bluuebunny/crossref_metadata_2025 huggingface dataset:
Fitting Attitudes and Welfare
Authors: Heathwood Chris
Published: November 2023

The purpose of this paper is to present a new argument against so-called fitting-attitude analyses of intrinsic value, according to which, roughly, for something to be intrinsically good is for there to be reasons to want it for its own sake. The argument is indirect. First, I submit that advocates of a fitting-attitude analysis of value should, for the sake of theoretical unity, also endorse a fitting-attitude analysis of a closely related but distinct concept: the concept of intrinsic value for a person, that is, the concept of welfare. Then I argue directly against fitting-attitude analyses of welfare. This argument, which is the focus of the paper, is based on the idea that whereas whether an event is good or bad for a person doesn’t change over time, the attitudes there is reason to have towards such an event can change over time. Therefore, one cannot explain the former in terms of the latter, as fitting-attitude analyses of welfare attempt to do.
Cats, Dogs, and so on
Authors: Burgess John P
Published: November 2023

The discovery of the note cards for Quine ‘s previously unpublished 1946 lecture on nominalism provides an obvious occasion for commenting on the differences between the issue of nominalism as Quine first publicized it to a wide philosophical audience and the issue of nominalism as debated among Quine ‘s successors today. Yet as I read and reread the text of Quine ‘s lecture, I found myself struck less by the differences between Quine ‘s position there and the positions of present-day writers than by differences between Quine ‘s position there and the positions of Quine himself in later writings — and not his writings from many years later but his writings from the next few years, and especially one of his writings from the very next year, his notorious joint paper with Goodman.
A World of Concrete Particulars
Authors: Melia Joseph
Published: November 2023

This chapter is not going to be a defence of Nominalism, but it is going to defend Nominalism from some Quinean worries. Like Quine, I find Nominalism congenial. Quine eventually abandoned the position. I shall urge that this was hasty. Quine characterizes Nominalism as the view that there are no universals, only particulars. Nowadays, Nominalism is frequently identified with the view that there are no abstract objects, only concrete ones and it is this aspect of Nominalism that I will mainly focus on in this chapter. Since Quine takes particulars, in both his Mental and Physical versions of Nominalism, to be concrete objects, it seems that the Quine of that time was partial to both views.
Sociolinguistic typology and complexification
Authors: Trudgill Peter
Published: November 2023

In previous work in sociolinguistic typology (e.g. Trudgill 1983, 1989, 1992, 1996a, b, 1998, 2002) I have suggested that it might be possible to argue that the distribution of linguistic features over languages may not be just random or areal.1 Rather, it may be the case that certain types of society, or social structure, tend to produce certain types of language, or linguistic structure. In the context of the present volume, therefore, the suggestion is that certain types of social factor may predispose languages to demonstrate greater or lesser degrees of complexity.
Orality versus literacy as a dimension of complexity
Authors: Maas Utz
Published: November 2023

In this chapter, I will look at complexity of language from a functional perspective, taking the full array of linguistic practices into account: There are differences within the various tasks, usually defined by different domains of language practice, and there are differences between the linguistic resources employed to cope with these domains.
Layering of grammar: vestiges of protosyntax in present-day languages
Authors: Progovac Ljiljana
Published: November 2023

In this section I identify two sets of data available in present-day languages, which clearly defy the rules and principles of present-day morphosyntax: Root Small Clauses (RootSCs), and verb-complement exocentric compounds (ExCs).1 In section 2 I show that these data instantiate a grammar/syntax measurably simpler than that of more typical sentential speech, leading to the proposal in section 3 that they can be seen as vestiges/“living fossils” of a protosyntax stage in language evolution. This (evolutionary) approach starts to shed light on the very nature of clausal derivation: modern syntax analyses even finite clauses/sentences as being built upon the layer of the small clause. Metaphors of evolutionary layering have been invoked in various other domains, as discussed in section 4. Section 5 offers some corroborating evidence for the proposal, including language acquisition.
The Question of Ontology
Authors: Fine Kit
Published: November 2023

Philosophers ask ‘do numbers exist?’, ‘do chairs and tables exist?’, ‘do elementary particles exist?’. But what are they asking when they ask such questions? There is an answer to this meta-question that derives from Quine [1984]and is commonly accepted in contemporary ontology (it is accepted in one form or another by all of the other contributors to the present volume,for example).
The Metaontology of Abstraction
Authors: Hale Bob , Wright Crispin
Published: November 2023

We can be pretty brisk with the basics. Paul Benacerraf famously wondered how any satisfactory account of mathematical knowledge could combine a face-value semantic construal of classical mathematical theories, such as arithmetic, analysis and set-theory — one which takes seriously the apparent singular terms and quantifiers in the standard formulations — with a sensibly naturalistic conception of our knowledge-acquisitive capacities as essentially operative within the domain of causal law. The problem, very simply, is that the entities apparently called for by the face-value construal — finite cardinals, reals and sets — do not, seemingly, participate in the causal swim. A refinement of the problem, due to Field, challenges us to explain what reason there is to suppose that our basic beliefs about such entities, encoded in standard axioms, could possibly be formed reliably by means solely of what are presumably naturalistic belief-forming mechanisms. These problems have cast a long shadow over recent thought about the epistemology of mathematics.
Ontology and Alternative Languages
Authors: Hirsch Eli
Published: November 2023

Rudolph Carnap said that issues of ontology amount to nothing more than choosing one language or another. My position is roughly Carnapian, but with three qualifications. First, whereas Carnap ‘s formulation sometimes seems to suggest an anti-realist or verificationist perspective, my position is robustly realist. I take it for granted that the world and the things in it exist for the most part in complete independence of our knowledge or language.
Metaphysics after Carnap: The Ghost Who Walks?
Authors: Price Huw
Published: November 2023

Imagine a well-trained mid-twentieth-century American philosopher, caught in a rare traffic jam on the New Jersey Turnpike, one still summer afternoon in 1950. He dozes off in his warm car ... and awakes in the same spot on a chill Fall evening in 2008, remembering nothing of the intervening years.
The Theoretical Practices of Physics
Authors: Hughes R I G
Published: November 2023

R.I.G Hughes presents a series of eight philosophical essays on the theoretical practices of physics. The first two essays examine these practices as they appear in physicists' treatises (e.g. Newton's Principia and Opticks) and journal articles (by Einstein, Bohm and Pines, Aharonov and Bohm). By treating these publications as texts, Hughes casts the philosopher of science in the role of critic. This premise guides the following 6 essays which deal with various concerns of philosophy and physics such as laws, disunities, models and representation, computer simulation, explanation, and the discourse of physics.
Evidence-based health care: What roles for patients?
Authors: Thornton Hazel
Published: November 2023

The optimistic foreword by Richard Grol to the first edition of this book, published in 2001, ended with the words ‘And, it manages to show us the way to a potential future: health care provision where patients and professionals operate as real partners with shared goals, playing an equal music in deciding on the best management of the health problems’ (Grol, R. 2001). Forging and maintaining real partnerships of any kind requires a settled environment in which to develop them, continued desire and determination of both parties to make them work, a shared set of values, good communication, and constant hard work. I will examine the changing nature of health care consultations in this chapter, starting first with a broader view of health care developments and of research in particular, as I believe these are important contexts and influences on the everyday business of patients seeing clinicians in consultations.
Using decision-making theory to inform clinical practice
Authors: Bekker Hilary L
Published: November 2023

Strategy to process information: heuristic processing (intuitive, ‘rules-of-thumb’, unconscious, and system 1) and systematic processing (analytic, conscious, and system 2) (see Chaiken, 1980; Eagly and Chaiken, 1993; Payne and Bettman, 2004; Hammond, 2007; Acker, 2008). The latter requires the decision maker to exert a considerable amount of conscious effort in evaluating completely the details of the decision information; the former is a simpler strategy, requiring less cognitive effort, as the decision maker evaluates a part of the decision information that initiates a general, often subconscious, rule to guide the choice. Although heuristic processing tends to lead to satisfactory decisions being made most of the time, it is more likely to result in the wrong choice being made if a systematic strategy is employed (Chaiken, 1980; Baron, 1994; Payne and Bettman, 2004).
Measuring ‘decision quality’: Irresolvable difficulties and an alternative proposal
Authors: Elwyn Glyn , Elwyn, Benjamin , Miron-Shatz Talya
Published: November 2023

Although the task of involving patients in decision-making tasks has become the focus of increasing attention over the last decade, there is also a realization that we struggle to measure what would constitute success in this area. Important questions remain, such as what constitutes a good decision or a high-quality decision and how to measure decision quality. We recognize that definitions of decision quality and other similar terms have been put forward. In this paper, it is our intention to examine these definitions, to highlight the ways in which they converge, and to explain why we have some concerns about their emphasis on post hoc evaluations. We proceed to offer an alternative, which parses ‘decisions’ into a pre-decisional process and a post-decisional outcome.
A practical approach to measuring the quality of preference-sensitive decisions
Authors: Sepucha Karen R , Mulley Albert G
Published: November 2023

A patient with knee osteoarthritis and her doctor schedule surgery to replace her knee. A decision has been made but not yet enacted, and one might ask whether this is a good decision. This decision and many like it have certain features worth highlighting. First, there is a decision to be made because more than one reasonable alternatives are available to the patient and her doctor. Second, clinical evidence and clinical information, such as results of x-rays or even patient-reported symptoms scores though necessary, are not sufficient to determine the best alternative. Third, patients feel differently about the impact of the illness in their lives and the importance of the potential good and bad outcomes of the options. In these situations, the best treatment is the one that reflects what is most important to patients who are well informed about the options and potential outcomes.
Examining the theoretical foundation of decision support technologies
Authors: Durand Marie-Anne , Elwyn Glyn
Published: November 2023

Many decision-making theories exist and their applications have improved our understanding of how individuals make decisions, but the association between decision-making theories and decision support tools is relatively rare in practice. This chapter is based on a theoretical review of existing decision support technologies (DSTs) for patients facing treatment or screening decisions (Durand et al., 2008) and examines the current use of theory in designing and evaluating DSTs.
Should patient stories be used in decision aids?
Authors: Winterbottom Anna , Bekker Hilary
Published: November 2023

The use of patient stories in decision aids is popular yet the evidence base supporting their use is less clear. Many questions remain about the optimal way of presenting such stories in decision aids. This chapter explores how their inclusion might bias the decision-making process and how research in this area is hampered by a lack of a cohesive definition or guidelines on their usage. To date, four reviews of the literature exist providing mixed evidence of the persuasive effect of patient stories on decision-making. More research into the impact of using patient stories is needed and the use of real world settings to explore such ideas is discussed. We recommend that until there is a greater understanding of how patient stories might affect decision-making processes, decision aids that include patient stories should be implemented in practice with caution.
‘It’s what we do around here’: Shared decision-making as a future organizational competence
Authors: Elwyn Glyn , Edwards Adrian
Published: November 2023

You tend to know when someone takes you seriously. They listen and they indicate that they are doing so. They signal that they have understood. They might disagree but at least they have bothered to take your views seriously. It may not lead to better outcomes or to decisions which you would make yourself but it feels like a good process and is a clear mark of respect. Something similar may be said of involving patients in decisions and doing so with genuine intent (Edwards et al., 2001).
Harm Reduction Research: Ethics and Compliance
Authors: Iltis∗ Ana S
Published: November 2023

Using the examples of the perinatal HIV transmission trials conducted in developing nations and the Kennedy Krieger lead abatement study conducted in Baltimore, both during the 1990s, Nancy Kass explains the background conditions that sometimes lead to harm reduction interventions and research, defends the need for some harm reduction research, and argues that harm reduction research can be permissible in principle as long as certain threshold criteria are met. I echo Kass ‘s general claim that harm reduction research can be permissible in principle in the face of background inequalities, injustices, or circumstances of inaccess.
Fundamental Concepts of Spatial Conservation Prioritization
Authors: Wilson Kerrie A , Cabeza Mar , Klein Carissa J
Published: November 2023

The conservation of biodiversity is constrained by limited resources, and hence our investments in conservation must be prioritized. Spatial conservation prioritization is the process of using spatial analysis of quantitative data to identify locations for conservation investment. The process is regarded as more systematic, rigorous, and accountable than the opportunistic allocation of conservation funds (Margules and Pressey 2000). Priority areas can be identified not only for protected area establishment but also for investment in a variety of conservation activities, ranging from fire management and invasive species control, to land restoration (Wilson et al. 2007) (Chapters 3 and 12). Since its origin in the early 1980s, the field of spatial conservation prioritization has influenced planning processes, the development of conservation policies, and the expansion of protected areas. As a consequence, the number of publications concerning the development and application of spatial prioritization techniques has increased rapidly over the past two decades (Chapters 1 and 19).
Spatial Population Viability Analysis
Authors: McCarthy Michael A
Published: November 2023

If we are concerned about long-term conservation of species, prioritization requires information about how likely different species are to persist under alternative management options. Population viability analysis (PVA) is the process of making these predictions by integrating information on life history with effects of management (Soulé 1987; Boyce 1992; Burgman et al. 1993; Beissinger and McCullough 2002). PVAs developed from Shaffer’s (1981) original work on grizzly bears, in which the risk of extinction of the Yellowstone population was assessed. The development of PVA models has benefitted from models and methods were developed previously for other applications in population ecology (Burgman et al. 1993).
The C-Plan Conservation Planning System: Origins, Applications, and Possible Futures
Authors: Pressey Robert L , Watts Matthew E , Barrett Thomas W , Ridges Malcolm J
Published: November 2023

Work on the development of C-Plan began in 1995. The idea of an interactive software system to present spatial options for conservation management arose from previous work on irreplaceability in the early 1990s (Pressey 1992, 1999; Pressey et al. 1993, 1994b) (Chapter 2). At that time, this research on irreplaceability added a new dimension to the problem of selecting indicative sets of sites to achieve quantitative targets for features such as vegetation types or species (the set covering problem, Camm et al. 1996). The basic ingredients for the set covering problem are: (a) planning units, the sites to be assessed and compared as potential conservation areas, (b) maps of biodiversity features, (c) a target for each feature (e.g. number of hectares of each vegetation type and number of locality records for each species), and (d) a data matrix listing the extent or occurrence of each feature in each planning unit (see Chapter 3). Using these same ingredients, irreplaceability was conceived and implemented as a solution to an important limitation of reserve selection software at the time. The limitation was that any selected set of sites required to achieve targets is usually only one of the many possible sets, all of which differ to some extent in their composition and configuration of individual sites. Therefore, while a single set of sites was, and remains, a useful indication of the requirements for achieving all targets, it provides no information on the relative importance of unselected sites for achieving targets.
The Basics: A Little Chemistry
Authors: Gratzer Walter
Published: November 2023

The fundamentals are simple enough. Understanding the nature of polymers, whether proteins, carbohydrates, DNA, or synthetic fibres and moulded plastics, requires first of all a modest grasp of the rules governing the architecture of organic molecules.
Storage: Of Food and Information
Authors: Gratzer Walter
Published: November 2023

Carbohydrates are polymers made up of chains of sugars. Sugars are ring compounds and in nature there are two simple kinds: the pentoses (the best known of which is fructose, or fruit sugar) have five-membered rings, while the hexoses (such as glucose−) have six-membered rings. These serve as building blocks for more complex sugars. Thus sucrose (cane or beet sugar) is made up of one glucose and one fructose unit linked together.
Hesiod, Prodicus, And The Socratics On Work And Pleasure
Authors: Wolfsdorf David
Published: November 2023

since poetry, especially the epic poetry of Homer and Hesiod, was central to Greek culture in the late archaic and classical periods, those individuals engaged in the formation and early development of philosophy, in many ways a reaction and alternative to conventional culture and forms of expression, inevitably engaged with their illustrious predecessors. Plato’s criticism of poetry in the Republic is the most obvious example. But in general, philosophers’ engagements range from criticism of the poets as established authorities to employment of them, in various ways, as constructive models or as corroborators of their ideas.
The Self, The Soul, And The Individual In The City Of The Laws
Authors: Sassi Maria Michela
Published: November 2023

the question of the role played in Plato’s Laws by his conception of the soul, and in particular by his understanding of psychological conflict, has experienced changing fortunes in Plato scholarship. In 1957 D. A. Rees noted that the question of the division of the soul in Plato’s last work ‘seems to have been on the whole neglected by scholars’, while at the same time observing that the tripartite conception presented in the Republic plays a notably diminished role in the later dialogues—with the exception, of course, of the Timaeus.
Doubts about the Supervenience of the Evaluative
Authors: Sturgeon Nicholas L
Published: November 2023

That the evaluative (or, in different versions, the ethical, the normative, or the moral) supervenes on the natural (or, again in different versions, on the non-evaluative, or on the descriptive, or on the factual) has until quite recently had the status of a commonplace among academic philosophers. Of course, with so many different accounts of what is supposed to supervene and of what it is supposed to supervene upon, there is more than one doctrine here. It will not matter to my discussion, however, which of the first four terms we use; so I shall normally just speak of the evaluative, understood broadly enough to include anything that might count as ethical, normative, or moral.
How to be a Cognitivist about Practical Reason
Authors: Ross Jacob
Published: November 2023

Cognitivism about practical reason is the view that intentions involve beliefs, and that the rational requirements on intentions can be explained in terms of the rational requirements on the beliefs that figure in intentions. In particular, cognitivists about practical reason have sought to provide cognitive explanations of two basic requirements of practical rationality: a consistency requirement, according to which it is rationally impermissible to have intentions that are jointly inconsistent with one’s beliefs, and a means–end coherence requirement, according to which, to a first approximation, it is rationally impermissible to intend an end while failing to intend what one regards as a necessary means to this end.
The Elizabethan Stage
Authors: Chambers E K
Published: November 2023

First volume of a reissue of the E. K. Chambers’s seminal four-volume account of the private, public, and court stages, together with other forms of drama and spectacle surviving from earlier times, from the beginning of the reign of Elizabeth until the death of Shakespeare. Haled in its day as a comprehensive compendium of ‘practically all the discoverable evidence upon the various parts of the subject, collected, weighed, sorted, classified and built up with immense care into a logical and beautiful structure’ (New Statesman), the work is still much consulted by by today’s scholars and historians. From the author’s Preface: ‘My First Book is devoted to a description, perhaps disproportionate, of the Elizabethan Court, and of the ramifications in pageant and progress, tilt and mask, of that instinct for spectacular mimesis, which the Renaissance inherited from the Middle Ages, and of which the drama is itself the most important manifestation. The Second Book gives an account of the settlement of the players in London, of their conflict, backed by the Court, with the tendencies of Puritanism, and of the place which they ultimately found in the monarchical polity. To the Third and Fourth belong the more pedestrian task of following in detail the fortunes of the individual playing companies and the individual theatres, with such fulness and the available records permit. The Fifth deals with the surviving plays, not in their literary aspect, which lies outside my plan, but as documents helping to throw light upon the history of the institution which produced them.’
Elizabeth And James
Authors: Chambers E K
Published: November 2023

Gardiner, History of England from the Accession of James I to the Outbreak of the Civil War (1863–84). A beginning towards filling the gap has been made in vol. i of E. P. Cheyney, History of England from the Defeat of the Jfrmada to the Death of Elizabeth (1914), in which the organization of the court and administration is very fully treated. For specifically social history may be added J. R. Green, History of the English People (1877–80), an expansion of the same writer’s Short History of the English People (1874), and H. D. Traill, Social England (1893–7).
The Roy Al Household
Authors: Chambers E K
Published: November 2023

There is no systematic history of the household, but the growing tendency, notable in such recent works as those of Professor Baldwin and Professor Tout, to dwell on the administrative, as distinct from the ‘ constitutional ‘, aspect of politics suggests that the gap maysome day be filled. A useful short study is R.H. Gretton, The King’s Government (1913). Of the numerous books bearing more or less directly on the subject, I give here mainly those which I have found of practical value in writing this chapter. Professor Tout’s Chapters in the Administrative History of Mediaeval England, of which the first two volumes have subsequently (1920) appeared, is of course of fundamental importance. The best worked section is that of mediaeval origins.
Pageantry
Authors: Chambers E K
Published: November 2023

THE tradition of pageantry had its roots deep in the Middle Ages. But it made its appeal also to the Renaissance, of which nothing was more characteristic than the passion for colour and all the splendid external vesture of things while the ranging curiosity of the Renaissance was able to stimulate into fresh life the fading imaginative energies of the past, weaving its new fancies from classical mythology, from epic and pastoral, from the explorations of history and folk-lore,
The Elizabethan Stage
Authors: Chambers E K
Published: November 2023

A reissue of the E. K. Chambers’s seminal four-volume account of the private, public, and court stages, together with other forms of drama and spectacle surviving from earlier times, from the beginning of the reign of Elizabeth until the death of Shakespeare. Haled in its day as a comprehensive compendium of ‘practically all the discoverable evidence upon the various parts of the subject, collected, weighed, sorted, classified and built up with immense care into a logical and beautiful structure’ (New Statesman), the work is still much consulted by by today’s scholars and historians. From the author’s Preface: ‘My First Book is devoted to a description, perhaps disproportionate, of the Elizabethan Court, and of the ramifications in pageant and progress, tilt and mask, of that instinct for spectacular mimesis, which the Renaissance inherited from the Middle Ages, and of which the drama is itself the most important manifestation. The Second Book gives an account of the settlement of the players in London, of their conflict, backed by the Court, with the tendencies of Puritanism, and of the place which they ultimately found in the monarchical polity. To the Third and Fourth belong the more pedestrian task of following in detail the fortunes of the individual playing companies and the individual theatres, with such fulness and the available records permit. The Fifth deals with the surviving plays, not in their literary aspect, which lies outside my plan, but as documents helping to throw light upon the history of the institution which produced them.’
Lung Cancer
Authors: Falk Stephen , Williams Chris
Published: November 2023

Lung cancer is the most common cancer affecting the industrialized world and affects the lives of thousands of people, including patients' friends and family, every year. The most common cause of lung cancer is long-term exposure to tobacco smoke. The occurrence of lung cancer in nonsmokers, who account for as many as 15% of cases, is often attributed to a combination of genetic factors, radon gas, asbestos, and air pollution, including secondhand smoke. The aim of this book is to give, in a clear and simple way, succinct information about all aspects of this type of cancer, with a stress on the practical side of its treatment. The book also details how care is likely to be organised and what patients can do to help themselves, both if they have the disease and also how to stop smoking. Fully updated for this third edition, the book includes information on getting the best treatment and living with cancer, both of which are new approaches to the disease in the UK.
Persian Cosmos and Greek Philosophy: Plato’s Associates and the Zoroastrian Magoi
Authors: Horky Phillip Sidney
Published: November 2023

According to ancient biographical accounts, when Plato was a very old man and ill with fever, he received Persian magoi who had travelled to Athens to meet the eminent sage; apparently, one of these men entertained Plato and delighted him as he was nearing death. In one version of the story, preserved by the Roman philosopher Seneca the Younger (first centuryce), upon his death (on his birthday at the age of 81) the magoi sacrificed to Plato because he had completed the perfect number of nine times nine.
Molecular structure and biology of interleukin-2
Authors: Kenney W C , Boone, T , Hunt P
Published: November 2023

Interleukin-2 (IL-2), originally described as T cell growth factor, is significant to the growth and function of a variety of cell types. Its original purification resulted from the development of standardized bioassay methodology , and the identification of a suitable cellular source (the Jurkat cell line). Subsequent cloning and expression of the gene sequence made available recombinant DNA derived material which was biologically indistinguishable from the naturally occurring protein.
Cellular biotherapy of cancer: generation, characterization, and use of anti-tumour effector cells
Authors: Yannelli J , Maleckar J , Oldham W West,And R
Published: November 2023

The heterogeneity of human cancer has been long recognized. Attempts to manage heterogeneity therapeutically using both conventional and biological methodologies have met with limited success. Heterogeneity is based on cell cycle, cell differentiation, tissue, or organ distribution, as well as the condition of the tumour and results in many changes, including differential cell surface antigen expression.4−8 This variability supports the use of the recently discovered-12 population of cytolytic effector cells called lymphokine-activated killer (LAK) cells. Although some reactivity against normal cells has been reported, the bulk of cytolytic activity is seen against autologous or allogeneic tumour cells. Alternatively, methods are available to generate tumour reactive cytotoxic Tlymphocytes (CTL). These cells, because of their specificity, are less likely to destroy normal host tissue.
The catabolism of extracellular matrix components
Authors: Fisher Susan J , Werb Zen A
Published: November 2023

Breaching of the extracellular matrix (ECM) barrier by cells involves proteolytic enzymes capable of degrading the ECM components. The most important of these enzymes is the collagenase family of metalloproteinases which have been recently reviewed (1, 2). The members of this multigene family include Pump-1, three types of stromelysin, interstitial collagenase, and the 72 and 92 kDa gelatinases/type IV collagenases. These enzymes possess sequences necessary for maintenance of the zymogen forms, a zinc-binding catalytic domain, and various numbers of structural regions resembling those found in ECM components. The wide range of specificity that the metallo proteinases exhibit is important in growth, debridement after injury, tissue morphogenesis and remodelling, and invasion. For example, stromelysin degrades fibronectin, elastin, proteoglycan core proteins, and laminin as well as the non-helical regions of collagen types IV, V, VII, and IX and the amino terminus of collagen type I. Interstitial collagenases can degrade collagens of types I, II, III, VIII, and X, but the degradation of basement membrane collagens requires specialized enzymes that degrade type IV collagen. The latter proteinases can also degrade collagens of types V, VII, and X as well as fibronectin, denatured collagens, and casein. Tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, members of the serine proteinase family, also play an important role in ECM degradation and these have been recently reviewed (3). They may act directly, cleaving fibronectin and other components. Alternatively, PAs may act as part of a proteinase cascade in which plasmin activates procollagenase and prostromelysin.
Splicing of mRNA precursors in mammalian cells
Authors: Eperon Ian C , Krainer Adrian R
Published: November 2023

Splicing has attracted and intrigued researchers ever since the first reports of split genes. The first studies attempted to define the signals which were required for splicing. This work also produced some indications of the importance of intrans and splicing for efficient expression. Later experiments on cis-acting signals, particularly in mammalian systems, have been directed towards understanding the mechanisms by which the correct splice sites can be selected in the face of a plethora of candidates. In some cases, of course, the process of selection is affected by the stage of the cell cycle or cell differentiation. Most of this work has been done in vivo, involving the introduction of mutant substrates into cells and subsequent analysis of the mRNA expressed. More recently, two major developments have provided the means to analyse the molecular processes involved in splicing. The first of these is splicing in vitro, using extracts from nuclei or whole cells. This technique led to the discovery that splicing appeared to proceed in two steps, the first of which produced intermediates comprising the 5’ exon and a lariat form of the intron-3’ exon moiety. Furthermore, splicing in vitro provided opportunities to test existing hypotheses about the roles of small nuclear ribonucleoprotein particles (snRNPs), to study their incorporation with the substrate into multicomponent assemblages, and to fractionate the extracts in order to isolate splicing factors. The second key development has been the use of genetic analysis in yeast in combination with splicing in vitro.
Analysis of ribonucleoprotein interactions
Authors: Will Cindy L , Kastner Berthold , Lührmann Reinhard
Published: November 2023

Elucidation of the precise function of small ribonucleoprotein particles (snRNPs) in RNA processing will be greatly aided by information regarding their biochemical composition and higher order structure. To date, significant biochemical and structural information has been gathered for the mammalian spliceosomal snRNPs Ul, U2, U5, and U4/U6, although their characterization is far from complete. The snRNA component of these functionally important RNP particles has been shown to be evolutionarily conserved and, with the exception of U6, possesses a unique 5’ cap structure, namely 2,2,7-trimethylguanosine (m3G). The spliceosomal snRNPs share a set of eight common proteins (referred to as B, B’ , Dl, D2, D3, E, F, and G) which are tightly associated with the snRNA component of the snRNP (1). Particle-specific proteins are also associated with several snRNP species (Ul, U2, U5, and the tri-snRNP [U4/U6.U5] complex), although in many cases their interaction is highly dependent on the ionic strength of the particle’ s environment (1). For this reason, the sedimentation coefficient of an individual snRNP may vary. At intermediate salt concentrations (approximately 0.3-0.5 M), Ul, U2, and U4/U6 sediment as 12S particles and U5 as a 20S particle, whereas at lower ionic strengths, a 17S U2 and a 25S [U4/U6.U5] tri-snRNP particle are also observed. Investigation of intermolecular interactions within RNP particles can be accomplished by a variety of procedures. Since most structural studies are facilitated by the analysis of individual RNP complexes in the absence of contaminating macromolecules, this chapter starts by describing the approaches commonly used for the isolation of snRNP particles. Several procedures are then described which are particularly useful for analysing RNA-protein interactions and/or RNP higher order structure. These include snRNP reconstitution, immunoprecipitation, RNA-protein cross-linking, nuclease protection, and immunoelectron microscopy.
Steroid Hormone Action
Authors: Parker Malcolm G
Published: November 2023

A comprehensive overview of the molecular mechanisms by which these hormones regulate the expression of specific target genes. The book covers the structure of steroid receptors, transcriptional activation and repression, and also contains chapters on steroid binding proteins and steroidogenesis. Steroid receptors represent one of the best characterized transcription factors so that the book will be of general interest to molecular biologists studying eucaryotic gene regulation. Chapters on the mechanisms of action of steroid antagonists and defective receptors in target cells will be of particular interest to endocrinologists and clinicians. In such a rapidly progressing field it is difficult to keep up with all the literature but this book, written by international experts, focuses on the most important advances that have been made recently.
Determination of carbonyl groups in oxidized proteins
Authors: Shacter Emily , Williams Joy A , Stadtman Earl R , Levine Rodney L
Published: November 2023

There is now a bewildering array of biological processes in which free radicals have been implicated (2), and we assume that enzymes and structural proteins may be attacked whenever free radicals are generated. As a con sequence, oxidative modification of proteins may occur in a variety of physiological and pathological processes. Although the distinction is. some times arbitrary, these modifications may be primary or secondary. Primary modifications occur in metal-catalysed oxidation, radiation-mediated oxidation, and in oxidation by ozone or oxides of nitrogen. Secondary modifications occur when proteins are modified by molecules generated by oxidation of other molecules. One important example is the covalent modification of proteins by hydroxynonenal produced by oxidation of lipids (3).
In vivo selection of specific RNA binding polypeptides using a transcription anti-termination reporter assay
Authors: Harada Kazuo , Frankel Alan D
Published: November 2023

The recognition of specific RNA structures by proteins plays an important role in gene regulation. both at the transcriptional and post-transcriptional levels. but our understanding of the basic principles of recognition is still at an early stage. To help further our understanding. it will he useful to have in hand a set of methods by which to screen molecular libraries for specific RNA binding molecules. In this chapter we describe a method for selecting RNA binding polypeptides from combinatorial libraries.
Determination Of Protease Mechanism
Authors: Dunn Ben M
Published: November 2023

The opening chapter of this volume has outlined the four mechanistic classes: serine and cysteine proteases (those that form covalent enzyme complexes) and aspartic and metalloproteases (those that do not form covalent enzyme complexes). This distinction into two major mechanistic groups is of profound con sequence since the strategy for inhibition is totally different for these two classes. Those enzymes of the first general class have strongly nucleophilic amino acids at their catalytic site. These are usually aligned with hydrogen bond acceptors to promote the dissociation of the nucleophile in the approach to the transition state and, thus, increase the fraction in the hyperreactive state, Design and synthesis of inhibitors of this broad class will therefore be concentrated on introduction of electrophilic groups (-C=C-, -C-C(=O)-Cl, etc,) that will chemically modify the nucleophile or general base. This will render the catalytic apparatus inactive and prevent the action of that protease. The second category of proteolytic enzymes includes two classes that catalyse the hydrolysis of peptide bonds without nucleophilic attack by a functional group of the enzyme. These enzymes rely more upon general acid/general base catalysis of the attack of a water molecule and therefore the catalytic residues lack the aggressive nucleophilicity of the serine or cysteine proteases. Inhibitor design for this second broad group relies on more subtle means of complexation, including a greater necessity for secondary binding interactions along the active-site cleft and transition state analogues. The metalloproteinases offer an additional handle for inhibitors, since functional groups such as -SH can be introduced at precise points to lead to nearly irreversible metal ion chelation.
Inhibition Of Proteolytic Enzymes
Authors: Salvesen Guy S , Nagase Hideaki
Published: November 2023

The two most frequent questions asked by those not working on proteases every day are: ‘ How do I prevent proteolysis in my particular system?’ and ‘ How do I find out which protease is cutting my protein?’ There are no ‘ bullet-proof’ recipes to help with these questions, possibly because of the many varied or even overlapping specificities and catalytic strategies adopted by proteases. Nevertheless, there are a number of general issues and specific techniques that we and others use to address these and other related questions. This usually involves employing natural and synthetic protease inhibitors in complex bio logical environments such as tissue fluids or cells in culture. Many of the methods rely on the theoretical backgrounds illustrated in Chapter 6.
Analysis of transcription factor modifications
Authors: Thomas N Shaun B
Published: November 2023

Transcription factors are regulated by being modified by phosphorylation and glycosylation. Each can cause changes in protein charge, shape, hydrophilicity, and mass, all of which can be exploited in differentiating the modified from the unmodified protein. This chapter will cover how these post-transcriptional modifications can be analysed, the methods most frequently used, and the problems and limitations associated with each. I will assume that the transcription factor has been cloned and sequenced and that you have basic reagents to detect your factor—in particular, antibodies that can be used for Western blotting and immunoprecipitation. Thereafter, the questions to be answered will necessarily dictate which methods are most appropriate. In this chapter I shall start by introducing simple techniques to determine whether a given protein is phosphorylated or glycosylated before covering more complex and costly procedures to determine which sites are modified and the physiological relevance of such modifications.
Measuring inositol 1,4,5-trisphosphate- evoked 45Ca2+ release from intracellular Ca2+ stores
Authors: Taylor Colin W , Marchant Jonathan S
Published: November 2023

The receptors for inositol 1,4,5-trisphosphate (Ins(l,4,5)P3) are intracellular Ca2+ channels which open in response to the concerted effects of cytosolic Ca2+ and Ins(l,4,5)P3, and thereby allow Ca2+ stored within the lumen of the endoplasmic reticulum to leak into the cytosol. The resulting increase in cytosolic [Ca2+] regulates many aspects of cellular behaviour. In the twentyfive years since Ins(l,4,5)P3 was shown to provide the link between receptors in the plasma membrane that stimulate polyphosphoinositide hydrolysis and the release of Ca2+ from intracellular stores (1), novel experimental approaches have often provided the impetus for the steps towards our current understanding. Simple methods to separate [3H]-inositol phosphates, and the use of u+ to block the final step in their degradation (2), allowed the effects of numerous stimuli on polyphosphoinositide hydrolysis to be established in many cells. Methods that allowed selective permeabilization of the plasma membrane, without destroying the integrity of intracellular organelles (3), were instrumental in allowing the effects of Ins(l,4,5)P3 on intracellular Ca2+ stores to be demonstrated (1).
Isothermal titration calorimetry of biomolecules
Authors: O’Brien Ronan , Ladbury John E
Published: November 2023

One of the primary goals of contemporary molecular biology is to gain an understanding of the molecular basis of specificity and recognition phenomena, between proteins and ligands. Proteins can specifically recognize, and reversibly bind to small molecular weight target molecules, other macromolecules (e.g. proteins, nucleic acids) and to macromolecular assemblies. Characterization of these interactions necessarily involves investigation of the inter-relationship between function, structure (including dynamics), kinetics, and energetics (i.e. thermodynamics) of a system under defined physico-chemical conditions. In this chapter we focus on the determination of the latter of these quantities. The measurement of thermodynamic parameters is important because all reversible biomolecular interactions involve a redistribution of non-covalent bonds. The most experimentally accessible of the thermodynamic quantities occurring on a protein going from the free (unbound) to the bound state is the heat (enthalpy) uptake or release.
Cell cycle checkpoints
Authors: Forbes Kristi Chrispell , Enoch Tamar
Published: November 2023

During each yeast cell cycle, chromosomes must be copied faithfully and segregated accurately between daughter cells. Surveillance systems termed ‘checkpoints’ ensure the fidelity of chromosome duplication by detecting abnormal structures and blocking cell cycle transitions while problems are corrected. Studies in Saccharomyces cerevisiae and Schizosaccharomyces pombe have identified a plethora of checkpoint genes and proteins. Remarkably, as was predicted in 1989 by Hartwell and Weinert (1), the same checkpoint proteins that maintain the yeast genomes play a crucial role in preventing cancer in mammals (2, 3). Thus studies in yeasts have helped to elucidate an important cause of genomic instability and cancer. Now that many checkpoint proteins have been identified, current investigations are aimed at understanding how these checkpoints work in molecular detail. As this review will detail, considerable progress has been made in this area in the last 10 years. Because many of the checkpoint proteins arc conserved in higher eukaryotes, yeasts will continue to prove their value as model systems for the study of mechanisms that maintain the genome.
The morphology of larval and adult zebrafish
Authors: Schilling Thomas F
Published: November 2023

With its emergence as a popular model system in developmental genetic studies, the zebrafish, Dania rerio (Teleostei,Cyprinidae), needs accurate anatomical descriptions and guides to staging (1). Staging by morphology helps resolve the problem of asynchrony during development and provides better accuracy in developmental analyses. There is a staging series for the embryonic period in zebrafish (2), but not for larvae and adults. This chapter brings together information on larval and adult morphology, most of which has been published separately in experimental papers. Although not a detailed staging series or atlas, it is meant to serve as a brief guide to late stages of zebrafish development in the laboratory, and to summarize knowledge and publications on zebrafish anatomy.