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This book covers a wide range of topics that illustrate the various functions of autophagy in stem cells and offers insights on the mechanisms by which autophagy can regulate stem-cell self-renewal and facilitate specific differentiation programs. Stem cells are unique cells present in most multicellular animals and are essential for their survival. They have two unique properties: the ability to self-renew and the ability to differentiate into one or more cell types. These characteristics of stem cells have found immense therapeutic potential in regenerative medicine. Autophagy is a crucial membrane trafficking pathway that is essential for maintaining cellular homeostasis that involves sequestration of non-functional proteins, protein aggregates and damaged organelles in double-membraned vesicles called autophagosomes, which are subsequently targeted to the lysosome for degradation. The primary aim of this book is to provide knowledge of recent developments in our understanding of the role of autophagy in stem cells, including germline stem cells.Autophagy is considered a promising target for many diseases. Significant efforts are being developed to identify specific modulators of autophagy, which will aid in designing combinatorial therapeutic strategies that will allow significant improvements in regenerative medicine.

Autophagy in Health and Disease, Second Edition provides a comprehensive overview of the process of autophagy and its impact on human physiology and pathophysiology. It expands on the scope of the first edition by covering a wider range of cell types, developmental processes, and organ systems. The second edition is an international effort by investigators from 15 different countries whose many contributions are comprised in 28 chapters organized into six sections. The first section (Chapters 1-7) covers foundational concepts, including history, trajectory of the research field, mechanisms of autophagy, and autophagy regulation. The second section (Chapters 8-11) details developmental aspects, including stem cells, embryogenesis, hematopoiesis, and paligenosis. The subsequent sections are devoted to the role of autophagy in specific organ systems involved in metabolic control and diabetes (Chapters 12-15), the cardiovascular system (Chapters 16-18), and the nervous system (Chapters 19-20). The final section (Chapters 21-28) addresses autophagy in other organ systems vital to human health and longevity. Also included are chapters on microautophagy, chaperone-mediated autophagy, and the potential for autophagy as a therapeutic target.Autophagy in Health and Disease is invaluable to anyone new to the field as well as established investigators looking for a broader understanding of autophagy from outside their specific field of study. - Provides a comprehensive overview of the process of autophagy and its impact on human physiology and pathology - Offers extended coverage of the mechanisms that mediate autophagy - Covers the role of autophagy in stem cells and induced pluripotent stem cells, as well as the regenerative process of paligenosis - Highlights important questions that remain to be addressed

Non-canonical Autophagy: Mechanisms and Pathophysiological Implications outlines the differences between'canonical'and'non-canonical'forms of autophagy, highlighting the discoveries concerning the molecular mechanisms underlying these unconventional forms of autophagy and the advancements in pathophysiological features of'non-canonical'autophagy. The book discusses all forms of'non-canonical'autophagy and the complexity of autophagy-dependent cell death. Readers will gain a better understanding of mechanisms underlying'non-canonical'autophagy so that they can interpret the biological effects of autophagy correctly and identify reliable, novel and effective treatment strategies. - Presents the most advanced information surrounding the molecular mechanisms underlying non-canonical autophagy - Outlines the increasing evidence regarding the involvement of non-canonical autophagy in multiple physiological and pathological processes - Discusses the therapeutic potential of autophagy modulators and the obstacles that have limited their development

Advances in Cancer Research, Volume 150, the latest release in this ongoing series, covers the relationship(s) between autophagy and senescence, how they are defined, and the influence of these cellular responses on tumor dormancy and disease recurrence. Specific sections in this new release include Autophagy and senescence, converging roles in pathophysiology, Cellular senescence and tumor promotion: role of the unfolded protein response, autophagy and senescence in cancer stem cells, Targeting the stress support network regulated by autophagy and senescence for cancer treatment, Autophagy and PTEN in DNA damage-induced senescence, mTOR as a senescence manipulation target: A forked road, and more. - Addresses the relationship between autophagy and senescence in cancer therapy - Covers autophagy and senescence in tumor dormancy - Explores autophagy and senescence in disease recurrence

Autophagy in Health and Disease, Volume 175, presents the latest insights from renowned experts in the field who discuss the key role of autophagic responses in the preservation of cellular and organismal homeostasis and how defects in the molecular apparatus for autophagy drive or accompany disease. Specific chapters in this new release include Crosstalk between autophagy and cell death signaling: mechanisms and therapeutic relevance, C. elegans to model autophagy-related human disorders, Autophagy in Kidney Disease: advances and therapeutic potential, Autophagy in Chronic Lung Disease, Autophagy in motoneuronal disorders, Strategies employed by viruses to manipulate autophagy, and much more. - Provides an outstanding panel of recognized experts in the field who discuss the latest in autophagy - Includes critical discussions of autophagy in the context of each major human disorder - Models autophagy-related human pathologies in lower eukaryotes

How can you lose weight, ease chronic conditions, and stay healthier longer? Discover how to “rewrite your health destiny” (David Perlmutter, MD, #1 New York Times bestselling author of Grain Brain) with this accessible book that teaches you how to flip the switch on your metabolism with intermittent fasting, protein cycling, and keto. Within each of us is an ancient mechanism that eliminates toxic materials, initiates fat burning, and protects cells from becoming dysfunctional—or turning cancerous. It's called autophagy, and when it's turned on, the complex operation not only can slow down the aging process, it can optimize biological function as a whole, helping to stave off all manner of diseases and affording us the healthy life spans we never thought possible. It's the body's ultimate switch to life. So how can we positively activate this switch? How frequently should we fast and for how long? Which foods dial up autophagy or, conversely, turn it down? How much exercise and what types are recommended? What's the sweet spot between intermittent fasting, protein cycling, and ketogenic eating? Backed by a wealth of scientific data and featuring a gallery of guidelines to follow for lasting results, “The Switch offers a paradigm shift in the way we think about health—and how to avoid decline and illness. This is a must read” (Mark Hyman, #1 New York Times bestselling author).

Autophagy and Cardiometabolic Diseases: From Moleculer Mechanisms to Translational Medicine covers the science of autophagy in relation to cardiometabolic diseases and the future therapeutic potentials of autophagy regulation in these processes. Processes are not described in isolation, but in concert with other cellular and/or metabolic processes, such as lipogenesis, glucose, energy metabolism and apoptosis. This approach recognizes the multifactorial nature of cardiometabolic diseases, including obesity, diabetes, insulin resistance, hypertension and dyslipidemia. The book provides explanations, while also distinguishing the delicate role for autophagy in pathogenesis and exploring complications for cardiometabolic diseases. By targeting autophagy, it offers new avenues for drug discovery and treatment for cardiometabolic anomalies. It is a perfect resource for cardiology researchers, scientists and medical practitioners. - Explains the processes inherent in the protein quality control for pathogenesis and complications of cardiometabolic diseases - Provides knowledge from internationally recognized contributors in the field - Incorporates a translational approach, covering the basic cellular biology of autophagy and presenting the role of autophagy regulation for both pathogenesis and complication in cardiometabolic diseases - Contains access to a companion website with additional illustrations

This timely volume explores the impact of autophagy in various human diseases, emphasizing the cell biological aspects and focusing on therapeutic approaches to these diseases. The chapters cover autophagy and its potential applications on diseases ranging from obesity, osteoarthritis, pulmonary fibrosis, and inflammation, through ALS, Parkinson's, retinal degeneration, breast cancer, alcoholic liver disease and more. The final chapters round out the book with a discussion of autophagy in drug discovery and'bench to bedside'. Chapters are contributed by leading authorities and describe the general concepts of autophagy in health and disease, marrying cell biology and pharmacology and covering: studies derived from preclinical experiments, manufacturing considerations,and regulatory requirements pertaining to drug discovery and manufacturing and production. This volume will be useful for basic scientists as well as already practicing cliniciansand advanced graduate students.

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging is an eleven volume series that discusses in detail all aspects of autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. This series discusses the characterization of autophagosome-enriched vaccines and its efficacy in cancer immunotherapy. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward-thinking, these books offer a valuable guide to cellular processes while also inciting researchers to explore their potentially important connections. - Presents the most advanced information regarding the role of the autophagic system in life and death - Examines whether autophagy acts fundamentally as a cell survivor or cell death pathway or both - Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation - Features recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities, including atherosclerosis and CNS tumors, and their development and treatment - Includes chapters authored by leaders in the field around the globe—the broadest, most expert coverage available

Molecular Characterization of Autophagic Responses, Part B presents a collection of methods for the qualitative and quantitative evaluation of virtually all the morphological, biochemical, and functional manifestations of autophagy, in vitro, ex vivo and in vivo, in organisms as distant as yeast and man. Autophagy is an evolutionarily conserved mechanism for the lysosomal degradation of superfluous or dangerous cytoplasmic entities, and plays a critical role in the preservation of cellular and organismal homeostasis. Monitoring the biochemical processes that accompany autophagy is fundamental for understanding whether autophagic responses are efficient or dysfunctional. - Offers a detailed overview of the protocols used to study autophagy and various aspects of autophagic responses - Written in an accessible style by renowned experts in the field

Molecular Characterization of Autophagic Responses, Part A, presents a collection of methods for the qualitative and quantitative evaluation of virtually all the morphological, biochemical, and functional manifestations of autophagy, in vitro, ex vivo and in vivo, in organisms as distant as yeast and man. Autophagy is an evolutionarily conserved mechanism for the lysosomal degradation of superfluous or dangerous cytoplasmic entities, and plays a critical role in the preservation of cellular and organismal homeostasis. Monitoring the biochemical processes that accompany autophagy is fundamental for understanding whether autophagic responses are efficient or dysfunctional. - Offers a detailed overview of the protocols used to study autophagy and various aspects of autophagic responses - Written in an accessible style by renowned experts in the field

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 12 discusses and details almost all aspects of the autophagy machinery in the context of health, cancer and other pathologies. Autophagy is more widely accepted as beneficial given its role in eliminating'toxic assets'and promoting cell viability, hence, it has emerged as a new and potent modulator of disease progression that is both scientifically intriguing and clinically relevant. As the latest release in the Autophagy book series, users will find a detailed explanation of the role of molecular mechanisms. - Presents the most advanced information regarding the role of the autophagic system in life and death - States recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities - Summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease - Authored by global leaders in the field, bringing the broadest, most expert coverage available

Autophagy principally serves an adaptive function to protect organisms against diverse human pathologies, including cancer and neurodegeneration. Recent developments using in vitro, ex vivo and in vivo models show the involvement of the autophagy pathway in immunity and inflammation. Moreover, direct interactions between autophagy proteins and immune signalling molecules have also been demonstrated. Defects in autophagy - similar to cancer, neurodegenerative diseases and aging - through autophagy gene mutation and/or microbial antagonism, may underlie the pathogenesis of many infectious diseases and inflammatory syndromes. In spite of the increasing awareness of the importance of autophagy in these pathophysiological conditions, this process remains underestimated and is often overlooked. As a consequence, its role in the initiation, stability, maintenance, and progression of these diseases are still poorly understood. This book reviews the recent advances regarding the functions ofthe autophagy pathway and autophagy proteins in immunity and inflammation, focusing on their role in self-nonself distinction, their implications in innate and adaptive immune responses and their dysregulation in the pathology of certain inflammatory and autoimmune diseases.

Volume 8 Autophagy and Human Diseases, concentrates on the role of Autophagy in human diseases, including tumorigenesis. The diseases discussed include melanoma, liver cancer, pancreatic cancer, and neurodegenerative disorders. Loss of autophagy in the central nervous system causes neurodegeneration (Alzheimers disease, Huntington's disease, Parkin's disease, and Amyotrophic Lateral Sclerosis). Melanoma is one of the most serious diseases in humans. Autophagy plays a key role in the anticancer response to Chemotherapy. However, autophagy can increase or decrease the effectiveness of chemotherapy. The reasons for these contradictory effects are explained. Autophagy also plays a role in idiopathic inflammatory diseases, infection, and immunity. An explanation is given how autophagy is closely linked to control of innate and adaptive immune responses in host defense in part by regulating cytokine production. The role of autophagy in cutaneous malignant melanoma is discussed in detail and expression of Beclin 1 and LC3 autophagic genes in melanoma is included to explain the molecular mechanisms underlying this very serious disease, which tends to metastasize to the brain. The effect of the treatment of this disease using Terfenadine through the induction of autophagy and apoptosis is also included. Autophagy and apoptosis are two main mechanisms involved in programmed cell death. - Presents the most advanced information regarding the role of the autophagic system in life and death and whether autophagy acts fundamentally as a cell survivor, or cell death pathway, or both - Introduces new, more effective therapeutic strategies, in the development of targeted drugs and programmed cell death, providing information that will aid on preventing detrimental inflammation - States recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 10 offer a valuable guide to both cellular processes, while encouraging researchers to explore their potentially important connections. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. This is the tenth volume of the multivolume series that discusses, in detail, almost all aspects of the autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. Volume 10 of the Autophagy series discusses the role of a novel binuclear palladacycle complex that inhibits melanoma growth through apoptosis and autophagy. - Presents the most advanced information regarding the role of the autophagic system in life and death - Contains a direct focus on the role of a novel binuclear palladacycle complex that inhibits melanoma growth - Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation - States recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities - Edited work with chapters authored by leaders in the field from around the globe—the broadest, most expert coverage available

This volume will detail the current state and perspectives of autophagy-based cancer therapy. Covering a wide range of topics, it will include an overview of autophagy as a therapeutic target in cancer, autophagy modulators as cancer therapeutic agents, implications of micro-RNA-regulated autophagy in cancer therapy, modulation of autophagy through targeting PI3 kinase in cancer therapy, targeting autophagy in cancer stem cells, and roles of autophagy in cancer immunotherapy. In addition, the volume will review applications of system biology and bioinformatics approaches to discovering cancer therapeutic targets in the autophagy regulatory network. The volume will be beneficial for a variety of basic and clinical scientists, including cancer biologists, autophagy researchers, pharmacologists, and clinical oncologists who wish to delve more deeply into this field of cancer research.This volume will be the first book to focus solely on autophagy as a target in cancer therapy. As well, it will comprehensively discuss the roles of autophagy in most currently available cancer treatments.

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging: Volume 9: Human Diseases and Autophagosome offers a valuable guide to both cellular processes while helping researchers explore their potentially important connections. Volume 9 emphasizes the role of autophagy in diseases, such as leukemia, antifungal and antibacterial immunity, and transplantation. This volume also explains, in detail, the molecular mechanism(s) underlying the formation of autophagosomes, including the progression of omegasomes to autophagosomes. This information is important because one of the major functions of autophagy is to degrade and eliminate excessive, old, and harmful materials from the cell. Autophagosomes receive these materials (cellular cargo) and transport them to lysosomes for degradation. Lysosomes contain the digestive enzymes (hydrolases) that breakdown proteins, lipids, carbohydrates, etc. (self-digestion). To further explain this phenomenon, the role of the endoplasmic reticulum (ER) in the formation of autophagosomes is discussed. ULK1 and Beclin 1 proteins are also important in the initial formation of autophagosomes, and are also discussed. Because much of the early research in this area was carried out using yeast cells, the role of Golgi complex in the autophagosome formation in these cells is explained. This volume also includes an explanation of the role of the autophagy-related gene ATG5 in cancer (e.g., gastrointestinal cancer). Paradoxically, autophagy is a'double-edged sword because it eliminates some pathogens, whereas it can be used by some intracellular pathogens to multiply and cause infection. This book is an asset to newcomers, providing a concise overview of the role of autophagy in necrosis and inflammation, while also serving as an excellent reference for more experienced scientists and clinicians. - Presents the most advanced information regarding the role of the autophagic system in life and death - emphasizes autophagy in diseases, such as leukemia - Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation - States recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities - Edited work with chapters authored by leaders in the field from around the globe—the broadest, most expert coverage available

Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and up-to-date, this book offers a valuable guide to these cellular processes whilst inciting researchers to explore their potentially important connections. Volume 7 provides coverage of the latest developments in autophagosome biogenesis and regulation; the role of autophagy in protein quality control; and the role of autophagy in apoptosis. Attention is given to autophagy in the cardiovascular system, with particular insights into the role of autophagy in atherosclerosis and the distinctive behavior of autophagy in the sinoatrial node. Cutting-edge findings in the relationships between autophagy and lifestyle are explored with the regulation of macroautophagy in response to exercise, as well as the promotion of carcinogenesis via autophagy in response to cigarette smoking. Volume 7 highlights the importance of understanding the role of autophagy in context, as the complexity of autophagic function becomes increasingly clear. Autophagy may be differentially regulated, and may perform distinctive cell-specific functions even within a single tissue. The overall significance of autophagy thus cannot be oversimplified, and must be explored with granular detail of the specific role, function, and area of impact.This book is an asset to newcomers as a concise overview of the complex significance of autophagy, while serving as an excellent reference for more experienced scientists and clinicians looking to update their knowledge. Volumes in the Series

Volume 6 provides coverage of the mechanisms of regulation of autophagy; intracellular pathogen use of the autophagy mechanism; the role of autophagy in host immunity; and selective autophagy. Attention is given to a number of mechanistic advances in the understanding of regulation, particularly the importance of nutrient availability; microRNAs; and cross-talk with other protein degradation pathways. Intracellular pathogen repurposing of autophagy for pathogenic benefit is also provided, with coverage of Herpesvirus protein modulation of autophagy; the varicella-zoster virus and the maintenance of homeostasis; and the relationship between autophagy and the hepatitis b virus. The significance of autophagy in host defense is elucidated, providing a specific focus on facilitation of antigen presentation; participation in thymic development; and the sharing of regulatory nodes with innate immunity. Selective autophagy for the degradation of mitochondria and endocytosed gap junctions are also explored. This book is an asset to newcomers as a concise overview of the regulation of autophagy, its role in host defense and immunity, and selective autophagy, while serving as an excellent reference for more experienced scientists and clinicians looking to update their knowledge. Volumes in the Series

The relationship between infection and immunity and autophagy, a pathway of cellular homeostasis and stress response, has been a rapidly growing field of study over the last decade. While some cellular processes are pro- or anti-infection, autophagy has been proven to be both: a part of the innate immune response against some microbes, and a cellular pathway subverted by some pathogens to promote their own replication. Autophagy, Infection, and the Immune Response provides a unified overview of the roles of cellular autophagy during microbial infection. Introductory chapters ground the reader by delineating the autophagic pathway from a cellular perspective, and by listing assays available for measuring autophagy. Subsequent chapters address virus interactions with autophagy machinery, the various roles of autophagy parasitic infection, and interactions of bacteria with the autophagic pathway. Concluding chapters explore the relationships of autophagy to systemic immune responses, including antigen presentation, ER stress, and production of IFN-gamma. Designed as a resource for those interested in initiating studies on the relationship between autophagy and infection or immunity, Autophagy, Infection, and the Immune Response combines practical state-of the art technique descriptions with an overview of the wide variety of known interactions between pathogens and the autophagic pathway.

Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and up-to-date, this book offers a valuable guide to these cellular processes whilst encouraging researchers to explore their potentially important connections. Volume 3 explores the role of autophagy in specific diseases and developments, including: Crohn's Disease, Gaucher Disease, Huntington's Disease, HCV infection, osteoarthritis, and liver injury. A full section is devoted to in-depth exploration of autophagy in tumor development and cancer. Finally, the work explores the relationship between autophagy and apoptosis, with attention to the ways in which autophagy regulates apoptosis, and the ways in which autophagy has been explored in Lepidoptera, elucidating the use of larval midgut as a model for such exploration. From these well-developed foundations, researchers, translational scientists, and practitioners may work to better implement more effective therapies against some of the most devastating human diseases. Volumes in the Series

Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and up-to-date, this book offers a valuable guide to these cellular processes whilst inciting researchers to explore their potentially important connections. Volume 5 comprehensively describes the role of autophagy in human diseases, delivering coverage of the antitumor and protumor roles of autophagy; the therapeutic inhibition of autophagy in cancer; and the duality of autophagy's effects in various cardiovascular, metabolic, and neurodegenerative disorders. In spite of the increasing importance of autophagy in the various pathophysiological conditions mentioned above, this process remains underestimated and overlooked. As a consequence, its role in the initiation, stability, maintenance, and progression of these and other diseases remains poorly understood. This book is an asset to newcomers as a concise overview of the diverse disease implications of autophagy, while serving as an excellent reference for more experienced scientists and clinicians looking to update their knowledge. Volumes in the Series

Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection and Aging, Volume 4 - Mitophagy presents detailed information on the role of mitophagy, the selective autophagy of mitochondria, in health and disease, by delivering an in-depth treatment of the molecular mechanisms involved in mitophagy initiation and execution, as well as the role of mitophagy in Parkinson's Disease, cardiac aging, and skeletal muscle atrophy. The most current understanding of the proteins and pathways involved in mitophagy are covered, with specific attention to Nix and Bnip3, PINK1/Parkin, Atg32, and FUNDC1. The role of mitophagy in cancer, neurodegeneration, aging, infection, and inflammation is also discussed providing essential insights into the pathogenesis of a variety of mitochondria dysfunction-related diseases. This book is an asset to newcomers as a concise overview of the current knowledge on mitophagy, while serving as an excellent update reference for more experienced scientists working on other aspects of autophagy. From these well-developed foundations, researchers, translational scientists, and practitioners may work to better implement more effective therapies against some of the most devastating human diseases. Volumes in the Series

Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward thinking, these books offer a valuable guide to both cellular processes while inciting researchers to explore their potentially important connections. Considering that autophagy is associated with numerous biological processes, including cellular development and differentiation, cancer (both antitumor and protumor functions), immunity, infectious diseases, inflammation, maintenance of homeostasis, response to cellular stress, and degenerative diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and prion diseases, there is a great need to understanding its role. Cell homeostasis is achieved by balancing biosynthesis and cellular turnover. In spite of the increasing importance of autophagy in various pathophysiological situations (conditions) mentioned above, this process remains underestimated and overlooked. As a consequence, its role in the initiation, stability, maintenance, and progression of these and other diseases (e.g., autoimmune disease) remains poorly understood. Volumes in the Series