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Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

This article analyses the use of the example markers for example and for instance in exemplifying, selective and argumentative constructions. Of these three uses, exemplification—twofold sequences with a first general unit or hyperonym and a second more specific item or hyponym—has received recurrent attention in the literature, whereas selection—constructions where the first element is omitted—and argumentation—the use of example markers to connect whole chunks of discourse—have long been ignored. The present study, using data from ARCHER 3.2, shows that the three uses have coexisted since at least the second half of the seventeenth century and that argumentation prevails in both British and American English. Moreover, example markers are very productive in certain genres, such as science, sermons and advertising. Additionally, even though the primary function of example markers is to introduce their scope domain, they have developed different pragmatic values that bring them closer to the category of discourse markers. Thus, for example, their use as mitigators makes them an optimal tool for smoothing interaction and hence reducing the risk of offending our interlocutor. Este artículo analiza el uso de los marcadores for example y for instance en construcciones ejemplificativas, selectivas y argumentativas. De estos tres usos, la ejemplificación—a saber, estructuras con una primera unidad más genérica o hiperónimo y un segundo elemento más específico o hipónimo—ha recibido una atención recurrente en la literatura, mientras que la selección—construcciones donde se omite el primer elemento genérico—y la argumentación—el uso de marcadores para conectar fragmentos completos de discurso—han sido ignoradas durante mucho tiempo. Este estudio, basado en datos de ARCHER 3.2, muestra que los tres usos coexisten desde al menos la segunda mitad del siglo diecisiete y que la argumentación prevalece tanto en inglés británico como americano. Además, estos marcadores son muy productivos en ciertos géneros, como la ciencia, los sermones y la publicidad. Por otro lado, aunque la función principal de for example y for instance es introducir ejemplos, ambos han desarrollado diferentes valores pragmáticos que los acercan a la categoría de marcadores del discurso. Así, por ejemplo, su uso como mitigadores los convierte en una herramienta óptima para suavizar la interacción y, por tanto, reducir el riesgo de ofender a nuestro interlocutor.

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

The fictional Dr. Strabismus sets out to write a new comprehensive theory of music. But music's tendency to deconstruct itself combined with the complexities of postmodernism doom him to failure. This is the parable that framesThe Sense of Music,a novel treatment of music theory that reinterprets the modern history of Western music in the terms of semiotics. Based on the assumption that music cannot be described without reference to its meaning, Raymond Monelle proposes that works of the Western classical tradition be analyzed in terms of temporality, subjectivity, and topic theory. Critical of the abstract analysis of musical scores, Monelle argues that the score does not reveal music'ssense.That sense--what a piece of music says and signifies--can be understood only with reference to history, culture, and the other arts. Thus, music is meaningful in that it signifies cultural temporalities and themes, from the traditional manly heroism of the hunt to military power to postmodern \"polyvocality.\" This theoretical innovation allows Monelle to describe how the Classical style of the eighteenth century--which he reads as a balance of lyric and progressive time--gave way to the Romantic need for emotional realism. He argues that irony and ambiguity subsequently eroded the domination of personal emotion in Western music as well as literature, killing the composer's subjectivity with that of the author. This leaves Dr. Strabismus suffering from the postmodern condition, and Raymond Monelle with an exciting, controversial new approach to understanding music and its history.

Derived from the colorful traditions of vaudeville, burlesque, revue, and operetta, the musical has blossomed into America's most popular form of theater. Scott McMillin has developed a fresh aesthetic theory of this underrated art form, exploring the musical as a type of drama deserving the kind of critical and theoretical regard given to Chekhov or opera. Until recently, the musical has been considered either an \"integrated\" form of theater or an inferior sibling of opera. McMillin demonstrates that neither of these views is accurate, and that the musical holds true to the disjunctive and irreverent forms of popular entertainment from which it arose a century ago. Critics and composers have long held the musical to the standards applied to opera, asserting that each piece should work together to create a seamless drama. But McMillin argues that the musical is a different form of theater, requiring the suspension of the plot for song. The musical's success lies not in the smoothness of unity, but in the crackle of difference. While disparate, the dancing, music, dialogue, and songs combine to explore different aspects of the action and the characters. Discussing composers and writers such as Rodgers and Hammerstein, Stephen Sondheim, Kander and Ebb, Leonard Bernstein, and Jerome Kern,The Musical as Dramadescribes the continuity of this distinctively American dramatic genre, from the shows of the 1920s and 1930s to the musicals of today.

This paper demonstrates the value of analyzing sequences of function calls for forensic analysis. Although this approach has been used for intrusion detection (that is, determining that a system has been attacked), its value in isolating the cause and effects of the attack has not previously been shown. We also look for not only the presence of unexpected events but also the absence of expected events. We tested these techniques using reconstructed exploits in su, ssh, and lpr, as well as proof-of-concept code, and, in all cases, were able to detect the anomaly and the nature of the vulnerability.

It has long been argued that opera is all about sex.Siren Songsis the first collection of articles devoted to exploring the impact of this sexual obsession, and of the power relations that come with it, on the music, words, and staging of opera. Here a distinguished and diverse group of musicologists, literary critics, and feminist scholars address a wide range of fascinating topics--from Salome's striptease to hysteria to jazz and gender--in Italian, English, German, and French operas from the eighteenth to the twentieth centuries. The authors combine readings of specific scenes with efforts to situate these musical moments within richly and precisely observed historical contexts. Challenging both formalist categories of musical analysis and the rhetoric that traditionally pits a male composer against the female characters he creates, many of the articles work toward inventing a language for the study of gender and opera. The collection opens with Mary Ann Smart's introduction, which provides an engaging reflection on the state of gender topics in operatic criticism and musicology. It then moves on to a foundational essay on the complex relationships between opera and history by the renowned philosopher and novelist Catherine Clément, a pioneer of feminist opera criticism. Other articles examine the evolution of the \"trouser role\" as it evolved in the lesbian subculture offin-de-siècleParis, the phenomenon ofopera seria's\"absent mother\" as a manifestation of attitudes to the family under absolutism, the invention of a \"hystericized voice\" in Verdi'sDon Carlos,and a collaborative discussion of the staging problems posed by the gender politics of Mozart's operas. The contributors are Wye Jamison Allanboork, Joseph Auner, Katherine Bergeron, Philip Brett, Peter Brooks, Catherine Clement, Martha Feldman, Heather Hadlock, Mary Hunter, Linda Hutcheon and Michael Hutcheon, M.D., Lawrence Kramer, Roger Parker, Mary Ann Smart, and Gretchen Wheelock.

Before the nineteenth century, instrumental music was considered inferior to vocal music. Kant described wordless music as \"more pleasure than culture,\" and Rousseau dismissed it for its inability to convey concepts. But by the early 1800s, a dramatic shift was under way. Purely instrumental music was now being hailed as a means to knowledge and embraced precisely because of its independence from the limits of language. What had once been perceived as entertainment was heard increasingly as a vehicle of thought. Listening had become a way of knowing. Music as Thought traces the roots of this fundamental shift in attitudes toward listening in the late eighteenth and early nineteenth centuries. Focusing on responses to the symphony in the age of Beethoven, Mark Evan Bonds draws on contemporary accounts and a range of sources--philosophical, literary, political, and musical--to reveal how this music was experienced by those who heard it first.

The book description for \"Chronology of the Works of Guillaume Dufay\" is currently unavailable.

Music, and folk music in particular, is often embraced as a form of political expression, a vehicle for bridging or reinforcing social boundaries, and a valuable tool for movements reconfiguring the social landscape. Reds, Whites, and Blues examines the political force of folk music, not through the meaning of its lyrics, but through the concrete social activities that make up movements. Drawing from rich archival material, William Roy shows that the People's Songs movement of the 1930s and 40s, and the Civil Rights Movement of the 1950s and 60s implemented folk music's social relationships--specifically between those who sang and those who listened--in different ways, achieving different outcomes.