bluuebunny/crossref_metadata_2025 huggingface dataset:
The Topology of S
1
Authors: Calegari Danny
Published: November 2023

In this chapter we establish basic properties of the point set topology of S  1 which will be used throughout the rest of the book.
Peano Curves
Authors: Calegari Danny
Published: November 2023

In this chapter we reconcile (to some extent) the view of a foliated manifold developed in Chapters 7 and 8 with the geometry of the underlying manifold.
Gauge field theory
Authors: Dunajski Maciej
Published: November 2023

In Chapter 5 we have given examples of Lagrangians invariant under the action of symmetry groups. These symmetry transformations were identical at every point of space time. This is referred to as global symmetry in the physics literature. In this chapter we shall introduce a concept of gauge symmetry, where the symmetry transformation is allowed to depend on a space-time point. This is what physicists call local symmetry. This type of symmetry is already present in Maxwell’s electrodynamics.
Symmetry reductions and the integrable chiral model
Authors: Dunajski Maciej
Published: November 2023

Most integrable systems arise as symmetry reductions of ASDYM, where the potential one-form is assumed not to depend on one or more coordinates on the space-time. The resulting system will admit a (reduced) Lax pair with a spectral parameter as well as a twistor correspondence, and thus will be integrable. This leads to a classification of those integrable systems that can be obtained by reduction from the ASDYM equations as well as a unification of the theory of these equations by reduction of the corresponding theory for the ASDYM equations. The programme of reducing the ASDYM equations to various integrable equations has been proposed and initiated by Ward [171] and fully implemented in the monograph [118].
Anti-self-dual conformal structures
Authors: Dunajski Maciej
Published: November 2023

All gravitational instantons discussed in Chapter 9 (with the exception of the analytically continued Schwarzschild solution (9.1.1)) had ASD Riemannian tensor. This ASD property underlies the existence of many explicit examples as well as ‘implicit’ solution generation techniques. In this chapter we shall consider a more general situation where only the conformal Weyl curvature in four dimensions is ASD.
Scattering From General Populations
Authors: Field Timothy R
Published: November 2023

In this chapter we derive the stochastic dynamics for scattering of a wavelike field from a large population of scatterers whose dynamics is arbitrary. This leads to a result concerning the observability of the scattering cross-section in terms of the resultant phase fluctuations that is independent of the population dynamics. An emergent concept is a certain notion of an ideal filter. The dffusion-based model of K-scattering arises, encountered in Chapter 8, as a special case. The experimental implications of the results in a variety of contexts are discussed later in Part III.
Renewals
Authors: Grimmett Geoffrey R , Stirzaker David R
Published: November 2023

Planes land at Heathrow airport at the times of a renewal process with interarrival time distribution function F. Each plane contains a random number of people with a given common distribution and finite mean. Assuming as much independence as usual, find an expression for the rate of arrival of passengers over a long time period.
Teaching Statistics
Authors: Gelman Andrew , Nolan Deborah
Published: November 2023

Students in the sciences, economics, psychology, social sciences, and medicine take introductory statistics. Statistics is increasingly offered at the high school level as well. However, statistics can be notoriously difficult to teach as it is seen by many students as difficult and boring, if not irrelevant to their subject of choice. To help dispel these misconceptions, Gelman and Nolan have put together this fascinating and thought-provoking book. Based on years of teaching experience the book provides a wealth of demonstrations, examples and projects that involve active student participation. Part I of the book presents a large selection of activities for introductory statistics courses and combines chapters such as, 'First week of class', with exercises to break the ice and get students talking; then 'Descriptive statistics' , collecting and displaying data; then follows the traditional topics - linear regression, data collection, probability and inference. Part II gives tips on what does and what doesn't work in class: how to set up effective demonstrations and examples, how to encourage students to participate in class and work effectively in group projects. A sample course plan is provided. Part III presents material for more advanced courses on topics such as decision theory, Bayesian statistics and sampling.
Introduction
Authors: Gelman Andrew , Nolan Deborah
Published: November 2023

We have taught introductory statistics to college students for several years. There are a variety of good textbooks at this level, all of which cover the material pretty well. However, we found it a challenge to keep students motivated in class. Statistics is problem-solving. Watching the instructor solve a problem on the blackboard is not as effective or satisfying for students as actively involving themselves in problems. To improve participation, we and our colleagues have been collecting and developing tools, tricks, and examples for statistics teaching. Many teachers have their own special teaching methods but they are not always disseminated widely; as a result, some of the best ideas (for example, the survey of family sizes presented here on page 56 and the coin-flipping demonstration on page 105) have been rediscovered several times. We put together this book to collect all the good ideas that we have heard about or developed in our own courses.
First week of class
Authors: Gelman Andrew , Nolan Deborah
Published: November 2023

On the first day of class, in addition to introducing the concepts of probability and statistics, and giving an overview of what the students will learn during the term, we include class-participation demonstrations and examples. Then we start with descriptive statistics, as discussed in the next chapter. We often begin the first class with an activity on variation, such as the age-guessing demonstration or the cancer example described here. In the first week, we also discuss numeracy, address the question of why statistics is important, and collect data on students to use later in the course. We like to get students involved right away and set the expectation for plenty of class participation.
Statistical literacy and the news media
Authors: Gelman Andrew , Nolan Deborah
Published: November 2023

An important theme in an introductory statistics course is the connection between statistics and the outside world. We describe here some assignments that have been useful in getting students to learn how to gather and process information presented in the newspaper articles and scientific reports they read. We developed these assignments with the help of several undergraduate research assistants; we devote an entire chapter to this topic in order to give a sense of the details that are needed to get students on track with this sort of long-form assignment. Tracking down reports from newspaper articles can be difficult, and this assignment seems to work well only when students have direction about how to do this kind of research.
Statistical inference
Authors: Gelman Andrew , Nolan Deborah
Published: November 2023

We begin this chapter with a very successful demonstration illustrating many of the general principles of statistical inference, including estimation, bias, and the concept of the sampling distribution. We then present various demonstrations and examples that take the students on the transition from probability to hypothesis testing, confidence intervals, and more advanced concepts such as statistical power and multiple comparisons.
Directed projects in a mathematical statistics course
Authors: Gelman Andrew , Nolan Deborah
Published: November 2023

In this chapter we present a model for using case studies in undergraduate mathematical statistics courses. Statistics teachers at many institutions have created innovative data-based homework assignments; we focus on these case studies because we hope the suggestions in this chapter will be helpful for you in implementing your own data-analysis assignments.
Mosaic evolution of subterranean mammals
Authors: Nevo Eviatar
Published: November 2023

Life underground has evolved among different groups of mammals all over the globe. It is an extraordinary environment - with relatively constant temperature, few opportunities to meet organisms other than the immediate family, and a completely different sensory environment. Locomotion, communication, food-finding, navigation, circadian rhythms, and indeed the whole of the animals' physiology may be specialized to cope with underground life. From burrowing to blindness, magnetic communication to the weird bee-like eusociality of naked mole rats, specialization has been extreme - and, in turn, has led to speciation in a whole range of new contexts. That the subterranean way of life occurs in different species of mammals across the globe has provided scientists with one of nature's best studied global evolutionary demonstrations of adaptive radiation and speciation. The revolution in molecular biology that has occurred over the last ten years has massively expanded these horizons, allowing scientists to explore, map, and clone the genes underlying the basis of adaptation and speciation and translate their fascinating structural and functional evolution into genes and genomic language. This book draws together the burgeoning literature about all aspects of the biology of subterranean mammals. Beginning with their evolutionary history and the processes that led to the subterranean way of life, the author goes on to review ecology, behaviour, and physiology within the context of the highly stressful subterranean context, consider the specializations that have evolved in response, and then to compare the 11 families of extant subterranean mammals. The extraordinary circumstances surrounding subterranean mammals present a unique, global, 'natural experiment' in evolution that has implications throughout biology. As such this comprehensive survey will stand as an invaluable reference in years to come.
Evolutionary theory: past, present, and future
Authors: Nevo Eviatar
Published: November 2023

Evolutionism, the world view that considers constant change a central process of nature, emerged in Greek philosophy in its attempt to explain the origin and structure of the physical and organic worlds (Russell, 1949). However, evolutionary biological thinking appeared only in the 18th century, following the great geographical discoveries (Eisley, 1958), replacing the static world view of creationism and species permanency. Evolutionary theory has been crystallized in the early to mid-19th century, first genuinely proposed by Lamarck (1809), and formalized by Darwin (1859) in the Origin of Species. Darwin proposed that natural selection between individuals is the mechanism of evolution rather than by the individuals’ direct perfection, as suggested by Lamarck. Darwinian evolutionism introduced the idea of individual variation as central to the process of environmental selection. Darwinism holds that organic evolutionary change from a common descent with gradual modification results from the interplay between variation and natural selection through differential survival and reproduction of individual variants. Since the theory was propounded by Darwin, it has been modified and explicated by the science of genetics. The fruitful interdisciplinary link between Darwinism and Mendelism provided the organizing principle of biology (Lewontin, 1974).
Moles: insectivorous subterranean mammals
Authors: Nevo Eviatar
Published: November 2023

Talpid distribution is temperate Holarctic (Fig. 5.1). In North America, talpids range from southern Canada to northern Mexico and discontinuously from the Atlantic to the Pacific coasts. In Eurasia, the family ranges from the 63rd parallel to Malaya and the Mediterranean Sea. Fifteen genera and 40 species are extant (Wilson and Reeder, 1993; see also Yates, 1984, who reported 17 genera and 31 extant species; Yates and Moore, 1990), (Appendix 2). See Appendices 2 to 4 and Figs 15.1 to 15.17 for family data analysis.
Structure, adaptiveness, and evolution of tunnel system architecture in subterranean mammals
Authors: Nevo Eviatar
Published: November 2023

The subterranean ecotope (Whittaker et al., 1973) is structurally simple. It is essentially a sealed system (Elton and Miller, 1954), microclimatically relatively stable (i.e. permanent and predictable), highly specialized, and presumably low in productivity (MacArthur, 1972; Southwood et al., 1974). According to theory (Leigh, 1975; Levins, 1968; MacArthur, 1972), the greater buffering and predictability of underground as compared to above ground environments, both physically (microclimate) and biotically (food supply, low predation, parapatry), should lead to a greater degree of specialization (i.e. narrow niche) underground. The relative constancy and periodicity of physical factors result in high predictability underground (Colwell, 1974). Predictability of temperature, relative humidity (daily or seasonal), darkness, and air currents are consistently greater in underground than in above ground habitats (Dubost, 1968; Kennerly,, 1954; McNab, 1966; Nevo, 1979; Altuna, 1991; and their references), primarily because of constancy (i.e. the levels characteristic of the different phases in the cycle are equal to one another) (Colwell, 1974).
Digging strategies: structure and function
Authors: Nevo Eviatar
Published: November 2023

Subterranean rodents loosen soil primarily with the incisors (e.g. Spalax, Bathyergus, Ctenomys) or use incisors and claws (Geomys), whereas subterranean insectivores (e.g. Talpa, Chrysospalax) use only claws (Nevo, 1979). In rodent teeth-diggers the incisors are large, strong, and with roots extending close to or into the mandible condyle, and, in the upper jaw, to or behind the maxillary cheekteeth (Fig. 9.1). Lower incisors are used more than the upper incisors in digging, hence they wear and grow faster. In Thomomys, the upper incisors grow about 0.58 mm per day, and about twice as much for the lower incisors (Miller, 1958). Generally, incisors of subterranean geomyids grow two to four times as fast as those ofnon-fossorial rodents. The incisors are self-sharpening because enamel covers the soft dentine only anteriorly (Fig. 9.1).
Ecological adaptive strategies
Authors: Nevo Eviatar
Published: November 2023

The optimal area hypothesis assumes that the home range of animals, the area they know and patrol (Burt, 1943), is large enough to yield an adequate supply of energy. The home ranges of subterranean mammals are generally also their exclusive and defended territories (Brown and Orians, 1970), except for brief periods during the breeding season when multiple occupancies by both sexes occur. The social subterranean animals are the exception where colonies involve from several individuals to several hundreds of individuals (e.g. Sherman et al., 1991).
Genetic adaptive strategies
Authors: Nevo Eviatar
Published: November 2023

Chromosomal evolution through major structural rearrangements may lead either to speciation through reproductive isolation, caused by hybrid sterility and extensive homozygous fixation, and/or to local adaptive genetic polymorphism through reorganization of new coadapted supergenes (White, 1973, 1978). Chromosomal sibling species, based on Robertsonian whole-arm rearrangements and/or pericentric inversions and reciprocal translocations, are widespread in unrelated subterranean herbivores (Nevo, 1979, 1999).
Regional molecular polymorphism analysis
Authors: Nevo Eviatar
Published: November 2023

We have used Israel, with its remarkable physical and biotic diversities, as a large-scale ecological-genetic laboratory (Nevo, 1986c, 1988a,b, 1990a) and conducted an ecological test of protein polymorphism in 13 unrelated genera of plants, invertebrates, and vertebrates, involving 21 species, 142 populations, and 5474 individuals (Nevo and Beiles, 1988a), following our extensive studies of allozyme diversity in 38 species in Israel (Nevo, 1983a).
Theory of ecological, behavioural, and physiological adaptive strategies
Authors: Nevo Eviatar
Published: November 2023

The relatively constant and climatically predictable subterranean ecotope presumably leads to convergent K-selection along the K-selection continuum in subterranean mammals (Nevo, 1979). The latter comprise ‘equilibrium species’, that is, those at or near the carrying capacity of the environment, selected for their ability to harvest food efficiently through resource competition but without overshoot and resource destruction. Even when perturbed, they return quickly to equilibrium.
Speciation theory
Authors: Nevo Eviatar
Published: November 2023

Species and speciation have always been problematic in evolutionary studies. The synthetic theory of evolution replaced the typological species concept and advanced the now classic biological concept of species, despite its rejection by some evolutionary biologists and others (e.g. Sokal, 1973; Ehrlich, 1961; Hennig, 1966; Raven, 1977; L0vtrup, 1979, but see Mayr, 1988b). This concept is based on reproductive isolation preventing interbreeding between groups of populations occupying a specific niche in nature, rather than on morphological differences, defining morphospecies. An extensive literature has been published on different species concepts and speciation mechanisms (e.g. Darwin, 1859; Dobzhansky, 1937; Cain, 1954;.
Introduction
Authors: Daly M de Burgh
Published: November 2023

The pattern of the autonomic responses evoked by selective stimulation of the carotid and aortic body chemoreceptors depends on changes in a number of variables occurring at the same time. There is the arterial blood pressure per seas well as alterations in arterial baroreceptor discharge as a result of variations in blood pressure. The concomitant increase in respiratory minute volume modulates the effectiveness of the input from the carotid chemoreceptors through changes in the central inspiratory neuronal activity and the activity of slowly adapting pulmonary stretch receptors, and changes in PaCO2 The autonomic responses are also influenced by the extent to which the brainstem defence areas are activated, which in turn depends on the potency of the chemoreceptor stimulus and the level of activity existing in the defence areas, and by the effects of the reflex secretions of suprarenal catecholamines.
Respiratory mechanisms modulating cardiovascular responses of chemoreceptor origin
Authors: Daly M de Burgh
Published: November 2023

The primary respiratory, cardiac, and peripheral vascular responses to stimulation of the carotid body chemoreceptors are hyperventilation, bradycardia, and vasoconstriction in most vascular territories. The cardiac and vascular responses may, however, be suppressed or even reversed by mechanisms occurring secondarily to the hyperventilation. Important amongst these mechanisms are an increase in central respiratory activity, an increase in activity of lung stretch afferents, and a fall in PaCO2 These respiratory mechanisms account for the tachycardia and vasodilatation seen in the spontaneous breathing animal on selective stimulation of the carotid bodies.
Role of brainstem defence areas
Authors: Daly M de Burgh
Published: November 2023

Stimulation of the carotid body chemoreceptors in animals in which conventional anaesthetics are used, such as chloralose, urethane, or a barbiturate, causes an increase in respiratory minute volume, bradycardia, and selective peripheral vasoconstriction, responses which may be suppressed or even reversed by mechanisms secondary to the hyperventilation. These anaesthetics are known to depress transmission through the brainstem defence areas. When transmission is preserved by using high decerebrate unanaesthetized animals or animals under light Althesin anaesthesia, stimulation of the carotid bodies causes not bradycardia and selective peripheral vasoconstriction but a pattern of response indistinguishable from that of direct excitation of the brainstem defence areas, namely hyperventilation, tachycardia, vasoconstriction in the mesenteric and renal circulations, and vasodilatation in skeletal muscle due to activation of sympathetic cholinergic vasodilator fibres or inhibition of sympathetic vasoconstrictor fibres.
Interactions between arterial chemoreceptors and other inputs
Authors: Daly M de Burgh
Published: November 2023

There are considerable differences in the way the carotid bodies are integrated with other inputs. The carotid chemoreceptor reflex vasoconstrictor response is enhanced by unloading and diminished by stimulating the carotid baroreceptors, respectively. Thus, gain of the carotid baroreceptor reflex response relating carotid sinus pressure to vascular resistance in muscle is increased during carotid chemoreceptor activation. Stimulation of atrial receptors brings about a reflex increase in renal blood flow due to vasodilatation, a response which is enhanced when carried out on a background ofvasoconstriction evoked by excitation of the carotid bodies. The reflex cardioaccelerator response occurring on stimulation of the atrial receptors is mediated entirely by way of sympathetic efferents which constitute a separate group of fibres, there being no convergence of projections of the atrial receptors with either the carotid chemoreceptors or baroreceptors.
Bird Families Of The World: Pelicans, Cormorants And Their Relatives
Authors: Nelson J Bryan , Mackay Andrew , Busby John
Published: November 2023

The pelecaniformes are a large and important group of seabirds, containing many spectacular species. This book addresses the breeding biology of the six pelecaniform families, which comprise the closely-related core groups (pelicans, cormorants/shags, darters, gannets/boobies) and their more distant relatives, the frigate birds and tropic birds. Many fundamental questions can be addressed through the pelecaniformes: Why do they breed in colonies? What are the links between their feeding methods and their reproduction? What part does territorial and pairing behaviour play in their life-cycles? These and scores of comparable issues, including those related to man, are woven here into a richly interpretative text. The author’s approach to the subject is threefold. First, the pelecaniformes are placed within the framework of four discrete disciplines, with chapters on evolutionary relationships, comparative behaviour, ecology, and the birds’ relationship with humans. Secondly, each of the six families is discussed, elucidating the range of taxonomy, behaviour, and ecology within each. Finally, we progress to specific level, using the same structure as for the family accounts. In this way, each of the 60-odd species can be understood not just as discrete units, but as part of their family and order. The book is unique in its coverage of the entire order and in its combination of facts and interpretation. Pelicans, Cormorants, and their Allies will enable readers not only to identify the many spectacular species which make up this large and important group of seabirds, but also to understand their breeding biology.
General Introduction
Authors: Nelson J Bryan , Mackay Andrew , Busby John
Published: November 2023

Every seabird addresses the same basic issues and has evolved its own adaptive web. The various ways in which the pelecaniforms deal with their social requirements, such as breeding space and the relationship between partners and between parents and young, throws light on social behaviour in general. Similarly, the links between feeding/for aging and the entire complex edifice of breeding strategy in the different pelecaniforms is relevant to those same issues in other seabirds. Combining the general and the particular in this book has been complicated by the need to deal with six variably divergent families, two of which (tropicbirds and frigatebirds) are very different from the remainder and may not even belong within the Pelecaniformes.
Cormorants and Shags
Authors: Nelson J Bryan , Mackay Andrew , Busby John
Published: November 2023

ADULT M PRE-BREEDING: Head, neck, lower back, rump, underparts glossed green; upper back, scapulars, wing-coverts greyish, with black edges to feathers. Wings, tail blackish. Straggly ear-plumes vary from whitish (W) to black (E). Eye bright green, eyelids blue with (floridanus)white spots, or orange-yellow. Gape startlingly blue; lores, face, gular skin orange; bill black mottled grey or yellow, upper mandible pale yellow-blue with darker lines and blotches. Legs, feet black.
Anhinga and Darter
Authors: Nelson J Bryan , Mackay Andrew , Busby John
Published: November 2023

ADULT M PRE-BREEDING: Black body plumage; green-glossed, head and neck browner due to elongated, transitory brownish white filoplumes on hindneck and head, bordering central mane. Elongated scapulars, wing-coverts and longest proximal secondaries silvery white; other wing feathers black; alulars unusually long. Longest wing-covert feathers corrugated. All 14 tail feathers black (mid-pair corrugated with c. 30 transverse flutings) becoming browner towards tip and tipped with brownish white. Bill nondescript dusky greenish on upper mandible, more yellow lower mandible; early in courtship becomes orange red.
Tropicbirds
Authors: Nelson J Bryan , Mackay Andrew , Busby John
Published: November 2023

ADULT M PRE-BREEDING: Mainly silky white, may be suffused with variable amounts pink. Conspicuously black wing-tips on upper surface due to black outer four primaries and their coverts and some black on inner secondaries. Underwing white. Large patch of blackish vermiculations on back extends onto upper tail. Black eyestripe may continue onto nape but much reduced or absent in Red Sea–Indian Ocean. Underparts white with some grey on flanks. Long white tail streamers with black shafts. Bill stout and red, iris dark brown. Legs pale, webs black. On Ascension feet varied from pale pink to chrome yellow.
The evolutionary and ecological importance of environmental stress
Authors: Hoffmann Ary A , Parsons Peter A
Published: November 2023

Periods of extreme environmental stress have been emphasized in many areas of the evolutionary and ecological literature. We briefly describe some of these areas to give an overview of the biological importance of environmental stress, including patterns in the fossil record, the impact of unusual climatic conditions on populations and the association between climatic extremes and species distributions. Attempts to classify organisms by the nature of their habitats also incorporate stress, and these are briefly discussed along with the interaction between stress and competition.
Stress and Protein variation
Authors: Hoffmann Ary A , Parsons Peter A
Published: November 2023

We start an overview of genetic variation in stress response at the protein level, before moving to the chromosomal, developmental, and organismic levels in Chapters 4 and 5. Here we consider effects of environmental stress on enzymes and heat-shock proteins, and conclude by discussing the importance of stress in selection on protein polymorphisms.
General stress resistance
Authors: Hoffmann Ary A , Parsons Peter A
Published: November 2023

Resistance to environmental stress may involve mechanisms that are highly specific for one type of stress, such as detoxification pathways restricted to a particular class of insecticide, or may cover different stresses, and have a common physiological/biochemical basis. We have already encountered a general resistance mechanism in the form of heat shock proteins that are induced by a variety of agents and may provide protection against a range of stresses (Section 3.2). If such general mechanisms are common, then individuals may have high or low resistance levels for a range of stresses, and selection for increased resistance to one stress will increase resistance to other stresses.
The evolution of gametes-from motility to double fertilization
Authors: Bruce Knox R , Ducker Sophie C
Published: November 2023

Considerable advances have occurred in the understanding of the structure and evolution of the male gamete of plants. Motile sperm were animalcules in the seventeenth century, and the flagellated sperms of plants were not recognized until the end of the eighteenth century. With the advent of high resolution electron microscopy in the twentieth century, together with molecular approaches including monoclonal antibody technology, analysis of their structural and heritable characteristics is a reality. Motile male gametes are most complex in early gymnosperms, the cycads and Ginkgo. What cytological changes have accompanied the evolution of motile sperm in these systems?
Competition and marine plant-animal interactions
Authors: Underwood A J
Published: November 2023

Competitive interactions for food are widespread amongst marine invertebrate grazers. The common occurrence of such interactions is due to the unpredictable increases in density of grazers that can occur as a result of large fluctuations in the timing and intensity of settlement or recruitment from planktonic stages. In addition, the supplies of algal foods, particularly microalgae that are consumed by many intertidal grazing gastropods, are also variable. Thus, a superfluity of grazers, or shortage of resource, may happen in any area without regard to any previous abundances of the food or its consumers. Despite the widespread nature of competitive interactions for food, general synthesis is not yet possible about many aspects of this process. These include the nature of symmetry or asymmetry of competition, particularly where grazers have different modes of feeding. It is not yet clear whether competition will necessarily lead to local exclusion of species from patches of a habitat. These areas of uncertainty are discussed with respect to suitable designs of experimental analyses of this widespread process in benthic systems.
Distribution of brain neuronal CCK. An in situ hybridization study
Authors: Vanderhaeghen J -J , Schiffmann S N
Published: November 2023

CCK-like immunoreactivity was discovered in the vertebrate central nervous system in the mid 1970s (Vanderhaeghen et al. 1975). It was shown later that most of the immunoreactivity corresponds to the carboxyl terminal octapeptide of CCK (Dockray 1976) in its sulphated biologically active form (Robberecht et al. 1978). Several immunohistochemical studies have mapped the distribution of CCK octapeptide (CCK-8) in rat brain (Innis et al. 1979; Larsson and Rehfeld 1979; Vanderhaeghen et al. 1980, 1981; Vanderhaeghen 1985). Preprocholecystokinin (preproCCK) has been cloned in the rat (Deschenes et al. 1984) as well as in man (Takahashi et al. 1985), and is identical in brain and gut. Localization of CCK mRNA has been conducted using Northern blot analysis (Burgunder and Young 1988; Voigt and Uhl 1988; Iadarola et al. 1989). Recently, two extensive mapping studies of CCK mRNA using in situ hybridization histochemistry (ISHH) (Ingram et al. 1989; Schiffmann and Vanderhaeghen 1991) have confirmed the immunohistochemical studies. In addition, some selected regions such as the thalamus and the mesencephalon have also been reported to contain CCK mRNA (Siegel and Young 1985; Burgunder and Young 1988, 1989a, b; Savasta et al. 1988, 1989, 1990; Voigt and Uhl 1988; Seroogy et al. 1989). In addition, studies on human brain material have recently been performed (Palacios et al. 1989; Schalling et al. 1989; Savasta et al. 1990). CCK mRNA is also present in large motoneurons of the rat spinal cord (Schiffmann and Vanderhaeghen 1991). Identification of CCK mRNA has changed our understanding of the brain distribution of CCK. Indeed, immunohistochemistry, particularly on human tissue, favours visualization of terminals, whereas ISHH favours visualization of neuronal perikarya. In this chapter we summarize our experience of the use of ISHH for mapping CCK perikarya in the rat brain.
Blood-brain transfer of the CCK antagonists L-365,260 and devazepide
Authors: Hargreaves Richard J , Lin Juinn H
Published: November 2023

The concept of a blood-brain barrier was first formulated at the turn of the century as a result of experiments which showed that some dyes and pharmacologically active compounds did not stain or affect the brain when injected into the bloodstream, but did so when injected into the cerebrospinal fluid. It was not until the 1960s that it became clear that the anatomical basis of the blood-brain barrier comprised the cerebral capillary endothelium in which adjacent cells were joined together at all points of contact by tight intercellular junctions making a virtually continuous monocellular layer. In an early paper on ionic exchange across living membranes, Krogh (1946) suggested that the permeability properties of the cerebral capillaries were those of the endothelial cell membrane and that the design of drugs intended to act in the CNS should concentrate on lipid solubility as one of the primary factors determining rate of entry into the brain. Most solutes that pass through the blood-brain barrier must do so by dissolution in the membranes and cytoplasm of the capillary endothelial cells. As a result, transcellular movement is influenced by the lipid (membrane) solubility of a compound and its diffusion rate. In turn, these factors are dependent upon the fraction of drug in capillary plasma that is not ionized at physiological pH and upon molecular size. Brain uptake of solutes may also be affected by plasma protein binding. It was hypothesized that protein bound drug was not available for transfer from capillary plasma to brain since the high molecular weight, and sometimes electrical charge, of plasma proteins prevented their movement with bound drug from the vascular compartment. However, studies have now indicated that this may be an over simplification since the brain penetration of many drugs and hormones that are plasma protein bound is greater than would be predicted from free drug concentrations (Pardridge and Landaw 1984).
Introduction
Authors: Smith G P
Published: November 2023

It is almost 20 years since CCK was first reported to inhibit food intake (Gibbs et al. 1973). The chapters in this part of the volume provide a reasonably complete review of the current understanding of this phenomenon. Given that the editors chose the topics and the authors did not consult one another, it is interesting that the chapters read like a family album - each chapter shares common features with the others, but each is distinctly different.
CCK-monoamine interactions and satiety in rodents
Authors: Cooper Steven J
Published: November 2023

At first sight, the problem posed by satiety is quite straightforward. To illustrate this, I begin by drawing a comparison between the feeding habits of a laboratory rat, housed alone, and driving a car. To achieve the required degree of experimental control, the rat is normally given free access to diet of standard composition (or the food is given on a fixed schedule of restricted access) and environmental factors (such as temperature, lighting, capacity of the living space) are held constant. We can appreciate the analogy between the rat’s living under such uniform conditions and its eating requirements, and the task of driving a vehicle under constant conditions and having to take account of fuelling requirements.There are occasions when we drive a car on a straight flat road with a good surface; there may be little additional traffic, low wind resistance, a constant load, and a constant speed to maintain. If a fuel of known quality is used and the available quantity is monitored, then the question of anticipating fuel requirements on the journey is simple to answer. The decision to stop for fuel can occur at any time, provided that the fuel does not run out and there is a petrol station available, at that time.In a similar way, approaching the question of satiety solely in relation to the normal laboratory-maintained rat encourages us to see a simple process operating by virtue of simple mechanisms. In the case of driving a car under constant conditions, ‘satiety’ signifies the end of refuelling and usually indicates that enough fuel has been taken for the next leg of a predictable journey. In the rat, satiety signifies the end of feeding and indicates that enough food has been consumed until the next meal.
Does hippocampal CCK influence dopaminergic input to the nucleus accumbens? Some anatomical observations
Authors: Totterdell S , Smith A D
Published: November 2023

The peptide CCK is widely distributed in the brain, where it is thought to act as a neurotransmitter/neuromodulator (Crawley, 1988). Concentrations are high in the cerebral cortex and also in the hippocampus (Beinfeld, 1983), where it is considered to be located in intrinsic and projection neurons (Handelman et al. 1983). Levels of CCK are reported to be decreased post mortem in the hippocampus and amygdala of patients diagnosed as schizophrenic (Roberts et al. 1983).Neurons in the hippocampus project to the nucleus accumbens (Kelley and Domesick 1982), an area which also receives dopaminergic input from the ventral tegmental area (VTA). There is considerable evidence that CCK coexists with dopamine in at least some of the VTA neurons which project to the nucleus accumbens (Hokfelt et al. 1980), and this has led to studies of the interactions between CCK and dopamine release in the nucleus accumbens. However, it might also be possible for CCK in the hippocampus to influence dopamine activity in the nucleus accumbens. Therefore we investigated whether the neurons which project from the hippocampus to the nucleus accumbens receive input from intrinsic hippocampal CCK neurons, and whether this hippocampal input forms contacts with the same neurons in the nucleus accumbens that receive input from the VTA.
CCK in experimental models of dyskinesia
Authors: Jon Stoessl A , Szczutkowski E
Published: November 2023

Dyskinesias are involuntary movements which are usually rapid and relatively stereotyped. A number of different aetiologies are recognized, and a relative excess of dopaminergic activity is frequently thought to underly the movements. Tardive dyskinesia refers to those movements attributed to long-term use of neuroleptic medications, and it affects approximately 20 per cent of those individuals so exposed. Based on observations of enhanced dopamine receptor binding (Burt et al. 1977) and behavioural supersensitivity to dopamine agonists following chronic neuroleptic use (Tarsy and Baldessarini 1973), it has long been assumed that dopamine receptor upregulation is the critical underlying abnormality. That this is an oversimplification has been well argued by Fibiger and Lloyd (1984), and is further supported by recent electrophysiological (Jiang et al. 1990) and molecular biological (Van Tol et al. 1990) data. We were interested in the possible role of CCK in tardive dyskinesia for a variety of reasons:1. Chronic neuroleptics alter brain levels of CCK (Frey 1983; Fukamauchi et al. 1987a) and possibly also CCK binding (Chang et al. 1983; Fukamauchi et al. 1987b).2. There are complex biochemical, electrophysiological, and behavioural interactions between CCK and dopamine.3. Preliminary clinical reports indicated a beneficial effect of ceruletide in a few patients with tardive dyskinesia (Nishikawa et al. 1986).As a model of tardive dyskinesia, we have used the development of vacuous chewing mouth movements (VCMs) in rats, as previously described by others (Iversen et al. 1980; Waddington et al. 1983).
Behavioural and neurochemical evidence for an interaction of CCK with D1 dopamine receptors
Authors: Dourish C T , Hutson P H , Kitchener S J , O’Neill, M F , Suman-Chauhan N
Published: November 2023

The neuropeptide CCK has complex effects on brain dopaminergic neurotransmission, and both enhancement and inhibition of dopamine-mediated responses have been reported after treatment with CCK (Voigt and Wang 1984; Crawley et al. 1985). CCK has been shown to coexist with dopamine in a subpopulation of mesolimbic neurons that project from the ventral tegmental area of the mid-brain and innervate the posteromedian nucleus accumbens (Hokfelt et al. 1980). It has been proposed that CCK specifically enhances dopamine-mediated behaviour in brain regions that are innervated by CCK/ dopamine-containing neurons (Crawley et al. 1984, 1985). Thus injection of CCK into the posteromedian nucleus accumbens enhances the stimulant action of the dopamine agonist apomorphine injected into the same site (Crawley et al. 1985). In contrast, injection of CCK into the anterolateral region of the nucleus accumbens, which is innervated by dopamine neurons that do not contain CCK, blocks dopamine-mediated behaviour (Vaccarino and Rankin 1989).
CCK and opioid analgesia: introduction
Authors: Iversen Susan D
Published: November 2023

There has been a growing awareness that CCK and the opioids have opposite physiological effects on food intake, motor behaviour, and the responsiveness of animals to painful stimuli. The experimental findings in support of this statement have been reviewed in a number of the chapters in this volume. Furthermore, it appears likely that the CCK and opioid systems are not functionally independent. Drugs which increase or decrease CCK function modify the response to morphine, and a number of anatomical and neuropharmacological studies have demonstrated a functional interaction between CCK and opioids at various levels of the neural axis. It is in the area of pain perception that these findings have immediate clinical significance since morphine and related opioids are so widely used as analgesics. Opioid analgesics have many disadvantages: beyond the serious problem of tolerance and dependence are serious acute side-effects, including respiratory depression and constipation.The observation that CCK at physiological doses blocks opioid analgesia (ltoh et al. 1982; Faris et al. 1983) is now well confirmed, with the important corollary that CCK antagonist drugs which act on the CNS could be important adjuncts to morphine in the treatment of pain. The interaction between CCK and opioids in relation to food intake and motor behaviour has been less intensively investigated to date. It would be interesting to discover more about the anatomical relationships of CCK and opioid substrates in the circuitry mediating the control of food intake and motor behaviour, since diseases involving these systems may well offer additional targets for CCK antagonist or agonist drugs. It should not be assumed, however, that all the effects of CCK in the CNS involve an interaction with opioid systems. For example, there is no evidence at present that the anxiogenic effect of CCK-4 and the anxiolytic effect of CCK antagonists involve opioid systems (De Montigny 1989).
CCK and opioid analgesia
Authors: Kellstein David E , Mayer David J
Published: November 2023

CCK is the most abundant gastro-intestinal peptide in the CNS (Beinfeld 1983; Crawley 1985), where it may function as a neurotransmitter and/ or a neuromodulator (Morley 1982; Baber et al. 1989). Although several forms of CCK with amino acid chains of different lengths have been isolated, the sulphated octapeptide variant predominates within the mammalian CNS (Rehfeld 1978; Larssen and Rehfeld 1979) and exhibits the greatest potency (Mutt 1982). Therefore, in this chapter CCK will refer to this form of the peptide.Anatomical studies strongly suggest a functional interaction between CCK and opioids. The CNS distribution of CCK closely parallels that of endogenous opioids within the brain (e.g. nucleus raphe magnus and periaqueductal grey (Beinfeld and Palkovits 1982), and hypothalamus, basal ganglia, and dorsomedial thalamus (Stengaard-Pedersen and Larsson 1982)) and the spinal cord (e.g. the substantia gelatinosa; Stengaard-Pedersen and Larsson 1981). Further, CCK and enkephalins have been colocalized within neurons in nociceptive areas of the brainstem and thalamus (Gall et al. 1987). Accordingly, the brain and spinal cord distribution of CCK binding sites is very similar to that of opioid receptors (Saito et al. 1980; Zarbin et al. 1983; Van Dijk et al. 1984; Hill et al. 1988).Results of functional studies indicate that CCK and opioid systems generally interact in an antagonistic manner. For example, CCK and opioids have opposite effects on satiety (Della-Fera and Baile 1979; Morley and Levine 1983), respiration (Gillis et al. 1983; Jensen et al. 1983), gut motility (Zetler 1979), locomotion (Schnur et al. 1986), and thermoregulation (Kapas et al. 1989). In addition, there is considerable evidence to suggest that CCK functions as an endogenous antagonist of opioid analgesia and may also be involved in opioid tolerance. The widespread use of opioid analgesics in the management of chronic pain, and the adverse effects and tolerance development associated with such use, make the study of CCK antagonism of opioid analgesia clinically important. In this chapter we review developments in this field and suggest future directions for investigation.
The role of CCK in electro-acupuncture analgesia and electro-acupuncture tolerance
Authors: Han J S
Published: November 2023

From the functional point of view, one of the most important characteristics of neuropeptides compared with classical neurotransmitters appears to be the extreme complexity and plasticity of their role in signal transmission. A bellshaped dose-response curve is very often encountered, yet the physiological implication of the paradoxical effects induced by the same peptide at different doses may not be clear at first sight.With regard to the physiological effect of CCK* on nociception, opposite results have been reported: it is antagonistic to opioid analgesia in low doses (ltoh et al. 1982; Faris et al. 1983; Han et al. 1985), and analgesic when administered alone at high doses (Jurna and Zetler 1981; Hill et al. 1987b; Hong and Takemori 1989). Common sense suggests that the effect induced by threshold doses is more likely to be physiological in nature, and that of submaximal doses to be pharmacological. However, in order to document the physiological function of a peptide clearly, it is necessary to observe not only changes accompanying its accelerated release, but also (and even more importantly) changes resulting from the blockage of its function by a receptor antagonist or by antibodies against it (Han 1987).
Magnetic fields and cancer: more information is still needed
Authors: Ahlbom Anders , Yang, Qiner , Feychting Maria
Published: November 2023

Since 1979 several studies have appeared that indicate that children living in homes near power lines or other electric transmission facilities, or in homes with measured elevated magnetic fields, have an increased risk of cancer. There are also studies on adults showing the same thing. In addition, several studies have shown that ‘electrical workers’ might be at increased risk of leukaemia and brain cancer in particular. We have reviewed the studies available at the end of 1988 (Ahlborn 1988; Ahlborn and Feychting 1990). The objective of the present article is to take into account the studies that have been made available after our previous reviews, and to make an evalua¬ tion that takes all the currently available information into consideration. For a description of the studies, previous as well as new studies, refer to Table 2.1. The main results of the available studies are presented in Figs 2.1-2.4.