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Angiogenesis is the growth of blood vessels from the existing vasculature. The field of angiogenesis has grown enormously in the past 30 years, with only 40 papers published in 1980 and nearly 6000 in 2010. Why has there been this explosive growth in angiogenesis research? Angiogenic therapies provide a potential to conquer cancer, heart diseases, and more than 70 of life's most threatening medical conditions. The lives of at least 1 billion people worldwide could be improved with angiogenic therapy, according to the Angiogenesis Foundation. In this little book, we provide a simple approach to understand the essential elements of the angiogenic process, we critique the most powerful angiogenesis assays that are used to discover proangiogenic and antiangiogenic substances, and we provide an in-depth physiological perspective on how angiogenesis is regulated in normal, healthy tissues of the human body. All tissues of the body require a continuous supply of oxygen to burn metabolic substrates that are needed for energy. Oxygen is conducted to these tissues by blood capillaries: more capillaries can improve tissue oxygenation and thus enhance energy production; fewer capillaries can lead to hypoxia and even anoxia in the tissues. This means that angiogenic therapies designed to control the growth and regression of blood capillaries can be used to improve the survival of poorly perfused tissues that are essential to the body (heart, brain, skeletal muscle, etc.) and to rid the body of unwanted tissues (tumors). Table of Contents: Overview of Angiogenesis / Angiogenesis Assays / Regulation: Metabolic Factors / Regulation: Mechanical Factors / Glossary / References / Author Biographies

This book gives a basic and broad but innovative view of autism. It seeks to rupture stereotypes and stigmas and starts with the story and paintings of the artist Camila Falchi, who has an Autism Spectrum Disorder (ASD). Camila's art is evidence of the complexity of her internal world and its variety of themes, intensity of feelings, daydreaming, fantasy, and dreams. This complexity compels us to question and rethink our perceptions of the autism spectrum, the mind, and creativity. As a neurologist and a neuroscientist, our goal with this book is to disseminate knowledge about autism, its characteristics, and potentials by means of the example of this artist.

This book offers a comprehensive overview of Alexander disease, a rare and devastating neurological disorder that often affects the white matter of the brain and spinal cord. Its distinctive neuropathology consists of abundant Rosenthal fibers within astrocytes (one of the four major cell types of the central nervous system). Nearly all cases are caused by variants in the gene encoding the intermediate filament protein GFAP, but how these changes in GFAP lead to the widespread manifestations of disease is poorly understood. Astrocytes, while discovered over a century ago, are themselves still much of a mystery. They exhibit considerable diversity, defy precise definition, and yet actively regulate many aspects of nervous system functioning. We also have incomplete understanding of Rosenthal fibers, odd structures that contain GFAP as just one of many components. Whether they are toxic or protective is unknown. Moreover, Rosenthal fibers are not absolutely unique to Alexander disease, and are seen sporadically in a wide variety of other conditions, including brain tumors and multiple sclerosis. GFAP is the third unknown. It is an ancient protein, arising early in the evolution of vertebrates, but its role in normal biology is still a matter of debate. Yet Alexander disease shows, without a doubt, that changing just a single of its 432 amino acids can lead to catastrophe, not just in the astrocytes where GFAP is produced but also in the other cells with which astrocytes interact. Despite all of the unknowns, much has been learned in the past 20 years, and it is time to share this knowledge. This book is intended for recently diagnosed patients and families, as well as non-specialist researchers interested in this neurological disease. It covers historical origins, the state of current knowledge, and prospects for what lies ahead, with citations to the primary literature given throughout.

Scientists are deciphering the biology of the tumor cell at a level of detail that would have been hard to imagine just a decade or so ago. The development of high-throughput DNA sequencing and genomics technologies have allowed an understanding of the development, growth, survival, and spread of cancer cells in the body. From this information, we now have a basic blueprint or roadmap of how a single damaged cell can develop into a pre-malignant lesion, a primary tumor, and finally, a lethal tumor that may spread throughout the body and resist both medical therapy and host immune responses. In this book, we provide an overview of our current understanding of this cancer blueprint, which has been aided both by the study of familial cancer syndromes, in vitro studies of cancer cells, and animal models. Three classes of genes have emerged from these studies: tumor suppressor genes needed for normal growth control and DNA repair; oncogenes that regulate cell growth and survival, and epigenetic modifiers, enzymes that regulate the modification of DNA and the proteins that form chromatin. Each of these three classes of genes is mutated or altered at least once in virtually all malignant cancer cells. Current technologies permit the DNA sequencing of cancer exomes (coding gene sequencing), whole genomes, transcriptome (all expressed genes), and DNA methylation profiling. These studies show that all tumors have unique constellations of mutated, rearranged, amplified, and deleted genes. Single-cell sequencing further shows that there is extensive variation in individual cells in the tumor; that cancers evolve, and have many of the properties of a multi-cellular entity. Lastly, cancer cells, through mutations in epigenetic modifiers, can reprogram the genome and unlock entire developmental and gene expression pathways to adapt and survive in changing conditions. This reprogramming allows the tumor to elude the host body's defenses, radiotherapy, chemotherapy, and targeted therapy that we use in cancer treatment. Understanding this cancer blueprint paves the way for the development of future therapies to treat and eliminate cancer.

The nematode C. elegans is one of the most important model organisms for understanding neurobiology. Its completely mapped neural connectome of 302 neurons and fully characterized and stereotyped development have made it a prototype for understanding nervous system structure, development, and function. Fifty-six out of C. elegans'total of 959 somatic cells are classified as neuroglia. Although research on worm glia has lagged behind studies focused on neurons, there has been a steep upswing in interest during the past decade. Information arising from the recent burst of research on worm glia supports the idea that C. elegans will continue to be an important animal model for understanding glial cell biology. Since the developmental lineage of all cells was mapped, each glial cell in C. elegans is known by a specific name and has research associated with it. We list and describe the glia of the hermaphrodite form of C. elegans and summarize research findings relating to each glial cell. We hope this lecture provides an informative overview of worm glia to accompany the excellent and freely available online resources available to the worm research community.

This book focuses on the structural, biochemical, and diverse functional properties of the endothelial luminal membrane glycocalyx (ELMG), an organelle which constitutes the endothelial cell'membrane.'It is intended to provide the newcomer with a broad, basic, and brief perspective of the luminal endothelial vascular membrane, and for the more established investigator, a basic overview and integrated perspective of the'universe'we explore. The endothelium is an assortment of heterogeneous regulatory cells whose cytoplasm and cell membranes are joined, forming functional units. There is a tremendous amount of literature on the endothelial cell, constituting seemingly isolated and distinct fields of encapsulated research. However, the multifunctional properties of some molecules give rise to an overlap of findings, frequently ignored between the different fields. The book is divided into three parts. The first part concentrates on the structure of the ELMG, with emphasis on morphological and biochemical composition. The importance of the chemical composition to the physiological functions of the ELMG, such as sieving properties, pharmacology, and flow sensing, is the focus of the second part of the book. Finally, some of the pathologies associated with ELMG dysfunction are explored in the last section. The aim is to provide basic and well-established knowledge in the various individual fields, identify the current concepts in each area, and discuss their respective strengths and weaknesses (including hidden problems). Finally, the overall goal is to integrate areas where overlap is clearly indicated, bringing them all together to provide the first ever basic, integrative, panoramic bird's-eye view of the field.

The liver is a vital organ involved in numerous metabolic processes such as cholesterol and bile acid metabolism, biliary lipid secretion, and bile formation. Cholesterol balance across the liver has a crucial effect on influencing plasma total and LDL cholesterol levels and biliary cholesterol concentrations. Cholesterol and bile acid biosyntheses are primarily modulated by negative feedback regulatory mechanisms through the sterol regulatory element-binding protein isoform 2 (SREBP-2) and the farnesoid X receptor (FXR) pathways, respectively. The conversion of cholesterol to bile acids in the liver can balance the fecal excretion of bile acids, which is an important route for the removal of cholesterol from the body. Bile formation begins in the bile canaliculi, and maintenance of the enterohepatic circulation of bile acids results in a continuous secretion of bile. Hepatic secretion of biliary lipids is determined mainly by a group of ATP-binding cassette (ABC) transporters that are located on the canalicular membrane of hepatocytes, which are regulated by various nuclear receptors. Bile acids promote bile flow by their osmotic effects. Also, they are essential for the intestinal absorption of cholesterol, fatty acids, and fat-soluble vitamins and play an important role in aiding the digestion of dietary fat. Bile acids function as signaling molecules and anti-inflammatory agents to regulate lipid, glucose, and energy metabolism by rapidly activating nuclear receptors and cell signaling pathways. This eBook summarizes the progress in the molecular and cellular mechanisms of cholesterol and bile acid metabolism and the physical-chemistry of biliary lipids, with emphasis on biliary lipid metabolism that is regulated by nuclear receptors in the hepatobiliary system.

The brains of males and females, men and women, are different, that is a fact. What is debated is how different and how important are those differences. Sex differences in the brain are determined by genetics, hormones, and experience, which in humans includes culture, society, and parental and peer expectations. The importance of nonbiological variables to sex differences in humans is paramount, making it difficult if not impossible to parse out those contributions that are truly biological. The study of animals provides us the opportunity to understand the magnitude and scope of biologically based sex differences in the brain, and understanding the cellular mechanisms provides us insight into novel sources of brain plasticity. Many sex differences are established during a developmental sensitive window by differences in the hormonal milieu of males versus females. The neonatal testis produces large amounts of testosterone which gains access to the brain and is further metabolized into active androgens and estrogens which modify brain development. Major parameters that are influenced by hormones include neurogenesis, cell death, neurochemical phenotype, axonal and dendritic growth, and synaptogenesis. Variance in these parameters results in sex differences in the size of particular brain regions, the projections between brain regions, and the number and type of synapses within particular brain regions. The cellular mechanisms are both region and endpoint specific and invoke many surprising systems such as prostaglandins, endocannabinoids, and cell death proteins. Epigenetic modifications to the genome both establish and maintain sex differences in the brain and behavior. By understanding when, why, and how sex differences in the brain are established, we may also learn the source of strong gender biases in the relative risk and severity of numerous neurological diseases and disorders of mental health. Boys are much more likely to be diagnosed with autism spectrum or attention and hyperactivity disorders, as well as speech and language deficits, compared to girls. By contrast, women are more likely to suffer from affective disorders, such as depression, anxiety, compulsion, and eating disorders and more likely to experience autoimmune and neurodegenerative disorders. Schizophrenia with an early onset is more common in males but a late-onset version is markedly more frequent in females. Male biased disorders have origins in development while female biased disorders are almost exclusively post-puberty. This remarkable shift in disease risk demands our attention. Novel insights into the biological origins of disease are also gained by comparing and contrasting the same processes in different sexes.

For the past decade or more, much of cell biology research has been focused on determining the key molecules involved in different cellular processes, an analytical problem that has been amenable to biochemical and genetic approaches. Now, we face an integrative problem of understanding how all of these molecules work together to produce living cells, a challenge that requires using quantitative approaches to model the complex interactions within a cell, and testing those models with careful quantitative measurements. This book is an introductory overview of the various approaches, methods, techniques, and models employed in quantitative cell biology, which are reviewed in greater detail in the other volumes in this e-book series. Particular emphasis is placed on the goals and purpose of quantitative analysis and modeling, and the special challenges that cell biology holds for understanding life at the physical level.

This book focuses on the role of the endocannabinoid system in local and systemic inflammation, with individual chapters written by experts in the field of cannabinoid research and medicine. The topics explore the actions of the endocannabinoid system on the immune system, including neuroinflammation in autoimmune disorders such as multiple sclerosis, and in neurodegenerative disorders such as Huntington's and Alzheimer's, as well as local and systemic inflammatory conditions affecting organs including the eye (uveitis and corneal inflammation), the bladder (interstitial cystitis), pancreas (diabetes), cardiovascular system (stroke), joints (arthritis), and sepsis. The objective of this book is to provide knowledge transfer on the use of cannabinoids in inflammatory disease by critically examining preclinical and clinical research on the immunomodulatory actions of the endocannabinoid system, with specific emphasis on the actions of cannabinoids in diseases where inflammation is a prominent component. By drawing these results together, we seek to provide further understanding of the complexities of endocannabinoid system modulation of immune function and identify potential uses and limitations for cannabinoid-based therapeutics.

Osteogenesis imperfecta (OI) is a disease encompassing a group of disorders mainly characterized by bone fragility and is the commonest form of heritable bone fragility. In this book, the clinical presentations with particular emphasis on rare phenotypes associated with OI are discussed together with molecular advances in diagnosis and treatment of OI. There is a broad spectrum of clinical severity in OI, ranging from multiple fractures in utero and perinatal death, to near-normal adult stature and low fracture incidence. Facial dysmorphism has been noted, but is not well described, nor is it an invariable feature. Sillence et al., in 1979, provided the clinical classification, which has been further expanded. Genetic defects in type 1 collagen can be identified in 85% of patients with a clinical diagnosis of OI, that is, mutations in COL1A1/COL1A2, which follows an autosomal dominant pattern of inheritance. Several genes have now been implicated in autosomal recessive forms of OI and X-linked osteoporosis. Given the possible antenatal presentation and prognosis associated with OI, it is important to make this diagnosis early and be able to distinguish this from other lethal skeletal dysplasias. It is also important to distinguish nonaccidental injury from a pathological cause of fractures, such as OI, and diagnose this promptly in these situations. However, this is not always possible due to variability in presentation and inability to pinpoint the precise genetic etiology despite extensive genetic testing. OI is one such rare genetic condition where treatment is available in the form of bisphosphonates, which has a huge impact on quality of life. Despite advances in medical therapy, multidisciplinary management including physiotherapy remains the mainstay of treatment and improved outcomes in OI.

The mammalian gastrointestinal mucosa is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through the strict regulation of epithelial cell proliferation, growth arrest, and apoptosis. The control of the growth of gastrointestinal mucosa is unique and, compared with most other tissue in the body, complex. Mucosal growth is regulated by the same hormones that alter metabolism in other tissues, but the gastrointestinal mucosa also responds to host events triggered by the ingestion and presence of food within the digestive tract. These gut hormones and peptides regulate the growth of the exocrine pancreas, gallbladder epithelium, and the mucosa of the oxyntic gland region of the stomach and the small and large intestines. Luminal factors, including nutrients or other dietary factors, secretions, and microbes that occur within the lumen and distribute over a proximal-to-distal gradient, are also crucial for maintenance of normal gut mucosal regeneration and could explain the villous-height-crypt-depth gradient and variety of adaptation, since these factors are diluted, absorbed, and destroyed as they pass down the digestive tract. Recently, intestinal stem cells, cellular polyamines, and noncoding RNAs are shown to play an important role in the regulation of gastrointestinal mucosal growth under physiological and various pathological conditions. In this book, we highlight key issues and factors that control gastrointestinal mucosal growth and homeostasis, with special emphasis on the mechanisms through which epithelial renewal and apoptosis are regulated at the cellular and molecular levels.

Adolescent brain development is a fascinating, newly developing field that has so much to offer almost anyone interested in learning more. Adolescence has only come to be established as a unique developmental phase in the last few decades or so. We now know that the human brain undergoes dramatic developmental changes in the postnatal period, not only early after birth but also extending all the way into adulthood. These changes are not uniform, in that the brain regions undergoing the most change during adolescence are not the same as the regions that changed most in the early life period, and the processes of change also differ as we age. Some of the most important changes that we see during the adolescent period are: 1) pruning (or removal) of excessive neural connections, 2) increases in white matter, the portion of brain matter that allows different regions to communicate with one another, and 3) thinning of the cortex, which is comprised of the outer layers of brain matter. Compared with other areas of the brain, the frontal and temporal cortices undergo the most protracted changes in their structure, implying that developments in these areas play a large role in providing the foundation for adolescent behavioural changes. In this book, we compare adolescent behavioural changes with ongoing changes in the brain and discuss potential implications for health and educational policy-making.

Hypertension is defined by an increase in systemic blood pressure above limits considered normal, currently set at 140 mmHg for systolic and 90 mmHg for diastolic pressure. Assuming central venous pressure to be near zero, mean arterial pressure is determined by the product of total peripheral resistance and cardiac output. In most cases of essential hypertension, as well as in animal models of hypertension, cardiac output and its main determinants, stroke volume and heart rate, are normal, whereas total peripheral resistance is increased. Total peripheral resistance is influenced by a number of factors described by the Poiseuille's law, the most significant of which by far is the diameter of blood vessels of the arterial tree. Since blood vessel diameter is a reflection of both vascular structure and active regulation of vascular tone through mechanisms of vasoconstriction and vasodilatation, it is generally considered that alterations in total peripheral resistance are directly determined by alterations in vascular smooth muscle structure and/or function. Thus, complex blood pressure regulation systems, including renal, nervous, endocrine, immune, and others, in their turn influenced by genetic or environmental factors, converge upon the same molecular mechanisms that control the structure and function of vascular smooth muscle. In this work, rather than providing the exhaustive list of modifications in the blood pressure regulating systems that ultimately affect the vasculature in hypertension, we will focus on the structural and functional alterations of vascular smooth muscle per se during hypertension.

This book reviews the molecular genetics of the thalassemia syndromes, inherited hemoglobin disorders that comprise the commonest monogenic disorders globally. Thalassemias are found in high frequencies in tropical regions corresponding to the malaria belt. Beta thalassemia traits show high HbA2 by HPLC, and β-globin mutations (commonly point mutations) are detected by using ARMS-PCR, reverse dot-blot analysis and β-globin gene sequencing. Globally >300 β globin gene mutations exist, however regional mutations are limited to 5-6 common ones. Alpha globin gene defects can only be identified by molecular tests, the exception being HbH disease that shows'golf ball'appearance in HbH preparation, pre-integration peaks on HPLC and a fast-moving band on hemoglobin electrophoresis. Multiplex Gap-PCR identifies common α-globin gene deletions. Specific PCR across the junction caused by the unequal crossing over can detect α-gene triplication. However, heterozygosity or homozygous triplication cannot be resolved by this technique. Non-deletional α-thalassemia can be characterized by specific α-globin gene sequencing. Identification of unusual deletions requires Multiplex Ligation-dependent Probe Amplification. In conclusion, the molecular characterization of human globin gene disorders is required to resolve the phenotypically heterogeneous thalassemia syndromes. Molecular analysis is also an important tool to prevent these disorders by offering prenatal screening in regions with a high disease burden.

Current knowledge of the etiology of congenital malformations of the human gastrointestinal tract is covered in this book, prefaced by some introductory notes on embryological development. Malformations involving the esophagus, stomach, small and large intestine, anus and rectum, pancreas, and hepato-billiary system are covered. There is a focus on covering those malformations for which a molecular genetic etiology is understood, but other causations, including environmental exposures, twinning, and unknown etiology are also included. For completeness, some disorders are included which are not, strictly, malformations, or which do not, strictly, involve the gastrointestinal tract. Such disorders include Hirschsprung disease, congenital diaphragmatic hernia, omphalocele, and gastroschisis. Suggested approaches to clinical evaluation of individuals with gastrointestinal malformations are included.

Animal behaviors and emotions are fine-tuned via signal transmission and communication between cells. The nervous system gives instructions and transmits signals to different parts of an organism to produce coordinated activities. Neurons are core components of the nervous system and they use various chemical messengers to communicate with one another. Neuropeptides (NPs), which are small chains of amino acids, represent the largest class of signaling molecules. Since NPs are directly involved in modulating many physiological processes, such as metabolism, reproduction, learning, memory, and social behaviors–there is a growing interest in studying their structures, functions, and distributions. This book aims to summarize advances in invertebrate NP studies concerning molecular diversities, distributions, and biological functions. In addition, the emerging mass spectrometric techniques have been discussed extensively as a powerful tool enabling accelerated invertebrate NP studies.

The present outline of astrocytic metabolic pathways involved in glucose and amino acid metabolism provides detailed information about the enzymatic pathways involved, as well as a description of the basic properties of the enzymes including regulatory mechanisms. Hence, the glycolytic pathway and glycogen metabolism are outlined, followed by a detailed account of pyruvate oxidation and its role as a substrate for the tricarboxylic acid (TCA) cycle. Moreover, a detailed description of the main enzymes involved in glutamate metabolism is provided and the role of the glutamate-glutamine cycle is explained. Since this text is primarily covering astrocytic metabolism, an emphasis has been placed on a discussion of the significance of the astrocyte specific enzymes pyruvate carboxylase and glutamine synthetase, which enable these cells to perform a net synthesis of glutamine, the precursor for synthesis of glutamate and γ-aminobutyrate (GABA), the main neurotransmitters of the brain. With this, we have underlined the fundamental importance of astrocytic metabolism for neuronal function with a particular emphasis on the fact that, without continuous support from the astrocytic partners in synaptic function, glutamatergic and GABAergic neurotransmission would not be possible. It is thought provoking that these neurotransmission processes, which account for the vast majority of synaptic activity in the brain, have been made totally dependent on astrocytic metabolic support, particularly with regard to replenishment of the respective neurotransmitters.

This book represents my experience teaching graduate students in Biomedical Science at Hood College. Being science majors, the students have a limited background in philosophy and ethics. Most of the graduate students are employed at area research laboratories while also pursuing a Master of Science degree. Their practical day-to-day experience in scientific research is helpful in discussions of responsible conduct of research cases. Being aware of increased cases of misconduct the United States established the Office of Research Integrity (ORI). Their publication, Introduction to the Responsible Conduct of Research, defines misconduct as fabrication, falsification, and plagiarism. Concern for the breach of public trust with repercussions in scientific funding has led to mandates for courses in ethics for students pursuing a scientific career. In addition, the Human Genome Project megaproject funded Ethical, Legal, and Social Implications Research (www.genome.gov/ELSI/) recognizing that the genetic information produced by the project would come with applied ethical dilemmas. Teaching can be understood as conveying knowledge from generation to generation. Likewise systems of morality are collective acquisitions built up over millennia with social norms and values that aim to maintain social order. Research does not support the premise that knowing the rules of conduct will prevent misconduct. Indeed, compliance with rules can give a false sense of security, especially if the ethical reasoning grounding the rules is not understood. Therefore, I try to sketch a path through the potential phases and avenues of a scientific career, imagining that a person may do basic research, serve on ethics committees, and engage the public in ethical use of new advances in genetics. As a result the content of this text is divided into three parts. The first part deals with foundational material on science and ethics and cases that highlight proper scientific professional conduct. The second part deals with clinical research through which a research discovery is moved to the bedside of patients and the ethical parameters of the transition. The third part sketches the ethical dilemmas evolving from progress in genetic information to clinical applications. Helping students find a moral compass, a grounding of why one ought to behave in ethical ways in their profession and more generally in life is challenging. Doing so increases their awareness and mine of potential dilemmas and how to deal with them ethically.

Astrocytes can be defined as the glia inhabiting the nervous system with the main function in the maintenance of nervous tissue homeostasis. Classified into several types according to their morphological appearance, many of astrocytes form a reticular structure known as astroglial syncytium, owing to their coupling via intercellular channels organized into gap junctions. Not only do astrocytes establish such homocellular contacts, but they also engage in intimate heterocellular interactions with neurons, most notably at synaptic sites. As synaptic structures house the very core of information transfer and processing in the nervous system, astroglial perisynaptic positioning assures that these glial cells can nourish neurons and establish bidirectional communication with them, functions outlined in the concepts of the astrocytic cradle and multi-partite synapse, respectively. Astrocytes possess a rich assortment of ligand receptors, ion and water channels, and ion and ligand transporters, which collectively contribute to astrocytic control of homeostasis and excitability. Astroglia control glutamate and adenosine homeostasis to exert modulatory actions affecting the real-time operation of synapses. Fluctuations of intracellular calcium can lead to the release of various chemical transmitters from astrocytes through a process termed gliotransmission. Sodium fluctuations are closely associated to those of calcium with both dynamic events interfacing signaling and metabolism. Astrocytes appear fully integrated into the brain cellular circuitry, being an indispensable part of neural networks.

In 1851, Heinrich Müller discovered what he called “radial fibers” and what we now call Müller cells, as the principal glial cells of the vertebrate retina. Later on, other glial cell types were found in the retina, including astrocytes, microglia, and even oligodendrocytes. It turned out that retinal glial cells are essential constituents of the tissue. For instance, Müller cells appear to constitute the “core” of columnar units of clonally and functionally related groups of neurons. Their primary function is to support neuronal functioning by guiding the light towards the photoreceptor cells, removing excess neurotransmitter molecules from extracellular space, and performing efficient clearance of excess extracellular potassium ions. The latter two functions are also crucial for neuronal survival and are coupled to water clearance which is also essential. Müller cells are capable of “sensing” neuronal activity and modifying it by the release of signal substances (gliotransmitters). In cases of retinal injuries the Müller cells become reactive, and all above-mentioned functions are impaired. However, such de-differentiated Müller cells may proliferate, and may even serve as stem cells for the regeneration of a damaged retina. As well as the Müller cells, retinal astrocytes and microglial cells are important players in retinal development and function. This book gives a comprehensive survey of the present knowledge on retinal glia.

Pulmonary endothelium forms the inner lining of blood vessels, where it interprets the complex mechanical and chemical environment within the circulation and adjusts its behavior to facilitate vascular homeostasis. Although endothelium fulfills many essential functions, including regulation of vascular pressure, circulating cell transmigration, coagulation, and hormone metabolism and/or delivery, a principal role is to form a semi-permeable barrier that limits fluid, solute and macromolecular access to the interstitial space. Physiological properties that govern such permeability characteristics are defined by the Starling equation, which assumes that endothelial cells throughout the circulation are all alike. However, in recent years it has become evident that endothelial cells in pulmonary arteries, capillary and veins are heterogeneous in structure and function. Here, we review evidence for endothelial heterogeneity among these pulmonary vascular segments, and consider the implications for such heterogeneity in lung fluid balance, especially as it relates to the Starling equation.

The understanding of the pathophysiology of erectile dysfunction (ED) has advanced significantly over the past two decades. In this ebook, we provide an in-depth analysis of the current knowledge of the pathophysiology of ED in order to provide the reader with an up-to-date and comprehensive understanding of the pathophysiology of ED, which is complex but fascinating. Intensive and intricate mechanisms govern the development of ED. These mechanisms involve complex interaction between vascular, hormonal and neural regulation. Current research on the central regulation of ED is key for the advancement of our understanding of this complex disease. Recent advances in our knowledge of the vascular mechanisms regulating penile erection led to appreciation of ED as an early symptom of cardiovascular disease. Major health concerns such as atherosclerosis, hyperlipidemia, hypertension and diabetes have become well integrated into the investigation of ED. Extensive research on the mechanisms involved in the regulation of penile erection have led to unparalleled advances in the understanding of general vascular regulation. However, many unknowns remain, which provides vast opportunities for future basic and clinical investigations. Table of Contents: Anatomy of the Penis / General Pathophysiology / Diabetes and ED / ED and Cardiovascular Disease / Drugs Causing ED / References / Author Biographies

“A Journey Through Genetics Part II” is designed to continue on the incredible journey initiated in Part I to explore the exciting discoveries in genetics and molecular biology. In Part I, the reader embarked on a genetic odyssey that started with the “Father of Genetics,” Gregor Mendel, and culminated in the invention of one of the most powerful tools in molecular biology—the polymerase chain reaction. The second part of the book will take the reader on a journey to explore the frontiers of genetic diversity, gene cloning, the human journey, and the human genome project! The book is targeted toward undergraduate non-majors and also as a “companion” to a standard genetics textbook for biology majors. The book will also prove to be useful for anyone that wants to understand the stories behind the science of genetics.

Alzheimer's Disease is characterized pathologically by two principal hallmark lesions: the senile plaque and the neurofibrillary tangle. Since the identification of each over 100 years ago, the major protein components have been elucidated. This has led in turn to the elaboration of metabolic cascades involving amyloid-β production in the case of the senile plaque, and phosphorylated-tau protein in the case of the neurofibrillary tangle. The pathogenesis and histogenesis of each have been the source of extensive investigation and some controversy in recent years, as both cascades have been implicated in the pathogenesis of Alzheimer's Disease, relied upon in the diagnostic criteria for Alzheimer's Disease at autopsy, and targeted for therapeutic intervention. With the accumulation of data and expansion of knowledge of the molecular biology of Alzheimer's Disease, it appears that the enthusiasm for successful intervention has been premature. In this book, we detail the discovery and characterization of the major pathological lesions, their associated molecular biology, their relationship to clinical disease, and potential fundamental errors in understanding that may be leading scientific investigators in unintended directions.

The gastrointestinal mucosal defense system serves to minimize mucosal injury by either ingested or endogenously produced noxious substances. The mucosal defense system is stratified into pre-epithelial (alkaline mucus), epithelial (dynamic epithelial lining), and post-epithelial (microcirculation) components. The mucus lining the epithelial surface presents a diffusional barrier to ingested material (e.g., lipids) and also serves as an unstirred layer in which a pH gradient can be established to prevent acid-induced injury. The epithelial lining prevents entrance of any toxic material to the interstitium and, should it be damaged, it is rapidly resealed by migration of adjacent viable epithelial cells to cover the defect. Any acid or other material that has entered the interstitium is washed out by an intense neurogenic hyperemia. In general, the mucosal defense system is quite effective and any adverse gastrointestinal effects associated with the normal course of nutrient assimilation are minimal. However, there are two situations in which the mucosal defense system is known to be ineffective and result in gastric mucosal injury: inadvertent ingestion of H. pylori. or intentional ingestion of NSAIDs. H. pylori can penetrate the mucus layers and cause epithelial injury and inflammation, while at the same time preventing its clearance by the host immune system. NSAIDs weaken the mucus layer and cause epithelial cell injury. Table of Contents: Acknowledgments / Introduction / The Mucus Layer / Epithelial Lining / Gastrointestinal Circulation / Integration of Mucosal Defense / Mucosal Defense System: Physiologic / Mucosal Defense System: H. pylori / Mucosal Defense System: Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) / Overall Summary and Conclusions / References / Author Biographies

A Journey Through Genetics is designed to take the reader on an incredible journey to explore the exciting discoveries in genetics and molecular biology. In Part I, the reader will embark on a genetic odyssey starting with the''Father of Genetics,''Gregor Mendel, leading on to the amazing story of photo 51 and the discovery of the structure of the DNA double helix, and culminating with the invention of one of the most powerful tools in molecular biology: the polymerase chain reaction. The reader will discover the stories behind the science of genetics while going behind the scenes to take a glimpse into the lives of pioneering scientists and will ultimately come to understand that people are just as important as the science they undertake to do. In short, scientists are human too! This book is targeted toward undergraduate non-majors and also as a''companion''to a standard genetics textbook for Biology majors. The book will also be useful for anyone that wants to understand the stories behind the science of genetics.

Necrotizing enterocolitis is an acute inflammatory necrosis of bowel that primarily afflicts premature infants in the neonatal intensive care unit setting. Although patients who develop this disease have high morbidity and mortality rates, the pathogenesis is poorly understood, and therefore there are no specific preventive or treatment strategies that have been clearly effective. Recent studies have suggested that the pathophysiology of necrotizing enterocolitis includes alterations in the inflammatory response leading to dysregulated pro-inflammatory signaling in premature infants, as well as abnormal intestinal bacterial colonization patterns that can activate these inflammatory pathways, and these factors are discussed in depth in the following chapters. While human milk feedings are currently the standard of care for the prevention of this challenging condition, new approaches will be described based on sound evidence that might have a significant impact for premature infants throughout the world.

Many of the mechanisms responsible for cardiovascular disease and hypertension are well known, and gender is an independent risk factor in many cohorts. How gender contributes to cardiovascular disease has not been completely elucidated. Even in normotensive populations, blood pressure is higher in men than women, although why this occurs is unclear. While both men and women suffer from high incidences of cardiovascular disease, women are typically protected against cardiovascular disease until after menopause, so that on average they are about 10 years older than men when these diseases develop, making aging a confounding problem contributing to increased morbidity. Because hypertension is one of the leading causes of cardiovascular disease in both men and women, this review will focus on hypertension, and the mechanisms that have been found to play a role in mediating blood pressure control and how they differ in men and women.

Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited, tumour predisposition syndrome affecting 1/3,000-4,000 individuals worldwide. This inherited disorder results from the mutational inactivation of the NF1 gene on human chromosome 17. The NF1 gene contains 61 exons that give rise to 12kb mRNA encoding neurofibromin. The 327kDa (2,818 amino acid) neurofibromin protein is expressed in most tissues and has a number of alternative isoforms. Neurofibromin is a tumour suppressor protein and down-regulates cellular Ras. Increased active Ras-GTP levels also stimulate the important PI3K/AKT/mTOR signalling pathway that protects cells from apoptosis. The major clinical featues of NF1 include multiple café-au-lait macules, skinfold freckles, iris Lisch nodules, and neurofibromas. The diagnostic criteria for clinical diagnosis have been well established. However, there are a small number of cases in which the diagnosis is not certain. The germline mutation rate for the NF1 gene is 10-fold higher than that observed for most other inherited diseases. Using a combination of different techniques, almost 95% of germline mutations can be detected. To date, only two firm genotype phenotype correlations have been reported. NF1 phenotype exhibits large variations within a family, evidence for modifying loci regulating the expression of an NF1 gene is beginning to emerge. We also are gaining knowledge on the molecular mechanisms associated with the development of different types of tumours. It is encouraging that the results of recent laboratory and clinical research are finally being translated into clinical trials. With the availability of high-throughput technologies, sophisticated animal models, and multi-centre clinical trials, the future for NF1 sufferers is looking optimistic. This book aims to provide an overview of the genetic and clinical aspects of NF1 and its role in both NF1-associated and sporadic tumour development. It emphasizes the recent developments in this field and some of the promising on-going clinical trials.

Dengue is a major public health concern throughout the tropical and sub-tropical regions of the world. It is the most rapidly spreading mosquito-borne viral disease, with a 30-fold increase in global incidence over the past 50 years. Infection with any of the Dengue virus serotypes can be asymptomatic, cause the classic dengue fever, or evolve to severe disease, which leads to hypovolemic shock and death if untreated. There is no approved specific treatment, prognostic markers, or vaccines for dengue, in part because there is insufficient knowledge of dengue pathogenesis. In this e-book, we will focus on what we believe to be a true challenge in dengue research: to understand host–pathogen interactions. Disease development results from the interaction between host and viral factors, in which the host immune response is critical. Recent advances in dengue experimental models together with clinical data have provided useful information indicating that severe dengue hallmarks (excessive production of pro-inflammatory cytokines, endothelial activation, and plasma leakage) are immune-mediated events. We hope to present readers with a comprehensive description of the immune response to the Dengue virus, detailing how DENV unbalances host homeostasis.

This book is the introduction to a series of e-books dedicated to the physiology and pathophysiology of neuroglia. The topic of neuroglia is generally overlooked in neuroscience curricula across the world, the main attention being focused on the description of excitability of neurons and neuronal networks. The neuroglia, being electrically non-excitable, are universally regarded as supportive cells which do not contribute to information processing. This oversimplified view, however, ignores the tremendous importance of brain homeostasis, which is imperative for the ongoing activity of neuronal networks. It also ignores the truth that specialization of neurons and their ability for rapid propagation and multi-level integration of signals become possible only because of delegation of homeostatic abilities to neuroglia. Furthermore, glial cells contribute to information processing as they can modulate neuronal synaptic transmission. Finally, neuroglia provide the only system of brain defense and as such these cells are intimately involved in all types of neuropathologies, and contribute to both neuroprotection and regeneration of the nervous system. The e-books in this series provide a platform for in-depth learning of all aspects of neuroglial cells function in health and disease.

Multiple sclerosis [MS] is one of the most common auto-immune-mediated diseases of the human central nervous system [CNS] which affects young adults and usually causes significant neurological disability. Currently, the causes of MS are still unclear, a cure for MS remains elusive and the effectiveness of treatment varies significantly among individuals. Clinical features and neurological deficits stemming from this progressive neurological disease are diverse since MS potentially affects human CNS at all levels from brain to the end of spinal cord. The triggering event for development of MS remains unknown. Immunopathogenesis of MS involves a number of steps which include activation of peripheral leukocytes against putative CNS antigen(s), interactions of the activated leukocytes with inflamed cerebral endothelial cells, transendothelial migration of activated lymphocytes and macrophages to the CNS milieu, and further propagation of the massive immune response within the CNS. Such massive immune activation leads to loss of myelin-oligodendrocyte complex. Several immune cell types and mediators of the immune-inflammatory response actively contribute to pathogenesis of MS. Genetic factors are also believed to play a central role in the development of most forms of MS. Another important but much unrecognized and under-researched feature of MS immunopathology is “neurodegeneration.” Neuronal loss and axonal degeneration are the core components of irreversible and permanent CNS atrophy and disability in MS. What we call MS in reality is a heterogeneous group of diseases and at least four distinct immunopathological subtypes of MS with dissimilar responses to therapy with immunomodulatory agents exist. MS is a clinical diagnosis, however, its diagnostic process is much facilitated by utilization of laboratory and neuroimaging studies. Present therapies of MS are either immunomodulatory agents or immunosuppressive and mainly target the peripheral immune system with the intention to ameliorate the severity of acute relapses, decrease annual relapse rate, and improve MRI lesions. Currently, much research activity is being conducted to better understand the fundamental disease mechanisms of MS and find more effective and safer treatments for this incurable disease. This book presents an overview of MS as a disease with neuroinflammatory and neurodegenerative features and the authors discuss the most recent findings about MS and its treatment. Table of Contents: Introduction / Clinical Features of Multiple Sclerosis / Pathophysiology of Multiple Sclerosis / Neuroimaging of Multiple Sclerosis / Diagnosis of Multiple Sclerosis / Treatment of Multiple Sclerosis / Prognosis of Multiple Sclerosis / Concluding Remarks. References

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.

In the vast majority of patients, hypertension has no identifiable cause. Moreover, despite decades of discovery and therapeutic development, approximately only half of the hypertensive patients are achieving clinically recommended blood pressure control. For these reasons, there has been continued interest in studying the factors that underlie the pathogenesis of hypertension. One area of research that has garnered significant attention is the potential link between immune system activation and blood pressure. Several lines of evidence, dating back several decades, support the concept for this association. This monograph gives a history of the early studies linking immune system function with hypertension and an overview of the large number of studies published in the past decade. The major focus is on the components of the innate and adaptive immune systems for which there is considerable evidence of their contributions to blood pressure control.

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.

This volume deals with the history, aetiology, pathophysiology, symptoms, signs, prognosis, and rational treatment of ascites. During the past decade, our knowledge of the pathophysiology of ascites has increased substantially and more specific therapies are now based on aetiology and pathophysiology. It is the intention of this book to review recent progress in pathophysiology of ascites and therapies based on pathophysiology. Although the different types of ascites have a different aetiology and very different pathophysiology, the development of fluid in the peritoneal cavity is always a bad clinical sign. It has a severe prognosis, which is mainly dependent on the aetiology and progression of the underlying disease. However, among patients with ascites, the prognosis may be very different, mainly owing to the presence of portal venous hypertension, malignancy in the abdominal cavity, and end-stage congestive heart failure. The addition of complications like the hepatorenal syndrome and bacterial peritonitis, whether spontaneous or secondary, adds heavily to the bad prognosis. Since hepatic ascites are by far the most complex with respect to pathophysiology, complications, and treatment, emphasis is put on the description of this entity. Ascites of other aetiologies are mentioned along with hepatic ascites, in particular, if the pathophysiology differs from ascites of hepatic origin.

X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy and the most frequent peroxisomal disorder, with an estimated incidence of 1:17,000. This complex neurodegenerative disorder is characterized by a huge clinical variability both in the age of onset and in symptoms. The two main forms are the childhood cerebral ALD (ccALD) characterized by inflammatory demyelination of the central nervous system, and the adult form called adrenomyeloneuropathy (AMN), characterized by a non-inflammatory slowly progressive demyelination affecting spinal cord and peripheral nerves. Adrenal insufficiency is usually associated with the nervous symptoms, X-ALD being the main cause of Addison's disease. The main biochemical defect is the accumulation of very-long-chain fatty acids (VLCFA, fatty acids with a chain length of more than 22 carbon atoms), particularly in the cholesterol ester fraction of the adrenal gland and brain white matter. X-ALD is associated with mutations in the ABCD1 gene, which encodes for a peroxisomal ATPBinding Cassette (ABC) transporter predicted to allow VLCFA-CoA to enter into the peroxisome for their β-oxidation. In spite of animal models, the physiopathogenesis of the disease remains poorly understood. However, several therapeutic strategies have been investigated. Among them, allogeneic bone marrow transplantation has proven effective and, more recently, the first gene therapy trial ended with a resounding success.

Multi-cellular organisms eliminate individual cells through a self-destruct process known as apoptosis. Apoptosis is critical for proper development and maintenance of tissue homeostasis. The importance of this process is highlighted by the fact that too much or too little apoptosis is the underlying cause of pathologies such as cancer, autoimmune diseases (e.g., lupus, arthritis), and neurodegenerative disorders (e.g., Parkinson's, Alzheimer's). In the early days, apoptotic cells were identified strictly by cell morphology. Now we know that biochemical signatures define a number of death programs, of which apoptosis is the most widely understood. In this review, we discuss genetic insights gained from C. elegans, the importance of caspases, engulfment of apoptotic cells, apoptotic signals, the role of mitochondria, the Bcl-2 family, and the link between dysfunctional apoptosis and disease. Within each topic, we highlight landmark studies that contributed to our current understanding of apoptosis. All together, this research exemplifies tremendous scientific synergy between the disciplines of genetics, biochemistry, developmental cell biology, and structural biology. Continued exploration into mechanisms that regulate apoptosis will undoubtedly lead to insights into disease processes with potential therapeutic strategies.

Many membranes in eukaryotic cells are inhomogeneous structures in which various membrane components are nonrandomly distributed, forming diverse types of ‘domains.'Some membrane domains have long been well known, because they are sufficiently large, long-lived, and morphologically well defined to be characterized using classical microscopic and biochemical approaches. However, new technologies have revealed the presence in membranes of smaller, often highly dynamic ‘nanodomains'that also play key roles in membrane function. Our current understanding of the diversity, the properties, and the functions of nanodomains is still very limited and, in some cases, controversial. Nonetheless, it is clear that many important aspects of membrane biology arise from features of membrane organization that ‘play out'on spatial and temporal scales that are only now becoming experimentally accessible in living systems. In this book, we will discuss properties and interactions of membrane molecules that lead to nanodomain formation, new and emerging technologies by which nanodomains can be studied, and experimental examples that illustrate both highlights and current limitations of our present knowledge of the properties of membrane nanodomains in various cell types.

The major purpose of this book is to review the evidence supporting the concept that intrinsic cell survival programs can be activated by a variety of mildly noxious stimuli or pharmacologic agents to confer protection against the deleterious effects of ischemia/reperfusion (I/R). We begin with a discussion of the concept of hormesis (a term used most extensively in the toxicologic literature which refers to biphasic cellular responses that depend on concentration or intensity of a stimulus), review the seminal studies that led to the discovery of the cardioprotective effects of ischemic preconditioning, and outline its therapeutic potential (Chapter 1). This is followed by a summary of our current understanding of the mechanisms of I/R injury (Chapter 2), as this provides several points of intervention in limiting postischemic tissue injury that may be targeted by the adaptive programs invoked by conditioning stimuli. Chapters 3 and 4 focus on the mechanisms underlying ischemic pre-, post-, and remote conditioning, which establishes the mechanistic rationale for development of pharmacologic conditioning strategies that may mimic the remarkably powerful effects of ischemic conditioning (and are covered in Chapter 5). Lifestyle interventions, including exercise, caloric restriction, and consumption of alcoholic beverages and/or phytochemicals, that may induce hormetic responses will also be reviewed in this chapter. While the promise for conditioning as a therapeutic approach is enormous, there are obstacles to its practical application in patients, which are covered in Chapter 6. The final chapter (Chapter 7) examines the extension of our mechanistic understanding of the signaling pathways invoked by conditioning stimuli into the realm of gene therapy and to the preservation of stem cell viability in the harsh ischemic environment as natural translational outgrowths of preconditioning into therapeutics.

Are stem cells patentable? What is the patenting process? What rights does a patent provide? Why should I patent? Applying for and obtaining a patent is a process that can be unpredictable and intimidating, although it does not necessarily need to be. Novice and experienced inventors often have questions regarding patenting and the patenting process. This e-book is provided to answer many questions regarding the patenting process before the United States Patent and Trademark Office (“USPTO”). It also generally describes the technologies typically patented in connection with regenerative medicine. This e-book is provided for informational purposes only and should not replace legal advice, which is necessary to anticipate and address the nuances of the patenting process. In addition, there are issues that should be considered and addressed when considering patenting isolated stem cells and associated technologies—such as the process for obtaining patent rights outside the United States, post-grant procedures for challenging patents, non-patent protection of intellectual property, and enforcement of patents through litigation—which are beyond the scope of this chapter.

The involvement of key factors operating independently or in cooperation with others contributes to physical and physiological mechanisms to help engineer a vertebrate hypothalamus. The actions of these key factors influence developmental mechanisms including neurogenesis, cell migration, cell differentiation, cell death, axon guidance, and synaptogenesis. On a molecular level, there are several ways to categorize the actions of factors that drive brain development. These range from the actions of transcription factors in cell nuclei that regulate the expression of developmental genes, to external factors in the cellular environment that mediate interactions and cell placements, and to effector molecules that contribute to signaling from one cell to another. Sexual dimorphism is a hallmark of the vertebrate hypothalamus that may arise as a direct consequence of hormone actions or gene actions. These actions may work through any of the mechanisms outlined above. Given the arrangement of cells in groups within the hypothalamus, cell migration may be one particularly important target for early molecular actions that help build the bases for appropriate functions.

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.

The airways are lined with a film of fluid 10 μm deep that acts as the first line of defense against inhaled pathogens, dirt, and noxious vapors. Transepithelial fluid movements driven by active transepithelial ion transport serve to regulate the depth of this “airway surface liquid”. In the larger airways, a mucus gel derived from both glands and surface epithelium entraps inhaled particles, which are then removed by the coordinated beating of cilia. Both glands and epithelium secrete a wide variety of antimicrobial and other protective substances in addition to mucins. Substances released across the basolateral surface of the epithelium attract leukocytes and influence neighboring tissues. Here, after reviewing the basic structure of mammalian airway epithelium, I discuss its various defensive functions and how they are altered in airway disease.

The human brain does not develop in a vacuum according to a set of predetermined blueprints—it is involved in a dynamic interplay with the environment that influences gene expression and ultimately structure and function. Some cortical regions, such as the prefrontal cortex (PFC) undergo structural changes throughout the adolescent period and into early adulthood, making their structure and functions particularly interesting to study with respect to gene-environment interactions. Repeated exposure to stress is a predisposing factor in the emergence of various mental illnesses, such as anxiety and depression, although this is by no means an absolute relationship. While some people appear to be vulnerable to the effects of repeated stressors, others are resilient, and this individual variability is partly due to developmental programming of brain regions involved in modulating stress responding, such as the PFC. In the present book, we will discuss features of adolescent brain development that may provide a basis for neural plasticity in stress responding: the highly protracted development of the PFC, the profound change in interconnectedness among cortical and subcortical brain regions, and the characteristic ‘rise and fall'pattern for many of the late-developing aspects of neural architecture in PFC and other stress-related brain regions.

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.

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.

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.

Breathing is usually automatic and without conscious effort; yet our breathing is a complex motor function requiring the coordinated activation of a number of respiratory muscles that span from our heads to our abdomen. Some of our respiratory muscles serve to pump air into and out of our lungs (ventilation). These pump muscles act on the thoracic and abdominal walls and are all skeletal muscles. Other respiratory muscles in our bodies control the caliber of the passageway for air to enter our lungs. These airway muscles include skeletal muscles of the head (e.g., tongue and suprahyoid muscles) and neck (infrahyoid, pharyngeal and laryngeal muscles), as well as smooth muscles that line our trachea and bronchi down to the alveoli where gas exchange occurs. This book provides an overview of the anatomy and physiology of our respiratory muscles, including their neural control. This book also includes an overview of the basic structure and function of both skeletal and smooth muscles. The two basic types of respiratory muscles (skeletal and smooth muscle) vary considerably in the organization of their contractile proteins and the underlying mechanisms that lead to force generation and contraction, including their neural control.