bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular replacement
Authors: Giacovazzo Carmelo
Published: November 2020

Modern phasing methods may be subdivided into: (a) ab initio approaches, which include direct methods, Patterson techniques, charge flipping, and VLD (vive la difference). These approaches do not use (but, suitably modified, some of them can) any prior information on the molecular geometry. (b) non-ab initio methods. In this category, we include molecular replacement (MR), isomorphous derivatives (SIR-MIR) and anomalous dispersion (SAD-MAD) approaches. MR exploits information on the molecular geometry (i.e. the target molecule is known to be similar to that present in another previously solved structure), SIR-MIR uses the supplementary information contained in the experimental data from one or more isomorphous structures, and SAD-MAD exploits anomalous dispersion effects (we will see that such effects simulate isomorphism). It is immediately clear that classification into ab initio and non-ab initio categories may be questionable, because it hides substantial diversities in the prior information. For example, SAD-MAD, unlike SIR-MIR, may use the native protein data only, and no prior information on the molecular geometry is necessary; apparently, this may be considered to belong to the ab initio category. MR does not use supplementary experimental data, and therefore seems not to be similar to SAD-MAD and SIR-MIR. The latter two techniques are often referred to as experimental phasing approaches, but also this appellation is questionable; indeed, the experiment does not provide phases, these are derived by treating the experimental data, as in any other phasing approach. The above considerations suggest that a more precise, even if conventional, definition for ab initio methods is necessary; in this book, they are identified as those techniques which do not use the molecular geometry as prior information and exploit only native data, without anomalous dispersion effects. We have seen in Section 12.8 that some approaches use low-level prior information, not specific to the current structure, but valid for a large range of compounds (e.g. the coordination of some heavy atoms and corresponding bond angles and distances). Also such procedures may be considered as ab initio approaches; to this category we add ARCIMBOLDO, which combines the ‘trivial’ information that a protein consists of smaller molecular fragments of known geometry (among which are α-helices) with MR. ARCIMBOLDO is summarized in Section 13.9.
Mortuary practices, problems, and analysis
Authors: Harding Dennis
Published: November 2020

Archaeological investigation is sometimes likened to opening a window on to the past. The problem is that, except in cases of unexpected and sudden disaster, for example where a shipwreck has been preserved untouched or a town was engulfed by volcanic ash, the archaeologist never examines a site as it was in its living heyday, only as it was after it had been abandoned, leaving only what survives of what its occupants chose to leave behind. Burials likewise represent only what communities chose to deposit for whatever reason, modified by taphonomic factors that determine the state of surviving evidence. Other ephemeral forms of disposal, and any elaborate or protracted rituals that preceded the final act of deposition that did not involve substantive structures, will pass unremarked in the archaeological record. It has been suggested in Chapter 1 that human remains may have been buried either in a dedicated cemetery where the dead were segregated or confined, perhaps in the equivalent of consecrated ground, or integrated within the environs of settlements, whether as complete or near-complete bodies or as fragmented parts or individual bones. A third option, of course, and one which would certainly contribute to the difficulty of tracing a regular burial rite archaeologically, would be segregated burial on an individual basis rather than in a community group, however small or selective. The concept of a cemetery assumes a degree of social cohesion in Iron Age practice which may not have been universal. An obvious question must be why should there have been these alternatives, and what might have governed the decision as to which alternative should be adopted? Ethnographic analogies suggest that the spirits of the dead could have been regarded as malevolent, more especially during the interim phase between death and completion of decomposition. So it might make sense to consign the dead directly to a dedicated cemetery that was detached from the settlement, or to confine them initially within a secure location, such as a hillfort, for excarnation or interim burial, before final disposal.
Communities of the dead
Authors: Harding Dennis
Published: November 2020

Burial monuments of the Neolithic and Bronze Age, individual or in cemeteries, were often located in topographically prominent positions, or in zones of concentration that might qualify as ‘sacred landscapes’. In the Iron Age by contrast it is not obvious what governed the choice of location for cemeteries and smaller burial grounds, whether they were sited in relationship to settlement or whether there were traditional locations dedicated to burial. For some of the eastern Yorkshire square-ditched barrow cemeteries Bevan (1999: 137–8) considered proximity to water may have been a factor. Dent (1982: 450) stressed the siting of Arras type barrows and cemeteries adjacent to linear boundaries and trackways, a factor that is very apparent in the linear spread at Wetwang Slack. Though we may distinguish burials that are integrated into settlements from those that are segregated into cemeteries, therefore, there is no implication that cemeteries were remote from settlements. In fact, the contrary is often demonstrably the case. There is some evidence that small cemeteries or burial grounds were located immediately beyond the enclosure earthworks of hillforts. At Maiden Castle, Dorset (Fig. 3.1; Wheeler, 1943), the picture is prejudiced by the dominance of the ‘war cemetery’ in the eastern entrance, but the reality is that there had been a burial ground just outside the ramparts well before the conquest. A possible parallel is Battlesbury, where Mrs Cunnington (1924: 373) recorded the discovery of human skeletons from time to time in a chalk quarry just outside the north-west entrance to the camp. Some of these were contracted inhumations, and apparently included one instance of an adult and child buried together. The attribution of a ‘war cemetery’ (Pugh and Crittall, 1957: 118 evidently refers to this external burial site, which should be distinguished from the burials excavated more than a century earlier by William Cunnington within the hillfort at its north-west end (Colt Hoare, 1812: 69). Iron Age inhumations were also found, just within the rampart circuit, at Grimthorpe in Yorkshire (Mortimer, 1905: 150–2; Stead, 1968: 166–73). One of these was the well-known warrior burial, found in 1868.
Musculoskeletal medicine
Authors: Emmett Stevan R. , Hill Nicola , Dajas-Bailador Federico
Published: November 2020

Osteoarthritis (OA) is best described as a chronic pain syndrome affecting one, or more frequently, multiple joints. It most commonly affects the knees, hips, hands, neck and lower back, although any joint can be affected. Defining OA by pathological changes is no longer con­sidered best practice, as the correlation between path­ology and symptoms is frequently discordant, i.e. patients with severe structural changes may present with min­imum symptoms and vice versa. For this reason, patients should be assessed using a biopsychosocial model, which takes into consideration impact on social and psycho­logical well- being, alongside pathological changes. OA can create substantial mobility problems and is the most common cause of disability in elderly people in the devel­oped world. Prevalence rises with age such that approxi­mately one- third of people in the UK over 45 have sought treatment for OA compared with 40– 50% of people over the age of 75. In the pathological conditions of OA, there are specific hallmarks of damage that affect load- bearing articular cartilage, the formation of new bone at the joint mar­gins (osteophytosis), subchondral bone changes (scler­osis), thickening of the joint capsule, loss of cartilage, and joint space narrowing (Figure 7.1B). In general, struc­tural changes seen on X- ray or CT do not correlate with the pain of OA, but an association does occur between the presence of synovitis, subchondral bone oedema and osteophytes. In OA the vasculature of the osteochondral junction also expresses higher levels of nerve growth fac­tors (NGF) so pain sensitization associated with inflam­mation is likely to occur. OA is considered by some to be the result of physio­logical processes originally targeted at joint repair that, over time, cause tissue damage resulting in symptomatic OA. In many cases, severe trauma or pathological repair processes may be contributory factors. Other risk factors for OA include genetic and patient factors, such as age and obesity (see Box 7.1). Anti- NGF drugs may be of benefit, primarily via pain modulation, but OA is not considered to be a disease of inflammation and the mainstay of treatment relies on effective analgesia. The presence of synovitis in late disease is controversial and the presence of joint crys­tals may confound inflammation in OA. It is clear that wear, tear, and damage is associated with the break­down of collagen and increased presence of proteo­lytic enzymes called matrix metalloproteinases (MMPs).
Ethnographic Models
Authors: Harding Dennis
Published: November 2020

Evaluating the contribution that a study of ethnographic models can make to an understanding of the role of hillforts in Iron Age society is as fraught with difficulties as is a critical assessment of documentary sources. Divorced in space and time from the Iron Age in Britain and north-western Europe, there can plainly be no direct cultural association or expectation that the social, political, economic, or belief systems that governed behaviour were necessarily comparable. Nevertheless, the basic requirements of providing food, shelter from the environment, and protection from hostile threat are universal, and communities widely separated in time and space may respond independently to similar situations in ways that may potentially illuminate the archaeological issues under review. As with experimental archaeology, we cannot say as a result of studying ethnographic analogies, that Iron Age communities in Britain built hillforts for such-and-such purposes or in the process believed this or that; only that these possibilities might be examined as potentially satisfying the available evidence. When it comes to social reconstruction, it may be possible to identify broad categories of social structures in which patterns of behaviour are recurrent, and more tentatively the same might be inferred for cognitive systems. The fact that we may never know what Iron Age communities believed is no reason for failing to address the question, which is not the same as simply asserting what they believed without presenting evidence or due qualification. Modern or early modern ethnographic models suffer from the inevitable disadvantage that they derive from contact between the native communities and European colonists. In consequence there is the probability that, as with Roman records of contacts with Gaulish or British Iron Age communities, native behaviour will in some measure have adapted to the alien cultural presence. This would apply even if the nature of contact were peaceable exploration, commercial, or evangelical, since the introduction of new technology and novel goods and practices would inevitably impact on local conventions. In the context of any defensive sites or protected settlements, the introduction of firearms plainly will have transformed any established convention of warfare that pertained in the pre-colonial era. Establishing the native tradition from earlier periods is not an easy or wholly reliable exercise, especially given that practices may have changed significantly if slowly over generations.
Hepatobiliary surgery
Authors: Wood James
Published: November 2020

The reaction of most students to questions about hepatobiliary dis­ease is a sinking feeling of despair! ‘Lots of biochemistry and anatomy together with a bunch of funny eponymous syndromes to remember!’ Well, hepatobiliary disease is remarkably logical; knowledge of the basic principles of biliary metabolism and the key anatomical facts is usually more than enough if it is coupled with a sound appreciation of the com­mon clinical presentations. These presentations are extremely common; most days on call will see the surgical team looking after at least one patient with one of the range of hepatopancreaticobiliary problems that can present as an emergency. This chapter will review the basic principles of liver and pancreatic disease and the anatomy that goes with it. Both elective and emergency surgical presentations will also be covered, allowing you to revise knowl­edge of key clinical presentations in practice.
Orthopaedic surgery
Authors: Dawson-Bowling Sebastian
Published: November 2020

Sound knowledge of anatomy and understanding of musculoskeletal function underpins good orthopaedic practice. Bones and joints may be affected by genetic and degenerative conditions, by infection, primary and secondary neoplasia, by endocrine and metabolic anomalies, and by trauma. As in other areas of surgery, a comprehensive history and thorough examination are essential in leading the clinician to a correct diagno­sis. Appropriate imaging complements clinical acuity. The plain X-ray remains the primary modality of investigation for visualizing bony injuries and pathology, but MRI is a valuable adjunct for investigating soft tissues and joints. Principles of fracture healing, reduction and fixation, and knowledge of consequences of complications which delay healing, or cause non-union, are integral to the practice of orthopaedic surgery. This chapter will help you to revise basic tenets of orthopaedic prac­tice and the common injuries and conditions encountered by the ortho­paedic surgeon.
Diseases of the oral mucosa
Authors: Robinson Max , Hunter Keith , Pemberton Michael , Sloan Philip
Published: November 2020

The oral mucosa lines the oral cavity and comprises a surface squamous epithelium with underlying lamina propria. Below the mucosa is the submucosa, which is composed of fibrous tissue and adipose tissue, and contains lobules of minor salivary glands and neurovascular bundles. In places, there is no submucosa and the lamina propria is continuous with periosteum, forming the resilient mucoperiosteum that covers the maxilla and mandible. The squamous epithelium is composed of keratinocytes arranged in lay­ers: there is a basal cell layer that rests on the basement membrane, a prickle cell layer, and usually a keratinized layer. The keratino­cytes are attached to each other by desmosomes and the basal keratino­cytes are attached to the basement membrane by hemi- desmosomes. The basement membrane is important in maintaining the integrity of the mucosa by sticking the squamous epithelium to the underlying lamina propria. There are two patterns of keratinization: par­akeratosis and orthokeratosis. In parakeratinized epithelium the surface keratinocytes become flattened and the nucleus becomes dark and shrunken (pyknotic). These terminally differentiated squamous cells are eventually lost at the surface by desquamation. In orthokeratiniza­tion, there is a granular cell layer (containing numerous keratohyaline granules) between the prickle cell layer and the keratinized layer. The surface squames become flattened and do not contain any discernible nuclear material. Whilst the majority of cells in squamous epithelium are keratinocytes, there are also accessory cells such as melanocytes, Langerhans cells, and neurosensory cells (Merkel cells and taste buds). The lamina propria is the connective tissue that lies immediately below the epithelium. It is divided into the superficial papil­lary layer (sometimes referred to as the corium) and the deeper reticu­lar layer. The lamina propria is composed of fibrous tissue with a rich neurovascular supply and contains fibroblasts that elaborate collagen and elastin fibres along with other extracellular matrix proteins. The lamina propria also contains components of the mucosal immune defence system such as Langerhans cells, macrophages, mast cells, and lymphocytes. The clinical appearance of the oral mucosa is dependent on the thick­ness of the epithelium, the amount of surface keratinization, melanin (and other) pigmentation, and the vascularity of the lamina propria.
Oral manifestations of systemic disease
Authors: Robinson Max , Hunter Keith , Pemberton Michael , Sloan Philip
Published: November 2020

This chapter emphasizes the importance of oral disease in the context of systemic disease. Oral disease may be the first sign of an underlying systemic disorder, which should trigger further investigations or referral to a medical or specialist practitioner, expediting early diagnosis and appropriate clinical care. In those patients with known illnesses, dental healthcare professionals should have an appreciation of the effects of these diseases on the oro- facial complex; patients can then benefit from the supportive care of the dental team. Coeliac disease (gluten-induced enteropathy) is a genetically deter­mined inflammatory small bowel disease that is induced by gluten in the diet. Gluten is present in wheat, rye, and barley. The inflammatory reaction results in malabsorption due to morphological abnormalities in the small intestinal mucosa. It was once thought of as a rare disease of childhood, but now it is understood to be a common disease that can be diagnosed at any age. Studies undertaken since the advent of sero­logical screening indicate a prevalence of 0.5–1% in the population, with adult presentations now more frequent than childhood ones. This new appreciation has led to the concept of the ‘coeliac iceberg’. At the tip of the iceberg are those with overt disease, with the lower groups classified in order as: silent coeliac disease, latent coeliac disease, and healthy individuals with genetic susceptibility. Severe presentations in childhood classically were of diarrhoea, failure to thrive, and weakness. However, it is now understood that patients with coeliac disease may have minimal gastrointestinal symptoms of malabsorption at presenta­tion and experience other rather non-specific symptoms of the disease. The increasing recognition of the disease is attributed to several factors, including new serological assays, advances in flexible endoscopy allow­ing clinicians to take duodenal biopsies more easily, and an increased index of suspicion in looking for the disease. The disease is associated with an increased rate of osteoporosis, infertility, autoimmune diseases, and malignancy, especially lymphoma. Treatment should involve a gluten-free diet, which is a major undertaking and for which dietetic advice is essential.
Principles of Pharmacology
Authors: Brack Graham , Franklin Penny , Caldwell Jill
Published: November 2020

From the previous chapters you will see that understanding the pharmacological aspects of the drugs you are administering is vital to keeping your patients safe. Nurses need to understand the pharmacodynamics of a medicine, or how it actually works within the body, since this will need to be explained to patients and carers. For example, how will you ensure that a patient understands the importance of taking their treatment for hypertension (especially if they are experiencing no symptoms) if you are unable to explain how the medicine will be working? Similarly, your understanding of the pharmacokinetics (the absorption, distribution, metabolism, and excretion) of individual medicines is vital to ensure compromised patients are not administered inappropriate medicines. For example, you would question the prescribing of a non-steroidal anti-inflammatory drug (NSAID) to a patient with significant renal impairment, because the kidney is essential to the elimination of NSAIDs so the drug could accumulate if the kidneys are not functioning properly. From the point of view of ensuring patient safety, you will need to understand the principles of drug interactions so that you can understand how two medicines (or food and medicine) could interact and be alert to signs that this may be happening. There are several good textbooks dealing with the uses and actions of individual medicines, including interactions. However, these will not be discussed here because at this stage of your career you are not expected to have a detailed knowledge of particular medicines, but rather an understanding of the key principles. As nurses, we are concerned with how the body handles medicines (pharmacokinetics) so that we can see how this may be affected by age, genetics, or illness, and how the actions of medicines may conflict with one another or produce toxicity because their effects are additive. Equally, we need to look at occasions in which two medicines produce the same response by two different routes; such interactions can be beneficial to the patient and avoid having to give large doses of a single medicine because the same result can be achieved with smaller doses of two medicines, thereby reducing the risk of adverse effects.
Puzzles
Authors: Levitin Anany , Levitin Maria
Published: November 2020

1. A Wolf, a Goat, and a Cabbage A man finds himself on a riverbank with a wolf, a goat, and a head of cabbage. He needs to transport all three to the other side of the river in his boat. However, the boat has room for only the man himself and one other item (either the wolf, the goat, or the cabbage). In his absence, the wolf would eat the goat, and the goat would eat the cabbage. Show how the man can get all these “passengers” to the other side. 2. Glove Selection There are 20 gloves in a drawer: 5 pairs of black gloves, 3 pairs of brown, and 2 pairs of gray. You select the gloves in the dark and can check them only after a selection has been made. What is the smallest number of gloves you need to select to guarantee getting the following? (a) At least one matching pair (b) At least one matching pair of each color 3. Rectangle Dissection Find all values of n > 1 for which one can dissect a rectangle into n right triangles, and outline an algorithm for doing such a dissection. 4. Ferrying Soldiers A detachment of 25 soldiers must cross a wide and deep river with no bridge in sight. They notice two 12-year-old boys playing in a rowboat by the shore. The boat is so tiny, however, that it can only hold two boys or one soldier. How can the soldiers get across the river and leave the boys in joint possession of the boat? How many times does the boat pass from shore to shore in your algorithm? 5. Row and Column Exchanges Can one transform the left table in Figure 2.1 into the right table by exchanging its rows and columns? 6. Predicting a Finger Count A little girl counts from 1 to 1000 using the fingers of her left hand as follows. She starts by calling her thumb 1, the first finger 2, middle finger 3, ring finger 4, and little finger 5.
Organization of the Endocrine System
Authors: Ojeda Sergio R. , Kovacs William J.
Published: November 2020

Multicellular organisms are endowed with coordinating systems that regulate and integrate the function of the different cells composing these organisms. Two main interacting systems perform this critical function: the nervous system and the endocrine system. The former employs electrochemical signals to convey regulatory inputs to peripheral organs and to receive information from them; the latter produces chemical agents that, in general, are transported systemically by the bloodstream to the target organs. The two systems are closely interconnected. The most conspicuous connection is that of the hypothalamus and the pituitary gland. Hypothalamic neurosecretory cells produce substances that are delivered to the portal blood vessels (see Chapter 5) and transported to the anterior pituitary (adenohypophysis), where they regulate the secretion of adenohypophyseal hormones. Other hypothalamic neurons send their axons to the posterior pituitary, from which they release their neurosecretory products directly into the bloodstream. The nervous system also innervates most, if not all, endocrine glands, including the gonads, the thyroid, and the adrenals. The nerves control not only blood flow but also the secretion of hormones. In turn, the endocrine system regulates the function of the nervous system. For example, gonadal and adrenocortical hormones act directly on the central nervous system to either inhibit or to stimulate the secretion of neuropeptides involved in the control of the pituitary-gonadal and pituitary-adrenal axes, respectively (i.e., gonadotrophin-releasing hormone [GnRH], also known as luteinizing hormone-releasing hormone [LHRH], and corticotropin-releasing hormone [CRH]; see Chapter 5). Although conventional definitions of the nervous and endocrine systems emphasize their differences, the two systems also display similarities. For instance, the nervous system produces not only substances that act across synapses, but it also releases signaling molecules that reach distant target cells via the bloodstream.
Sexual Differentiation
Authors: Mcphaul Michael J. , Auchus Richard J.
Published: November 2020

Sexual differentiation is a sequential process that begins at fertilization with the establishment of chromosomal sex, continues with the determination of gonadal sex, and culminates in the development of secondary sexual characteristics that comprise the male and female phenotypes. This basic paradigm was formulated by Alfred Jost to explain the results of castration experiments in fetal rabbits. If the gonads (ovaries or testes) were removed before sexual differentiation, female sexual differentiation inevitably ensued. The male pathway could be partly restored by testosterone implants, suggesting that hormones produced by the testes mediate male sexual development. Thus, the concept arose that the testes induce a male pattern of differentiation on an embryo that otherwise would follow the female pathway. Cytogenetic studies shortly thereafter showed that the critical genetic determinant of sex is the presence or absence of the Y chromosome, leading to the proposal that the Y chromosome directs the gonad to differentiate into a testis, which then produces hormone(s) that cause male sexual differentiation. The chromosomal sex of the embryo generally corresponds to its phenotypic sex. Occasionally, however, the process of sexual differentiation goes awry, resulting in individuals with disorders of sexual differentiation (DSD). Clinically recognized disorders of sexual development occur at many levels, ranging from relatively common disorders in the terminal steps of male differentiation (e.g., testicular descent, growth of the penis) to more fundamental abnormalities that lead to varying degrees of ambiguity of phenotypic sex. Although most of these abnormalities impair reproduction, they usually are not life threatening. Thus, humans and experimental animals with naturally occurring defects in sexual differentiation survive to reach the attention of physicians and scientists. This chapter reviews the sequence of events in normal sexual development and describes disorders of this process — many of which result from single-gene mutations — that have provided valuable insights into the mechanisms of sexual differentiation. Normally, human somatic cells have 22 pairs of autosomes and 1 pair of sex chromosomes.
The Mathematics of Causal Relations
Authors: Pearl Judea
Published: November 2020

Almost two decades have passed since Paul Holland published his highly cited review paper on the Neyman-Rubin approach to causal inference (Holland, 1986). Our understanding of causal inference has since increased severalfold, due primarily to advances in three areas: 1. Nonparametric structural equations 2. Graphical models Symbiosis between counterfactual and graphical methods 3. These advances are central to the empirical sciences because the research questions that motivate most studies in the health, social, and behavioral sciences are not statistical but causal in nature. For example, what is the efficacy of a given drug in a given population? Can data prove an employer guilty of hiring discrimination? What fraction of past crimes could have been avoided by a given policy? What was the cause of death of a given individual in a specific incident? Remarkably, although much of the conceptual framework and many of the algorithmic tools needed for tackling such problems are now well established, they are hardly known to researchers in the field who could put them into practical use. Why? Solving causal problems mathematically requires certain extensions in the standard mathematical language of statistics, and these extensions are not generally emphasized in the mainstream literature and education. As a result, large segments of the statistical research community find it hard to appreciate and benefit from the many results that causal analysis has produced in the past two decades. This chapter aims at making these advances more accessible to the general research community by, first, contrasting causal analysis with standard statistical analysis and, second, comparing and unifying various approaches to causal analysis. The aim of standard statistical analysis, typified by regression, estimation, and hypothesis-testing techniques, is to assess parameters of a distribution from samples drawn of that distribution. With the help of such parameters, one can infer associations among variables, estimate the likelihood of past and future events, as well as update the likelihood of events in light of new evidence or new measurements.
Causal Thinking for Objective Psychiatric Diagnostic Criteria: A Programmatic Approach in Therapeutic Context
Authors: Klein Donald F.
Published: November 2020

Terms such as disorder, illness, disease, dysfunction, and deviance embody the preconceptions of historical development (Klein, 1999). That individuals become ill for no apparent reason, suffering from pain, dizziness, malaise, rash, wasting, etc., has been known since prehistoric days. The recognition of illness led to the social definition of the patient and the development of various treatment institutions (e.g., nursing, medicine, surgery, quacks, and faith healers). Illness is an involuntary affliction that justifies the sick, dependent role (Parsons, 1951). That is, because the sick have involuntarily impaired functioning, it is a reasonable social investment to exempt them (at least temporarily) from normal responsibilities. Illness implies that something has gone wrong. However, gaining exemption from civil or criminal responsibilities is often desired. Therefore, if no objective criteria are available, an illness claim can be viewed skeptically. By affirming involuntary affliction, diagnosis immunizes the patient against charges of exploitative parasitism. Therefore, illness may be considered a hybrid concept, with two components: (1) the necessary inference that something has actually, involuntarily, gone wrong (disease) and (2) the qualification that the result (illness) must be sufficiently major, according to current social values, to ratify the sickness exemption role. The latter component is related to the particular historical stage, cultural traditions, and values. This concept has been exemplified by the phrase ‘‘harmful dysfunction’’ (Wakefield, 1992). However, this does not mean that the illness concept is arbitrary since the inference that something has gone wrong is necessary. Beliefs as to just what has gone wrong (e.g., demon possession, bad air, bacterial infection) as well as the degree of manifested dysfunction that warrants the sick role reflect the somewhat independent levels of scientific and social development (for further reference, see Lewis, 1967). How can we affirm that something has gone wrong if there is no objective evidence? The common statistical definition of abnormality simply is ‘‘unusual.’’ Something is abnormal if it is rare. Although biological variability ensures that someone is at an extreme, there is a strong presumption that something has gone wrong if sufficiently extreme.
Why Think Up New Molecules?
Authors: Hoffmann Roald
Published: November 2020

Some theoreticians in chemistry, myself included, like to think about molecules that do not (yet) exist. I use the simple word “think” advisedly, for the design need not use fancy-schmancy computer-intensive “first-principles” calculations. We conjure up the chemical future in so many ways—simple model building, qualitative thinking, and from ever-more-reliable quantum chemical calculations. Even in dreams, as Henning Hopf reminded me, Kekulé’s ouroboric benzene in mind. But why do we try to imagine new molecules? Aren’t there enough molecules already on earth, be they natural or synthetic? A potpourri of reasons follows. Synthesis, the making of molecules, is at the heart of chemistry—the art, craft, business, and science of substances (molecules at the microscopic level) and their transformations. Of course you need to know what substances are, so analysis is a parallel, lively enterprise. As is figuring out why molecules have the colors or other properties they do, why they react in certain ways and not others. Chemists make the objects of their own contemplation. And, of course, study the beautiful evolved world around and within them. By being as much (if not more) in the work of creation as discovery, chemistry is close to art. And lest we get too puffed up on that, creation brings chemistry also close to engineering (which certainly can have artistic elements in it!). I love explaining. But as a theoretician, I also want to take part in the work of creation. I can do so by thinking up interesting molecules not yet made. Maybe, just maybe, an experimentalist will try to make the molecule. Actually, given human nature, a hypothetical molecule will be made more expeditiously if it is thought up by the synthesizer, rather than by me. Since chemistry is a semi-infinite macrocosm of structure, there are many interesting molecules waiting to be made. And still many more that might as well wait a while longer. Few of the 355 dodecanes (C12H26) are extant. For good reasons—new principles, new properties are most unlikely to be found among them. So it’s not just predicting any molecule that does not exist, it’s predicting one that’s in some way “interesting.” That loose word has both cognitive and emotional sides to it, and is definitely subjective. Nevertheless, I find “interesting” works very well, in evoking the psychological mix that makes the intelligent graduate student’s mind hop to.
Protean
Authors: Hoffmann Roald , Laszlo Pierre
Published: November 2020

Science often advances upon willful transgression of a seeming interdiction. Examples which leap to a chemist’s mind are noble gas compounds, strained hydrocarbons such as tetrahedranes, activation (by organometallics) of even methane, and, to mention just one brilliant, more recent achievement, inclusion of an allene within the confines of a six-membered ring while preventing its conversion into a benzenoid. Such feats put all the cunning of a scientist into coaxing and, yes, coercing the system at hand to obey instructions from one’s daring imagination. As always, it is hard. Not for nothing is our playroom called a laboratory. And when the task is done and the time arrives to convey to others (who might not be privy to the anguish of the work) all that struggle and the majesty of the achievement, the scientist quite naturally lapses into metaphor. One such, founded in male 19th century language as much as in history, is some more or less prurient variant of “Unveiling the Secrets of Nature.” Another, evoking the thorny, twisted path to understanding and the long hours of toil in the laboratory, is “Wrestling with Nature.” The latter metaphor has been central to experimental science at least since the Elizabethan Age, and is the subject of this small essay. While the roots of the metaphor lie in Greek myth, it makes a striking debut in a seminal brief for experiment in science. This arresting phrase also marks a bifurcation in the way science is viewed by nonscientists, even—and especially so—in our day. The proof text here is that of Francis Bacon (1561–1626), in his 1605 Of the Advancement of Learning. Bacon writes: . . . For like a man’s disposition is never well known till he be crossed, nor Proteus ever changed shapes till he was straitened and held fast; so the passages and variations of nature cannot appear so fully in the liberty of nature, as in the trials and vexations of art. . . . He repeats the imagery in his remarkable 1620 Novum Organum. Bacon’s 1620 book was a clarion call to replace what passed as Aristotelian reasoning about the world with experiment.
The Say of Things
Authors: Hoffmann Roald , Laszlo Pierre
Published: November 2020

In search of a chemical conversation, we are on a farm in Uniow, a little Ukrainian village in Austro-Hungarian Galicia, just before the onset of World War I. In the farm yard we see a big, steaming, lead-lined iron pot. The men have mixed some potash in it (no, not the pure chemical with composition KOH from a chemical supply company, but the real ash from burning good poplar) and quicklime, to a thickness that an egg—plenty of eggs here, judging from the roaming chickens—floats on it. Elsewhere in the yard, women are straining kitchen grease, suet, pig bones, rancid butter, the poor parts skimmed off the goose fat (the best of which had been set to cool, cracklings and all). This mix doesn’t smell good; they would rather toss the kitchen leavings and bones into the great iron pot, but the fat must be free of meat, bones, and solids for the process to work. They are making soap. Not that we had to go that far, near where one of us was born, for soap was prepared in this way on farms from medieval times until the twentieth century. Fat was boiled up with lye (what the potash and quicklime made). The reaction was slow—days of heating and stirring until the lye was used up, and a chicken feather would no longer dissolve in the brew. One learned not to get the lye on one’s hands. The product of a simple chemical reaction was then left in the sun for a week, stirred until a paste formed. Then it was shaped into blocks and set out on wood to dry. And inside the steaming pot, deep inside, where the fat and the lye are reacting? There is the conversation we are after, a hellishly animated molecular conversation. The lye that formed was an alkaline mixture of KOH, Ca(OH)2, and NaOH. In the vat one had hydroxide (OH-) ions, and K+, Ca2+, Na+ all surrounded in dynamic array and disarray by water molecules. Contaminants aside, the fat molecules are compounds called esters, in which an organic base, glycerol, combines with three long-chain hydrocarbon chains.
Best Synthetic Methods: Oxidation and Reduction
Authors: Taber Douglass
Published: November 2020

Although methods both for reduction and for oxidation are well developed, there is always room for improvement. While ketones are usually reduced using metal hydrides, hydrogen gas is much less expensive on scale. Charles P. Casey of the University of Wisconsin has devised (J. Am. Chem. Soc. 2007, 129, 5816) an Fe-based catalyst that effects the transformation of 1 to 2. Note that the usually very reactive monosubstituted alkene is not reduced and does not migrate. Takeshi Oriyama of Ibaraki University has developed a catalyst, also Fe-based (Chemistry Lett. 2007, 38) for reducing aldehydes to ethers. Using this approach, an alcohol such as 3 can be converted into a variety of substituted benzyl ethers, including 5. Simple aliphatic aldehydes and alcohols also work well. Oxidation of alcohols to aldehydes or ketones is one of the most common of organic transformations. Several new processes catalytic in metal have been put forward. Tharmalingam Punniyamurthy of the Indian Institute of Technology, Guwahati has found (Adv. Synth. Cat. 2007, 349, 846) that catalytic V(IV) oxide on silica gel, stirred with t-butyl hydroperoxide in t-butyl alcohol at room temperature smoothly oxidized 6 to 7. After the reaction, the catalyst was separated by filtration. Another carbonyl can also serve as the hydride acceptor, but then the transfer can be reversible. Jonathan M. J. Williams of the University of Bath has shown (Tetrahedron Lett. 2007, 48, 3639) that with a Ru catalyst, methyl levulinate 9 could serve as the hydride acceptor, with the byproduct alcohol being drained off as the lactone 11. Hansjörg Grützmacher of the ETH Zürich developed an Ir catalyst (Angew. Chem. Int. Ed. 2007, 46, 3567) with benzoquinone as the net oxidant. that showed marked preference for the oxidation of primary over secondary alcohols. Yasuhiro Uozumi of the Institute for Molecular Science, Aichi, has devised (Angew. Chem. Int. Ed . 2007, 46, 704) a nanoencapsulated Pt catalyst that worked well with O2 or even with air. The catalyst was easily separated from the product, and maintained its activity over several cycles.
Reduction, Oxidation and Homologation of Alkenes
Authors: Taber Douglass
Published: November 2020

Alkenes are usually reduced by catalytic hydrogenation. Diimide reduction is a mild and neutral alternative. Keith R. Buszek, now at the University of Missouri, Kansas City, has shown (J. Org. Chem. 2007, 72, 3125) that the reduction can conveniently be carried out on resin-bound alkenes, using 2-NBSH (o-nitrobenzenesulfonylhydrazide) with Et3 N for convenient room temperature diimide generation. Ozone can be difficult to dispense accurately on small scale. Masahito Ochiai of the University of Tokushima has uncovered (J. Am. Chem. Soc. 2007, 129, 2772) an alternative, using acid-promoted Ph-I=O. Isolated alkenes also work well. MCPBA is the reagent most commonly used for alkene epoxidation. Payne oxidation (H2O2 /CH3CN) is a convenient and inexpensive alternative. In the course of a study of the enantioselective enzymatic hydrolysis of 6, Takeshi Sugai of Keio University has described (Tetrahedron Lett. 2007, 48, 979) a practical procedure for multigram Payne epoxidation of 5. Several procedures have been put forward for functionalizing terminal alkenes, exemplified by 7. Stefan Grimme and Armido Studer of the Universität Münster have developed (J. Am. Chem. Soc. 2007, 129, 4498) a free radical alkene amination, represented by the conversion of 7 to 9. Tehshik P. Yoon of the University of Wisconsin has found (J. Am. Chem. Soc. 2007, 129, 1866) that Cu catalyzes the addition of oxaziridines such as 10 to alkenes, to make 11. Shinji Nakamura of the University of Tokyo and Masanobu Uchiyama of the University of Tokyo and RIKEN have established (J. Am. Chem. Soc. 2007, 129, 28) that the anion from Cu promoted addition of the silyl zinc reagent to alkenes is long-lived enough to be trapped by electrophiles, including H+ to give 12. Hideki Yorimitsu and Koichiro Oshima of Kyoto University have developed (J. Am. Chem. Soc. 2007, 129, 6094) a complementary transformation, Ni-catalyzed addition of 13 to give 14. The conversion of 7 to 15 reported (Organic Lett. 2007, 9, 53) by Li-Biao Han of the National Institute of Advanced Industrial Science and Technology, Tsukuba, is likely also a free-radical process.
Enantioselective Preparation of Alcohols and Amines
Authors: Taber Douglass
Published: November 2020

Enzymatic reduction of a ketone can proceed in high enantiomeric excess, but this would require a stoichiometric amount of a reducing agent. Wolfgang Kroutil of the Karl-Franzens-Universität Graz devised (Angew. Chem. Int. Ed. 2008, 47, 741) a protocol for preparing the alcohol 2 in high ee starting from the racemic alcohol. The alcohol dehydrogenase chosen was selective for the R-alcohol, and the microorganism reduced the ketone so produced selectively to the S alcohol. James M. Takacs of the University of Nebraska established (J. Am. Chem. Soc. 2008, 130, 3734) that chiral Rh catalyzed addition of pinacolborane to a β,γ-unsaturated N-phenyl amide 3 proceeded with high enantiocontrol. The product organoborane was oxidized to the alcohol 4 . J. R. Falck of the UT Southwestern Medical Center used (J. Am. Chem. Soc. 2008, 130, 46) an organocatalyst to effect addition of phenylboronic acid to the γ-hydroxy enone 5, to give, after hydrolysis, the diol 6. John F. Hartwig of the University of Illinois effectively telescoped (Angew. Chem. Int. Ed. 2008, 47, 1928) alcohol formation and protection into a single step, by developing a procedure for the direct conversion of a primary allylic acetate 7 to the enantiomerically-enriched secondary benzyl ether 8. Tsutomu Katsuki of Kyushu University designed (Chemistry Lett. 2008, 37, 502) a catalyst for the enantioselective hydrocyanation of an aldehyde 9, by HCN transfer from the inexpensive 10. Mei-Xiang Wang of the Chinese Academy of Sciences, Beijing and Jieping Zhu of CNRS, Gif-sur-Yvette devised (Angew. Chem. Int. Ed. 2008, 47, 388) a catalyst for a complementary one-carbon homologation, the enantioselective Passerini three-component coupling of an aldehyde 12, an isonitrile 13, and an acid 14. Joseph M. Ready, also of UT Southwestern, developed (J. Am. Chem. Soc. 2008, 130, 7828) the preparation of enol benzoates such as 17 from the corresponding alkynes. Sharpless asymmetric dihydroxylation of 17 proceeded with high ee to give, after reduction, the diol 18. Toshiro Harada of the Kyoto Institute of Technology described (Angew. Chem. Int. Ed. 2008, 47, 1088) a potentially very practical enantioselective homologation, the catalyzed addition of an alkyl titanium, prepared in situ from the corresponding Grignard reagent, to the aldehyde 19, to give 21 in high ee.
Enantioselective Construction of Arrays of Stereogenic Centers
Authors: Taber Douglass
Published: November 2020

An impressive array of new catalysts for enantioselective homologation have been reported. Carlos F. Barbas III of Scripps/La Jolla has found (Angew. Chem. Int. Ed. 2007, 46, 5572 ) that the commercial amino acid 3 mediated the addition of dihydroxyacetone 2 to an aldehyde such as 1 to give the triol 4 with high enantio- and diastereocontrol. Takashi Ooi of Nagoya University has devised (J. Am. Chem. Soc. 2007, 129, 12392) the catalyst 6 for the anti addition (Henry reaction) of nitro alkanes such as 5 to aldehydes. Takayoshi Arai of Chiba University has developed (Organic Lett. 2007, 9, 3595) a complementary catalyst (not shown) that mediated syn addition. Jonathan A. Ellman of the University of California, Berkeley has uncovered (J. Am. Chem. Soc. 2007, 129, 15110) the catalyst 10 for the aza-Henry reaction. Yian Shi of Colorado State University has found (J. Am. Chem. Soc. 2007, 129, 11688) ligands for Pd that direct the absolute sense of the addition of 13 to dienes such as 12. Bernhard Breit of Albert-Ludwigs-Universität, Freiburg has devised conditions (Adv. Synth. Cat. 2007, 349, 1891) for the Rh-catalyzed hydroformylation of α-olefins such as 15, and same-pot proline-catalyzed condensation of the linear aldehyde so produced with a branched aldehyde such as 17 to give, after reductive workup, the branched diol 18. Scott G. Nelson of the University of Pittsburgh has established (J. Am. Chem. Soc. 2007, 129, 11690) conditions, using Cinchona alkaloid derived catalysts, for the condensation of the imine surrogate 19 with the ketene precursor 20, to give the Mannich product 21. Scott E. Schaus of Boston University has developed (J. Am. Chem. Soc. 2007, 129, 15398) a complementary approach, based on catalyzed addition of isolated allyl borinates such as 23 to the activated imine 22. Kálmán J. Szabó of Stockholm University has found (J. Am. Chem. Soc. 2007, 129, 13723) that substituted allyl borinates can be prepared and reacted in situ. Martin Hiersemann of the Universität Dortmund has reported (Organic Lett. 2007, 9, 4979) the remarkable Cu*-catalyzed Claisen rearrangement of the prochiral 24, leading to 25 and thus to the versatile intermediate 27.