Use of high throughput genomic tools for the study of endothelial cell biology

The endothelium is an active, dynamic and heterogeneous organ. It lines the vessels in every organ system and regulates diverse and important biological functions. Over the past several years researchers have gained enormous insights into endothelial cell function in physiological processes such as coagulation and vascular reactivity, and pathophysiological disease states such as inflammation and atherosclerosis. Despite our expanding knowledge of endothelial cell biology, the molecular mechanisms underlying these functions remain largely unknown. The newly developed high throughput genomic tools and accompanying analytical methods provide powerful approaches for identifying new endothelial cell genes and characterizing their role in health and disease. Here, we review some of the recent genomics and proteomic advances that are providing new methodologies for endothelial cell and vascular biology research.     

Bioarcheology has a “health” problem: Conceptualizing “stress” and “health” in bioarcheological research

This article provides a critical historical overview of the stress concept in bioarcheological research and critically evaluates the term “health” in reference to skeletal samples. Stress has a considerable history in 20th century physiological research, and the term has reached a critical capacity of meaning. Stress was operationalized around a series of generalized physiological responses that were associated with a deviation from homeostasis. The term was incorporated into anthropological research during the mid-20th century, and further defined in bioarcheological context around a series of skeletal indicators of physiological disruption and disease. Emphases on stress became a predominate area of research in bioarcheology, and eventually, many studies utilized the terms “health” and “stress” interchangeably as part of a broader, problem-oriented approach to evaluating prehistoric population dynamics. Use of the term “health” in relation to skeletal samples is associated with the intellectual history of bioarcheological research, specifically influences from cultural ecology and processualist archeology and remains problematic for two reasons. First, health represents a comprehensive state of well-being that includes physiological status and individual perception, factors that cannot be readily observed in skeletal samples. Second, the categorization of populations into relative levels of health represents a typological approach, however unintentional. This article advocates for the integration of methodological and theoretical advances from human biology and primatology, while simultaneously incorporating the theoretical constructs associated with social epidemiology into bioarcheological research. Such an approach will significantly increase the applicability of bioarcheological findings to anthropological and evolutionary research, and help realize the goal of a truly relevant bioarcheological paradigm. Am J Phys Anthropol 155:186–191, 2014. © 2014 Wiley Periodicals, Inc.     

Extracellular matrix bioengineering and systems biology approaches in liver disease

The extracellular matrix (ECM) in the liver as well as in many organs comprises a peripheral network linking numerous macromolecules typically classified into collagens, microfibrillar proteins, proteoglycans, chemokines, growth factors and glycoproteins. In addition to its role as an essential structural and physiological component, it plays a vital role in driving key cellular events such as cell adhesion, migration, proliferation, differentiation and survival. Any structural inherited or acquired defect and/or metabolic or pathologic alteration in the hepatic ECM may cause cellular and organ responses leading to the development or progression of liver disease. Therefore, the ECM molecules are key players in tissue engraftment and in the pathophysiology of liver disease. In this review we provide a snapshot on current efforts for understanding its role in physiological and non-physiological states, by describing how tissue engineering platforms can enhance in vitro and in vivo models of liver disease, by providing examples where bioengineered ECM can serve as systems biology approaches to study the ECM, and then by evaluating pathological protein regulatory networks in the liver using systems biology tools. These approaches hold great promise for future research.     

Fish models in prion biology: Underwater issues

Transmissible spongiform encephalopathies (TSEs), otherwise known as prion disorders, are fatal diseases causing neurodegeneration in a wide range of mammalian hosts, including humans. The causative agents - prions - are thought to be composed of a rogue isoform of the endogenous prion protein (PrP). Beyond these and other basic concepts, fundamental questions in prion biology remain unanswered, such as the physiological function of PrP, the molecular mechanisms underlying prion pathogenesis, and the origin of prions. To date, the occurrence of TSEs in lower vertebrates like fish and birds has received only limited attention, despite the fact that these animals possess bona fide PrPs. Recent findings, however, have brought fish before the footlights of prion research. Fish models are beginning to provide useful insights into the roles of PrP in health and disease, as well as the potential risk of prion transmission between fish and mammals. Although still in its infancy, the use of fish models in TSE research could significantly improve our basic understanding of prion diseases, and also help anticipate risks to public health. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.     

From “Us vs. Them” to “Shared Risk”: Can Animals Help Link Environmental Factors to Human Health?

Linking human health risk to environmental factors can be a challenge for clinicians, public health departments, and environmental health researchers. While it is possible that nonhuman animal species could help identify and mitigate such linkages, the fields of animal and human health remain far apart, and the prevailing human health attitude toward disease events in animals is an “us vs. them” paradigm that considers the degree of threat that animals themselves pose to humans. An alternative would be the development of the concepts of animals as models for environmentally induced disease, as well as potential “sentinels” providing early warning of both noninfectious and infectious hazards in the environment. For such concepts to truly develop, critical knowledge gaps need to be addressed using a “shared risk” paradigm based on the comparative biology of environment–host interactions in different species.     

S-nitrosylation in health and disease

S-nitrosylation is a ubiquitous redox-related modification of cysteine thiol by nitric oxide (NO), which transduces NO bioactivity. Accumulating evidence suggests that the products of S-nitrosylation, S-nitrosothiols (SNOs), play key roles in human health and disease. In this review, we focus on the reaction mechanisms underlying the biological responses mediated by SNOs. We emphasize reactions that can be identified with complex (patho)physiological responses, and that best rationalize the observed increase or decrease in specific classes of SNOs across a spectrum of disease states. Thus, changes in the levels of various SNOs depend on specific defects in both enzymatic and non-enzymatic mechanisms of nitrosothiol formation, processing and degradation. An understanding of these mechanisms is crucial for the development of an integrated model of NO biology, and for effective treatment of diseases associated with dysregulation of NO homeostasis.     

Algorithms for mapping of mRNA targets for microRNA

MicroRNAs (miRNAs) are involved in human health and disease as endogenous suppressors of the translation of coding genes. At this early point of time in miRNA biology, it is important to identify specific cognate mRNA targets for miRNA. Investigation of the significance of miRNAs in disease processes relies on algorithms that hypothetically link specific miRNAs to their putative target genes. The development of such algorithms represents a hot area of research in biomedical informatics. Lack of biological data linking specific miRNAs to their respective mRNA targets represents the most serious limitation at this time. This article presents a concise review addressing the most popular concepts underlying state-of-the-art algorithms and principles aimed at target mapping for specific miRNAs. Strategies for improvement of the current bioinformatics tools and effective approaches for biological validation are discussed.     

New ways of thinking about (and teaching about) intestinal epithelial function

This article summarizes a presentation made at the Teaching Refresher Course of the American Physiological Society, which was held at the Experimental Biology meeting in 2007. The intestinal epithelium has important ion transport and barrier functions that contribute pivotally to normal physiological functioning of the intestine and other body systems. These functions are also frequently the target of dysfunction that, in turn, results in specific digestive disease states, such as diarrheal illnesses. Three emerging concepts are discussed with respect to ion transport: the complex interplay of intracellular signals that both activate and inhibit chloride secretion; the role of multiprotein complexes in the regulation of ion transport, taking sodium/hydrogen exchange as an example; and acute and chronic regulation of colonic sodium absorption, involving both sodium channel internalization and de novo synthesis of new channels. Similarly, recently obtained information about the molecular components of epithelial tight junctions and the ways in which tight junctions are regulated both in health and disease are discussed to exemplify ways to teach about intestinal barrier properties. Finally, both genetically determined intestinal diseases and those arising as a result of infections and/or inflammation are described, and these can be used as the means to enhance the basic and clinical relevance of teaching about intestinal epithelial physiology as well as the impact that the understanding of such physiology has had on associated therapeutics. The article also indicates, where relevant, how different approaches may be used effectively to teach related concepts to graduate versus medical/professional student audiences.     

The functional genomics of guanylyl cyclase/natriuretic peptide receptor-A: perspectives and paradigms

The cardiac hormones atrial natriuretic peptide and B-type natriuretic peptide (brain natriuretic peptide) activate guanylyl cyclase (GC)-A/natriuretic peptide receptor-A (NPRA) and produce the second messenger cGMP. GC-A/NPRA is a member of the growing family of GC receptors. The recent biochemical, molecular and genomic studies on GC-A/NPRA have provided important insights into the regulation and functional activity of this receptor protein, with a particular emphasis on cardiac and renal protective roles in hypertension and cardiovascular disease states. The progress in this field of research has significantly strengthened and advanced our knowledge about the critical roles of Npr1 (coding for GC-A/NPRA) in the control of fluid volume, blood pressure, cardiac remodeling, and other physiological functions and pathological states. Overall, this review attempts to provide insights and to delineate the current concepts in the field of functional genomics and signaling of GC-A/NPRA in hypertension and cardiovascular disease states at the molecular level.     

Using measures of single‐cell physiology and physiological state to understand organismic aging

Genetically identical organisms in homogeneous environments have different lifespans and healthspans. These differences are often attributed to stochastic events, such as mutations and ‘epimutations’, changes in DNA methylation and chromatin that change gene function and expression. But work in the last 10 years has revealed differences in lifespan‐ and health‐related phenotypes that are not caused by lasting changes in DNA or identified by modifications to DNA or chromatin. This work has demonstrated persistent differences in single‐cell and whole‐organism physiological states operationally defined by values of reporter gene signals in living cells. While some single‐cell states, for example, responses to oxygen deprivation, were defined previously, others, such as a generally heightened ability to make proteins, were, revealed by direct experiment only recently, and are not well understood. Here, we review technical progress that promises to greatly increase the number of these measurable single‐cell physiological variables and measureable states. We discuss concepts that facilitate use of single‐cell measurements to provide insight into physiological states and state transitions. We assert that researchers will use this information to relate cell level physiological readouts to whole‐organism outcomes, to stratify aging populations into groups based on different physiologies, to define biomarkers predictive of outcomes, and to shed light on the molecular processes that bring about different individual physiologies. For these reasons, quantitative study of single‐cell physiological variables and state transitions should provide a valuable complement to genetic and molecular explanations of how organisms age.     

Molecular and physiological manifestations and measurement of aging in humans

Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time‐dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age‐related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well‐described molecular and cellular hallmarks and discuss physiological changes of aging at the organ‐system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging.     

Review: What innovations in pain measurement and control might be possible if we could quantify the neuroimmune synapse?

It has taken more than 40 years for the fields of immunology and neuroscience to capture the potential impact of the mechanistic understanding of how an active immune signalling brain might function. These developments have grown an appreciation for the immunocompetent cells of the central nervous system and their key role in the health and disease of the brain and spinal cord. Moreover, the understanding of the bidirectional communication between the brain and the peripheral immune system has evolved to capture an understanding of how mood can alter immune function and vice versa. These concepts are rapidly evolving the field of psychiatry and medicine as a whole. However, the advances in human medicine have not been capitalised upon yet in animal husbandry practice. Of specific attention are the implications that these biological systems have for creating and maintaining heightened pain states. This review will outline the key concepts of brain–immune communication and the immediate opportunities targeting this biology can have for husbandry practices, with a specific focus on pain.     

Physiological anthropology: past and future

Environmental studies in adaptive human biology by North American anthropologists have a history of strong investigative research. From both laboratory and field work, we have gained major insights into human response to physical and social challenges. While these results were considered by most professionals to belong within evolutionary biology, in fact the intellectual structure sprang almost entirely from physiological equilibrium models. Consequently, physiological process itself was the focus. Further, most of the physiological patterns were not linked directly to important outcomes such as work output, reproductive success or survival.About 1975, American physiological anthropologists, led by Paul Baker, turned to studies of health, change and stress response. These studies were strong, but were still neither genetic nor evolutionary in intellectual structure. Evolutionary human biology was taken over by a new body of theory now called "behavior ecology", positing that selfish genes control human behavior to promote their own reproduction. This was paralleled by strong use of evolutionary theory in some areas of molecular biology. However, although physiological anthropologists have not focused on evolution, we have been developing powerful causal models that incorporate elements of physiology, morphology, physical environment and cultural behavior. In these "proximate" biocultural models, it is of little importance whether outcomes such as work or energy management are genetically based.Our future offers two major challenges. First, we must confirm causal links between specific physiological patterns and outcomes of practical importance to individuals and societies. Second, if we are to take our place in evolutionary biology, the one overarching theory of life on earth, we must understand the heritability of physiological traits, and determine whether they play a role in survival and reproduction.     

Metabolic pathway analysis: basic concepts and scientific applications in the post-genomic era.

This article reviews the relatively short history of metabolic pathway analysis. Computer-aided algorithms for the synthesis of metabolic pathways are discussed. Important algebraic concepts used in pathway analysis, such as null space and convex cone, are explained. It is demonstrated how these concepts can be translated into meaningful metabolic concepts. For example, it is shown that the simplest vectors spanning the region of all admissible fluxes in stationary states, for which the term elementary flux modes was coined, correspond to fundamental pathways in the system. The concepts are illustrated with the help of a reaction scheme representing the glyoxylate cycle and adjacent reactions of aspartate and glutamate synthesis. The interrelations between pathway analysis and metabolic control theory are outlined. Promising applications for genome annotation and for biotechnological purposes are discussed. Armed with a better understanding of the architecture of cellular metabolism and the enormous amount of genomic data available today, biochemists and biotechnologists will be able to draw the entire metabolic map of a cell and redesign it by rational and directed metabolic engineering.     

The emerging role for rat models in gene discovery

Rat models have been used for many decades to study physiological and pathophysiological mechanisms. Prior to the release of the rat genome and new technologies for targeting gene manipulation, the rat had been the underdog in the genomics era, despite the abundance of physiological data compared to the mouse. The overarching goal of biomedical research is to improve health and advance medical science. Translating human disease gene discovery and validation in the rat, through the use of emerging technologies and integrated tools and databases, is providing power to understand the genetics, environmental influences, and biology of disease. In this review we briefly outline the rat models, bioinformatics tools, and technologies that are changing the landscape of translational research. The strategies used to translate disease traits to genes to function, and, ultimately, to improve human health is discussed. Finally, our perspective on how rat models will continue to positively impact biomedical research is provided.     

In search of differentially expressed genes and proteins

A great challenge for modern cell biology is the successful examination of the co-expression of thousands of genes under physiological or pathological conditions and how the expression patterns define the different states of a single cell, tissue or a microorganism. Gene expression can be analyzed today on a large scale by advanced technical approaches for differential screening of proteins and mRNAs. The identification of differentially expressed mRNAs has been successfully applied to understand gene function and the underlying molecular mechanism(-s) of differentiation, development and disease state. Analysis of gene expression by the systematic mapping of thousands of proteins present in a cell or tissue can be achieved by the use of two-dimensional (2D) gel electrophoresis, quantitative computer image analysis, and protein identification techniques. In this article, we comment on some of these techniques and try to stress their advantages and drawbacks. We show how data from RNA/DNA mapping, sequence information from genome projects and protein pattern profiling can be linked with each other and annotated. These comprehensive approaches permit the study of differential gene and protein expressions in cells or tissues.     

Demystifying computer science for molecular ecologists

In this age of data‐driven science and high‐throughput biology, computational thinking is becoming an increasingly important skill for tackling both new and long‐standing biological questions. However, despite its obvious importance and conspicuous integration into many areas of biology, computer science is still viewed as an obscure field that has, thus far, permeated into only a few of the biology curricula across the nation. A national survey has shown that lack of computational literacy in environmental sciences is the norm rather than the exception [Valle & Berdanier (2012) Bulletin of the Ecological Society of America, 93, 373–389]. In this article, we seek to introduce a few important concepts in computer science with the aim of providing a context‐specific introduction aimed at research biologists. Our goal was to help biologists understand some of the most important mainstream computational concepts to better appreciate bioinformatics methods and trade‐offs that are not obvious to the uninitiated.