Interest in sexuality and reproductive function does not cease when people begin to age. Instead, a new set of questions arises. Women want to know if it is safe to have babies in their late thirties and early forties. They want to know more about hot flashes and other symptoms of menopause-which ones are dangerous and which are merely uncomfortable. They are eager to learn about the relative risks and benefits of estrogen replacement therapy. Men, too, are concerned about age-related changes in their sexual function. Experts in reproductive physiology, gerontology, and genetics met at the National Institutes of Health in June of 1984 to discuss these and other concerns about aging and the reproductive system. The conference on Aging, Reproduc tion, and the Climacteric was sponsored by the American Fertility Society, The National Institute on Aging, and the National Institute of Child Health and Human Development. This volume is based on the proceedings of that confer ence."

It must be considered that there is nothing more difficult to carry out, nor more doubtful of success, nor more dangerous to handle, than to initiate a new order of things. Machiavelli: The Prince (1513) These are the Proceedings of a Conference on Temperature and Environmental Factors and the Testis which took place at New York University School of Medicine, December 8th and 9th, 1989. There is good reason to believe that this was the first of its kind to address, exclusively, the implications of temperature for this highly thermosensitive organ and its precious genetic cargo. The organizers of the Conference hoped to stimulate interest in this area which, paradoxically, has a considerable literature but which has received scant attention and sometimes outright opposition from clinicians expert in male infertility. There have been studies of the relationship of temperature to reproduction starting in the mid-18th Century with observations of the relationship of water temperature to spawning of fish. There is also a vast literature on the deleterious effects of externally applied heat upon spermatogenesis but little study of the possibility that intrinsic heat may be an important etiologic factor in subfertile semen. Today, fertility research has largely ignored this in favor of research in areas which have not produced successes, in terms of live births, comparable to what can be obtained by varicocelectomy (when appropriate) or scrotal hypothermia: viz. 1. Concentration upon the endocrine aspects of testicular function and its relation to spermatogenesis.

This 1999 edition of The Neural Crest contains comprehensive information about the neural crest, a structure unique to the vertebrate embryo, which has only a transient existence in early embryonic life. The ontogeny of the neural crest embodies the most important issues in developmental biology, as the neural crest is considered to have played a crucial role in evolution of the vertebrate phylum. Data that analyse neural crest ontogeny in murine and zebrafish embryos have been included in this revision. This revised edition also takes advantage of recent advances in our understanding of markers of neural crest cell subpopulations, and a full chapter is now devoted to cell lineage analysis. The major research breakthrough since the first edition has been the introduction of molecular biology to neural crest research, enabling an elucidation of many molecular mechanisms of neural crest development. This book is essential reading for students and researchers in developmental biology, cell biology, and neuroscience.

I am pleased to include this book as Volume 6 of Developmental Biology: A Comprehensive Synthesis. It has been edited by two of the foremost investiga tors in the study of genomic adaptability. lowe a special debt of gratitude to Dr. Marie A. DiBerardino, who developed the concept of the volume. Dr. DiBerar dino is also a very active member of the editorial board for this series. Much of the success of this series is due to her valuable advice. This series was established to create comprehensive treatises on specific topics in developmental biology. Such volumes serve a useful role in develop mental biology, since it is a very diverse field that receives contributions from a wide variety of disciplines. This series is a meeting ground for the various practitioners of this science, facilitating an integration of heterogeneous infor mation on specific topics. Each volume is intended to provide the conceptual basis for a comprehen sive understanding of its topic as well as analysis of the key experiments upon which that understanding is based. The specialist in any aspect of developmen tal biology should understand the experimental background of the field and be able to place that body of information in context to ascertain where additional research would be fruitful. At that point, the creative process generates new experiments. This series is intended to be a vital link in that process of learning and discovery."

It is a source of great satisfaction to us that a Second Edition of this treatise should be called for, especially because it has given us the opportunity to produce, we believe, a better book. Eighteen chapters, amounting to one-third of the whole, are new, and of these, 13 deal with subjects not covered at all in the First Edition. We have paid more attention to embryonic and fetal growth, with chapters on cell differentiation (Lehtonen and Saxen), embryonic growth (O'Rahilly and Muller), control of fetal size (Snow), regulation of fetal growth (D'Ercole and Underwood), and ultrasonic studies offetal growth (Meire). At last the data are available for a chapter on the evolution of the human growth curve, by Eliz- abeth Watts. Large parts of the endocrine section have been rewritten (by Michael Preece, and by William Crowley and Margaret Wierman), and the genetics section has been largely recast, with new contributions by William Mueller and Ronald Wilson. Reynaldo Marto- rell has contributed a new chapter on growth in developing countries, and Tanner discusses growth surveys and standards as well as catch-up growth. Finally, there are two new chap- ters dealing with growth as a monitor of the health of populations-one by Tadeusz Bie- licki, considering the contemporary scene, and the other by Robert Fogel, on the contri- bution that such studies are making to the economic history of the eighteenth and nineteenth centuries.

The subject of this book is reproduction-specifically, the interplay between reproductive physiology (especially neural and endocrine events) and behavior. In presenting this topic, there are two expository goals. The first is to study repro- duction at all of the major levels of biological organization-from the molecular (e. g. , hormone receptors in the brain), through the cellular (e. g. , ovarian morphogene- sis), systemic (e. g. , operation of the hypothalamo-pituitary-ovarian axis), and the organismic levels of organization. Analogously, behavior is treated from the most molecular, elementary, and fundamental components (e. g. , copulatory reflexes), through behavior in the reproductive dyad (e. g. , analysis of female sexual behav- ior), to complex social behavior (e. g. , the interaction of social context and behav- ioral sex differences). To the extent that these levels of biological and behavioral organization rep- resent a "vertical axis" in behavioral neurobiology, a second goal is to treat the "horizontal axis" of biological organization, viz. , time. There are, therefore, treat- ments of evolutionary origins (e. g. , a phylogenetic survey of psychosexual differ- entiation), genetic origins in the individual (e. g. , sexual organogenesis), ontoge- netic development (e. g. , behavioral sexual differentiation), and the immediate physiological precursors of behavior (e. g. , hormonal and nonhormonal initiation of maternal behavior). In addition to tracing the origins of reproduction and reproductive behavior, one extends the time-line from the behavior to its physio- logical consequences (e. g. , neuroendocrine consequences of sexual behavior).

HOWARD C. TAYLOR, JR. Medicine, through its long history, has continually striven to enlarge its scope. Success in these endeavors has come in sudden bursts with long intervals of relative quiescence between. As a result of the spectacular discoveries in the basic sciences during the last decades, medicine is again in a period of revolutionary advance in many fields. One of these is the subject of this report, "The Intrauterine Patient." Until recently the fetus signalized his presence only by the mother's enlarging abdomen and by his own movements, perceived by the preg nant woman herself and evident to the examining midwife and physician. Later, the sounds of the fetal heart heard by auscultation and the varia tions in its rate became the single important means by which the welfare of the fetus might be roughly determined and threats to his survival per haps detected. Otherwise, the fetus remained isolated, his condition unknown and any therapy consequent on diagnosis, except for the induc tion or termination of labor, nonexistent."

The aimoftheHypospadiasand Genital Symposium, held at theUniversityof California,SanFrancisco,wastoprovideaforumforauthoritativeinvestigatorswhoare activelyinvolvedinthevariousdisciplineswhichdefinetheleadingedgesofhypospadias and genital research. It is important for such investigators to continue to meet for the purpose of discussing the latest developments in their individual fields, to analyze the significanceofcurrent research, to discuss new tactics for unresolved problems and to develop new theories andapproaches asneeded. The two day conference on hypospadiasandgenitaldevelopment research was organizedintothreesections: 1)HumanStudies;2)MechanismofGenitalDevelopment; and 3) Endocrine Disruptors and Sexual Dimorphism in the Animal Kingdom. Each sessionwasintroducedbyanexpertmoderatorfollowedtheinvitedspeakerswithtimefor extensiveinteractionbetweeninvestigators. Thisbookdocumentstheproceedingsofthe HypospadiasandGenitalDevelopmentSymposium. Iwould especially like to thank Kari Gaudette for editorial assistants, Cynthia Ashe, Selcuk Yucel, Antonio Souza and the administrative staffinthe Departmentof Urology. Ihopeyoufindthisresourceuseful. Laurence S. Baskin,M. D. ProgramChair ChiefPediatricUrology UCSF vii ACKNOWLEDGEMENTS Supportforthissymposiumisgratefullyacknowledged TheNationalInstituteofHealthGrant#R13DK*HDS997 UCSFDepartmentofUrology AmericanUrologicAssociation CONTENTS Introduction...1 SECTIONI. HUMANSTUDIES EpidemiologyofHypospadias...*...*...25 J. DavidErickson EndocrineEvaluationofHypospadias...31 G. HyunandT. Kolon EndocrineAbnormalitiesinBoyswithHypospadias...45 R. I. Silver GeneticandClinicalStudiesonHypospadias...***...**...*...73 A. Nordenskjold SECTIONII. MECHANISMOFGENITALDEVELOPMENT DevelopmentofthePenileUrethra. . 87 G. CunhaandL. Baskin AnatomicalStudiesoftheMouseGenitalTubercle...103 L. Baskin,W. Liu,J. Bastacky,andS. Yucel AnatomicalStudiesoftheFibroblastGrowthFactor-l0Mutant,Sonic HedgeHogMutant,andAndrogenReceptorMutantMouseGenital Tubercle...*. **. . 123 S. Yllcel,W. Liu,DCordero,A. Donjacour,G. Cunha,andL. Baskin DevelopmentalGeneticsofHypospadias...149 M. Cohn xiii xiv Contents DevelopmentoftheMouseExternalGenitalia: UniqueModelof Organogenesis...159 K. Suzuki, K. Shiota,Y. Zhang,L. Lei,andG. Yamada NewConceptsontheDevelopmentoCtheVagina...173 E. Shapiro. H. Huang,andX. R. Wu SECTIONIII. ENDOCRINEDISRUPTORSANDSEXUAL DIMORPHISMINTHEANIMALKINGDOM EndocrineDisruptionOverview: AreMalesatRisk? 189 T. Colburn EndocrineDisruptionandHypospadias...203 G. Steinhardt Toxicant-InducedHypospadiasintheMaleRat * 217 L. E. Gray. . I. Ostby,J. Fun,C. Wolf,C. Lambright,V. Wilson, and N. Noreiga MasculinizationofFemaleMammals: LessonsfromNature...243 N. J. PI:H'candS. Glickman Index...255 SectionI Introduction HYPOSPADIAS LaurenceS. Baskin* M. D. ,FAAP 1.

The overall scope of this new series will be to evolve an understanding of the genetic basis of (1) how early mesoderm commits to cells of a heart lineage that progressively and irreversibly assemble into a segmented, primary heart tube that can be remodeled into a four-chambered organ, and (2) how blood vessels are derived and assembled both in the heart and in the body. Our central aim is to establish a four-dimensional, spatiotemporal foundation for the heart and blood vessels that can be genetically dissected for function and mechanism. Since Robert DeHaan's seminal chapter "Morphogenesis of the Vertebrate Heart" published in Organogenesis (Holt Rinehart & Winston, NY) in 1965, there have been surprisingly few books devoted to the subject of cardiovascular mor phogenesis, despite the enormous growth of interest that occurred nationally and internationally. Most writings on the subject have been scholarly compilations of the proceedings of major national or international symposia or multiauthored volumes, often without a specific theme. What is missing are the unifying concepts that can make sense out of a burgeoning database of facts. The Editorial Board of this new series believes the time has come for a book series dedicated to cardio vascular morphogenesis that will serve not only as an important archival and didac tic reference source for those who have recently come into the field but also as a guide to the evolution of afield that is clearly coming of age.

This volume comprises normal tables (description of normal development) for protozoa and invertebrates widely used in developmental biology studies. The species chosen reflect their advantages for laboratory studies, the information avail able, and their availability for experimentation. Chapter 11, which contains the normal tables for the starfish Asterina pectinifera, was written specially for this edi tion, which is the invertebrate section of the revised and augmented translation of Ob"ekty Biologii Razvitiya published in Russian in 1975 as a volume in the series of monographs Problemy Biologii Razyitiya (Problems of Developmental Biology) by Nauka Publishers, Moscow. The description of every species is preceded by an introduction in which the advantages of working with the particular animal are stated and the problems stud ied (with the main references) are outlined. Data are also provided on its taxonomic status and distribution of the animal, and conditions of keeping the adult animals in laboratory. Methods of obtaining gametes, methods of artificial fertilization, meth ods of rearing embryos and larvae, and tables of normal development are also given."

The World Congress of In Vitro Fertilization and Alternate Assisted Reproduction, held in Jerusalem, Israel, 2-7 April, 1989, was the sixth in the sequence of these Congresses, but was the first to emphasize the major importance and the place of assisted reproductive technologies in the treatment of infertility. The eternal City of Jerusalem witnessed the gathering of more than 1500 participants from allover the world who shared and exchanged knowledge and up-to-date experience in this ever-evolving field. The high quality scientific contributions to the Congress culminated in the publication of this Proceedings. It embraces all-important aspects in the field of in vitro fertilization and alternate assisted reproduction. Papers on controversies and diversities of methods to stimulate the ovaries, imaging techniques, basic research and state-of-the-art papers on ovarian physiology, the role of GnRH and its analog, clinical aspects of IVF treatment and cryopreservation, up-to-date techniques in assisted reproductive technologies that are quickly developing in conjunction with IVF, were included. When should IVF be preferable to surgery? What are the ex pected up-to-date world results and what are the psychological, moral, ethical and religious implications? These are all the concerns of the treating team and are addressed here. Male factor infertility remains a frustrating problem, but advances in the understanding of sperm-egg interaction, sperm evaluation and preparation are reported. Micromanipulation emerges as a possible alternative to bring some relief to this problem, but it also promises to be central in promoting the field of prenatal genetic analysis."

How do hormones and growth factors regulate animal growth in the developing embryo and after injury? What processes at the molecular level determine the growth patterns of different tissues? In this diverse synthesis of recent research the regulation of growth in response to environmental and genetic stimuli is discussed at the level of the animal, tissues and cells. Contrasts are drawn between regulation in foetal and adult tissues, and in different tissues such as the CNS, bone and muscle. Functional chapters focus on the molecular links between mechanical tension and muscle growth, for example, while other chapters review the roles of specific molecules such as growth hormone. This state-of-the-art review will be of significant interest to graduate students and research scientists in the fields of animal growth, endocrinology and cell biology.

With the emergence of the new field of evolutionary developmental biology we are witnessing a renaissance of Darwin s insights 150 years after his Origin of Species. Thus far, the exciting findings from evo-devo have only been trickling into college courses and into the domain of non-specialists. With its focus on the human organism, Quirks of Human Anatomy opens the floodgates by stating the arguments of evo-devo in plain English, and by offering a cornucopia of interesting case studies and examples. Its didactic value is enhanced by 24 schematic diagrams that integrate a host of disparate observations, by its Socratic question-and-answer format, and by its unprecedented compilation of the literature. By framing the hows of development in terms of the whys of evolution, it lets readers probe the deepest questions of biology. Readers will find the book not only educational but also enjoyable, as it revels in the fun of scientific exploration.

Following on from the success of his two previous books, Remarkable Mathematicians and Remarkable Physicists, Ioan James now profiles 38 remarkable biologists from the last 400 years. The emphasis is on their varied life-stories, not on the details of their achievements, but when read in sequence their biographies, which are organised chronologically, convey in human terms something of the way in which biology has developed over the years. Scientific and biological detail is kept to a minimum, inviting any reader interested in biology to follow this easy path through the subject s modern development.

Many complex molecular interactions are involved in the development of the mammalian brain. Molecules serving as guidance cues for migratory cells, growing axons and for recognition of postsynaptic targets are a major topic for research because they are directly involved in the formation of neuronal circuits, thus creating the foundation for subsequent functional refinement through interactions with the environment. In addition, most guidance cue molecules are also involved in plasticity, damage repair and regeneration in the adult brain.

This volume reviews current knowledge on major classes of molecules involved in: guidance of growing axons; tau proteins involved in the establishment of axonal polarity, outgrowth and contact recognition; gangliosides and lectins involved in neuronal migration, neurite outgrowth and contact recognition; and myelin molecules that inhibit nerve regeneration.

Early embryonic loss is a continuing social and economic global problem. In human populations the estimates of interruptions early in pregnancy range from 35-60%. In animal husbandry (swine, ruminants) fully 30% of pregnancies fail to survive early events of gestation. The futility associated with this persistant high risk is even more unsettling because of advances made in assisted reproductive technology which, although this very selective methodology has added to our knowledge of embryo-endometrial interactions, has resulted in a birth rate of only 14%. These studies have instigated comparisons of the live relative contributions of the embryo and the uterus to the outcome of pregnancy. These analyses have shown that we have learned significantly less about the role of the uterus in deciding the outcome of either natural or assisted pregnancies. In 1979 a quotation by George Corner was used to set the tone of a meeting that was devoted to discussion of the cellular and molecular aspects of implantation. In spite of the proliferation in research activity which occurred in the following 15 years our real understanding of the embryo transfer process has fallen short of our expectations. We use the Corner quotation, once again, to preface this symposium so that we may recall that the fundamental nature of the process which regulates embryo-endometrial interactions still escapes us.

The auditory system has a remarkable ability to adjust to an ever-changing environment. The six review chapters that comprise Plasticity of the Central Auditory System cover a spectrum of issues concerning this ability to adapt, defined by the widely applicable term "plasticity." With chapters focusing on the development of the cochlear nucleus, the mammalian superior olivary complex, plasticity in binaural hearing, plasticity in the auditory cortex, neural plasticity in bird songs, and plasticity in the insect auditory system, this volume represents much of the most current research in this field. The volume is thorough enough to stand alone, but is closely related a previous SHAR volume, Development of the Auditory System (Volume 9) by Rubel, Popper, and Fay. The book fully addresses the difficulties, challenges, and complexities of this topic as it applies to the auditory development of a wide variety of species.

Each new volume of this publication brings the privilege of expressing some of my thoughts on subjects of interest to its readers. In the past year or so public concern about environmental and societal dangers has largely turned to those of cosmic proportion-Chernobyl, the thinning ozone layer, AIDS, and the like-and thankfully our subject matter has been allowed a respite. Even the miniepidemic of craniofacial and other malformations caused by the retinoid antiacne drug Accutane made no headlines. Incidentally, this might have been a tragedy of far greater proportions had it not been nipped in the bud by the historical ground work that quickly permitted it to be recognized as due to an environ mental teratogen-the sort of fact the public and authorities inadequately appreciate. But there is a warning connected with this abeyance of media focus on teratological matters. Disquiet over cosmic imbalances will sub side as they are corrected or horrendous projections fail to materialize, and even cures for dread infectious diseases, or Puritan revolution in terdicting such plagues, will be forthcoming, and these things will occur long before congenital malformations are no more. And as the year-in and year-out recurrence of over 100,000 an nual births of seriously malformed infants in the United States alone continues to force itself on the public consciousness, we can expect a heightened demand that "a cure" be found, because "if we can land a man on the moon, if we can prevent polio, why can't we . . ."

In the last decade, since the publication of the first edition of Scanning Electron Microscopy and X-ray Microanalysis, there has been a great expansion in the capabilities of the basic SEM and EPMA. High resolution imaging has been developed with the aid of an extensive range of field emission gun (FEG) microscopes. The magnification ranges of these instruments now overlap those of the transmission electron microscope. Low-voltage microscopy using the FEG now allows for the observation of noncoated samples. In addition, advances in the develop ment of x-ray wavelength and energy dispersive spectrometers allow for the measurement of low-energy x-rays, particularly from the light elements (B, C, N, 0). In the area of x-ray microanalysis, great advances have been made, particularly with the "phi rho z" Ij)(pz)] technique for solid samples, and with other quantitation methods for thin films, particles, rough surfaces, and the light elements. In addition, x-ray imaging has advanced from the conventional technique of "dot mapping" to the method of quantitative compositional imaging. Beyond this, new software has allowed the development of much more meaningful displays for both imaging and quantitative analysis results and the capability for integrating the data to obtain specific information such as precipitate size, chemical analysis in designated areas or along specific directions, and local chemical inhomogeneities."

The overall scope of this new series will be to evolve an understanding of the genetic basis of (1) how early mesoderm commits to cells of a heart lineage that progressively and irreversibly assemble into a segmented, primary heart tube that can be remodeled into a four-chambered organ, and (2) how blood vessels are derived and assembled both in the heart and in the body. Our central aim is to establish a four-dimensional, spatiotemporal foundation for the heart and blood vessels that can be genetically dissected for function and mechanism. Since Robert DeHaan's seminal chapter "Morphogenesis of the Vertebrate Heart" pub lished in Organogenesis (Holt Reinhart & Winston, NY) in 1965, there have been surprisingly few books devoted to the subject of cardiovascular morphogenesis, despite the enormous growth of interest that occurred nationally and internationally. Most writings on the subject have been schol arly compilations of the proceedings of major national or international symposia or multiauthored volumes, often without a specific theme. What is missing are the unifying concepts that can make sense out of a burgeoning database of facts. The Editorial Board of this new series believes the time has come for a book series dedicated to cardiovascular morphogenesis that will serve not only as an important archival and didactic reference source for those who have recently come into the field but also as a guide to the evolution of a field that is clearly coming of age."

Why Efforts to Expand the Meaning of "Teratogen" Are Unacceptable Disagreement about nomenclature in teratology is not new. Dissent even about the very fabric of the discipline-what congenital malformations consist of-has often been voiced. Time, instead of resolving such diffi culties, has sometimes worsened them. For example, in the past it was agreed that congenital malforma tions are abnormalities of structure present at birth, but differences of opinion concerning where the line between normal and abnormal was to be drawn prevailed. It was obvious that, in order to discover the causes of congenital malformations and cast strategies for their prevention, it would be necessary to have knowledge of the baseline of their frequency, and that this required uniformity of definition of terms. Since malfor mations of primary social concern are those having grave outcomes (and are, paradoxically, also the commonest ones), it is logical that such condi tions were the first consideration of investigators and were the defects whose frequency was considered to comprise the required baseline.

Our understanding of the molecular mechanisms involved in mammalian brain development remains limited. However, the last few years have wit nessed a quantum leap in our knowledge, due to technological improve ments, particularly in molecular genetics. Despite this progress, the available body of data remains mostly phenomenological and reveals very little about the grammar that organizes the molecular dictionary to articulate a pheno type. Nevertheless, the recent progress in genetics will allow us to contem plate, for the first time, the integration of observation into a coherent view of brain development. Clearly, this may be a major challenge for the next century, and arguably is the most important task of contemporary develop mental biology. The purpose of the present book is to provide an overview that syn thesizes up-to-date information on selected aspects of mouse brain devel opment. Given the format, it was not possible to cover all aspects of brain development, and many important subjects are missing. The selected themes are, to a certain extent, subjective and reflect the interests of the contributing authors. Examples of major themes that are not covered are peripheral nervous system development, including myelination, the development of the hippocampus and several other CNS structures, as well as the developmental function of some important morphoregulatory molecules."

Life As we Know It covers several aspects of Life, ranging from the prebiotic level, origin of life, evolution of prokaryotes to eukaryotes and finally to various affairs of human beings. Although Life is hard to define, one can characterize it and describe its features. The information presented here on the various phenomena of Life were all written by highly qualified authors including scientists, a professional athlete and three Nobel Laureates.

No field of contemporary biomedical science has been more revolutionized by the techniques of molecular biology than developmental biology. This is an outstanding concise introduction to developmental biology that takes a contemporary approach to describing the complex process that transforms an egg into an adult organism. The book features exceptionally clear two-color illustrations, and is designed for use in both undergraduate and graduate level courses. The book is especially noteworthy for its treatment of development in model organisms, whose contributions to developmental biology were recognized in the 1995 Nobel Prize for physiology and medicine.

It is appropriate at the outset of this book to pose a question that was often asked --of the organizers before the meeting took place and later among those who participated in the meeting -- "What is meant by 'Systems Approaches' in the study of developmental neurobiology?" The answer, as we originally conceived it, can be succinctly summarized by the word "interactions". That brief epithet was expanded during the general discussion portion of the meeting, where the following definition was offered: "Systems approaches in developmental neurobiology are unified by attention to the emergent properties of the developing system under investigation and by a focus on the aspects of development of the nervous system that depend on interactions among its various elements, be they molecular, intracellular or multicellular. " As opposed to ignoring complexity or trying to wish it away, those of us who utilize a systems approach embrace the principle that complexity is what makes the nervous system special. We have come to recognize that wherever we look, we find interactions which are to be probed and eventually. understood. Even the so-called "simple systems", a term that has been used to describe many invertebrate preparations, are embraced under the above definition, since with further study it is becoming increasing clear that such systems are not as simple as once thought. We also include molecular genetics under the systems rubric. After all, genes regulate other genes which regulate others, and so it goes.