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Local Control of Microvascular Perfusion

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Local control of microvascular perfusion refers to the ability of individual tissues to maintain a relative constancy of hemodynamics in the face of changing perfusion pressure while meeting metabolic demands appropriately. The regulation of local blood flow, or autoregulation, and its underlying mechanisms have been a subject of considerable interest for over 100 years. Particular focus has been placed on the acute interaction of myogenic (pressure-induced) and metabolic (local production of vasodilator metabolites) parameters and how they interact with flow (shear stress)-dependent and conduction-based mechanisms to produce integrated local vascular network responses (for example, as seen during reactive and functional hyperemia). This monograph discusses each of these vasoregulatory phenomena while also considering evidence for their underlying cellular mechanisms. Further, an attempt is made to integrate the information into complex in vivo situations and consider their relevance to pathophysiological situations.

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Several physiological mechanisms act to regulate renal potassium excretion and distribution. Together they comprise an integrated control system that may be envisioned as being made up of several interacting negative feedback control mechanisms, all affecting removal of potassium from the extracellular fluid by renal excretion or transfer across cell membranes into or out of the intracellular compartment. The intent of this presentation is to describe the mechanisms of potassium regulation, beginning in Chapter 1 with an overview of the system, Chapter 2 with mechanisms that determine movement of potassium between the extracellular and intracellular compartments, in Chapter 3 focusing on renal tubular transport systems, and in Chapter 4 presenting the mechanisms of control of aldosterone secretion. Greatest emphasis will be on describing the integrated functions of the components, in Chapter 5, as they operate together in a system to regulate extracellular potassium concentration in response to commonly encountered challenges. In addition, interactions between potassium regulation and commonly used medications will be considered in Chapter 6, and in Chapter 7 the causes and treatment of dysregulation of potassium will be discussed.
Table of Contents: Preface / Introduction / Regulaton of Potassium Distribution / Potassium Transport in Segments of the Nephron / Regulation of Potassium Excretion / Control of Aldosterone Secretion / System Analysis of Potassium Regulation / Pharmacotherapeutics Interactions / Disorders of Potassium Control / References / Author Biography

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Stem Cells and Progenitors in Liver Development

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The human liver is a dynamic organ throughout life, but no more so than during prenatal development. The liver performs many essential functions associated with metabolism, immunity and blood production. These diverse functions are performed by a variety of cell types that have the capacity for growth, allowing the liver to regenerate cells lost due to aging, infection or injury. Various stem cell populations are at the core of the liver's potential for regeneration, which are most active during embryonic and fetal development, when the liver undergoes rapid growth. Consequently, the prenatal liver represents a unique opportunity to study the precursor cells that give rise to all liver cells at their time of greatest activity. Herein, we focus on the early development of the human liver from the perspective of the stem cells and their many lines of progeny that generate the hepatic, endothelial, mesenchymal and hematopoietic cells that comprise the fetal liver. Understanding the developmental relationships, growth control and cellular interactions among these cells is crucial to our understanding of liver development and function during prenatal life. This knowledge also provides insight into the development of cellular therapies, transplantation and the treatment of cancers.

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Emerging Roles for Hippocampal Adult Neural Stem Cells in Memory

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Approximately 50 years ago, newly generated neurons were discovered in the adult hippocampus of the rat brain. This discovery contradicted a key principle in mammalian developmental neurobiologythat all the neurons of the brain are made during early developmentand led to intensive study to find out how new neurons are generated and how the process of neurogenesis is regulated. Since then, a unique population of adult neural stem cells has been identified, and many of the molecular pathways that control their self-renewal, proliferation, and cell fate have been elucidated. However, the presence of new neurons in the adult brain also poses intriguing functional questions that have, as yet, gone largely unanswered. Why is adult neurogenesis restricted to select brain regions? What functional benefit do these new cells confer? Indeed, the field of adult neurogenesis offers a unique opportunity to study naive neurons as they mature, form connections with existing neural networks, and begin to participate in information processing. We review the basics of adult NSC biology and the maturation of newborn neurons. In particular, we focus on new neurons in the hippocampus, and how they contribute to function in this key memory-forming structure of the brain.

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The study of mental health disorders and the genetics behind these disorders can be greatly enhanced by the use of induced pluripotent stem cells (iPSC). Since many mental health disorders develop after puberty, the only way in which to study the genetic mechanism of these diseases previously was through cellular surrogates, such as blood or cultured fibroblasts. Having the ability to reprogram adult cells to the pluripotent stage provides the capacity to study the onset of these disorders during a culture model of neural development and to include the impact of genetic risk factors and potential environmental triggers. Working with the National Institute of Mental Health (NIMH), the Rutgers Cell and DNA Repository (RUCDR) has begun banking iPSC source cells and converting those source cells into iPSC for distribution to the scientific community. Although initial protocols were developed to reprogram fibroblasts, the ability to reprogram blood cells has several advantages including less invasive collection, less post collection manipulation, and the large number of samples in existing collections. Here, we provide detailed protocols for reprogramming either fibroblasts with retroviral vectors or cryopreserved lymphocytes with Sendai viral vectors. Our goal is to support the discovery of effective treatments for mental health disorders.

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Non-peptide Inhibitors of Proprotein Convertase Subtilisin Kexins (PCSKs)

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An Overall Review of Existing and New Data

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The Ca+2-dependent mammalian Proprotein Convertase Subtilisin Kexins (PCSKs) or Proprotein/ Prohormone Convertases (PCs) are a family of endoproteases that play critical roles not only in normal development and metabolism but also in various physiological and pathological conditions. These were initiated by the proteolytic processing of large inactive proproteins into their shorter bioactive mature forms by the PCSK enzymes. These events take place in a highly selective, orchestrated, and stepwise manner. Among the various proprotein substrates of PCSK enzymes, particularly important are the precursor growth factors that include proPDGF-A, B, proIGF-1, 2 and proVEGF-C because of their strong implications in neoplasia initiation, progression, and metastasis. As a result of these findings, PCSK enzymes, particularly furin or PCSK3, became a major target for possible interventions of cancer via the use of their selective inhibitors. Significant progress has been accomplished in the development of peptide and protein-based PCSK inhibitors. However, non-peptide PCSK9 inhibitors are more preferable because of their drug-like and other characteristics. So far, a few non-peptide inhibitors of PCSK enzymes of various types of chemical structures have been described in the literature. These include (i) Carbocyclic compounds of diterpene and streptamine class. (ii) Nitrogen (N)-based heterocyclic compounds of various types and chemical structures such as (a) pyrrolidine bis piperazines, (b) Cu/Zn chelating terpyridine derivatives; (iii) Oxygen (O)-based Heterocyclic compounds of varying types of chemical structures such as (a) Flavonoids, (b) Coumarins of simple and dimeric types, (c) Quinonoids, (d) Iridoids; (iv) Aromatic compounds such as (a) Aryl guanidino and amidino derivatives, (b) Naphthyl fluorescein derivative, and (c) Phenyl Arsonic acids; and (v) C2-symmetrical aromatic azo-compounds. When measured against a small peptidyl-MCA fluorogenic substrate, these inhibitors displayed IC50 values ranging from nM to M. A number of these inhibitors exhibited significant anti-PCSK activity when tested in ex vivo or cell culture conditions. This article provides an overall review of all non-peptide PCSK inhibitors so far reported in the literature along with those we identified recently for the first time and not yet published. The potential implications of these molecules as biochemical, therapeutical, or clinical agents will also be discussed.

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Ajoy Basak, Biswanath Dinda, Prasenjit Rudra Pal, Priyambada Mishra, Utpal Chandra De, A. Majid Khatib, Ph.D.

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Neuropeptides mediate their effects by binding and activating receptors that are responsible for converting these extracellular stimuli into intracellular responses. Most neuropeptides interact with G protein-coupled receptors that transduce the signal by activating heterotrimeric G proteins leading to alterations in second messenger systems to amplify the signal and elicit the intracellular response. In this review, we describe the general structure of G protein-coupled receptors including the information obtained from crystal structure determination that has given an insight into the activation mechanism of these receptors. In addition, we summarize the components of the signal transduction system (including G proteins, effectors and second messengers generally activated by the neuropeptide receptors). Using select examples of neuropeptide-receptor systems, we highlight the neuropeptides and corresponding receptors involved in modulation of pain and analgesia, body weight regulation, and hormonal regulation. Finally, we discuss the enzyme-linked tyrosine kinase receptors activated by growth factors and discuss the emerging concepts in targeting neuropeptide receptors for the identification of novel therapeutics targeting these systems.

Table of Contents: Abbreviations / Overview of Neuropeptide Receptors / G Protein-Coupled Receptors: General Structure & Function / G Protein-Coupled Receptor Signaling / Neuropeptide Processing and Regulation / Neuropeptide Receptors / Perspectives / References

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Steven D. Stockton Jr., Jonathan H. Wardman, Ivone Gomes

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Proprotein Convertases in Gynecological Cancers

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Gynecological cancers include neoplasias of internal female genital organs, mainly ovarian, endometrial and cervical tumors, and cancers of the external female genital structures. Current scientific evidence indicates that both up- and down-regulation of the expression of PCs are part of the multiple changes occurring in these gynecological tumors. Nevertheless, the physiological significance of this puzzling pattern of PC expression remains elusive. The fact that PCs can activate both pro- and anticarcinogenic substrates may indicate that the nature of the overexpressed substrates in certain cancer types could determine the final outcome; i.e., slowing or accelerating cancer development.

The expression of PCs in gynecological cancers and the correlation of this expression with other markers may facilitate preventive and therapeutic interventions in at-risk populations. Several studies single out furin as the main PC overexpressed in ovarian and endometrial cancers. For instance, furin expression has been associated with five-year survival in ovarian cancer, and measurements of furin activity in cells obtained by lavage constitute a non-invasive diagnostic tool for endometrial cancer. The other ubiquitously expressed PCs, PC5, PACE4, and PC7 do not show any changes with respect to normal controls or are decisively silenced, as indicated by studies on PACE4 expression and regulation in both ovarian and endometrial tumors.

PCs activate crucial substrates implicated in the progression of gynecological cancers, including adhesion molecules, metalloproteinases, and viral proteins. In the first place, furin, and possibly the other PCs, process both E- and N-cadherin. Processing of these molecules results in variations of cell adhesiveness. The pattern of expression of N- and especially E-cadherin varies during tumor development, as well as in the stages of either epithelial to mesenchymal or mesenchymal to epithelial transitions. E-cadherin is up-regulated during initial steps in ovarian tumor development, whereas N-cadherin follows a more complex expression pattern. Nevertheless, cadherin processing requires fully functional PC activity, a feature that may be explored for future therapeutics applications. Furthermore, PCs drive the activation of metalloproteinases, especially the membrane-type metalloproteases MMP-14 and MMP-15, and also possibly MMP-9. The activity of these metalloproteases promotes the invasion into the omentum and other peritoneal structures, facilitating the degradation of collagens and other extracellular components. Finally, the role of furin in enabling papilloma virus infection, one of the main etiological factors in the development of exocervical cancer, and possibly vaginal and vulvar carcinoma, cannot be overemphasized.

These experimental evidences suggest that careful targeting of PCs in gynecological cancer may represent a feasible strategy to deter tumor progression.

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Daniel Bassi, Jirong Zhang, Andres J.P. Klein-Szanto, A. Majid Khatib, Ph.D.

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Brain Development and Sexual Orientation

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Sexual orientation (homo- vs. heterosexuality) is one of many sex differences observed in humans. Sex differences can result from differential postnatal experiences (interaction with parents, environment) or from biological factors (hormones and genes) acting pre- or postnatally. The first option is often favored to explain sexual orientation although it is supported by little experimental evidence. In contrast, many sexually differentiated behaviors are organized during early life by an irreversible action of sex steroids. In particular, the preference for a male or female sex partner is largely determined in rodents by embryonic exposure to sex steroids. The early action of these steroids also seems to affect sexual orientation in humans. Indeed, clinical conditions associated with major endocrine changes during embryonic life often result in an increased incidence of homosexuality. Furthermore, multiple sexually differentiated behavioral, physiological, or even morphological traits that are known to be organized by prenatal steroids, at least in animals, are significantly different in homo- and heterosexual populations. Thus, prenatal endocrine (or genetic) factors seem to influence significantly human sexual orientation even if a large fraction of the variance remains unexplained to date. The possible interaction between biological factors acting prenatally and postnatal social influences remains to be investigated.

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Pattern formation has fascinated biologists since the time of Aristotle, but only recently have new tools begun to reveal the underlying mechanisms that create these patterns during development. In particular, the central nervous system is dynamically patterned and highly modular, ranging from nuclear cell clusters in the brain stem and spinal cord to the elaborate cytoarchitecture of the neocortex. Similar developmental processes divide brain structures such as the cerebral cortex, basal ganglia, superior colliculus, and cerebellum into these sub-compartments. The way neural modules form and the mechanisms that establish connectivity between these modules is one of the most complex problems in neuroscience and also one of the most important. This monograph focuses on pattern formation in the developing cerebellum.



Table of Contents: Background and Rationale / Overview of Cerebellar Organization / The Modular Cerebellum / Overview of Cerebellar Development / Establishment and Organization of the Cerebellar Anlage / Development and Patterning of Purkinje Cells / Development and Patterning of Granule Cells / Development of Afferent Projections / Patterning of Other Cells in the Cerebellum: Inhibitory Interneurons, Unipolar Brush Cells, and Glia / Neural Cell Death in Normal Development / Conclusion and Summary / Author Biographies

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From Immunotherapy of Cancer to the Discovery of Kidney Cancer Genes

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I had the good fortune to work at the National Cancer Institute from 1965 to 2005. The National Cancer Institute provided an environment that permitted my curiosity to flourish. Colleagues, particularly Marston Linehan, were essential to performance of the work.

The work described in this manuscript was performed during a period of rapid advances in genetics. I was able to apply my clinical training and new genetic tools to study human kidney cancer.

With the support of the National Cancer Institute, I was able to canvas physicians throughout the United States and Canada for referrals of families with multiple members affected with renal cancer. I was able to visit these families in their communities and determine the clinical and genetic features of their hereditary susceptibility to renal cancer, and to bring these families to Bethesda for comprehensive examinations.

Using DNA analytic tools, we were able to identify several tumor suppressor genes that play major roles in the pathogenesis of human renal carcinoma thus opening up new fields for biochemical research into the pathogenesis of human renal carcinoma.

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Clinical and Molecular Aspects of Motor Neuron Disease

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In this e-book, motor neuron disease (MND) shall refer to amyotrophic lateral sclerosis (ALS), the most common neurodegenerative disorder affecting both the upper and lower motor neurons. With the discovery of C9ORF72 expansions in approximately 10% of all MND cases, in certain populations, we stand at the brink of a new era of MND research and hopefully treatment facilitated by the ability to associate a relatively large group of patients with a similar disease mechanism. This review will summarise both current clinical management of MND and our present understanding of the molecular pathogenesis of MND. Study of C9ORF72-MND has the potential to rapidly advance both of these aspects in the coming years.

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Pamela J. Shaw, Thomas Jenkins, Johnathan Cooper-Knock

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The coronary circulation is unique in that it is responsible for maintaining adequate oxygen and substrate delivery to the organ that generates the pressure needed to drive blood throughout the entire circulatory system. In the simplest terms, coronary blood flow is directly proportional to the arterial pressure gradient across the coronary vasculature and inversely proportional to coronary vascular resistance. However, myocardial perfusion is collectively regulated by a complex variety of mechanisms which include: (1) extravascular compressive forces; (2) diastolic time fraction; (3) coronary perfusion pressure; (4) myocardial metabolism (local metabolic factors); (5) endothelial-derived substances; (6) neuro-humoral influences; and (7) arterial oxygen tension and content. This book considers each of these determinants with particular emphasis on the functional interaction between the physical and biological determinants of myocardial perfusion. Pathophysiologic aspects of coronary atherosclerosis and cardiovascular disease states are also considered.

Table of Contents: Abbreviations / Acknowledgments / Introduction / Basic Coronary Anatomy / Myocardial-Coronary Interaction / Arterial Pressure and Autoregulation / Local Metabolic Control / Endothelial-Dependent Control / Neural Activation and Circulating Hormones / Coronary Stenosis, Myocardial Ischemia, and Effects of Disease / Summary / Reference List / Author Biography

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The lung receives the entire cardiac output from the right heart and must load oxygen onto and unload carbon dioxide from perfusing blood in the correct amounts to meet the metabolic needs of the body. It does so through the process of passive diffusion. Effective diffusion is accomplished by intricate parallel structures of airways and blood vessels designed to bring ventilation and perfusion together in an appropriate ratio in the same place and at the same time. Gas exchange is determined by the ventilation-perfusion ratio in each of the gas exchange units of the lung. In the normal lung ventilation and perfusion are well matched, and the ventilation-perfusion ratio is remarkably uniform among lung units, such that the partial pressure of oxygen in the blood leaving the pulmonary capillaries is less than 10 Torr lower than that in the alveolar space. In disease, the disruption to ventilation-perfusion matching and to diffusional transport may result in inefficient gas exchange and arterial hypoxemia. This volume covers the basics of pulmonary gas exchange, providing a central understanding of the processes involved, the interactions between the components upon which gas exchange depends, and basic equations of the process.

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The Actin Cytoskeleton and the Regulation of Cell Migration

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The mammalian cytoskeleton is an internal framework of actin, tubulin, and intermediate filament proteins. Proteins of these three classes assemble non-covalently into filamentous polymers that support the structural integrity of the relatively fragile lipid plasma membrane. In addition, cytoskeletal polymers provide the mechanical strength that hold a cell together and anchor it to its growth substrate. The cytoskeleton must also have the capacity for rapid and substantial remodeling and provide the motive and tractor force necessary to drive motility. As such, the cytoskeleton has a functional duality: sufficiently rigid to prevent plasma membrane deformation but pliable enough to allow for cytokinesis; sufficiently adhesive to allow for traction but dynamic enough to allow movement from one place to another. A major research challenge in cytoskeleton biology is to understand how cytoskeletal proteins assemble and dissemble in support of physiological processes. This chapter will focus on the role of the actin cytoskeleton in cell migration. More specifically, we will focus on the actin cytoskeleton of vertebrate cells.

Table of Contents: Introduction / The Fundamentals of Actin Polymerization / Accessory Proteins Regulate Actin Polymerization and Assembly / Cellular Actin Structure / Cell Migration / Summary of Cell Migration / References / Author Biography

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Phagocytosis is an evolutionarily conserved mechanism that serves as the first line of host defense in multicellular organisms. The traditional definition of phagocytosis involves the engulfment and degradation of large solid particles (>0.5 m), initiated by receptor activation on phagocytes. It forms an essential aspect of innate immunity through the uptake and destruction of infectious pathogens, while also participating in the removal of apoptotic cells during tissue remodeling and development. Professional phagocytes, such as macrophages, neutrophils, and dendritic cells, are well equipped with a wide range of phagocytic receptors. In addition, these specialized leukocytes can signal to lymphocytes within the adaptive arm of host immunity. This review emphasizes the role of two well-characterized opsonic receptors, the Fc receptor and the complement receptor, CR3 in macrophages. In particular, it focuses on the different mechanisms employed by these receptors during particle recognition and phagocytic uptake. Bacterial species often manipulate phagocyte signaling in order to evade their engulfment and degradation and consequently provide further insight into key regulators of the phagocytic process. Finally, we draw attention to the physiological relevance of studying the simultaneous engagement of multiple phagocytic receptors, in order to better understand receptor crosstalk and the underlying coordination of downstream signaling for efficient phagocytosis.

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The ATP-binding cassette (ABC) transporter genes are ubiquitous in the genomes of all vertebrates so far studied. The human ABC transporter superfamily contains 48 genes, subdivided into 7 subfamilies ranging from A to G (based on sequence homology of their nucleotide binding domains). The ABC proteins encoded by these genes are ATP-driven transmembrane pumps, some of which possess the capacity to efflux harmful toxic substances and therefore play a key role in xenobiotic defense. ABC proteins have been evolutionarily conserved from bacteria to humans and multiple gene duplication and deletion events in the ABC genes indicate that the process of gene evolution is still ongoing. Polymorphisms and variations in these genes are linked to variations in expression, function, drug disposition, and drug response. Single nucleotide polymorphisms (SNPs) in these genes could be markers of individual risk for adverse drug reactions or susceptibility to complex diseases. The pharmacogenetics of this unique family of transporters is still under study; however, in the context of human health, it is a well-known fact that variations in these transporters are the underlying cause for several human diseases including cystic fibrosis, Pseudoxanthoma elasticum (PXE), and X-linked adenoleukodystrophy (X-ALD).

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Bioactive Peptides Produced by Limited Proteolysis

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Proteins are considered supremely important for the organization, survival, and functioning of living organisms. They were considered stable and static molecules until the early 1940s, when RudolphSchoenheimer demonstrated that proteins exist in a constant dynamic process of synthesis and degradation (proteostasis), absolutely essential for life. Since then, general and limited protein degradation became some of the most fascinating aspects of biological sciences. This book is focused on a particular aspect of protein degradation, namely, limited proteolysis, which gives rise to bioactive peptides as a result of the enzymatic action of proteinases and peptidases, which are enzymes that hydrolyze specific peptide bonds of proteins and peptides, respectively. In a broad sense, bioactive peptides are any fragment of endogenous or exogenous proteins able to elicit either physiological or pathological activities. Here, we aim at presenting to the readers that bioactive peptides are not merely produced through random processes during protein degradation, but rather through a well-organized enzymatic process that is deeply integrated in the homeostatic processes of living organisms.

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Endocrine Disruptors and The Developing Brain

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The field of endocrine disruption has been the focus of increasing attention from scientists and the general public in the past 30 years, amidst concerns that exposure to environmental chemicals with the potential to alter endocrine system function, known as endocrine disrupting chemicals (EDCs), may be contributing to an overall decline in wildlife populations and the reproductive health of humans. These concerns are based on observations of adverse effects of EDCs on marine and land animals, an increased incidence of reproductive and endocrine disease in humans, epidemiological evidence for links between body burden and disease, and endocrine disruption in laboratory animals following exposure to EDCs. Owing to its role in regulation of endocrine function as well as its responsiveness to hormones, the developing brain is an especially vulnerable target for many classes of EDCs. This book will address the evidence for EDC action on the developing brain, organized into 7 chapters. Topics covered include background about EDCs, evidence for exposures, concerns about EDC effects in the developing organism, and particularly on the developing nervous system, how EDCs perturb the brain's neuroendocrine systems, transgenerational epigenetic effects of EDCs, EDC effects on non-reproductive behaviors, and future perspectives. This is the first book completely dedicated to understanding links between EDCs and the developing brain, an area of emerging importance for human health.

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Epithelial cells exhibit an apicalbasolateral axis of polarity that is generated during embryogenesis, is maintained throughout adult life in the face of constant cell regeneration, and is perturbed in several epithelial-associated diseases. We examine the structural and functional organization of epithelial tissues, as well as the events critical for generating epithelial asymmetry including vectorial trafficking of proteins and lipids, association of signaling and polarity proteins with subdomains of the plasma membrane, and 3D orientation of epithelial cells in response to cellcell and cellmatrix interactions. As a paradigm to understand how these three processes are coordinated in time and space, we explore apical lumen formation. We also examine the final steps in epithelial morphogenesis, including brush border morphogenesis and ciliogenesis. Finally, we provide examples of disease processes that result from defects in epithelial polarity including diabetes insipidus, microvillar inclusion disease, hereditary deafness, ciliopathies, and cancer.