Precise DNA replication is fundamental for genetic inheritance. In eukaryotes, replication initiates at multiple origins that are first “licensed” and subsequently “fired” to activate DNA synthesis. Despite the success in identifying origins with specific DNA motifs in Saccharomyces cerevisiae, no consensus sequence or sequences with a predictive value of replication origins have been recognized in metazoan genomes. Rather, epigenetic rules and chromatin structures are believed to play important roles in governing the selection and activation of replication (...) origins. We propose that replication initiation is facilitated by a group of sequence‐specific “replication pioneer factors,” which function to increase chromatin accessibility and foster a chromatin environment that is conducive to the loading of the prereplication complex. Dysregulation of the function of these factors may lead to gene duplication, genomic instability, and ultimately the occurrence of pathological conditions such as cancer. (shrink)

RNA polymerase II (RNAP II) non‐coding transcription is now known to cover almost the entire eukaryotic genome, a phenomenon referred to as pervasive transcription. As a consequence, regions previously thought to be non‐transcribed are subject to the passage of RNAP II and its associated proteins for histone modification. This is the case for the nucleosome‐depleted regions (NDRs), which provide key sites of entry into the chromatin for proteins required for the initiation of coding gene transcription and DNA replication. (...) In this review, recent data on the effects of pervasive transcription through NDRs are summarized and a model is proposed to explain how RNAP II‐driven transcription is able to modify the nucleosomes flanking the NDRs, leading to nucleosome repositioning and NDR closure. Even though much of the mechanistic detail underlying these events remains to be elucidated, such a model provides a basis to explain how non‐coding transcription through NDRs can regulate the initiation of coding gene expression and DNA replication. (shrink)

Cellular identity and its response to external or internal signalling variations are encoded in a cell's genome as regulatory information. The genomic regions that specify this type of information are highly variable and degenerated in their sequence determinants, as it is becoming increasingly evident through the application of genome‐scale methods to study gene expression. Here, we speculate that the same scenario applies to the regulatory regions controlling where DNA replication starts in the metazoan genome. We propose that replication (...) origins cannot be defined as unique genomic features, but rather that DNA synthesis initiates opportunistically from accessible DNA sites, making cells highly robust and adaptable to environmental or developmental changes. (shrink)

The ability to initiate DNA replication is a critical step in the proliferation of all organisms. In bacteria, this process is mediated by an ATP‐dependent replication initiator protein, DnaA, which recognizes and melts replication origin (oriC) elements. Despite decades of biochemical and structural work, a mechanistic understanding of how DnaA recognizes and unwinds oriC has remained enigmatic. A recent study by Pelliciari et al. provides important new structural insights into how DnaA from Bacillus subtilis recognizes and processes (...) its cognate oriC, showing how DnaA uses sequence features encoded in the origin to engage melted DNA. Comparison of the DnaA‐oriC structure with archaeal/eukaryl replication origin complexes based on Orc‐family proteins reveals a high degree of similarity in origin engagement by initiators from di domains of life, despite fundamental differences in origin melting mechanisms. These findings provide valuable insights into bacterial replication initiation and highlight the intriguing evolutionary history of this fundamental biological process. (shrink)

Recent advances in our understanding of the mechanism and regulation of eukaryotic DNA replication have been expedited by the use of cell‐free systems capable of initiation of DNA replication. The system capable of replicating plasmid DNAs containing the SV40 origin of DNA replication in vitro is a paradigm for studies on the replication of other virus DNAs and the replication of cellular chromosomes. This review outlines some of the contemporary issues and developments related to (...) this complex problem. (shrink)

DNA replication initiates at many sites in eukaryotic chromosomes. It has been difficult to isolate such replication origins, but a family of sequences from the yeast genome have properties which suggest that they may serve this function. The identification of these sequences together with sophisticated methods of genetic analysis, make yeast a useful organism for the study of eukaryotic DNA replication.

Replication of the main chromosome in the halophilic archaeon Haloferax volcanii was recently reported to continue despite deletion of all active replication origins. Equally surprising, the deletion strain grew faster than the parent strain. It was proposed that origin‐less H. volcanii duplicate their chromosomes via recombination‐dependent replication. Here, we recall our present knowledge of this mode of chromosome replication in different organisms. We consider the likelihood that it accounts for the viability of H. volcanii deleted for (...) its main specific replication origins, as well as possible alternative interpretations of the results. The selective advantages of having defined chromosome replication origins are discussed from a functional and evolutionary perspective. (shrink)

The regulation of DNA replication is a fascinating biological problem both from a mechanistic angle—How is replication timing regulated?—and from an evolutionary one—Why is replication timing regulated? Recent work has provided significant insight into the first question. Detailed biochemical understanding of the mechanism and regulation of replication initiation has made possible robust hypotheses for how replication timing is regulated. Moreover, technical progress, including high‐throughput, single‐molecule mapping of replication initiation and single‐cell assays of (...) replication timing, has allowed for direct testing of these hypotheses in mammalian cells. This work has consolidated the conclusion that differential replication timing is a consequence of the varying probability of replication origin initiation. The second question is more difficult to directly address experimentally. Nonetheless, plausible hypotheses can be made and one—that replication timing contributes to the regulation of chromatin structure—has received new experimental support. (shrink)

Eukaryotic DNA replication initiates at multiple origins. In early fly and frog embryos, chromosomal replication is very rapid and initiates without sequence specificity. Despite this apparent randomness, the spacing of these numerous initiation sites must be sufficiently regular for the genome to be completely replicated on time. Studies in various eukaryotes have revealed that there is a strict temporal separation of origin “licensing” prior to S phase and origin activation during S phase. This may suggest that replicon (...) size must be already established at the licensing stage. However, recent experiments suggest that a large excess of potential origins are assembled along chromatin during licensing. Thus, a regular replicon size may result from the selection of origins during S phase. We review single molecule analyses of origin activation and other experiments addressing this issue and their general significance for eukaryotic DNA replication. BioEssays 25:116–125, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The replicon hypothesis, first proposed in 1963 by Jacob and Brenner(1), states that DNA replication is controlled at sites called origins. Replication origins have been well studied in prokaryotes. However, the study of eukaryotic chromosomal origins has lagged behind, because until recently there has been no method for reliably determining the identity and location of origins from eukaryotic chromosomes. Here, we review a technique we developed with the yeast Saccharomyces cerevisiae that allows both the mapping of replication (...) origins and an assessment of their activity. Two‐dimensional agarose gel electrophoresis and Southern hybridization with total genomic DNA are used to determine whether a particular restriction fragment acquires the branched structure diagnostic of replication initiation. The technique has been used to localize origins in yeast chromosomes and assess their initiation efficiency. In some cases, origin activation is dependent upon the surrounding context. The technique is also being applied to a variety of eukaryotic organisms. (shrink)

For evolution by natural selection to occur it is classically admitted that the three ingredients of variation, difference in fitness and heredity are necessary and sufficient. In this paper, I show using simple individual-based models, that evolution by natural selection can occur in populations of entities in which neither heredity nor reproduction are present. Furthermore, I demonstrate by complexifying these models that both reproduction and heredity are predictable Darwinian products (i.e. complex adaptations) of populations initially lacking these two properties but (...) in which new variation is introduced via mutations. Later on, I show that replicators are not necessary for evolution by natural selection, but rather the ultimate product of such processes of adaptation. Finally, I assess the value of these models in three relevant domains for Darwinian evolution. (shrink)

Just as the faithful replication of DNA is an essential process for the cell, chromatin structures of active and inactive genes have to be copied accurately. Under certain circumstances, however, the activity pattern has to be changed in specific ways. Although analysis of specific aspects of these complex processes, by means of model systems, has led to their further elucidation, the mechanisms of chromatin replication in vivo are still controversial and far from being understood completely. Progress has been (...) achieved in understanding: 1. The initiation of chromatin replication, indicating that a nucleosome‐free origin is necessary for the initiation of replication; 2. The segregation of the parental nucleosomes, where convincing data support the model of random distribution of the parental nucleosomes to the daughter strands; and 3. The assembly of histones on the newly synthesized strands, where growing evidence is emerging for a two‐step mechanism of nucleosome assembly, starting with the deposition of H3/H4 tetramers onto the DNA, followed by H2A/H2B dimers. (shrink)

The organisation of mammalian mitochondrial DNA (mtDNA) is more complex than usually assumed. Despite often being depicted as a simple circle, the topology of mtDNA can vary from supercoiled monomeric circles over catenanes and oligomers to complex multimeric networks. Replication of mtDNA is also not clear cut. Two different mechanisms of replication have been found in cultured cells and in most tissues: a strand‐asynchronous mode involving temporary RNA coverage of one strand, and a strand‐coupled mode rather resembling conventional (...) nuclear DNA replication. In addition, a recombination‐initiated replication mechanism is likely to be associated with the multimeric mtDNA networks found in human heart. Although an insight into the general principles and key factors of mtDNA organisation and maintenance has been gained over the last few years, there are many open questions regarding replication initiation, termination and physiological factors determining mtDNA organisation and replication mode. However, common themes in mtDNA maintenance across eukaryotic kingdoms can provide valuable lessons for future work. (shrink)

The chromosomes of eukaryotic cells possess many potential DNA replication origins, of which a subset is selected in response to the cellular environment, such as the developmental stage, to act as active replication start sites. The mechanism of origin selection is not yet fully understood. In this review, we summarize recent observations regarding replication origins and initiator proteins in various organisms. These studies suggest that the DNA‐binding specificities of the initiator proteins that bind to the replication (...) origins and promote DNA replication are primarily responsible for origin selection. We particularly focus on the importance of transcription factors in the origin selection process. We propose that transcription factors are general regulators of the formation of functional complexes on the chromosome, including the replication initiation complex. We discuss the possible mechanisms by which transcription factors influence the selection of particular origins. BioEssays 27:1107–1106, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Cunha and Caldieraro (2009) investigated whether sunk-cost effects, which are well documented in hypothetical situations involving monetary investments, also occur in choice situations with purely behavioral investments. Their results suggest that decision makers indeed fall prey to behavioral sunk-cost effects under certain circumstances. I have been unable to replicate their pattern of results in three separate investigations. In these studies, I attempted to recover the effect using two other behavioral effort manipulations in addition to the manipulation used by Cunha and (...) Caldieraro. This failure to replicate the pattern of results calls into question the robustness of the initial findings. (shrink)

Error‐free genome duplication and accurate cell division are critical for cell survival. In all three domains of life, bacteria, archaea, and eukaryotes, initiator proteins bind replication origins in an ATP‐dependent manner, play critical roles in replisome assembly, and coordinate cell‐cycle regulation. We discuss how the eukaryotic initiator, Origin recognition complex (ORC), coordinates different events during the cell cycle. We propose that ORC is the maestro driving the orchestra to coordinately perform the musical pieces of replication, chromatin organization, and (...) repair. (shrink)

Over 80% of the genes in the E. coli chromosome express fewer than a hundred copies each of their protein products per cell. It is argued here that transcription of these genes is neither constitutive nor regulated by protein factors, but rather, induced by the act of replication. The utility of such replication‐induced (RI) transcription to the temporal regulation of synthesis of determinate quantities of low copy number (LCN) proteins is described. It is suggested that RI transcription may (...) be necessitated, as well as facilitated, by the folding of the bacterial chromosome into a compact nucleoid. Mechanistic aspects of the induction of transcription by replication are discussed with respect to the modulation of transcriptional initiation by negative supercoiling effects, promoter methylation status and derepression. It is shown that RI transcription offers plausible explanations for the constancy of the C period of the E. coli cell cycle and the remarkable conservation of gene order in the chromosomes of enteric bacteria. Some experimental tests of the hypothesis are proposed. (shrink)

According to recent news reports, developments in biotechnology promise to transform our bodies and our lives. Stem cell research and cloning research are reported to offer us the prospect of being able to grow `spare' body parts and to replace diseased or damaged tissue, implying that there are no natural limits to life, and that the body-machine may be endlessly repaired, and even replicated. The birth of a cloned sheep, Dolly, announced in February 1997, is seen as a milestone development (...) in this regard, suggesting that it is possible to defy `nature' by `turning back the biological clock'. While the development was heralded by many as pointing to new medical therapies, it also served to fuel widespread fears that the technology would soon be applied to cloning humans. This article explores how the news media `framed' issues on human cloning in the aftermath of the announcement of Dolly and thus may have heightened public concerns about its implications, particularly for `individuality' or `identity'. It draws on articles appearing in Australian newspapers, beginning with the initial stories on Dolly through to May 1999, when it was reported that Dolly had shown signs of premature ageing. The article highlights the role of the media in shaping public debate on biotechnology, particularly with regard to its impacts on the body, self and society. (shrink)

The hardest part of replicating a genome is the beginning. The first step of DNA replication (called “initiation”) mobilizes a large number of specialized proteins (“initiators”) that recognize specific sequences or structural motifs in the DNA, unwind the double helix, protect the exposed ssDNA, and recruit the enzymatic activities required for DNA synthesis, such as helicases, primases and polymerases. All of these components are orderly assembled before the first nucleotide can be incorporated. On the occasion of the 50th (...) anniversary of the discovery of the DNA structure, we review our current knowledge of the molecular mechanisms that control initiation of DNA replication in eukaryotic cells, with particular emphasis on the recent identification of novel initiator proteins. We speculate how these initiators assemble molecular machines capable of performing specific biochemical tasks, such as loading a ring‐shaped helicase onto the DNA double helix. BioEssays 25:1158–1167, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Our potential for dissecting the complex processes involved in eukaryotic DNA replication has been dramatically increased with the recent development of cell‐free systems that recreate many of these processes in vitro. Initial results from these systems have drawn together work on the cell cycle, the enzymology of replication, and the structure of the nucleus.

It has been almost twenty‐five years since Huberman and Riggs first showed that there are multiple bidirectional origins of replication scattered at ∼100 kb intervals along mammalian chromosomal fibers. Since that time, every conceivable physical property unique to replicating DNA has been taken advantage of to determine whether origins of replication are defined sequence elements, as they are in microorganisms. The most thoroughly studied mammalian locus to date is the dihydrofolate reductase domain of Chinese hamster cells, which will (...) be used as a model to discuss the various methods of investigation. While several laboratories agree on the rough location of the [initiation locus] in this large chromosomal domain, different experimental approaches paint different pictures of the mechanism by which initiation occurs. However, a variety of new techniques and synchronizing agents promises to clarify the picture for this particular locus, and to provide the means for identifying and isolating other origins of replication for comparison. (shrink)

A hypothesis for the control of eukaryotic DNA replication at the chromosomal level is proposed. The specific regulatory problem arises from the subdivision of the genome into thousands of individually replicating units, each of which must be duplicated a single time during S‐phase. The hypothesis is based on the finding of direct repeats at replication origins. Such repeats can adopt, beyond the full‐length double helical structure, another configuration exposing two single‐stranded loops that provide suitable templates for the (...) class='Hi'>initiation of DNA replication. Any further initiation at the same origin is excluded as the single strandedness is eliminated by the replication process. Restoration of the initiable loop structure is proposed to occur by DNA‐protein rearrangements involved in chromosome condensation and duplication of the chromosomal protein backbone during mitosis. A possible role of the maturation promoting factor (MPF) is suggested. (shrink)

Genes are thought to have evolved from long-lived and multiply-interactive molecules in the early stages of the origins of life. However, at that stage there were no replicators, and the distinction between interactors and replicators did not yet apply. Nevertheless, the process of evolution that proceeded from initial autocatalytic hypercycles to full organisms was a Darwinian process of selection of favourable variants. We distinguish therefore between Neo-Darwinian evolution and the related Weismannian and Central Dogma divisions, on the one hand, and (...) the more generic category of Darwinian evolution on the other. We argue that Hull’s and Dawkins’ replicator/interactor distinction of entities is a sufficient, but not necessary, condition for Darwinian evolution to take place. We conceive the origin of genes as a separation between different types of molecules in a thermodynamic state space, and employ a notion of reproducers. (shrink)

Under certain conditions, the cell cycle can be arrested for a long period of time. Vertebrate oocytes are arrested at G2 phase, while somatic cells arrest at G0 phase. In both cells, nuclei have lost the ability to initiate DNA synthesis. In a pair of recently published papers,1,2 Méchali and colleagues and Coué and colleagues have clarified how frog oocytes prevent untimely DNA synthesis during the long G2 arrest. Intriguingly, they found only Cdc6 is responsible for the inability of immature (...) oocytes to replicate DNA. Cdc6 is a key component for replication licensing, and for G0 cells to re‐enter the proliferative stage. Strikingly similar strategies for preventing the untimely replication in both cells suggest that the suppression of replication licensing is a universal mechanism for securing the prolonged arrest of the cell cycle. BioEssays 25:313–316, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Recent work suggests that DNA replication origins are regulated by the number of multiple mini‐chromosome maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM – the replicative helicase which initiates DNA replication and replication kinetics determined by origin's location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology (...) are explained by the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins, and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research. (shrink)

Evolution in modern life requires high replication fidelity to allow for natural selection. A simulation model utilizing simulated phenotype data on cellular probability of survival was developed to determine how self-replication fidelity could evolve in early life. The results indicate that initial survivability and replication fidelity both contribute to overall fitness as measured by growth rates of the cell population. Survival probability was the more dominant feature, and evolution was possible even with zero replication fidelity. A (...) derived formula for the relationship of survival probability and replication fidelity with growth rate was consistent with the simulated empirical data. Quantitative assessment of continuity and other evidence was obtained for a saltation evolutionary process starting from low to moderate levels of survival probability and self-replication fidelity to reach the high levels seen in modern life forms. (shrink)

Several factors are contributing to an increased air of excitement about the eukaryotic DNA replication problem: new insights into the nature of origins of replication, a better appreciation of the factors that control initiation, and studies of a DNA polymerase α‐primase enzyme complex. In this review, recent research on the initiation, elongation and termination phases of DNA replication is critically examined and a coherent picture is formulated. In the not‐far‐distant future we expect to reproduce these (...) processes in biochemically defined systems. (shrink)

When, why, and how does interpersonal forgiveness occur? These questions guided recent research that compared the relative abilities of empathy versus motivated reasoning models to account for the influence of relationship closeness on interpersonal forgiveness. Consistent support was provided for the Model of Motivated Interpersonal Forgiveness. This model hypothesizes that following relationship transgressions, relationship closeness leads to a desire to maintain a relationship. Desire to maintain a relationship leads to motivated reasoning. And motivated reasoning fosters interpersonal forgiveness. The goal of (...) the present research was to examine two concerns that emerged from the initial support for the Model of Motivated Interpersonal Forgiveness. First, were the measures of motivated reasoning and interpersonal forgiveness conflated, thus reducing the potential for empathy to account for interpersonal forgiveness? Second, did the analytic estimation used reduce the power to detect the mediational role of empathy? The present research examined these questions. When motivated reasoning was measured by thought listings (in addition to the original questionnaire items) and when the analytic estimation provided greater power, the Model of Motivated Interpersonal Forgiveness was replicated. (shrink)

The eukaryotic helicase is an 11-subunit machine containing an Mcm2-7 motor ring that encircles DNA, Cdc45 and the GINS tetramer, referred to as CMG. CMG is “built” on DNA at origins in two steps. First, two Mcm2-7 rings are assembled around duplex DNA at origins in G1 phase, forming the Mcm2-7 “double hexamer.” In a second step, in S phase Cdc45 and GINS are assembled onto each Mcm2-7 ring, hence producing two CMGs that ultimately form two replication forks that (...) travel in opposite directions. Here, we review recent findings about CMG structure and function. The CMG unwinds the parental duplex and is also the organizing center of the replisome: it binds DNA polymerases and other factors. EM studies reveal a 20-subunit core replisome with the leading Pol ϵ and lagging Pol α-primase on opposite faces of CMG, forming a fundamentally asymmetric architecture. Structural studies of CMG at a replication fork reveal unexpected details of how CMG engages the DNA fork. The structures of CMG and the Mcm2-7 double hexamer on DNA suggest a completely unanticipated process for formation of bidirectional replication forks at origins. Here, we review the structure and function of CMG, the 11 subunit helicase for eukaryotic DNA replication. Two CMGs are assembled at origins starting from two Mcm2-7 hexamers oriented N-to-N. The orientation of CMG at a forked DNA implies that the two CMGs at an origin pass one another. (shrink)

Although initiation of DNA replication is considered to be highly coordinated through multiple protein–DNA and protein–protein interactions, it is poorly understood how particular locations within the eukaryotic chromosome are selected as origins of DNA replication. Here, we discuss recent reports that present structural information on the interaction characteristics of the archaeal orthologues of the eukaryotic origin recognition complex with their cognate binding sequences.1,2 Since the archaeal replication system is postulated as a simplified version of the one (...) in eukaryotes, by analogy, these works provide insights into the functions of the eukaryotic initiator proteins. BioEssays 30:208–211, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Chromosomal origins of DNA replication in higher eukaryotes differ significantly from those of E. coli (oriC) and the tumor virus, SV40 (ori sequence). Initiation events appear to occur throughout broad zones rather than at specific origin sequences. Analysis of four chromosomal origin regions reveals that they share common modular sequence elements. These include DNA unwinding elements, pyrimidine tracts that may serve as strong DNA polymerase‐primase start sites, scaffold associated regions, transcriptional regulatory sequences, and, possibly, initiator protein binding sites (...) and inherently destabilized regions. Based on the novel organization of chromosomal origin regions, we propose a model for initiation of DNA replication in higher eukaryotes. Unwinding of duplex DNA during initiation may be uncoupled, both temporally and spatially, from DNA synthesis, resulting in transient single‐stranded intermediates that function in lieu of conventional replication forks during chromosomal DNA replication. DNA synthesis begins subsequently at multiple sites Within the unwound regions rather than at specific origin sequences. (shrink)

This paper argues that some of the discussion around meta-scientific issues can be viewed as an argument over different “meta-hypotheses” – assumptions made about how different hypotheses in a scientific literature relate to each other. I argue that, currently, such meta-hypotheses are typically left unstated except in methodological papers and that the consequence of this practice is that it is hard to determine what can be learned from a direct replication study. I argue in favor of a procedure dubbed (...) the “limited homogeneity assumption” – assuming very little heterogeneity of effect sizes when a literature is initiated but switching to an assumption of heterogeneity once an initial finding has been successfully replicated in a direct replication study. Until that has happened, we do not allow the literature to proceed to a mature stage. This procedure will elevate the scientific status of direct replication studies in science. Following this procedure, a well-designed direct replication study is a means of falsifying an overall claim in an early phase of a literature and thus sets up a hurdle against the canonization of false facts in the behavioral sciences. (shrink)

Recent studies have shed light on the emergence of Southern sustainability initiatives in commodity-based value chains. These initiatives position themselves as countering the exclusionary nature of many global multi-stakeholder initiatives, as critically analysed by previous studies. However, a common theoretical perspective on the inclusiveness of MSIs is still lacking. By drawing on the theory of regimes of engagement, we develop a theoretical framework which helps understanding the overt and subtle practices of including or excluding different stakeholders in MSIs. We apply (...) this framework to ‘Trustea’, an Indian MSI for sustainable tea production, to further investigate the ‘inclusiveness paradigm’ of Southern sustainability initiatives. Our findings highlight the complexity of stakeholder engagement across the different phases of Trustea’s development, from initiation and code development to formal launch and roll-out. We find that different types of engagement can exist in parallel. Justifiable engagement is expressed in the participating organisations’ reference to a shared common goal of Trustea, whereas familiar engagement is linked to the rootedness of the individuals involved in the Indian tea industry. Strategic engagement, in turn, comes to the fore through the strong emphasis on developing an Indian code for sustainable tea production and promoting adoption among tea growers. The importance of reaching this objective has led to the replication of exclusionary patterns also noted for global MSIs, as small-scale producers and other weak actors have been largely excluded from decision-making processes, despite informal efforts aimed at substitution of representation. (shrink)

ABSTRACTIs lying in a different language easier or more difficult? The Emotional Distance and the Cognitive Load hypothesis give competing answers. Suchotzki and Gamer measured the time native German speakers needed to initiate honest and deceptive answers to German and English questions. Lie-truth differences in RTs were much smaller for the foreign compared to the native language. In our preregistered replication study in native Dutch speakers, we found that lie-truth differences in RTs were moderately smaller when participants were tested (...) in English than when tested in Dutch. These findings indicate that people struggle with quickly retrieving the truth in another language, and that foreign language use may diminish lie-truth differences. (shrink)

In the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the initiation of DNA replication is controlled at a point called START. At this point, the cellular environment is assessed; only if conditions are appropriate do cells traverse START, thus becoming committed to initiate DNA replication and complete the remainder of the cell cycle. The cdc2+ / CDC28+ gene, encoding the protein kinase p34, is a key element in this complex control. The identification of structural and functional homologues of (...) p34 suggests that it has a role in the control of DNA replication in all eukaryotes. The WHI1+, CLN1+ and CLN2+ gene products, identified in S. cerevisiae, are positive regulators that function at START and may interact with p34. Determining how passing the START control point leads to the initiation of DNA replication is a major outstanding challenge in cell cycle studies. (shrink)

Biochemical and cryo‐electron microscopy studies have just been published revealing interactions among proteins of the yeast replisome that are important for highly coordinated synthesis of the two DNA strands of the nuclear genome. These studies reveal key interactions important for arranging DNA polymerases α, δ, and ϵ for leading and lagging strand replication. The CMG (Mcm2‐7, Cdc45, GINS) helicase is central to this interaction network. These are but the latest examples of elegant studies performed in the recent past that (...) lead to a much better understanding of how the eukaryotic replication fork achieves efficient DNA replication that is accurate enough to prevent diseases yet allows evolution. (shrink)

Within the highly organized nuclear structure, specific nuclear domains (ND10) are defined by accumulations of proteins that can be interferon-upregulated, implicating ND10 as sites of a nuclear defense mechanism.Compatible with such a mechanism is the deposition of herpesvirus, adenovirus, and papovavirus genomes at the periphery of ND10. However, these DNA viruses begin their transcription at ND10 and consequently initiate replication at these sites, suggesting that viruses have evolved ways to circumvent this potential cellular defense and exploit it. Other ND10-associated (...) proteins belong to ubiquitin-related pathways. These findings, together with the accumulation of various overexpressed cellular and viral proteins, suggest that ND10 function as nuclear dumps or as nuclear depots. Consistent with the recruitment or deposition of various proteins and viral genomes adjacent to ND10, ND10 themselves may only be protein accumulations at specific but as yet undefined nuclear deposition sites. The concept of specific nuclear deposition sites may explain the juxtaposition of various nuclear bodies and allows testable predictions about a potential supramolecular regulatory mechanism whereby proteins are selectively segregated or released by global changes induced in nuclear functions such as viral infections, stress, or hormonal induction. BioEssays 20:660–667, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Research ethics review is a critical aspect of the research governance framework for human subjects research. This usually requires that research protocols be submitted to a research ethics committee for review and approval. This has led to very rapid developments in the domain of research ethics, as RECs proliferate all over the globe in rhyme with the explosion in human subjects research. The work of RECs has increasingly become elaborate, complex, and in many cases urgent, necessitating supporting rules and procedures (...) of operation. Guidelines for elaborating standard operating procedures for the functioning of RECs have also been proposed. The SOPs of well-placed and well-resourced RECs have tended to pay much attention to details, resulting, as a consequence, in generally long, elaborate, intricate and complex SOPs; a model that can hardly be replicated by other committees, equally under ethics review pressures, but working under much more constraining conditions in resource-destitute environments. In this paper, we looked at the content and length of SOPs from African RECs and compared them to the World Health Organization ’s guidelines as the gold standard. We also looked at the SOPs from the Ethics Review and Consultancy Committee of the Cameroon Bioethics Initiative that we elaborated in a simplified way in 2013, and compared them to the WHO’s guidelines and to the other SOPs. Sixteen SOPs from 14 African countries were collected from various sources. Their average length was of 30 pages. By comparison to the guidance of the WHO, only six of them were found acceptable with more than 70 % of the criteria from the gold standard that were fully described. Among those six, two of them were very long and detailed, while the four remaining SOPs ranged from 16 to 24 pages. The ERCC SOPs are seven pages long but maintain all that is of essence for the rigorous, efficient and timely review of protocols. We are convinced that, because of their brevity, simplicity, clarity and user-friendliness, the ERCC SOPs recommend themselves as a model template to, at least, committees similarly situated and/or circumstanced as the ERCC of the Cameroon Bioethics Initiative is. In fact, brevity, clarity, simplicity and user-friendliness are recognized values. Whatever is brief and clear is better than what is not and saves time. What is simple and user-friendly is better than what is not even though the two have the same aims because it saves both time and mental energy. And if this be true in general, it is even truer of the context and its peculiar constraints that we are addressing. (shrink)

In a recent work, we introduced a theoretical model for fulfillment in life that covers cognitive and affective components and distinguishes different time frames. The present study evaluates this model and describes the construction of the Fulfilled Life Scale to assess fulfillment regarding the whole lived life retrospectively. We investigated the scale in two samples. The model of the cognitive component combines three sources of fulfillment with three criteria, yielding nine facets. Employing hierarchical factor analysis, we inspected all solutions between (...) one and nine. We identified three optimal factors, which we labeled unfolded self and life, the worthwhile life, and positive impact and legacy. Next, we selected marker items and replicated the factor structure in Sample 2. The three scales were positively intercorrelated and showed good internal consistency in both samples. For the affective component, exploratory and confirmatory factor analyses established a one-factor structure in both samples, and high internal consistency was obtained. Across a range of related constructs, we demonstrated construct and criterion validity. Notably, cognitive and affective fulfillment incrementally predicted a global rating of a fulfilled life and mental well-being, even after controlling for subjective and eudaimonic well-being. Overall, the study proves that the FLS is necessary to capture people’s experience of a fulfilled life, which could not be assessed sufficiently with previous well-being measures. Both cognitive and affective fulfillment were able to predict additional variance in mental well-being. Moreover, the study reveals psychometric support for the FLS and presents the first evidence on its validity. Lastly, applications in research and practice are discussed, especially in the context of living and aging well in the second half of life. (shrink)

In vertebrates, single cell analyses of replication timing patterns brought to light a very well controlled program suggesting a tight regulation on initiation sites. Mapping of replication origins with different methods has revealed discrete preferential sites, enriched in promoters and potential G‐quadruplex motifs, which can aggregate into initiation zones spanning several tens of kilobases (kb). Another characteristic of replication origins is a nucleosome‐free region (NFR). A modified yeast strain containing a humanized origin recognition complex (ORC) (...) fires new origins at NFRs revealing their regulatory role. In cooperation with NFRs, the histone variant H2A.Z facilitates ORC loading through di‐methylation of lysine 20 of histone H4. Recent studies using genome editing methods show that efficient initiation sites associated with transcriptional activity can synergize over several tens of kb by establishing physical contacts and lead to the formation of early domains of DNA replication demonstrating a co‐regulation between replication initiation and transcription. (shrink)

Metacognitions, which are beliefs about our own thinking processes, can modulate worry and rumination and thereby influence emotional distress. This study aimed to develop a self-report measure of unhelpful pain-related metacognitions which might serve as a clinical and research tool to better understand pain catastrophizing, a significant risk factor for adverse pain outcomes. Two phases of validation are presented. Phase 1 reports on how the Pain Metacognitions Questionnaire (PMQ) was empirically developed through a qualitative study of 20 people with chronic (...) back ( n = 15) or knee ( n = 5) pain in secondary or tertiary care and then validated in a large internet sample of people experiencing pain ( N = 864). Rasch analysis yielded a 21-item scale with two dimensions (positive and negative metacognition) assessing how useful and problematic people believe rumination about pain to be, respectively. In Phase 2, further validation using a new sample ( N = 510) replicated initial findings. Both PMQ subscales have good retest reliability ( r = 0.76, r = 0.72) and internal consistency (0.86, 0.87). They correlate negatively with mindfulness and positively with pain intensity, disability, anxiety, depression, catastrophizing, rumination, and metacognition. The PMQ also predicts unique variance in catastrophizing when other variables are controlled and predicts ‘patient’ status for pain catastrophizing. Sensitivity analysis yielded preliminary suggestions for clinically meaningful cut-offs. Unhelpful pain metacognitions can be validly and reliably measured using a self-report instrument. Future studies using the PMQ might shed new light on pain-related thinking processes to develop better interventions for people prone to worry and rumination about their pain. (shrink)

The harmonious growth and cell‐to‐cell uniformity of steady‐state bacterial populations indicate the existence of a well‐regulated cell cycle, responding to a set of internal signals. In Escherichia coli, the key events of this cycle are the initiation of DNA replication, nucleoid segregation and the initiation of cell division. The replication initiator is the DnaA protein. In nucleoid segregation, the MukB protein, required for proper partitioning, may be a member of the myosin‐kinesin superfamily of mechanoenzymes. In cell (...) division, the FtsZ protein has a tubulin motif, is a GTPase and polymerizes in a ring around midcell during septation; the FtsA protein has an actin‐like structure. The nature of the internal signals triggering these events is not known but candidates include cell mass, the superhelical density of the chromosome and the concentration of two regulatory nucleotides, cyclic AMP and ppGpp. The involvement of cytoskeletal‐like proteins in key cycle events encourages the notion of a fundamental biological unity in cell cycle regulation in all organisms. (shrink)

Recent research indicates that interpersonal communication is noisy, and that people exhibit considerable insensitivity to problems in communication. Using a dyadic referential communication task, the goal of which is accurate information transfer, this study examined the extent to which interlocutors are sensitive to problems in communication and use other‐initiated repairs (OIRs) to address them. Participants were randomly assigned to dyads (N = 88 participants, or 44 dyads) and tried to communicate a series of recurring abstract geometric shapes to a partner (...) across a text–chat interface. Participants alternated between directing (describing shapes) and matching (interpreting shape descriptions) roles across 72 trials of the task. Replicating prior research, over repeated social interactions communication success improved and the shape descriptions became increasingly efficient. In addition, confidence in having successfully communicated the different shapes increased over trials. Importantly, matchers were less confident on trials in which communication was unsuccessful, communication success was lower on trials that contained an OIR compared to those that did not contain an OIR, and OIR trials were associated with lower Director Confidence. This pattern of results demonstrates that (a) interlocutors exhibit (a degree of) sensitivity to problems in communication, (b) they appropriately use OIRs to address problems in communication, and (c) OIRs signal problems in communication. (shrink)

It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so‐called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of (...) factors is required to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions. (shrink)

Georg Simon Ohm's work in the field of electricity led to what is now considered to be the most fundamental law of electrical circuits, Ohm's Law. Much less known is that only months earlier, Ohm had published another law—one that differed significantly from the now accepted one. The latter entailed a logarithmic relation between the length of the conductor and a parameter that Ohm called “loss of force.” This paper discusses how Ohm came up with an initial law that he (...) felt compelled to correct a few months later. We analyze Ohm's publication as well as his laboratory notes, relating them to our own laboratory experiences while using the replication method to study his work. We also discuss the conceptual background of Ohm's work. We conclude that he was significantly influenced by French studies in the field of electricity, most notably the ones by Charles Augustin Coulomb. (shrink)

The replicator dynamics have been used to study the evolution of a population of rational agents playing the Nash bargaining game, where an individual's "fitness" is determined by an individual's success in playing the game. In these models, a population whose initial conditions was randomly chosen from the space of population proportions converges to a state of fair division approximately 62% of the time. (Higher rates of convergence to final states of fair division can be obtained by introducing artificial correlations (...) into the models.) Spatial models of the Nash bargaining game exhibit considerably more robust convergence properties. These properties are considered at length, and a sufficient condition for convergence to fair division is proved. (shrink)

The most enigmatic feature of polytene chromosomes is their banding pattern, the genetic organization of which has been a very attractive puzzle for many years. Recent genome‐wide protein mapping efforts have produced a wealth of data for the chromosome proteins of Drosophila cells. Based on their specific protein composition, the chromosomes comprise two types of bands, as well as interbands. These differ in terms of time of replication and specific types of proteins. The interbands are characterized by their association (...) with “active” chromatin proteins, nucleosome remodeling, and origin recognition complexes, and so they have three functions: acting as binding sites for RNA pol II, initiation of replication and nucleosome remodeling of short fragments of DNA. The borders and organization of the same band and interband regions are largely identical, irrespective of the cell type studied. This demonstrates that the banding pattern is a universal principle of the organization of interphase polytene and non‐polytene chromosomes.Editor's suggested further reading in BioEssaysCaught in the act: Rapid, symbiont‐driven evolution AbstractFunction and evolution of sex determination mechanisms, genes and pathways in insects Abstract. (shrink)

ABSTRACT After initially pitting partisans against purists, the literature on the ethics of fandom has coalesced around a pluralist position: purists and partisans each have their own merits, and there is no ideal form of fandom. In this literature, however, the fair-weather fan continues to be viewed with dismissal and derision. While some fair-weather fans may earn this contempt, many fair-weather fans, we argue, are not only acceptable, they have important advantages over partisans and purists, and as such are in (...) a better position to navigate some of the moral complexities inherent in modern sports. We develop this argument first by clarifying the nature of the fair-weather fan. We then examine challenges that fans face in many modern sports, first owing to their economic nature and, second, due to the morally tainted status of many of them. We argue that the fair-weather fan meets these challenges in ways that the partisan and purist cannot replicate. (shrink)

Three proteins used to initiate DNA replication and carry out site‐specific recombination in E. coli generate organized nucleoprotein structures at their target sites. The association of proteins bound at multiple sites on DNA presumably folds or winds the DNA to produce a specific three‐dimensional conformation. This specialized nucleoprotein structure may be a general mechanism for achieving very high fidelity in DNA transactions in which even a rare mistake must be avoided. The overall interaction is more complex than that of (...) prokaryotic transcription regulators studied so far, but might be characteristic of eukaryotic transcription regulators, for which the problem of site‐localization is more difficult. (shrink)