified directional sensing, and cellular memory.

q-bio.CB↗

arXiv2014

Energy Demand and Metabolite Partitioning in Spatially Lumped and Distributed Models of Neuron-Astrocyte Complex

The degrees of freedom of multi-compartment mathematical models for energy metabolism of a neuron-astrocyte complex may offer a key to understand the different ways in which the energetic needs of the brain are met. In this paper we address the problem within a steady state framework and we use the techniques of linear algebra to identify the degrees of freedom first in a lumped model, then in its extension to a spatially distributed case. The interpretation of the degrees of freedom in metabolic terms, more specifically in terms of glucose and oxygen partitioning, is then leveraged to derive constraints on the free parameters needed to guarantee that the model is energetically feasible. We also demonstrate how the model can be used to estimate the stoichiometric energy needs of the cells as well as the household energy based on observed oxidative cerebral metabolic rate (CMR) of glucose, and the glutamate cycling. Moreover, our analysis shows that in the lumped model the direction of lactate dehydrogenase (LDH) in the cells can be deduced from the glucose partitioning between the compartments. The extension of the lumped model into a spatially distributed multi-compartment setting that includes diffusion fluxes from capillary to tissue increases the number of degrees of freedom, requiring the use of statistical sampling techniques. The analysis of distributed model reveals that some of the conclusions, e.g., concerning the LDH activity and glucose partitioning, based on a spatially lumped model may no longer hold.

q-bio.QM↗