Wiley Interdisciplinary Reviews-Systems Biology and Medicine最新文献

Cardiac electrophysiology models are among the most mature and well-studied mathematical models of biological systems. This maturity is bringing new challenges as models are being used increasingly to make quantitative rather than qualitative predictions. As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model. This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology. We discuss the classic and latest approaches to calibration in the electrophysiology field, at both the ion channel and cellular AP scales. We end with a discussion of the many challenges that work to date has raised and the need for reproducible descriptions of the calibration process to enable models to be recalibrated to new data sets and built upon for new studies. This article is categorized under: Analytical and Computational Methods > Computational Methods Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Cellular Models.

Detailed, mechanistic models of immune cell behavior across multiple scales in the context of cancer provide clinically relevant insights needed to understand existing immunotherapies and develop more optimal treatment strategies. We highlight mechanistic models of immune cells and their ability to become activated and promote tumor cell killing. These models capture various aspects of immune cells: (a) single-cell behavior by predicting the dynamics of intracellular signaling networks in individual immune cells, (b) multicellular interactions between tumor and immune cells, and (c) multiscale dynamics across space and different levels of biological organization. Computational modeling is shown to provide detailed quantitative insight into immune cell behavior and immunotherapeutic strategies. However, there are gaps in the literature, and we suggest areas where additional modeling efforts should be focused to more prominently impact our understanding of the complexities of the immune system in the context of cancer. This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models.

G protein-coupled receptors (GPCRs) are cell membrane associated signaling hubs that orchestrate a multitude of cellular functions upon binding to a diverse variety of extracellular ligands. Since GPCRs are integral membrane proteins with seven-transmembrane domain architecture, their function, organization and dynamics are intimately regulated by membrane lipids, such as cholesterol. Cholesterol is an extensively studied lipids in terms of its effects on GPCR structure and function. One of the possible mechanisms underlying modulation of GPCR function by cholesterol is via specific interaction of GPCRs with membrane cholesterol. These interactions of GPCRs with membrane cholesterol are often attributed to structural features of GPCRs that could facilitate their preferential association with cholesterol. In this backdrop, cholesterol interaction motifs represent putative interaction sites on GPCRs that could facilitate cholesterol-sensitive function of these receptors. In this review, we provide an overview of cholesterol interaction motifs found in GPCRs, which have been identified through a combination of crystallography, bioinformatics analysis, and functional studies. In addition, we will highlight, using specific examples, why mere presence of a cholesterol interaction motif at a given site may not directly implicate its role in interaction with membrane cholesterol. We therefore believe that experimental approaches, followed by functional analysis of cholesterol sensitivity of GPCRs, would provide a better understanding of the role played by these motifs in cholesterol-sensitive function. We envision that a comprehensive knowledge of cholesterol interaction sites in GPCRs would allow us to develop a better understanding of GPCR structure-function paradigm, and could be useful in future therapeutics. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Analytical and Computational Methods > Computational Methods Laboratory Methods and Technologies > Macromolecular Interactions, Methods.

We review the current state of mathematical modeling of cartilage pattern formation in vertebrate limbs. We place emphasis on several reaction-diffusion type models that have been proposed in the last few years. These models are grounded in more detailed knowledge of the relevant regulatory processes than previous ones but generally refer to different molecular aspects of these processes. Considering these models in light of comparative phylogenomics permits framing of hypotheses on the evolutionary order of appearance of the respective mechanisms and their roles in the fin-to-limb transition. This article is categorized under: Analytical and Computational Methods > Computational Methods Models of Systems Properties and Processes > Mechanistic Models Developmental Biology > Developmental Processes in Health and Disease Analytical and Computational Methods > Analytical Methods.

Precision Cardiology is a targeted strategy for cardiovascular disease prevention and treatment that accounts for individual variability. Computational heart modeling is one of the novel approaches that have been developed under the umbrella of Precision Cardiology. Personalized computational modeling of patient hearts has made strides in the development of models that incorporate the individual geometry and structure of the heart as well as other patient-specific information. Of these developments, one of the potentially most impactful is the research aimed at noninvasively predicting the targets of ablation of lethal arrhythmia, ventricular tachycardia (VT), using patient-specific models. The approach has been successfully applied to patients with ischemic cardiomyopathy in proof-of-concept studies. The goal of this paper is to review the strategies for computational VT ablation guidance in ischemic cardiomyopathy patients, from model developments to the intricacies of the actual clinical application. To provide context in describing the road these computational modeling applications have undertaken, we first review the state of the art in VT ablation in the clinic, emphasizing the benefits that personalized computational prediction of ablation targets could bring to the clinical electrophysiology practice. This article is characterized under: Analytical and Computational Methods > Computational Methods Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Translational, Genomic, and Systems Medicine > Translational Medicine.

Genomic imprinting is an epigenetically regulated process leading to gene expression according to its parental origin. Imprinting is essential for prenatal growth and development, regulating nutritional resources to offspring, and contributing to a favored theory about the evolution of imprinting being due to a conflict between maternal and paternal genomes for the control of prenatal resources-the so-called kinship hypothesis. Genomic imprinting has been mainly studied during embryonic and placental development; however, maternal nutrient provisioning is not restricted to the prenatal period. In this context, the mammary gland acts at the maternal-offspring interface providing milk to the newborn. Maternal care including lactation supports the offspring, delivering nutrients and bioactive molecules protecting against infections and contributing to healthy organ development and immune maturation. The normal developmental cycle of the mammary gland-pregnancy, lactation, involution-is vital for this process, raising the question of whether genomic imprinting might also play a role in postnatal nutrient transfer by controlling mammary gland development. Characterizing the function and epigenetic regulation of imprinted genes in the mammary gland cycle may therefore provide novel insights into the evolution of imprinting since the offspring's paternal genome is absent from the mammary gland, in addition to increasing our knowledge of postnatal nutrition and its relation to life-long health. This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease.

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) result from complex interactions between intrinsic and extrinsic factors, including genetics and exposure to obesogenic environments. These risk factors converge in aberrant gene expression patterns in the liver, which are underlined by altered cis-regulatory networks. In homeostasis and in disease states, liver cis-regulatory networks are established by coordinated action of liver-enriched transcription factors (TFs), which define enhancer landscapes, activating broad gene programs with spatiotemporal resolution. Recent advances in DNA sequencing have dramatically expanded our ability to map active transcripts, enhancers and TF cistromes, and to define the 3D chromatin topology that contains these elements. Deployment of these technologies has allowed investigation of the molecular processes that regulate liver development and metabolic homeostasis. Moreover, genomic studies of NAFLD patients and NAFLD models have demonstrated that the liver undergoes pervasive regulatory rewiring in NAFLD, which is reflected by aberrant gene expression profiles. We have therefore achieved an unprecedented level of detail in the understanding of liver cis-regulatory networks, particularly in physiological conditions. Future studies should aim to map active regulatory elements with added levels of resolution, addressing how the chromatin landscapes of different cell lineages contribute to and are altered in NAFLD and NAFLD-associated metabolic states. Such efforts would provide additional clues into the molecular factors that trigger this disease. This article is categorized under: Biological Mechanisms > Metabolism Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > Genetic/Genomic Methods.

The regulation of size and shape is a fundamental requirement of biological development and has been a subject of scientific study for centuries, but we still lack an understanding of how organisms know when to stop growing. Imaginal wing disks of the fruit fly Drosophila melanogaster, which are precursors of the adult wings, are an archetypal tissue for studying growth control. The growth of the disks is dependent on many inter- and intra-organ factors such as morphogens, mechanical forces, nutrient levels, and hormones that influence gene expression and cell growth. Extracellular signals are transduced into gene-control signals via complex signal transduction networks, and since cells typically receive many different signals, a mechanism for integrating the signals is needed. Our understanding of the effect of morphogens on tissue-level growth regulation via individual pathways has increased significantly in the last half century, but our understanding of how multiple biochemical and mechanical signals are integrated to determine whether or not a cell decides to divide is still rudimentary. Numerous fundamental questions are involved in understanding the decision-making process, and here we review the major biochemical and mechanical pathways involved in disk development with a view toward providing a basis for beginning to understand how multiple signals can be integrated at the cell level, and how this translates into growth control at the level of the imaginal disk. This article is categorized under: Analytical and Computational Methods > Computational Methods Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Cellular Models.

Tissue repair is a complex process that requires effective communication and coordination between cells across multiple tissues and organ systems. Two of the initial intracellular signals that encode injury signals and initiate tissue repair responses are calcium and extracellular signal-regulated kinase (ERK). However, calcium and ERK signaling control a variety of cellular behaviors important for injury repair including cellular motility, contractility, and proliferation, as well as the activity of several different transcription factors, making it challenging to relate specific injury signals to their respective repair programs. This knowledge gap ultimately hinders the development of new wound healing therapies that could take advantage of native cellular signaling programs to more effectively repair tissue damage. The objective of this review is to highlight the roles of calcium and ERK signaling dynamics as mechanisms that link specific injury signals to specific cellular repair programs during epithelial and stromal injury repair. We detail how the signaling networks controlling calcium and ERK can now also be dissected using classical signal processing techniques with the advent of new biosensors and optogenetic signal controllers. Finally, we advocate the importance of recognizing calcium and ERK dynamics as key links between injury detection and injury repair programs that both organize and execute a coordinated tissue repair response between cells across different tissues and organs. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Cell Signaling Laboratory Methods and Technologies > Imaging Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models.

It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate-induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti-tumor immune response. This article is characterized under: Biological Mechanisms > Metabolism.