Wiley Interdisciplinary Reviews-Systems Biology and Medicine最新文献

Cell fate decisions are controlled by complex intracellular molecular regulatory networks. Studies increasingly reveal the scale of this complexity: not only do cell fate regulatory networks contain numerous positive and negative feedback loops, they also involve a range of different kinds of nonlinear protein-protein and protein-DNA interactions. This inherent complexity and nonlinearity makes cell fate decisions hard to understand using experiment and intuition alone. In this primer, we will outline how tools from mathematics can be used to understand cell fate dynamics. We will briefly introduce some notions from dynamical systems theory, and discuss how they offer a framework within which to build a rigorous understanding of what we mean by a cell "fate", and how cells change fate. We will also outline how modern experiments, particularly high-throughput single-cell experiments, are enabling us to test and explore the limits of these ideas, and build a better understanding of cellular identities. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Cell Fates Models of Systems Properties and Processes > Cellular Models.

An effective adaptive immune response to microbial infection relies on the generation of heterogeneous T lymphocyte fates and functions. CD8 T lymphocytes play a pivotal role in mediating immediate and long-term protective immune responses to intracellular pathogen infection. Systems-based analysis of the immune response to infection has begun to identify cell fate determinants and the molecular mechanisms underpinning CD8 T lymphocyte diversity at single-cell resolution. Resolving CD8 T lymphocyte heterogeneity during adaptive immunity highlights the advantages of single-cell technologies and computational approaches to better understand the ontogeny of CD8 T cellular diversity following infection. Future directions of integrating single-cell multiplex approaches capitalize on the importance of systems biology in the understanding of immune CD8 T cell differentiation and functional diversity. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Biological Mechanisms > Cell Fates.

There has been a spurt in structural neuroimaging studies of the effect of hearing loss on the brain. Specifically, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) technologies provide an opportunity to quantify changes in gray and white matter structures at the macroscopic scale. To date, there have been 32 MRI and 23 DTI studies that have analyzed structural differences accruing from pre- or peri-lingual pediatric hearing loss with congenital or early onset etiology and postlingual hearing loss in pre-to-late adolescence. Additionally, there have been 15 prospective clinical structural neuroimaging studies of children and adolescents being evaluated for cochlear implants. The results of the 70 studies are summarized in two figures and three tables. Plastic changes in the brain are seen to be multifocal rather than diffuse, that is, differences are consistent across regions implicated in the hearing, speech and language networks regardless of modes of communication and amplification. Structures in that play an important role in cognition are affected to a lesser extent. A limitation of these studies is the emphasis on volumetric measures and on homogeneous groups of subjects with hearing loss. It is suggested that additional measures of morphometry and connectivity could contribute to a greater understanding of the effect of hearing loss on the brain. Then an interpretation of the observed macroscopic structural differences is given. This is followed by discussion of how structural imaging can be combined with functional imaging to provide biomarkers for longitudinal tracking of amplification. This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Translational, Genomic, and Systems Medicine > Translational Medicine Laboratory Methods and Technologies > Imaging.

Successful development depends on the precise tissue-specific regulation of genes by enhancers, genetic elements that act as switches to control when and where genes are expressed. Because enhancers are critical for development, and the majority of disease-associated mutations reside within enhancers, it is essential to understand which sequences within enhancers are important for function. Advances in sequencing technology have enabled the rapid generation of genomic data that predict putative active enhancers, but functionally validating these sequences at scale remains a fundamental challenge. Herein, we discuss the power of genome-wide strategies used to identify candidate enhancers, and also highlight limitations and misconceptions that have arisen from these data. We discuss the use of massively parallel reporter assays to test enhancers for function at scale. We also review recent advances in our ability to study gene regulation during development, including CRISPR-based tools to manipulate genomes and single-cell transcriptomics to finely map gene expression. Finally, we look ahead to a synthesis of complementary genomic approaches that will advance our understanding of enhancer function during development. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Laboratory Methods and Technologies > Genetic/Genomic Methods.

Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The "omics" revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross-talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems-level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Cellular Models.

The innate immune system is the first line of host defense against invading microorganisms. Polymorphonuclear leukocytes (PMNs or neutrophils) are the most abundant leukocyte in humans and essential to the innate immune response against invading pathogens. Compared to the acquired immune response, which requires time to develop and is dependent on previous interaction with specific microbes, the ability of neutrophils to kill microorganisms is immediate, nonspecific, and not dependent on previous exposure to microorganisms. Historically, studies of PMN-pathogen interaction focused on the events leading to killing of microorganisms, such as recruitment/chemotaxis, transmigration, phagocytosis, and activation, whereas postphagocytosis sequelae were infrequently considered. In addition, it was widely accepted that human neutrophils possessed limited capacity for new gene transcription and thus, relatively little biosynthetic capacity. This notion has changed dramatically within the past 20 years. Further, there is now more effort directed to understand the events occurring in PMNs after killing of microbes. Herein, we give an updated review of the systems biology-level approaches that have been used to gain an enhanced view of the role of neutrophils during host-pathogen interaction and neutrophil-mediated diseases. We anticipate that these and future systems-level studies will continue to provide information important for understanding, treatment, and control of diseases caused by pathogenic microorganisms. This article is categorized under: Physiology > Organismal Responses to Environment Physiology > Mammalian Physiology in Health and Disease Biological Mechanisms > Cell Fates.

Pluripotent stem cells have the ability to unlimitedly self-renew and differentiate to any somatic cell lineage. A number of systems biology approaches have been used to define this pluripotent state. Complementary to systems level characterization, genetic screens offer a unique avenue to functionally interrogate the pluripotent state and identify the key players in pluripotency acquisition and maintenance, exit of pluripotency, and lineage differentiation. Here we review how genetic screens have helped us decode pluripotency regulation. We will summarize results from RNA interference (RNAi) based screens, discuss recent advances in CRISPR/Cas-based genetic perturbation methods, and how these advances have made it possible to more comprehensively interrogate pluripotency and differentiation through genetic screens. Such investigations will not only provide a better understanding of this unique developmental state, but may enhance our ability to use pluripotent stem cells as an experimental model to study human development and disease progression. Functional interrogation of pluripotency also provides a valuable roadmap for utilizing genetic perturbation to gain systems level understanding of additional cellular states, from later stages of development to pathological disease states. This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration Developmental Biology > Developmental Processes in Health and Disease Biological Mechanisms > Cell Fates.