Wiley Interdisciplinary Reviews-Systems Biology and Medicine最新文献

Trauma with hypovolemic shock is an extreme pathological state that challenges the body to maintain blood pressure and oxygenation in the face of hemorrhagic blood loss. In conjunction with surgical actions and transfusion therapy, survival requires the patient's blood to maintain hemostasis to stop bleeding. The physics of the problem are multiscale: (a) the systemic circulation sets the global blood pressure in response to blood loss and resuscitation therapy, (b) local tissue perfusion is altered by localized vasoregulatory mechanisms and bleeding, and (c) altered blood and vessel biology resulting from the trauma as well as local hemodynamics control the assembly of clotting components at the site of injury. Building upon ongoing modeling efforts to simulate arterial or venous thrombosis in a diseased vasculature, computer simulation of trauma-induced coagulopathy is an emerging approach to understand patient risk and predict response. Despite uncertainties in quantifying the patient's dynamic injury burden, multiscale systems biology may help link blood biochemistry at the molecular level to multiorgan responses in the bleeding patient. As an important goal of systems modeling, establishing early metrics of a patient's high-dimensional trajectory may help guide transfusion therapy or warn of subsequent later stage bleeding or thrombotic risks. This article is categorized under: Analytical and Computational Methods > Computational Methods Biological Mechanisms > Regulatory Biology Models of Systems Properties and Processes > Mechanistic Models.

Dilated cardiomyopathy (DCM) is a form of severe failure of cardiac muscle caused by a long list of etiologies ranging from myocardial infarction, DNA mutations in cardiac genes, to toxics. Systems analysis integrating next-generation sequencing (NGS)-based omics approaches, such as the sequencing of DNA, RNA, and chromatin, provide valuable insights into DCM mechanisms. The outcome and interpretation of NGS methods can be affected by the localization of cardiac biopsy, level of tissue degradation, and variable ratios of different cell populations, especially in the presence of fibrosis. Heart tissue composition may even differ between sexes, or siblings carrying the same disease causing mutation. Therefore, before planning any experiments, it is important to fully appreciate the complexities of DCM, and the selection of samples suitable for given research question should be an interdisciplinary effort involving clinicians and biologists. The list of NGS omics datasets in DCM to date is short. More studies have to be performed to contribute to public data repositories and facilitate systems analysis. In addition, proper data integration is a difficult task requiring complex computational approaches. Despite these complications, there are multiple promising implications of systems analysis in DCM. By combining various types of datasets, for example, RNA-seq, ChIP-seq, or 4C, deep insights into cardiac biology, and possible biomarkers and treatment targets, can be gained. Systems analysis can also facilitate the annotation of noncoding mutations in cardiac-specific DNA regulatory regions that play a substantial role in maintaining the tissue- and cell-specific transcriptional programs in the heart. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Laboratory Methods and Technologies > Genetic/Genomic Methods Laboratory Methods and Technologies > RNA Methods.

Metabolic diseases such as obesity and diabetes are complex diseases resulting from multiple genetic and environmental factors, such as diet and activity levels. These factors are well known contributors to the development of metabolic diseases. One manner by which environmental factors can influence metabolic disease progression is through modifications to chromatin. These modifications can lead to altered gene regulatory programs, which alters disease risk. Furthermore, there is evidence that parents exposed to environmental factors can influence the metabolic health of offspring, especially if exposures are during intrauterine growth periods. In this review, we outline the evidence that chromatin modifications are associated with metabolic diseases, including diabetes and obesity. We also consider evidence that these chromatin modifications can lead to long-term disease risk and contribute to disease risk for future generations. This article is categorized under: Biological Mechanisms > Metabolism Developmental Biology > Developmental Processes in Health and Disease Physiology > Organismal Responses to Environment.

5-Methylcytosine, a chemical modification of DNA, is a covalent modification found in the genomes of both plants and animals. Epigenetic inheritance of phenotypes mediated by DNA methylation is well established in plants. Most of the known mechanisms of establishing, maintaining and modifying DNA methylation have been worked out in the reference plant Arabidopsis thaliana. Major functions of DNA methylation in plants include regulation of gene expression and silencing of transposable elements (TEs) and repetitive sequences, both of which have parallels in mammalian biology, involve interaction with the transcriptional machinery, and may have profound effects on the regulatory networks in the cell. Methylome and transcriptome dynamics have been investigated in development and environmental responses in Arabidopsis and agriculturally and ecologically important plants, revealing the interdependent relationship among genomic context, methylation patterns, and expression of TE and protein coding genes. Analyses of methylome variation among plant natural populations and species have begun to quantify the extent of genetic control of methylome variation vs. true epimutation, and model the evolutionary forces driving methylome evolution in both short and long time scales. The ability of DNA methylation to positively or negatively modulate binding affinity of transcription factors (TFs) provides a natural link from genome sequence and methylation changes to transcription. Technologies that allow systematic determination of methylation sensitivities of TFs, in native genomic and methylation context without confounding factors such as histone modifications, will provide baseline datasets for building cell-type- and individual-specific regulatory networks that underlie the establishment and inheritance of complex traits. This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Biological Mechanisms > Regulatory Biology.

Far from being just "bugs in our guts," the microbiota interacts with the body in previously unimagined ways. Research into the genome and the microbiome has revealed that the human body and the microbiota have a long-established but only recently recognized symbiotic relationship; homeostatic balance between them regulates body function. That balance is fragile, easily disturbed, and plays a fundamental role in human health-our very survival depends on the healthy functioning of these microorganisms. Increasing rates of cardiovascular, autoimmune, and inflammatory diseases, as well as epidemics in obesity and diabetes in recent decades are believed to be explained, in part, by unintended effects on the microbiota from vaccinations, poor diets, environmental chemicals, indiscriminate antibiotic use, and "germophobia." Discovery and exploration of the brain-gut-microbiota axis have provided new insights into functional diseases of the gut, autoimmune and stress-related disorders, and the role of probiotics in treating certain affective disorders; it may even explain some aspects of autism. Research into dietary effects on the human gut microbiota led to its classification into three proposed enterotypes, but also revealed the surprising role of blood group antigens in shaping those populations. Blood group antigens have previously been associated with disease risks; their subsequent association with the microbiota may reveal mechanisms that lead to development of nutritional interventions and improved treatment modalities. Further exploration of associations between specific enteric microbes and specific metabolites will foster new dietary interventions, treatment modalities, and genetic therapies, and inevitably, their application in personalized healthcare strategies. This article is categorized under: Laboratory Methods and Technologies > Metabolomics Translational, Genomic, and Systems Medicine > Translational Medicine Physiology > Mammalian Physiology in Health and Disease.

Primary treatment for many solid cancers includes surgical excision or radiation therapy, with or without the use of adjuvant therapy. This can include the addition of radiation and chemotherapy after primary surgical therapy, or the addition of chemotherapy and salvage surgery to primary radiation therapy. Both primary therapies, surgery and radiation, require precise anatomic localization of tumor. If tumor is not targeted adequately with initial treatment, disease recurrence may ensue, and if targeting is too broad, unnecessary morbidity may occur to nearby structures or remaining normal tissue. Fluorescence imaging using intraoperative contrast agents is a rapidly growing field for improving visualization in cancer surgery to facilitate resection in order to obtain negative margins. There are multiple strategies for tumor visualization based on antibodies against surface markers or ligands for receptors preferentially expressed in cancer. In this article, we review the incidence and clinical implications of positive surgical margins for some of the most common solid tumors. Within this context, we present the ongoing clinical and preclinical studies focused on the use of intraoperative contrast agents to improve surgical margins. This article is categorized under: Laboratory Methods and Technologies > Imaging.

Mapping the protein-protein interaction (PPi) landscape is of critical importance to furthering our understanding how cells and organisms function. Optogenetic methods, that is, approaches that utilize genetically encoded fluorophores or fluorogenic enzyme reactions, uniquely enable the visualization of biochemical phenomena in live cells with high spatial and temporal accuracy. Applying optogenetic methods to the detection of PPis requires the engineering of protein-based systems in which an optical signal undergoes a substantial change when the two proteins of interest interact. In recent years, researchers have developed a number of creative and effective optogenetic methods that achieve this goal, and used them to further elaborate our map of the PPi landscape. In this review, we provide an introduction to the general principles of optogenetic PPi detection, and then provide a number of representative examples of how these principles have been applied. We have organized this review by categorizing methods based on whether the signal generated is reversible or irreversible in nature, and whether the signal is localized or nonlocalized at the subcellular site of the PPi. We discuss these techniques giving both their benefits and drawbacks to enable rational choices about their potential use. This article is categorized under: Laboratory Methods and Technologies > Imaging Laboratory Methods and Technologies > Macromolecular Interactions, Methods Analytical and Computational Methods > Analytical Methods.

A fundamental aspect of life is the modification of anatomy, physiology, and behavior in the face of changing conditions. This is especially illustrated by the adaptive regulation of growth and form that underlies the ability of most organisms-from single cells to complex large metazoa-to develop, remodel, and regenerate to specific anatomical patterns. What is the relationship of the genome and other cellular components to the robust computations that underlie this remarkable pattern homeostasis? Here we examine the role of constraints defined at the cellular level, especially endogenous bioelectricity, in generating and propagating biological information. We review evidence that the genome is only one of several multi-generational biological memories. Focusing on the cell membrane and cytoplasm, which is physically continuous across all of life in evolutionary timeframes, we characterize the environment as an interstitial space through which messages are passed via bioelectric and biochemical codes. We argue that biological memory is a fundamental phenomenon that cannot be understood at any one scale, and suggest that functional studies of information propagated in non-genomic cellular structures will not only strongly impact evolutionary developmental biology, but will also have implications for regenerative medicine and synthetic bioengineering. WIREs Syst Biol Med 2018, 10:e1410. doi: 10.1002/wsbm.1410 This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration Physiology > Physiology of Model Organisms Models of Systems Properties and Processes > Cellular Models.

Small molecules have many important roles across the tree of life: they regulate processes from metabolism to transcription, they enable signaling within and between species, and they serve as the biochemical building blocks for cells. They also represent valuable phenotypic endpoints that are promising for use as biomarkers of disease states. In the context of engineering cell-based therapeutics, they hold particularly great promise for enabling finer control over the therapeutic cells and allowing them to be responsive to extracellular cues. The natural signaling and regulatory functions of small molecules can be harnessed and rewired to control cell activity and delivery of therapeutic payloads, potentially increasing efficacy while decreasing toxicity. To that end, this review considers small molecule-mediated regulation and signaling in bacteria. We first discuss some of the most prominent applications and aspirations for responsive cell-based therapeutics. We then describe the transport, signaling, and regulation associated with three classes of molecules that may be exploited in the engineering of therapeutic bacteria: amino acids, fatty acids, and quorum-sensing signaling molecules. We also present examples of existing engineering efforts to generate cells that sense and respond to levels of different small molecules. Finally, we discuss future directions for how small molecule-mediated regulation could be harnessed for therapeutic applications, as well as some critical considerations for the ultimate success of such endeavors. WIREs Syst Biol Med 2018, 10:e1405. doi: 10.1002/wsbm.1405 This article is categorized under: Biological Mechanisms > Cell Signaling Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Therapeutic Methods.

Metabolic changes accompany tumor progression and metastatic dissemination of cancer cells. Yet, until recently, metabolism has received little attention in the study of cancer metastasis. Cancer cells undergo significant metabolic rewiring as they acquire metastatic traits and adapt to survive in multiple environments with varying nutrient availability, oxygen concentrations, and extracellular signals. Therefore, to effectively treat metastatic cancer, it is important to understand the metabolic strategies adopted by cancer cells during the metastatic process. Here, we focus on the metabolic pathways known to play a role in cancer metastasis, including glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation, amino acid metabolism, and fatty acid metabolism. Recent studies have uncovered roles for these pathways in cellular events that promote metastasis, including reactive oxygen species-mediated signaling, epigenetic regulation, and interaction with the extracellular matrix. We also discuss the metabolic interplay between immune cells and cancer cells supporting metastasis. Finally, we highlight the current limitations of our knowledge on this topic, and present future directions for the field. WIREs Syst Biol Med 2018, 10:e1406. doi: 10.1002/wsbm.1406 This article is categorized under: Biological Mechanisms > Metabolism.