The eukaryotic nucleosome, the basic unit of chromatin, is thermodynamically stable and plays critical roles in the cell, including the maintenance of DNA topology and regulation of gene expression. At its C2 axis of symmetry, the nucleosome exhibits a domain that can coordinate divalent metal ions. This article discusses the roles of the metal‐binding domain in the nucleosome structure, function, and evolution.

Dicer is a key player in microRNA (miRNA) and RNA interference (RNAi) pathways, processing miRNA precursors and doublestranded RNA into ~21-nt-long products ultimately triggering sequence-dependent gene silencing. Although processing of substrates in vertebrate cells occurs in the cytoplasm, there is growing evidence suggesting Dicer is also present and functional in the nucleus. To address this possibility, we searched for a nuclear localization signal (NLS) in human Dicer and identified its C-terminal double-stranded RNA binding domain (dsRBD) as harboring NLS (...) activity. We show that the dsRBD-NLS can mediate nuclear import of a reporter protein via interaction with importins β, 7, and 8. In the context of full-length Dicer, the dsRBD-NLS is masked. However, duplication of the dsRBD localizes the full-length protein to the nucleus. Furthermore, deletion of the N-terminal helicase domain results in partial accumulation of Dicer in the nucleus upon leptomycin B treatment, indicating that CRM1 contributes to nuclear export of Dicer. Finally, we demonstrate that human Dicer has the ability to shuttle between the nucleus and the cytoplasm. We conclude that Dicer is a shuttling protein whose steady-state localization is cytoplasmic. (shrink)

The BTB domain is a protein–protein interaction motif that is found throughout eukaryotes. It determines a unique tri‐dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB‐containing proteins are numerous and control cellular processes that range from actin dynamics to cell‐cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the high variability of the (...) BTB has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB‐containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein–protein interaction domain. BioEssays 28: 1194–1202, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Metal roof enclosure system is an important part of steel structure construction. In recent years, it has been widely used in large-scale public or industrial buildings such as stadiums, airport terminals, and convention centers. Affected by bad weather, various types of accidents on metal roofs frequently occurred, causing huge property losses and adverse effects. Because of wide span, long service life and hidden fault of metal roof, the manual inspection of metal roof has low efficiency, poor (...) real-time performance, and it is difficult to find hidden faults. On the basis of summarizing the working principle of metal roof and cause of accidents, this paper classifies the fault types of metal roofs in detail and establishes a metal roof monitoring and fault diagnosis system using distributed multisource heterogeneous sensors and Zigbee wireless sensor networks. Monitoring data from strain gauge, laser ranging sensor, and ultrasonic ranging sensor is utilized comprehensively. By extracting time domain feature, the data trend characteristics and correlation characteristics are analyzed and fused to eliminate erroneous data and find superficial faults such as sensor drift and network interruption. Aiming to the hidden faults including plastic deformation and bolt looseness, an SVM fault diagnosis algorithm based on RBF kernel function is designed and applied to diagnose metal roof faults. The experimental results show that the RBF-SVM algorithm can achieve high classification accuracy. (shrink)

Cognitive functions like perception, memory, language, or consciousness are based on highly parallel and distributed information processing by the brain. One of the major unresolved questions is how information can be integrated and how coherent representational states can be established in the distributed neuronal systems subserving these functions. It has been suggested that this so-called ''binding problem'' may be solved in the temporal domain. The hypothesis is that synchronization of neuronal discharges can serve for the integration of distributed (...) neurons into cell assemblies and that this process may underlie the selection of perceptually and behaviorally relevant information. As we intend to show here, this temporal binding hypothesis has implications for the search of the neural correlate of consciousness. We review experimental results, mainly obtained in the visual system, which support the notion of temporal binding. In particular, we discuss recent experiments on the neural mechanisms of binocular rivalry which suggest that appropriate synchronization among cortical neurons may be one of the necessary conditions for the buildup of perceptual states and awareness of sensory stimuli. (shrink)

Cognitive scientists have long known that the modalities interact during perceptual processing. Cross-modal illusions like the ventriloquism effect show that the course of processing in one modality can alter the course of processing in another. But how do the modalities interact in the specific domain of object perception? This paper distinguishes and analyzes two kinds of multisensory interaction in object perception. First, the modalities may bind features to a single object or event. Second, the modalities may cooperate when differentiating (...) an object or event from its surroundings. I critically evaluate evidence for various forms of multisensory binding. I then consider the case for multisensory differentiation. I argue that existing evidence for multisensory differentiation is inconclusive. I highlight ways that the issue might be empirically resolved. (shrink)

Abstract:This article is based on results from research that addressed the ways young Black Metal musicians construct their musical learning and socialization. In this article we will focus on one of the strands in that study; a trace of a classic ideal from Bildung theory. Using Bildung theory, we explore similarities between the ideals and concepts in the expressed informal music education from Black Metal musicians and contemporary institutionalized music education. In this article the German and Nordic 18th (...) century concept of Bildung will be interpreted as the component that binds and contextualizes knowledge by a dialectic process with already inherited or internalized knowledge. Exploring, identifying, and comparing links between the educative process found within Black Metal and Bildung might at first sight seem to be both a pointless task and potentially reifying of problematic elements found within Black Metal. However, as we discuss, common features of Bildung and Black Metal, such as enlightenment through criticism of the taken-for-granted, a sublime Gesamtkunstwerk and a nihilist striving to become an image of God, help to reveal those ways Black Metal learning processes can be understood inthe light of Bildung theories. We do so in order to present tools for furthering the critical discussion of hegemonic music educational discourses. (shrink)

Indexicals are linguistic expressions whose meaning remain stable while their reference shifts from utterance to utterance. Paradigmatic cases in English are ‘I’, ‘here’, and ‘now’. Recently, a number of authors have argued that various constructions in our language harbor hidden indexicals. We say 'hidden' because these indexicals are unpronounced, even though they are alleged to be real linguistic components. Constructions taken by some authors to be associated, or to ‘co-habit’, with hidden indexicals include: definite descriptions and quantifiers more generally (hidden (...) indexical refers to a domain – Davies (1981), Westerstahl (1985), Soames (1986), Higginbotham (1988), Stanley and Williamson (1995)), propositional attitude verbs (hidden indexical refers to a mode of presentation – Richard (1990)), comparative adjectives (hidden indexical refers to comparison classes – Partee (1989), Kamp (1975), Ludlow (1989)). An interesting recent addition is the view that all nouns are associated with a hidden indexical referring to a domain restriction (Stanley and Szabo (2000), Stanley.. (shrink)

We considered peculiarities of the evolution of a region with sharp boundaries that is filled with a partially ionized plasma and is a part of the volume of a condensed target. The creation of such a region in the near-surface layer of the target can be related to the action of an external impulse symmetric ionizator or to the action of an intense small-extension shock wave on the target surface. We defined the conditions such that their fulfilment during the establishment (...) of the equilibrium between the Coulomb attraction of electrons and ions with atom ionization multiplicity Z* 1 and the kinetic pressure of electrons causes both the compression of this region and its ionization to the state with Z* 2 > Z* 1. The last leads to a further additional compression and ionization. Under these conditions, the spontaneous avalanche-like ionization of atoms of the target to the state of ‘‘bare’’ nuclei occurs synchronously with the avalanche-like metallization and the self-compression of the target. We showed that the avalanche-like ionization and the self-compression of the target happen in the case where the gas of degenerate electrons has drift momentum. If the region with initial ionization has the form of thin spherical layer, the process of avalanche-like ionization and self-compression of the target in this region is accompanied by the accelerated movement of the plasma layer to the target center. One of the reasons for the accelerated movement is the surface tension in a bounded domain of the nonequilibrium plasma layer neutralized by ions of the target. With increase in the velocity of movement of this layer to the target center, the additional self-compression of the system of electrons and nuclei to the state of degenerate electron gas occurs. At the leading edge of the running layer with extremely high electron density which is neutralized by nuclei of the target, the formation of a collapse of the electron--nucleus system proceeds, and the binding energy maximum for the electron--nucleus system shifts from A≈60 to A ≫ 60. This result makes possible the fast synthesis of superheavy nuclei. The decay of the collapse state, a partial restoration of the target structure, its rapid cooling, and the condensation of a part of the products of nuclear reactions happen in the target volume at the trailing edge of the moving plasma layer. Upon such a scanning propagation of the wave with high electron density, all the target substance is involved, step-by-step, to the process of nuclear transformations. At the target center, the moving plasma layer is squeezed with the formation of the state of quasistationary collapse under inertial confinement. Then the collapse state decays irreversibly. (shrink)

Metallothioneins (MTs) are ubiquitous proteins with the capacity to bind heavy metal ions (mainly Cd, Zn or Cu), and they have been found in animals, plants, eukaryotic and prokaryotic micro‐organisms. We have carried out a comparative analysis of ciliate MTs (Tetrahymena species) to well‐known MTs from other organisms, discussing their exclusive features, such as the presence of aromatic amino acid residues and almost exclusive cysteine clusters (CCC) present in cadmium‐binding metallothioneins (CdMTs), higher heavy metal‐MT stoichiometry values, and (...) a strictly conserved modular–submodular structure. Based on this last feature and an extensive gene duplication, we propose a possible model for the evolutionary history of T. thermophila MTs. We also suggest possible functions for these MTs from consideration of their differential gene expressions and discuss the potential use of these proteins and/or their gene promoters for designing molecular or whole‐cell biosensors for a fast detection of heavy metals in diverse polluted ecosystems. (shrink)

Metal ions may play an essential role in chromatin organization and, thus, be main actors in the gene expression drama. A model is proposed here for the interaction of DNA‐binding transcriptional regulatory proteins with histone H3 via coordinated metal ions and discussed in relation to the conversion of nucleosomal ‘closed’ to ‘open’ states.

It is well established that microRNAs (miRNAs) induce mRNA degradation by binding to 3′ untranslated regions (UTRs). The functionality of sites in the coding domain sequence (CDS), on the other hand, remains under discussion. Such sites have limited impact on target mRNA abundance and recent work suggests that miRNAs bind in the CDS to inhibit translation. What then could be the regulatory benefits of translation inhibition through CDS targeting compared to mRNA degradation following 3′ UTR binding? We (...) propose that these domain‐dependent effects serve to diversify the functional repertoire of post‐transcriptional gene expression control. Possible regulatory benefits may include tuning the time‐scale and magnitude of post‐transcriptional regulation, regulating protein abundance depending on or independently of the cellular state, and regulation of the protein abundance of alternative splice variants. Finally, we review emerging evidence that these ideas may generalize to RNA‐binding proteins beyond miRNAs and Argonaute proteins. (shrink)

Deamination of adenosine in RNA to form inosine has wide ranging consequences on RNA function including amino acid substitution to give proteins not encoded in the genome. What determines which adenosines in an mRNA are subject to this modification reaction? The answer lies in an understanding of the mechanism and substrate recognition properties of adenosine deaminases that act on RNA (ADARs). Our recent publication of X‐ray crystal structures of the human ADAR2 deaminase domain bound to RNA editing substrates shed (...) considerable light on how the catalytic domains of these enzymes bind RNA and promote adenosine deamination. Here we review in detail the deaminase domain‐RNA contact surfaces and present models of how full length ADARs, bearing double stranded RNA‐binding domains (dsRBDs) and deaminase domains, could process naturally occurring substrate RNAs. (shrink)

If the commands of authority are peremptory and content-independent directives, it is a great puzzle why any rational autonomous agent should accept them as morally binding, as Robert Paul Wolff and others have argued. I analyse the peremptory and content-independent quality of authoritative directives and argue that all earthly authorities operate within a specified domain. I investigate three candidates for the role of universally applicable boundary conditions–morality, harm to self, and absurdity. I conclude that commands are authoritative only (...) when intra vires, i.e. issued within the proper domain of the authority. Wolff's challenge is not met, hut it is shown to be less forbidding. (shrink)

The Y‐box proteins are the most evolutionarily conserved nucleic acid binding proteins yet defined in bacteria, plants and animals. The central nucleic acid binding domain of the vertebrate proteins is 43% identical to a 70‐amino‐acid‐long protein (CS7.4) from E. coli. The structure of this domain consists of an antiparallel fivestranded β‐barrel that recognizes both DNA and RNA. The diverse biological roles of these Y‐box proteins range from the control of the E. coli cold‐shock stress response to (...) the translational masking of messenger RNA in vertebrate gametes. This review discusses the organization of the prokaryotic and eukaryotic Y‐box proteins, how they interact with nucleic acids, and their biological roles, both proven and potential. (shrink)

Divergent evolution can explain how many proteins containing structurally similar domains, which perform a variety of related functions, have evolved from a relatively small number of modules or protein domains. However, it cannot explain how protein domains with similar, but distinguishable, functions and similar, but distinguishable, structures have evolved. Examples of this are the RNA‐binding proteins containing the RNA‐binding domain (RBD), and a newly established protein group, the cold‐shock domain (CSD) protein family. Both protein domains contain (...) conserved RNP motifs on similar single‐stranded nucleic acid‐binding surfaces. Apart from the RNP motifs, which have a similar function, the two families show little similarity in topology or amino acid sequence. This can be considered an interesting example of convergent evolution at the molecular level. Previously, a β‐sheet surface was found to interact with RNA in non‐homologous proteins from yeast, phage and man, revealing that this mode of RNA binding may be a widely recurring theme. (shrink)

ABSTRACTWhile metaphor researchers commonly use the word “mapping” in explanations of various types of figurative language, there is a lack of recognition that the term is itself metaphorical. In fact, the term has two metaphor-based working definitions, the more commonly cited being that relating to mathematical set theory and the less common definition originating in cognitive neuroscience. Perhaps not coincidentally, terminological inconsistencies relating to mapping have led to theoretical problems both for single-domain theories of metonymy and attempts to examine (...) Lakoff’s invariance hypothesis. This article will assert that expressing metonymic connectivity using the neuroscience term “binding” will both eliminate unnecessary theoretical confusion for cognitive linguists and provide common terminology to facilitate productive communication between cognitive linguists and cognitive neuroscientists. (shrink)

As an alternative dispute resolution procedure, Domain Name Arbitration addresses not only contentions regarding the ownership of web pages, but also infringements of the Intellectual Property law such as cyber squatting or Internet piracy. In this spirit, panelists of the World Intellectual Property Organization enact law in accordance with what the involved parties provide them as burden of proof. Following this line of thought, we can assume that one party may remain unrepresented when it is not able to accomplish (...) legal procedures successfully. Nevertheless, does this kind of asymmetry always function in the way that we presume? This paper sets out to study how WIPO panelists tackle knowledge asymmetries when being manifested in Domain Name Arbitration. In particular, this paper concentrates on comparing two Domain Name Arbitration processes in which knowledge asymmetries play a significant role in the panelist’s final-and legally binding- decision. This analysis also examines how specific text-internal features give us a hint of unbalanced relationships between the Complainant and the Respondent of a Domain Name Arbitration process. It endeavors, thus, to understand how lexical, rhetorical-grammatical and discursive features work within discourse and may reach to influence the communicative act itself. Following Vijay K. Bhatia’s critical discourse analysis as main theoretical framework, this paper tries to comprehend the role asymmetries play in enacting Domain Name law. (shrink)

Dyneins are a family of motor proteins that move along the microtubule. Motility is generated in the motor domain, which consists of a ring of six AAA+ (ATPases associated with diverse cellular activities) domains, the linker and the microtubule‐binding domain (MTBD). The cyclic ATP‐hydrolysis in the AAA+ ring causes the remodelling of the linker, which creates the necessary force for movement. The production of force has to be synchronized with cycles of microtubule detachment and rebinding to efficiently (...) create movement along the microtubule. The analysis of four dynein motor domain crystal structures in the essay presented here provides evidence that this crucial coordination is carried out by open/closed AAA+ ring conformations. (shrink)

PDZ (also called DHR or GLGF) domains are found in diverse membraneassociated proteins including members of the MAGUK family of guanylate kinase homologues, several protein phosphatases and kinases, neuronal nitric oxide synthase, and several dystrophin‐associated proteins, collectively known as syntrophins. Many PDZ domain‐containing proteins appear to be localised to highly specialised submembranous sites, suggesting their participation in cellular junction formation, receptor or channel clustering, and intracellular signalling events. PDZ domains of several MAGUKs interact with the C‐terminal polypeptides of a (...) subset of NMDA receptor subunits and/or with Shaker‐type K+ channels. Other PDZ domains have been shown to bind similar ligands of other transmembrane receptors. Recently, the crystal structures of PDZ domains, with and without ligand, have been determined. These demonstrate the mode of ligand‐binding and the structural bases for sequence conservation among diverse PDZ domains. (shrink)

The correct locus (or loci) of binding theory has been a matter of much discussion. Theories can be seen as varying along at least two dimensions. The rst is whether binding theory is con gurationally determined (that is, the theory exploits the geometry of a phrase marker, appealing to such purely structural notions as c-command and government) or whether the theory depends rather on examining the relations between items selected by a predicate (where by selection I am intending (...) to cover everything from semantic dependencies to syntactic subcategorization). The second is the level of grammar on which binding is de ned. Attempting to roughly equate levels across di erent theories, suggestions have included the semantics/lexical conceptual structure (Jackendo 1992), thematic structure (Jackendo 1972, Wilkins 1988), argument structure/D-structure/initial grammatical relations (Manning 1994, Belletti and Rizzi 1988, Perlmutter 1984), surface syntax/grammatical relations, logical form, linear order, pragmatics (Levinson 1991), and discourse (Iida 1992). The data is su ciently varied and complex that many theories end up as mixtures, variously employing a combination of elements along both dimensions (for instance, Chomsky (1986) relies purely on con gurational notions for the relationship between an anaphor and its antecedent, but uses concepts from selection in the de nition of the binding domain of an anaphor). LFG has always rejected a con gurational account of binding. For instancError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMapError: Illegal entry in bfrange block in ToUnicode CMape, Simpson (1991) argues that a con gurational theory of binding in Warlpiri cannot be maintained, among other reasons because nite clauses lack a VP.. (shrink)

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur both within (...) the hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

In a recent paper in this Journal, one of us argued against placing He above Be in Mendeleiev’s system of the elements. In it the goal was to dispute the notion that in Mendeleiev’s system of the elements the location of He should in fact lie above Be, which has a very similar electronic configuration, rather than above the noble gas column. That paper was based on rather old, Hartree–Fock limit studies on the strikingly limited non-additive contributions in the He3 (...) and He4 systems in contrast with the much larger non-additivity obtained for the Be3, Be4 and Be5 oligomers. In a recent benchmark multireference Averaged Quadratic Coupled Cluster results on Be2 and Be3 we showed that the delocalized non-additive contribution comprises 94 % of the binding energy of Be3. Here we use this and other pertinent information (drawn from the same paper) to conclude that He may not be associated with Be in Mendeleiev’s Table, despite their quite similar spectroscopic ground states. Furthermore, we use the new results to show that the large non-additivity implies that less than 2 % of the Be3 binding is located in each Be pair contained within the Be trimer. The rest of the interaction energy is necessarily delocalized over all three Be atoms. This might actually announce the bulk properties (i.e. “the electron gas”) that in solid-state physics explain the large electric and heat conduction for the solid Be metal. Thus, in the case of beryllium the metallic characteristics are already evident in Be3, a far cry from the monoatomic helium gas. (shrink)

In this paper, I will argue for a new account of presuppositions which is based on double indexing as well as minimal representational contexts providing antecedent material for anaphoric presuppositions, rather than notions of context defined in terms of the interlocutors’ pragmatic presuppositions or the information accumulated from the preceding discourse. This account applies in particular to new phenomena concerning the presupposition of quantifier domains. But it is also intended to be an account of presuppositions in general. The account differs (...) from the Satisfaction Theory and the Binding Theory of presuppositions in that it can be viewed as a conservative extension of traditional static semantics and in that it does not involve the notion of pragmatic presupposition. (shrink)

To explore whether the generation of new protein folds could be linked to metallic cofactor recruitment, we identified the oldest examples of folds for manganese, iron, zinc, and copper proteins by analyzing their fold‐domain mapping patterns. We discovered that the generation of these folds was tightly coupled to corresponding metals. We found that the emerging order for these folds, i.e., manganese and iron protein folds appeared earlier than zinc and copper counterparts, coincides with the putative bioavailability of the corresponding (...) metals in the ancient anoxic ocean. Therefore, we conclude that metallic cofactors, like organic cofactors, play an evolutionary role in the formation of new protein folds. This link could be explained by the emergence of protein structures with novel folds that could fulfill the new protein functions introduced by the metallic cofactors. These findings not only have important implications for understanding the evolutionary mechanisms of protein architectures, but also provide a further interpretation for the evolutionary story of superoxide dismutases. (shrink)

Pleckstrin homology (PH) domains are a family of compact protein modules defined by sequences of roughly 100 amino acids. These domains are common in vertebrate, Drosophila, C. elegans and yeast proteins, suggesting an early origin and fundamental importance to eukaryotic biology. Many enzymes which have important regulatory functions contain PH domains, and mutant forms of several such proteins are implicated in oncogenesis and developmental disorders. Numerous recent studies show that PH domains bind various proteins and inositolphosphates. Here I discuss PH (...) domains in detail and conclude that they form a versatile family of membrane binding and protein localization modules. (shrink)

The eukaryotic genome is organized into different domains by cis‐acting elements, such as boundaries/insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G1 phase during every (...) cell cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements. BioEssays 25:507–514, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Actin plays several essential roles in cellular processes and is a vital component in the contractile apparatus. To accomplish its many cellular tasks, actin must interact with a wide range of other proteins in addition to self‐assembling into filaments. Characterization of these functional domains and localized binding regions on the actin monomer is therefore an important undertaking. Strategies for elucidating the many interaction sites include X‐ray diffraction, NMR and fluorescence spectroscopy, chemical modification, chemical cross‐linking, protein cleavage, and the study (...) of sequence homologies between the many isotypes of actin. Based on these varied data, we discuss the possible spatial relationships between the interaction sites. (shrink)

The corporate social responsibility and industrial relations studies have evolved mostly in parallel. In this paper, we integrate the IR with the CSR perspective, highlighting their similarities and differences. In particular, the study adopts a framework which includes a wide set of CSR-related issues to explore what unions and companies negotiate under the umbrella of CSR. It analyses and compares the national sectoral agreements of two key industries in the Italian economy, i.e. Metal and Chemical. We find that these (...) two sectors exhibit differences because the CSR-related issues covered by the two contracts are formally labelled as CSR in the Chemical contract, and not labelled as CSR in the Metal contract. We also find similarities regarding the CSR-related issues covered and not covered by the national contracts, and the binding processes centrally negotiated for their implementation. We interpret the similarities in light of the specificities of the Italian IR system, and the differences in light of the negotiation traditions of the two sectors under study, which induce the actors in the Metal sector to focus more on what differentiates the CSR and IR perspectives, and the actors in the Chemical sector to focus more on what the CSR and IR perspectives share. (shrink)

The term functional domain is often used to describe the region containing the cis acting sequences that regulate a gene locus. “Strong” domain models propose that the domain is a spatially isolated entity consisting of a region of extended accessible chromatin bordered by insulators that have evolved to act as functional boundaries. However, the observation that independently regulated loci can overlap partially or completely raises questions about functional requirements for physically isolated domain structures. An alternative model, (...) the “weak” domain model, proposes that domain structure is determined by the distribution of binding sites for positively acting factors, without a requirement for functional boundaries. The domain would effectively be the region that contains these factor-binding sites. Specificity of promoter-enhancer interactions would play a major role in maintaining the functional autonomy of adjacent genes. Sequences that interfere with these interactions (frequently characterised as insulators) would be selected against if they occurred within the domain but not at the edges, or in the interdomain regions. As a result, insulators would often be found near the borders of domains without necessarily being selected to act as boundaries. BioEssays 22:657–665, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

The evolution of microstructure upon partial crystallization and its influence on the mechanical properties such as hardness, elastic modulus and viscosity in a La 55 Al 25 Cu 10 Ni 5 Co 5 bulk metallic glass alloy are studied. Specimens with various volume fractions of crystalline phases were obtained by annealing the as-cast amorphous alloy above its glass transition temperature and were characterized by transmission electron microscopy. Microscopic examination of the heat-treated samples shows short-range-ordered domains prior to nanocrystallization within the (...) amorphous matrix, followed by the growth and impingement of the crystallites. Whereas the hardness of the annealed samples increases linearly with increasing crystallinity, the elastic modulus and the viscosity both increase abruptly when the crystalline volume fraction is about 40 vol.%, with a only minor variation on either side of this range. The sudden rises in the modulus and viscosity are similar to those in the literature data on the fracture strength of partially crystallized bulk amorphous alloys that shows a steep drop in strength at 30-50 vol.% crystallinity. On the basis of the microscopic observations, it is suggested that the interaction and formation of rigid networks of crystalline phases upon the attainment of a critical second-phase volume fraction may be the possible reason for the sudden change in mechanical properties. Percolation theory is utilized in further substantiating this hypothesis. (shrink)

Villin, a calcium‐regulated actin‐binding protein, modulates the structure and assembly of actin filaments in vitro. It is organized into three domains, the first two of which are homologous. Villin is mainly produced in epithelial cells that develop a brush border and which are responsible for nutrient uptake. Expression of the villin structural gene is precisely regulated during mouse embryogenesis and is restricted in adults, to certain epithelia of the gastrointestinal and urogenital tracts. The function of villin has been assessed (...) by transfecting CV1 cells with a human cDNA encoding wild‐type villin or mutant villin. Synthesis of large amounts of villin in cells which do not normally produce this protein induces the growth of microvilli on the cell surface and the redistribution of F‐actin, concomitant with the disappearance of stress fibers. The complete villin sequence is required for the morphogenic effect. These results suggest that villin plays a key role in the morphogenesis of microvilli. (shrink)

Three apparently unrelated developmental processes – mammalian myogenesis, the choice of neural fate and sex determination in Drosophila – are controlled by a common mechanism. Most of the genes governing these processes encode transcriptional factors that contain the helix‐loop‐helix (HLH) motif. This domain mediates the formation of homo‐ or heterodimers that specifically bind to DNA through a conserved basic region adjacent to the HLH motif. Dimers differ in their affinity for DNA and in their ability to activate transcription from (...) HLH binding‐site containing promoters. In addition, the activity of HLH proteins is inhibited by dimerization with another class of HLH proteins that lack a basic domain entirely or have an altered one. These structural properties provide a molecular mechanism to explain the synergistic and antagonistic functional relations among the HLH encoding genes that control several developmental pathways. (shrink)

The Y‐box‐binding protein (YB‐1) represents the most evolutionary conserved nucleic‐acid‐binding protein currently known. YB‐1 is a member of the cold‐shock domain (CSD) protein superfamily. It performs a wide variety of cellular functions, including transcriptional regulation, translational regulation, DNA repair, drug resistance and stress responses to extracellular signals. As a result, YB‐1 expression is closely associated with cell proliferation. In this review, we will begin by briefly describing the characteristics of YB‐1 and will then summarize the pleiotropic functions (...) brought about via DNA–RNA transaction and protein–protein interactions. In addition, we will discuss the diverse range of potential physiological and pathological functions of YB‐1. BioEssays 25:691–698, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The present study investigates whether quantifier scope is computed incrementally during online sentence processing. We exploited the free word order in German to manipulate whether the verbal predicate preceded or followed the second quantifier in doubly quantified sentences that required the computation of inverse scope. A possessive pronoun in the first quantifier that had to be bound by the second quantifier was used to enforce scope inversion. We tested whether scope inversion causes difficulty and whether this difficulty emerges even at (...) a point before comprehenders have encountered the main verb. We report three pretests and two reading time experiments. The first two pretests were offline tests that established (1) that the sentences exhibited the assumed scope preferences and (2) that variable binding forced scope inversion. The third pretest employed self-paced reading to show that interpreting a bound variable is not difficult per se and that difficulty in the critical construction must thus be due to inverting scope. Incremental processing of quantifier scope was investigated in a self-paced reading experiment. We observed difficulty right after the second quantifier, but only if it appeared after the main verb, that is, after the predication was complete. Further evidence for late scope inversion comes from an eyetracking experiment. Again, a scope inversion effect could only be observed at the end of the sentence. Taken together, our study demonstrates that in German inverse scope is only computed at the sentence boundary. (shrink)

A diverse group of DNA‐binding regulatory proteins share a common structural domain which is homologous to the sequence of a highly conserved and abundant chromosomal protein, HMG‐1. Proteins containing this HMG‐1 box regulate various cellular functions involving DNA binding, suggesting that the target DNA sequences share a common structural element. Members of this protein family exhibit a dual DNA‐binding specificity: each recognizes a unique sequence as well as a common DNA conformation. The highly conserved HMG‐1/‐2 proteins (...) may modulate the binding of other HMG‐1 box proteins to bent DNA. We examine the structural and functional relationships between the proteins, identify their signature† and describe common features of their target DNA elements. (shrink)

To prevent domains from cyber-piracy, the WIPO offers private and confidential procedures tasked to address the legitimate use of a domain name. WIPO domain name arbitration consists of an alternative dispute resolution process in which one or more panelists make a binding decision over the legitimacy of a domain. This article investigates the structure of the discourse of this professional genre. Following Maley, this study focuses, first, on spotting the generic moves of WIPO domain name (...) arbitration decisions. Second, the analysis unveils patterns shaping WIPO domain name arbitration decisions, hence exploring how discursive features work within this specialized discourse. Third, it examines whether corpus data reveal that this type of professional discourse has entered into a process of standardization. The study is based on Bhatia’s multi-perspective four-space model of discourse. This analytical framework emphasizes a multidisciplinary and multidimensional perspective which highlights that discourse is indistinguishable from constructing reality. (shrink)

The dimensional structure of phenomenal space and its relation to the brain have not been widely focused on in brain and consciousness studies. This paper postulates that focusing on the dimensional structures displayed in the relation between phenomenal space and the brain is necessary for understanding the integration of distributed brain events in binding. A related issue is why items and events of phenomenal space and consciousness as they appear in experience seem to be beyond the reach of natural (...) scientific empirical observation. The proposed solution to these issues is postulated to require a fourth spatial dimension. A transcendence principle of detection (TPD) is introduced, which states that transcendent degrees of freedom of an n+1 dimension are a necessary condition for experiencing or detecting an n-dimensionally extended physical structure as an n-dimensionally extended phenomenal structure. It is postulated that the phenomenal outcome of binding, i.e. the threedimensionally distributed and extended phenomenal structure of human experience, is the expected first-person outcome of threedimensionally distributed neurophysical structures being monitored at the domain of a fourth spatial dimension. (shrink)

Vacuolar ATPases (V‐ATPases, V1Vo‐ATPases) are rotary motor proton pumps that acidify intracellular compartments, and, when localized to the plasma membrane, the extracellular space. V‐ATPase is regulated by a unique process referred to as reversible disassembly, wherein V1‐ATPase disengages from Vo proton channel in response to diverse environmental signals. Whereas the disassembly step of this process is ATP dependent, the (re)assembly step is not, but requires the action of a heterotrimeric chaperone referred to as the RAVE complex. Recently, an alternative pathway (...) of holoenzyme disassembly was discovered that involves binding of Oxidation Resistance 1 (Oxr1p), a poorly characterized protein implicated in oxidative stress response. Unlike conventional reversible disassembly, which depends on enzyme activity, Oxr1p induced dissociation can occur in absence of ATP. Yeast Oxr1p belongs to the family of TLDc domain containing proteins that are conserved from yeast to mammals, and have been implicated in V‐ATPase function in a variety of tissues. This brief perspective summarizes what we know about the molecular mechanisms governing both reversible (ATP dependent) and Oxr1p driven (ATP independent) V‐ATPase dissociation into autoinhibited V1 and Vo subcomplexes. (shrink)

Protein‐carbohydrate interactions have been found to be important in many steps in lymphocyte recirculation and inflammatory responses. A family of carbohydrate‐binding proteins or lectins, termed selectins, has been discovered and shown to be involved directly in these processes. The three known selectins, termed L‐, E‐ and P‐selectins, have domains homologous to other Ca2+‐dependent (C‐type) lectins. L‐selectin is expressed constitutively on lymphocytes, E‐selectin is expressed by activated endothelial cells, and P‐selectin is expressed by activated platelets and endothelial cells. Here, we (...) review the nature of the carbohydrate determinants in tissues recognized by these selectins. The expression of specific sialylated, fucosylated and sulfated carbohydrates in activated endothelium and high endothelial venules promotes interactions with L‐selectin on leukocyte surfaces. In contrast, E‐ and P‐selectins recognize specific carbohydrate determinants related to sialyl Lex antigen on neutrophil and monocyte surfaces. The discovery of the selectins has generated excitemient among glycoconjugate researchers that other carbohydrate‐binding proteins and their cognate ligands will be found to function in regulating many types of cellular interactions. (shrink)

The gelsolin gene family encodes a number of higher eukaryotic actin-binding proteins that are thought to function in the cytoplasm by severing, capping, nucleating or bundling actin filaments. Recent evidence, however, suggests that several members of the gelsolin family may have adopted unexpected nuclear functions including a role in regulating transcription. In particular, flightless I, supervillin and gelsolin itself have roles as coactivators for nuclear receptors, despite the fact that their divergence appears to predate the evolutionary appearance of nuclear (...) receptors. Flightless I has been shown to bind both actin and the actin-related BAF53a protein, which are subunits of SWI/SNF-like chromatin remodelling complexes. The primary sequences of some actin-related proteins such as BAF53a exhibit conservation of residues that, in actin itself, are known to interact with gelsolin-related proteins. In summary, there is a growing body of evidence supporting a biological role in the nucleus for actin, Arps and actin-binding proteins and, in particular, the gelsolin family of actin-binding proteins. (c) 2005 Wiley Periodicals, Inc. (shrink)

Protein–protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein–protein recognition mechanism, mediated by disordered regions longer than 20–30 residues. Bioinformatics predictions and well‐characterized examples, such as the kinase‐inhibitory domain of Cdk inhibitors and the Wiskott–Aldrich syndrome protein (WASP)‐homology (...) class='Hi'>domain 2 of actin‐binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains. (shrink)

Protein–protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein–protein recognition mechanism, mediated by disordered regions longer than 20–30 residues. Bioinformatics predictions and well‐characterized examples, such as the kinase‐inhibitory domain of Cdk inhibitors and the Wiskott–Aldrich syndrome protein (WASP)‐homology (...) class='Hi'>domain 2 of actin‐binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains. (shrink)

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and function. The latter point (...) is of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

In vertebrates, members of the cysteine‐rich protein (CRP) family are characterized by the presence of two LIM domains linked to short glycine‐rich repeats. These proteins mediate protein–protein interactions and are of fundamental importance for cell differentiation, cytoskeletal remodeling, and transcriptional regulation. To date, a vast amount of information about vertebrate CRPs has become available, including their biological functions, interacting partners, and three‐dimensional structures. Compatible with a molecular adapter role, structural data reveal that the LIM domains within these proteins represent completely (...) independent folded units bridged by flexible linker regions. The physiological roles for individual CRPs was determined by targeted gene disruption analysis and by identification of common and specific binding partners by means of yeast and mammalian two‐hybrid screens. Several CRP‐like LIM domain proteins with close structural and sequence similarity were identified in arthropods, protozoas and plants, supporting the notion that this subset of LIM domain proteins has been highly conserved over the span of evolution thereby emphasizing the importance of their function. BioEssays 25:152–162, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This volume brings together about 50 scientists and researchers from the four corners of the world to redefine and anticipate tomorrow's values, and reflect on ...

Heterogeneity within MDD has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary (...) IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A ([11C]WAY-100635), as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets. (shrink)