We propose for the first time to divide histone proteolysis into “histone degradation” and the epigenetically connoted “histone clipping”. Our initial observation is that these two different classes are very hard to distinguish both experimentally and biologically, because they can both be mediated by the same enzymes. Since the first report decades ago, proteolysis has been found in a broad spectrum of eukaryotic organisms. However, the authors often not clearly distinguish or determine whether degradation or (...) class='Hi'>clipping was studied. Given the importance of histone modifications in epigenetic regulation we further elaborate on the different ways in which histone proteolysis could play a role in epigenetics. Finally, unanticipated histone proteolysis has probably left a mark on many studies of histones in the past. In conclusion, we emphasize the significance of reviving the study of histone proteolysis both from a biological and an experimental perspective.Also watch the Video Abstract. (shrink)

Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system (...) that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. (shrink)

Expression of sexually dimorphic behaviors critical for reproduction depends on the organizational actions of steroid hormones on the developing brain. We offer the new hypothesis that transcriptional activities in brain regions executing these sexually dimorphic behaviors are modulated by estrogen‐induced modifications of histone proteins. Specifically, in preoptic nerve cells responsible for facilitating male sexual behavior in rodents, gene expression is fostered by increased histone acetylation and reduced methylation (Me), and, that the opposite set of histone modifications will (...) be found in females. Conversely, in ventromedial hypothalamic neurons that are responsible for coordinating female sexual behavior, transcriptional activities in genetic females are fostered by increased histone acetylation and reduced Me, and, further, that the opposite set of histone modifications will be found in males. Thus, these epigenetic events will guarantee that effects of sex hormone exposure during the neonatal critical period will be translated into lasting sex differences in adult reproductive behaviors. (shrink)

Histone acetylation is an important regulatory mechanism that controls transcription and diverse nuclear processes. While great progress has been made in understanding how localized acetylation and deacetylation control promoter activity, virtually nothing is known about the consequences of acetylation throughout entire chromosomal regions. An increasing number of genes have been found to reside in large chromatin domains that are controlled by regulatory elements many kilobases away. Recent studies have shown that broad histone acetylation patterns are hallmarks of chromatin (...) domains. The purpose of this review is to discuss how such patterns are established and their implications for regulating gene expression. BioEssays 23:820–830, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Histone variants are specialized histones which replace their canonical counterparts in specific nucleosomes. Together with histone post‐translational modifications and DNA methylation, they contribute to the epigenome. Histone variants are incorporated at specific locations by the concerted action of histone chaperones and ATP‐dependent chromatin remodelers. Recent studies have shown that the histone chaperone FACT plays key roles in preventing pervasive incorporation of two histone variants: H2A.Z and CenH3/CENP‐A. In addition, Spt6, another histone chaperone, was (...) also shown to be important for appropriate H2A.Z localization. FACT and Spt6 are both associated with elongating RNA polymerase II. Based on these two examples, we propose that the establishment and maintenance of histone variant genomic distributions depend on a transcription‐coupled epigenome editing (or surveillance) function of histone chaperones. (shrink)

The model of DNA-histones has the following elements: The hydrogen bonds between the complementary nucleotide bases function as informational gates. When the electrons π of one nucleotide base are excited, an exchange of protons is produced between the two complementary bases. The result is the displacement of the conjugated double bonds which facilitates the inter-molecular transmission of the electronic wave of excitation by electro-magnetic coupling. Each triplet of nucleotide bases of DNA fixes one definite amino acid . Between the nucleotide (...) bases and the amino acids there are constituted informational gates, which ensure the circulation of the electronic wave of excitation. An input signal molecule arrives at the receiver gene and unleashes the activity of the enzymes which introduce in the DNA-histones system the electronic wave of excitation. The electronic wave of excitation arises as a result of the break of the high-energy bonds of ATP. Then, the electronic excitation is transmitted to the productor gene where it represents the signal for starting the synthesis of the mRNA.Le modèle de système ADN-Histone a les éléments suivants: Les liaisons d'hydrogène entre les bases nucléotidiques complémentaires fonctionnent comme des portes informationnelles. Quand les électrons π d'une base nucléotidique sont excités, il se produit un échange de protons entre les bases complémentaires. Le résultat est un déplacement des doubles liaisons conjugées qui facilite la transmission de l'onde d'excitation électronique par un couplage électromagnétique. Chaque triplet de bases nucléotidiques de l'ADN fixe un certain amino-acide . Entre les bases nucléodiques et les amino-acides se constituent des portes informationnelles qui assurent la circulation de l'onde d'excitation dlectronique. Une molécule signal d'entrée arrive au gène récepteur et déclenche l'activité des enzymes qui introduisent dans le système ADN-histone l'excitation électronique. L'excitation électronique apparait comme résultat de la rupture des liaisons de haute énergie del' ATP. l'Onde d'excitation électronique est transmise au gène producteur, où elle rdprésente le signal pour faire commencer la synthèse de l'ARNm.Das Modell des DNS-Histonen Systems weist folgende Elemente auf: Die Wasserstoffbindungen zwischen den komplementäaren Nukleotidbasen funktionieren wie informationale Pforten. Wenn die π Elektronen einer Nukleotidbase erregt werden, ensteht ein Protonenwechsel zwischen den Komplementären Basen. Das Ergebnis ist eine Verschiebung der konjugierten Doppelbindungen, die die Weiterleitung der elektronischen Erregungswelle durch eine elektromagnetische Kupplung erleichtert. Jedes Nukleotidbasentriplett der DNS fixiert eine bestimmte Aminosäure . Zwischen den Nukelotidbasen und den Aminosäuren entstehen Informationspforten, welche den Umlauf der elektronischen Erregungswelle sichern. Ein Eintrittsignal Moleküul gelangt zur Rezeptorgen und löst die Aktivität von Enzymen aus, welche die elektronische Erregungswelle in das DNS-Histonen System einführen werden. Die elektronische Erregungswelle erscheint als Ergebnis der Spaltung der hochenergetischen Bindungen des ATP-s. Die elektronische Erregungswelle wird alsdann zur Produktorgen weitergeleitet, wo sie das Signal zum Beginn der Synthese der mRNS darstellt. (shrink)

The European Union ambassadors revenue are lost to fraud and crime,” the of the Council of Minister, Mr. in BiH follow very closely develrelease read. Papandreou, and Mr. Solana, urged the opments as regards the issue of “We also have in mind the positive effect authorities of BiH recently to reach a the adoption, at a state level of single..

The haploid male germ cell differentiation program controls essential steps of male gametogenesis and relies partly on a significant number of sex chromosome‐linked genes. These genes need to escape chromosome‐wide transcriptional repression of sex chromosomes, which occurs during meiosis and is largely maintained in post‐meiotic cells. A newly discovered histone lysine modification, crotonylation (Kcr), marks X/Y‐linked genes that are active in post‐meiotic male germ cells. Histone Kcr, by conferring resistance to transcriptional repressors, could be a dominant element in (...) maintaining these genes active in the globally repressive environment of haploid cell sex chromosomes. Furthermore, the same mark was found associated with post‐meiotically activated genes on autosomes. Histone Kcr therefore appears to be an indicator of the male haploid cell gene expression program and a notable element of genome programming in the post‐meiotic phases of spermatogenesis. (shrink)

The mammalian egg employs a wide spectrum of epigenome modification machinery to reprogram the sperm nucleus shortly after fertilization. This event is required for transcriptional activation of the paternal/zygotic genome and progression through cleavage divisions. Reprogramming of paternal nuclei requires replacement of sperm protamines with canonical and non‐canonical histones, covalent modification of histone tails, and chemical modification of DNA (notably oxidative demethylation of methylated cytosines). In this essay we highlight the role maternal histone variants play during developmental reprogramming (...) following fertilization. We discuss how reduced maternal histone variant incorporation in somatic nuclear transfer experiments may explain the reduced viability of resulting embryos and how knowledge of repressive and activating maternal factors may be used to improve somatic cell reprogramming. (shrink)

Histones occur in equal amounts to DNA in the cell nucleus and are largely responsible for the compaction of the genome into chromatin via the formation of nucleosomes and higher‐order structures. Whereas two of the five histone types exhibit little structural variation, the remaining three occur in many variant tissue‐ or species‐specific forms. Multiple postsynthetic enzymatic modifications accompanying virtually any type of genome activity, together with the programmed appearance of many histone variants during sea urchin embryogenesis (and other (...) differentiation events in a number of organisms) make histones a challenging enigma in eukaryotic molecular biology. (shrink)

Histone acetylation has been recognized as an important post‐translational modification of core nucleosomal histones that changes access to the chromatin to allow gene transcription, DNA replication, and repair. Histone acetyltransferases were initially identified as co‐activators that link DNA‐binding transcription factors to the general transcriptional machinery. Over the years, more chromatin‐binding modes have been discovered suggesting direct interaction of histone acetyltransferases and their protein complex partners with histone proteins. While much progress has been made in characterizing (...) class='Hi'>histone acetyltransferase complexes biochemically, cell‐free activity assay results are often at odds with in‐cell histone acetyltransferase activities. In‐cell studies suggest specific histone lysine targets, but broad recruitment modes, apparently not relying on specific DNA sequences, but on chromatin of a specific functional state. Here we review the evidence for general versus specific roles of individual nuclear lysine acetyltransferases in light of in vivo and in vitro data in the mammalian system. (shrink)

During the eukaryotic cell cycle, chromosomes undergo large structural transitions and spatial rearrangements that are associated with the major cell functions of genome replication, transcription and chromosome condensation to metaphase chromosomes. Eukaryotic cells have evolved cell cycle dependent processes that modulate histone:DNA interactions in chromosomes. These are; (i) acetylations of lysines; (ii) phosphorylations of serines and threonines and (iii) ubiquitinations of lysines. All of these reversible modifications are contained in the well‐defined very basic N‐ and C‐ terminal domains of (...) histones. Acetylations and phosphorylations markedly affect the charge densities of these domains whereas ubiquitination adds a bulky globular protein, ubiquitin, to lysines in the C‐terminal tails of H2A and H2B. Histone acetylations are strictly associated with genome replication and transcription; histone H1 and H3 phosphorylations correlate with the process of chromosome condensation. The subunits of histone H1 kinase have now been shown to be cyclins and the p34CDC2 kinase product of the cell cycle control gene CDC2. It is probable that all of the processes that control chromosome structure:function relationships are also involved in the control of the cell cycle. (shrink)

Immunofluorescent labelling demonstrates that human metaphase chromosomes contain hyperacetylated histone H4. With the exception of the inactive X chromosome in female cells, where the bulk of histone H4 is under‐acetylated, H4 hyperacetylation is non‐uniformly distributed along the chromosomes and clustered in cytologically resolvable chromatin domains that correspond, in general, with the R‐bands of conventional staining. The strongest immunolabelling is often found in T‐bands, the subset of intense R‐bands having the highest GC content. The majority of mapped genes also (...) occurs in R‐band regions, with the highest gene density in T‐bands. These observations are consistent with a model in which hyperacetylation of histone H4 marks the position of potentially active gene sequences on metaphase chromosomes. Since acetylation is maintained during mitosis, progeny cells receive an imprint of the histone H4 acetylation pattern that was present on the parental chromosomes before cell division. Histone acetylation could provide a mechanism for propagating cell memory, defined as the maintenance of committed states of gene expression through cell lineages. (shrink)

The N‐terminal domain of histone H4 has been implicated in various nuclear functions, including gene silencing and activation and replication‐linked chromatin assembly. Many of these have been identified by using H4 mutants in the yeast S. cerevisiae. In a recent paper, Megee et al.(1) use this approach to show that mutants in which all four N‐terminal H4 lysines are substituted with glutamines accumulate increased levels of DNA damage. A single lysine, but not an arginine, anywhere in the N‐terminal domain (...) suppresses this phenotype. It is suggested that histone H4 plays a role in maintaining genome integrity through the cell cycle, possibly by a mechanism involving lysine acetylation. (shrink)

In a note introduced into the second edition of Religion within the Boundaries of Mere Reason (1794), Kant assigns a systematic role to the General Remarks at the end of each Part of his book. He calls those Remarks, “as it were, parerga to religion within the boundaries of pure reason; they do not belong within it yet border on it” (RGV 6:52). As Kant sees them, the parerga are only a “secondary occupation” that consists in removing transcendent obstacles. This (...) paper is skeptical of Kant's view. It proposes an alternative account, according to which the parerga are essential to our moral education, since they force human reason to confront its own limitations and resist the urge to take refuge in spurious religious beliefs. That urge, I argue, is linked to the propensity to evil, and uses religious orthodoxy to undermine moral religion. By clipping our dogmatic wings, the parerga encourage reason to face its own dialectical tendencies and direct its speculative interest to immanent practical use. This redirection counteracts the debilitating effects of the propensity to evil and plays a key role in our moral regeneration. To consider the parerga “derivative,” as Kant himself does, is therefore a grave mistake. (shrink)

In a note introduced into the second edition of Religion within the Boundaries of Mere Reason (1794), Kant assigns a systematic role to the General Remarks at the end of each Part of his book. He calls those Remarks, “as it were, parerga to religion within the boundaries of pure reason; they do not belong within it yet border on it” (RGV 6:52). As Kant sees them, the parerga are only a “secondary occupation” that consists in removing transcendent obstacles. This (...) paper is skeptical of Kant's view. It proposes an alternative account, according to which the parerga are essential to our moral education, since they force human reason to confront its own limitations and resist the urge to take refuge in spurious religious beliefs. That urge, I argue, is linked to the propensity to evil, and uses religious orthodoxy to undermine moral religion. By clipping our dogmatic wings, the parerga encourage reason to face its own dialectical tendencies and direct its speculative interest to immanent practical use. This redirection counteracts the debilitating effects of the propensity to evil and plays a key role in our moral regeneration. To consider the parerga “derivative,” as Kant himself does, is therefore a grave mistake. (shrink)

Post-translational histone modifications and their biological effects have been described as a ‘histone code’. Independently, Barbieri used the term ‘organic code’ to describe biological codes in addition to the genetic code. He also provided the defining criteria for an organic code, but to date the histone code has not been tested against these criteria. This paper therefore investigates whether the histone code is a bona fide organic code. After introducing the use of the term ‘code’ in (...) biology, the criteria a putative organic code such as the histone code must conform to in order to be recognised as an organic code are described. Our current knowledge of histones and their major post-translational modifications, and the specific protein binding domains that recognise and translate these into specific biological effects, is then reviewed in detail. The histone modification system is then placed in the context of an organic code and it is concluded that it fulfils all the requirements of an organic code. The marks produced on histones by processes such as acetylation and methylation act as organic signs that are translated into unique biological effects, their biological meanings. These translations are accomplished by effector proteins that consist of a binding domain that recognises a specific histone mark and a regulatory domain that mediates the biological effect. Crucially, these domains can be experimentally interchanged between different effector proteins, thus altering the rules that specify the relationships between sign and meaning. The effector proteins therefore fulfil the role of adaptor molecules. (shrink)

Polycomb group proteins are evolutionary conserved chromatin‐modifying complexes, essential for the regulation of developmental and cell‐identity genes. Polycomb‐mediated transcriptional regulation is provided by two multi‐protein complexes known as Polycomb repressive complex 1 (PRC1) and 2 (PRC2). Recent studies positioned PRC1 as a foremost executer of Polycomb‐mediated transcriptional control. Mammalian PRC1 complexes can form multiple sub‐complexes that vary in their core and accessory subunit composition, leading to fascinating and diverse transcriptional regulatory mechanisms employed by PRC1 complexes. These mechanisms include PRC1‐catalytic activity (...) toward monoubiquitination of histone H2AK119, a well‐established hallmark of PRC1 complexes, whose importance has been long debated. In this review, the central roles that PRC1‐catalytic activity plays in transcriptional repression are emphasized and the recent evidence supporting a role for PRC1 complexes in gene activation is discussed. (shrink)

Article CLiPs (Cognitive Linguistics in Publications) Survey of collective volumes, monographs, MA, doctoral and post-doctoral theses, articles, papers and book reviews A selected and annotated bibliography of recent publications with a cognitive perspective was published on January 1, 1993 in the journal Cognitive Linguistics (volume 4, issue 1).

Article CLIPS (Cognitive Linguistics in Publications) Survey of collective volumes, monographs, MA, doctoral and post-doctoral theses, articles, papers and book reviews. A selected and annotated bibliography of recent publications with a cognitive perspective was published on January 1, 1991 in the journal Cognitive Linguistics (volume 2, issue 4).

Knockout experiments in Tetrahymena show that linker histone H1 is not essential for nuclear assembly or cell viability. These results, together with a series of biochemical and cell biological observations, challenge the existing paradigm that requires linker histones to be a key organizing component of higher‐order chromatin structure. The H1 Knockouts also reveal a much more subtle role for H1. Instead of acting as a general transcriptional repressor, H1 is found to regulate a limited number of specific genes. Surprisingly, (...) H1 can both activate and repress transcription. We discuss how this architectural protein might accomplish this important regulatory role. (shrink)

Histone post-translational modifications play important roles in transcriptional regulation. It is known that multiple histone modifications can act in a combinatorial manner. In this study, we investigated the effects of multiple histone modifications on expression levels of five gene categories in coding regions. The combinatorial patterns of modifications for the five gene categories were also studied in the regions. Our results indicated that the differences in the expression levels between any two gene categories were significant. There were (...) some corresponding differences in multiple histone modification levels among the five gene categories. Multiple histone modifications jointly impacted expression levels of every gene category. Four mutual combinations of histone modifications were found and analyzed. (shrink)

Acetylation of histones is an essential element regulating chromatin structure and transcription. MYST (Moz, Ybf2/Sas3, Sas2, Tip60) proteins form the largest family of histone acetyltransferases and are present in all eukaryotes. Surprisingly, until recently this protein family was poorly studied. However, in the last few years there has been a substantial increase in interest in the MYST proteins and a number of key studies have shown that these chromatin modifiers are required for a diverse range of cellular processes, both (...) in health and disease. Translocations affecting MYST histone acetyltransferases can lead to leukemia and solid tumors. Some members of the MYST family are required for the development and self‐renewal of stem cell populations; other members are essential for the prevention of inappropriate heterochromatin spreading and for the maintenance of adequate levels of gene expression. In this review we discuss the function of MYST proteins in vivo. (shrink)

Several metabolites serve as substrates for histone modifications and communicate changes in the metabolic environment to the epigenome. Technologies such as metabolomics and proteomics have allowed us to reconstruct the interactions between metabolic pathways and histones. These technologies have shed light on how nutrient availability can have a dramatic effect on various histone modifications. This metabolism–epigenome cross talk plays a fundamental role in development, immune function, and diseases like cancer. Yet, major challenges remain in understanding the interactions between (...) cellular metabolism and the epigenome. How the levels and fluxes of various metabolites impact epigenetic marks is still unclear. Discussed herein are recent applications and the potential of systems biology methods such as flux tracing and metabolic modeling to address these challenges and to uncover new metabolic–epigenetic interactions. These systems approaches can ultimately help elucidate how nutrients shape the epigenome of microbes and mammalian cells. (shrink)

Transcriptional repression and silencing have been strongly associated with hypoacetylation of histones. Accordingly, histone deacetylases, which remove acetyl groups from histones, have been shown to participate in mechanisms of transcriptional repression. Therefore, current models of the role of acetylation in transcriptional regulation focus on the acetylation status of histones and designate histone acetyltransferases, which add acetyl groups to histones, as transcriptional coactivators and histone deacetylases as corepressors. In recent years, an accumulation of studies have shown that these (...) enzymes also target non‐histone proteins and that histone deacetylases have clear roles as coactivators at a variety of genes, some of which are key regulators of cell growth and survival. This review summarizes the evidence for histone deacetylases as coactivators and provides models of coactivation mechanisms, some of which integrate roles of acetylated histones and non‐histone proteins in transcription. BioEssays 30:15–24, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with transcriptional activation in eukaryotes for more than three decades. Recent discoveries showing that several transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and deacetylase (HDAC) activities strongly suggest that histone acetylation and deacetylation each plays a causative role in regulating transcription. Intriguingly, several HATs have been shown an ability to acetylate nonhistone protein substrates (e.g., transcription factors) in vitro as well, suggesting the (...) possibility that internal lysine acetylation of multiple proteins exists as a rapid and reversible regulatory mechanism much like protein phosphorylation. This article reviews recent developments in histone acetylation and transcriptional regulation. We also discuss several important, yet unanswered, questions. BioEssays 20:615–626, 1998. © 1998 John Wiley & Sons Inc. (shrink)

This essay examines the results of my attempt to use humorous video clips in a course taught in the Fall of 2010 and 2011. The regular display of these clips was designed to enhance my students' understanding of the central concepts of the course, participation in class discussions and to encourage them to think more critically and creatively. The results of a survey I administered at the end of the semester suggest that there is a positive correlation between the use (...) of the humorous clips and my students' understanding of the content, engagement in the lessons and ability to think critically. Both the quantitative and qualitative results of the survey as well as other methods of data collection indicate that watching and analyzing the humorous clips provided the students with a very valuable perspective that illuminated the ideas that we read. The results of this study also suggest that a course on the philosophy of humor and laughter can be very effective in getting students to think philosophically and appreciate the value of philosophy for their lives. (shrink)

Although the great majority of genes are not subject to cell‐cycle controls, those that are could play a very important role in regulation of the cell cycle itself. The tubulin and histone genes of the naturally synchronous myxomycete, Physarum polycephalum, provide an excellent paradigm for such regulation. The transcription of both is highly periodic within the Physarum cycle, and curiously, both sets of genes appear to be activated at the same time. This activation appears to function as part of (...) a developmental program, since it serves to meet future needs for each gene's product. The significance of this activation event for cell‐cycle regulation is discussed with particular regard to the nature of the mitotic oscillator. (shrink)

There is now a wealth of information that histone proteins play a primary role in the structural and transcriptional properties of chromatin, the protein‐DNA complex which constitutes the eukaryotic genome1, 2. In light of the crucial role of histones in cellular function, it is not surprising that their structural genes are found to be controlled in conjunction with the cell cycle, with the synthesis of most histones tightly coupled to nuclear DNA replication. The evidence suggests that this linkage between (...) DNA replication and histone synthesis involves the regulated adjustment of histone mRNA levels through both transcriptional and posttranscriptional control process. The possible mechanisms underlying these diverse control processes are described here. (shrink)

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory suppressing (...) replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development. (shrink)

Williams Syndrome is a developmental disorder that is characterized by cardiovascular problems, particular facial features and several typical behavioral and neurological abnormalities. In Williams Syndrome patients, a heterozygous deletion is present of a region on chromosome 7q11.23 (the Williams Syndrome critical region), which spans approximately 20 genes. Two of these genes encode proteins that regulate dynamic aspects of the cytoskeleton of the cell, either via the actin filament system (LIM kinase 1, or LIMK1), or through the microtubule network (cytoplasmic linker (...) protein of 115 kDa, or CLIP‐115). The recent findings that knockout mice lacking LIMK1 or CLIP‐115 have distinct neurological and behavioural phenotypes, indicates that cytoskeletal defects might play a role in the development of neurological symptoms in Williams Syndrome patients. In this review, we discuss the properties of LIMK and CLIP family proteins, their function in the regulation of the actin and microtubule cytoskeletal systems, respectively, and the relationship with neurodevelopmental aspects of Williams Syndrome. BioEssays 26:141–150, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Histone modifications play a critical role in the control over activities of the eukaryotic genome; among these chemical alterations, the methylation of lysine K9 in histone H3 (H3K9) is one of the most extensively studied. The number of enzymes capable of methylating H3K9 varies greatly across different organisms: in fission yeast, only one such methyltransferase is present, whereas in mammals, 10 are known. If there are several such enzymes, each of them must have some specific function, and they (...) can interact with one another. Thus arises a complex system of interchangeability, “division of labor,” and contacts with each other and with diverse proteins. Histone methyltransferases specialize in the number of methyl groups that they attach and have different intracellular localizations as well as different distributions on chromosomes. Each also shows distinct binding to different types of sequences and has a specific set of nonhistone substrates. (shrink)

Those accustomed to viewing John Locke as the benign forefather of American Liberalism will be shocked by this book, for Locke was neither benign nor liberal nor even tolerant when it came to serious things in life like money, economic policy, and the Bank of England. In this careful and exhaustive study of Locke's philosophy of money, Caffentzis details the ways in which Locke sought to replace the concept of God, State, Law, and other ultimates with a much more empirically (...) reliable "substance"--money. Locke, it seems, was quite willing to allow any amount of exotica to pass for religion, but his tolerance gave out when it came to the coin of realm. (shrink)

The chromatin‐regulatory principles of histone post‐translational modifications (PTMs) are discussed with a focus on the potential alterations in chromatin functional state due to steric and mechanical constraints imposed by bulky histone modifications such as ubiquitin and SUMO. In the classical view, PTMs operate as recruitment platforms for histone “readers,” and as determinants of chromatin array compaction. Alterations of histone charges by “small” chemical modifications (e.g., acetylation, phosphorylation) could regulate nucleosome spontaneous dynamics without globally affecting nucleosome structure. (...) These fluctuations in nucleosome wrapping can be exploited by chromatin‐processing machinery. In contrast, ubiquitin and SUMO are comparable in size to histones, and it seems logical that these PTMs could conflict with canonical nucleosome organization. An experimentally testable hypothesis that by adding sterical bulk these PTMs can robustly alter nucleosome primary structure is proposed. The model presented here stresses the diversity of mechanisms by which histone PTMs regulate chromatin dynamics, primary structure and, hence, functionality. (shrink)

Ascorbic acid is a redox regulator in many physiological processes. Besides its antioxidant activity, many intriguing functions of ascorbic acid in the expression of immunoregulatory genes have been suggested. Ascorbic acid acts as a co‐factor for the Fe+2‐containing α‐ketoglutarate‐dependent Jumonji‐C domain‐containing histone demethylases (JHDM) and Ten eleven translocation (TET) methylcytosine dioxygenasemediated epigenetic modulation. By influencing JHDM and TET, ascorbic acid facilitates the differentiation of double negative (CD4−CD8−) T cells to double positive (CD4+CD8+) T cells and of T‐helper cells to (...) different effector subsets. Ascorbic acid modulates plasma cell differentiation and promotes early differentiation of hematopoietic stem cells (HSCs) to NK cells. These findings indicate that ascorbic acid plays a significant role in regulating both innate and adaptive immune cells, opening up new research areas in Immunonutrition. Being a water‐soluble vitamin and a safe micro‐nutrient, ascorbic acid can be used as an adjunct therapy for many disorders of the immune system. (shrink)

For more than eleven years, I worked with Dan Callahan as an editor, a liaison with journalists, and a sounding board for ideas. To Dan, every new writing project was a thrill, whether it was for the New Republic or a blog. He consumed a wide range of professional and scholarly literature, followed the news with the eye of a reporter, and called experts when he wanted to learn more about something he had read. The result was a volcanic bubbling (...) of story ideas. If he didn't turn them into articles or books, I sometimes had the feeling that he might burst. (shrink)