Linking Acetyl-Coa Metabolism and Histone Acetylation to Dynamic Gene Regulation in Yeast and Mouse Hippocampus

A compelling body of evidence suggests an intimate relationship between metabolic state and chromatin regulation. This link is manifested in key metabolites that participate in biochemical pathways as intermediates, and function as cofactors to regulate chromatin modifying enzymes. Of particular interest is the metabolite acetyl-CoA, given its central role as an intermediate of cellular energy metabolism and key determinant of all histone acetylation. How nuclear acetyl-CoA levels are regulated to, in turn, control histone acetylation is under intense investigation, and holds promise for increased understanding of the molecular mechanisms adapting gene expression to internal and external stimuli. We studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient‐induced cell cycle re-entry from quiescence in the yeast S. cerevisiae. ChIP‐seq and SILAC-based mass spec revealed genome‐wide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that histone acetylation, in contrast to methylation, rapidly responds to metabolic state, driving growth gene transcription in nutrient-induced cell cycle re-entry. Next, we set out to investigate how nuclear acetyl-CoA is regulated to control histone acetylation in mammalian cells. We reveal a previously unknown function of the central metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) as a chromatin-bound transcriptional coactivator that stimulates histone acetylation and gene expression. We show that ACSS2 is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. Our data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA, to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These findings reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation

From Admiration to Confrontation: Gunter Grass and the United States

Gunter Grass is. without doubt, the best known representative of postwar and contemporary German literature in the United States. A few random samples culled from reviews of Grass\u27s work in this country may suffice to illustrate this point. In 1964, on occasion of the English translation of Hundejahre (Dog Years), Newsweek wrote: Gunter Grass today is acknowledged as the author who put postwar German literature back in the world market. He is fast becoming a director of much of his country\u27s creative movement, a keeper of old myths and new methods. The Tin Drum, the novel that so far has determined Grass\u27s reception in this country-the voluminous and challenging The Flounder notwithstanding-was even credited with initiating the rebirth of German letters. The recent film version of The Tin Drum contributed to a revival of interest in the novel; in 1982 the novelist John Irving stated: Die Blechtrommel … has not been surpassed, it is the greatest novel by a living author.\u27\u27 Irving continued in his praise of the author of The Tin Drum by claiming that you can\u27t be well-read today if you haven\u27t read him. Gunter Grass is simply the most original and versatile writer alive. Although such lavish critical endorsement is not to be encountered in all quarters, at least one other segment of the reading public, the professional intermediaries of German literature, that is, the professors and teachers of German, seem to agree with Irving. In a literary opinion poll conducted by the Goethe Institute in Boston. Massachusetts, The Tin Drum ranked first among the professors\u27 favorite works of postwar German literature. Curiously, The Flounder attained second place-ahead of such redoubtable works as Thomas Mann\u27s Doctor Faustus, Heinrich Boll\u27s Group Portrait with Lady, and Max Frisch\u27s Homo Faber

The Desire to Achieve Normalcy - Peter Schneider\u27s Post-Wall Berlin Novel Eduard\u27s Homecoming

As one critic correctly observed on the occasion of Peter Schneider\u27s sixtieth birthday (21 April 2000), the author\u27s life and work have been defined by two momentous events whose import far surpasses that of happenings of merely local significance (see Karasek)..

Biblical Themes and Motifs in Brecht\u27s \u3cem\u3eHerr Puntila und sein Knecht Matti\u3c/em\u3e

Sie werden lachen: Die Bibel, Brecht replied on 1 October 1928 when asked by the editors of the fashionable Berlin magazine Die Dame about the strongest influence on his work. This pithy remark, which surely must be counted among the playwright\u27s better-known and often-quoted phrases, is quite literally true. Although the Biblical influence on Brecht\u27s work is all-pervasive—Reinhold Grimm called it Brecht\u27s lebenslange und höchst komplexe Abhängigkeit von der Bibel —as yet no comprehensive study exists which fully explores Brecht\u27s use of the Bible and Christianity. In the absence of such a comprehensive study it is in order to examine individual works in general and dramas in particular to determine the exact nature and function of Biblical influences

Celtic Mews, Menu

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Supporting the Everyday Work of Scientists: Automating Scientific Workflows

This paper describes an action research project that we undertook with National Research Council Canada (NRC) scientists. Based on discussions about their \ud difficulties in using software to collect data and manage processes, we identified three requirements for increasing research productivity: ease of use for end- \ud users; managing scientific workflows; and facilitating software interoperability. Based on these requirements, we developed a software framework, Sweet, to \ud assist in the automation of scientific workflows. \ud \ud Throughout the iterative development process, and through a series of structured interviews, we evaluated how the framework was used in practice, and identified \ud increases in productivity and effectiveness and their causes. While the framework provides resources for writing application wrappers, it was easier to code the applications’ functionality directly into the framework using OSS components. Ease of use for the end-user and flexible and fully parameterized workflow representations were key elements of the framework’s success. \u

Continuous-time state-space modelling of the hot hand in basketball

We investigate the hot hand phenomenon using data on 110,513 free throws taken in the National Basketball Association (NBA). As free throws occur at unevenly spaced time points within a game, we consider a state-space model formulated in continuous time to investigate serial dependence in players' success probabilities. In particular, the underlying state process can be interpreted as a player's (latent) varying form and is modelled using the Ornstein-Uhlenbeck process. Our results support the existence of the hot hand, but the magnitude of the estimated effect is rather small