Various in-vitro (induced pluripotent stem cells–derived) and in-vivo genetic models (animal models like Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and non-human primates) have been used to study movement disorders such as Parkinson’s disease, hereditary ataxia, Huntington’s disease, dystonia, and essential tremor. These genetic models have provided important clues on the underlying pathophysiologic mechanisms of these diseases and serve as useful platforms to unravel potential therapeutic targets. The next generation of genetic models is promising with the advancement of gene-editing techniques, such as CRISPR-Cas9, brain organoid technology, and identification of novel genes and loci from large-scale genetic studies will facilitate development of new genetic models.

The first chapter presents evidence in support of the claim that an interest in ruins was never widespread. It had to begin somewhere and at some time. There had also to be certain factors, which are set out in the chapter, that facilitated the interest. The main evidence for a lack of interest in ruins is seen in the motives for tourism in ancient Greece and Rome – indeed, tourism is one of the leading themes of the whole work. The indifference of the Greeks and Romans to ruins is also found in other cultures, notably China’s. What seems to be needed for the ruins of any culture to arouse interest and to make a favourable impression is a gap in the continuity of that culture, such as occurred in Roman culture from late antiquity to the early Middle Ages in Europe. Someone aiming to bridge that gap – a tourist, say – who surveys past Roman culture with a sympathetic eye and an understanding of its achievements is in a position to find the ruins, the material remains of Roman culture, as interesting as any of its other monuments.

Mitochondrial disease presents with a wide, diverse spectrum of clinical manifestations at any age, often characterized by multisystem dysfunction. Movement disorders are a frequent manifestation, and may include ataxia, parkinsonism, myoclonus, dystonia, chorea, tremor. The phenotype of mitochondrial disorders, including the spectrum of movement disorders, may be very variable, even in patients carrying the same genetic mutation. Mitochondrial dysfunction may also play an important role in sporadic neurodegenerative diseases with movement disorders. Identification of a genetic mitochondrial movement disorder is challenging, but has been facilitated by new technologies, such as next-generation sequencing, thus identifying causative genes and eventually expanding the phenotype spectrum in the case of nuclear mitochondrial mutations. Identification of the underlying genetic basis of a mitochondrial movement disorder is crucial for patient management, as potentially mitochondriotoxic agents should be avoided and special precautions taken with anesthesia. This chapter gives a comprehensive overview of the spectrum of movement disorders associated with mitochondrial disease.

In Parkinson’s disease, parkinsonism occurs due to the loss of dopaminergic neurons of the substantia nigra. Existing treatments can enhance dopaminergic activity in the brain, but cause adverse effects due to the non-targeted, non-physiologic dopamine delivery, so there is interest in developing regenerative therapies to restore dopaminergic tone in the striatum in a targeted, physiologic manner. Experimental approaches include using viral vectors to deliver genes encoding growth factors or enzymes involved in dopamine synthesis, or to target nucleic acids and gene expression. A number of cell types have been considered potential sources of cell-based therapies for PD and have been trialled in humans and animals, but all have been limited by either poor efficacy, poor graft survival, or logistical barriers. However, stem cells offer a renewable source of dopaminergic cells and hold great promise as potential regenerative treatments, and human trials have begun. Although these treatments remain experimental, some are entering clinical trials and there is hope that they will become available for clinical use in the future.

Conclusion: a reckoning. Liberty used to be defined as absence of dependence. Nowadays it is usually defined as absence of restraint. But the underlying aim of this book has been to establish that there are several reasons for thinking that the ideal of liberty as independence is to be preferred. We gain from it a better sense of how the mere fact of living in subjection -- whether or not we are restrained -- takes away our liberty. We also gain from it a more helpful way of thinking about fundamental rights. Rather than conceiving of them as universal moral claims, there may be good reasons for preferring to think of them as the creation of specific independent communities. Above all, the ideal of liberty as independence helps us to see the importance of cherishing the value of autonomy in relationships between states as well as individual citizens. It is difficult to see how the requirements of justice can be met in the absence of a commitment to the ideal of liberty as independence.

This chapter develops the first collection of results around change of enrichment along a (possibly nonsymmetric) multifunctor. As in Chapter 6, it is shown that this theory extends the classical theory for enrichment over (possibly symmetric) monoidal categories. Compositionality and 2-functoriality for the change-of-enrichment constructions are treated in Sections 7.4 and 7.5, respectively.

Chapter 9 illustrates the immediate counterblast to which Price’s critics were subjected by a number of writers who continued to insist that liberty is a matter of possessing an independent will, not merely of not unrestrained from acting as you choose. Some leading Anglicans took up this position in their support of Price, including Richard Watson and Peter Peckard. But it was Price himself who answered his critics most fully. He admitted (although not explicitly) that he had given too broad a definition of slavery, but forcefully denied that he had confused the state of being at liberty with that of possessing security for your liberty. He countered that, unless you are free from the possibility of being restrained, you are not in possession of your liberty, because you remain in a condition of subjection and servitude. The chapter concludes by noting that this way of thinking about liberty gained much additional support after the outbreak of the French Revolution in 1789. Burke denounced the revolution, but he was in turn denounced by Catharine Macaulay, Mary Wollstonecraft and Thomas Paine, all of whom saw in the revolution a successful uprising against arbitrary and despotic power in the name of liberty as independence.

This chapter describes the theory of self-enrichment for closed multicategories, and of standard enrichment for multifunctors between closed multicategories. The self-enrichment of the multicategory of permutative categories, from Chapter 8, is a special case. Compositionality of standard enrichment is discussed in Section 9.3, and applied to the factorization of Elmendorf–Mandell K-theory in Section 9.4.

INTRODUCTION. When and why did it come about that one prevailing way of understanding what it means to be free was replaced by a strongly contrasting account that came to be no less widely accepted, and still remains dominant? The argument of the book is that, in Anglophone political theory, the change happened quite suddenly in the closing decades of the eighteenth century. Before that time it was generally agreed that what it means to be free is that you are not subject to, or dependent on, the arbitrary will and power of anyone else. Liberty was equated with independence. But by the early nineteenth century it had come to be generally accepted that liberty simply consists in not being restrained from acting as you choose. What prompted the change, the book argues, was not the imperatives of commercial society, as has often been argued. Rather it was a growing anxiety, in the face of the American and French Revolutions, about the democratic potential of the ideal of liberty as independence.

The role of international diplomat developed for first ladies post–World War II. Although Edith Wilson and Eleanor Roosevelt set precedents, Jacqueline Kennedy solidified protocols for diplomatic behavior during the Cold War. First ladies use soft diplomacy as a counterbalance to military policy to advance civil society and democracy. This chapter examines travel as state diplomacy, skill in interpersonal relationship building, fashion and cultural diplomacy, and issue-based negotiation. Analysis includes Pat Nixon’s humanitarian travel and support of détente with China, Rosalynn Carter as surrogate president in Latin America and encourager of Middle East peace, Nancy Reagan as promoter of US–Soviet relations to end the Cold War, Hillary Clinton as a champion of women’s rights as human rights, Laura Bush’s support for Afghan women and girls, and Michelle Obama’s international efforts to promote girls’ education. These exemplary women indicate the power of first ladies to advance progress in education, health, foreign policy, and human rights.

The exact mechanisms underlying dysfunction of the basal ganglia that lead to Parkinson’s disease (PD) remain unclear. According to the standard model of PD, motor symptoms result from abnormal neuronal activity in dysfunctional basal ganglia, which can be recorded in human basal ganglia structures as functional neurosurgery for PD provides a unique opportunity to record from these regions. Microelectrode and local field potential recordings studies show alterations exist in basal ganglia nuclei as well as in the motor thalamus. Lesioning or stimulation of the basal ganglia results in significant improvement of PD symptoms, supporting the view that basal ganglia–thalamocortical circuits abnormality is important in parkinsonism generation. Different patterns of oscillatory neuronal activity plus changes in firing rate are associated with different parkinsonian motor subtypes. We present recordings of basal ganglia activity obtained with microelectrode recordings in parkinsonian patients, providing pathophysiology insight.

Martha Washington set countless precedents as first lady—including the use of enslaved labor in the Washingtons’ presidential household. One-third of America’s first ladies were born or married into slave–owning families, making it an important but often overlooked part of their identities and actions in the White House and beyond. The relationship between first ladies and race goes far beyond the subject of slavery. Throughout history, these women have used their platform to bring attention to issues affecting Americans, champion causes, and encourage the president to act. As unelected participants in an administration, first ladies have sometimes been able to pursue civil rights with more freedom and flexibility than their spouses, speaking out against lynching, segregation, and other concerns facing the Black community. This chapter will explore the complex role of first ladies in the fight for equal rights using case studies from the nineteenth and twentieth centuries.

This chapter provides an overview of legal drug-induced (neuroleptic and non-neuroleptic) movement disorders. Awareness of medications causing involuntary movements is critical to determine the appropriate treatment strategy. Certain movement disorders that are not typically associated with a central nervous system lesion (e.g., akathisia, tics, etc.) often do not require extensive testing beyond obtaining a thorough history and a neurologic exam, but other abnormal movements (e.g., ataxia, myoclonus, etc.) that are often caused by structural lesions may require neuroimaging for exclusion of an alternate etiology. In this chapter, we include all commonly used legal (marketed) drugs that have been implicated to induce movement disorders; nevertheless, due to the countless case reports, as well as the growing, endless list of such medications, our survey undoubtedly falls short on some compounds. The illegal parkinsonism-inducing drugs (street drugs) are discussed in Chapter 35.