The instability of microsatellite DNA repeats is responsible for at least 40 neurodegenerative diseases. Recently, Mirkin and co‐workers presented a novel mechanism for microsatellite expansions based on break‐induced replication (BIR) at sites of microsatellite‐induced replication stalling and fork collapse. The BIR model aims to explain single‐step, large expansions of CAG/CTG trinucleotide repeats in dividing cells. BIR has been characterized extensively in Saccharomyces cerevisiae as a mechanism to repair broken DNA replication forks (single‐ended DSBs) and degraded telomeric (...) DNA. However, the structural footprints of BIR‐like DSB repair have been recognized in human genomic instability and tied to the etiology of diverse developmental diseases; thus, the implications of the paper by Kim et al. (Kim JC, Harris ST, Dinter T, Shah KA, et al., Nat Struct Mol Biol 24: 55–60) extend beyond trinucleotide repeat expansion in yeast and microsatellite instability in human neurological disorders. Significantly, insight into BIR‐like repair can explain certain pathways of complex genome rearrangements (CGRs) initiated at non‐B form microsatellite DNA in human cancers. (shrink)

In this review, we discuss how two evolutionarily conserved pathways at the interface of DNA replication and repair, template switching and break-induced replication, lead to the deleterious large-scale expansion of trinucleotide DNA repeats that cause numerous hereditary diseases. We highlight that these pathways, which originated in prokaryotes, may be subsequently hijacked to maintain long DNA microsatellites in eukaryotes. We suggest that the negative mutagenic outcomes of these pathways, exemplified by repeat expansion diseases, are likely outweighed by their positive (...) role in maintaining functional repetitive regions of the genome such as telomeres and centromeres. Break-induced replication and template switching are conserved mechanisms of replication fork restart. They do not cause microsatellite instability in prokaryotes, but promote repeat expansion in eukaryotes. We suggest that TS and BIR persisted in eukaryotes despite their mutagenic potential because they help maintain long repetitive telomeres and centromeres. (shrink)

UV‐radiation‐induced lesions in DNA result in the formation of: (1) excision gaps (i.e. a lesion is excised, leaving a gap), (2) daughter‐strand gaps (i.e. a lesion can be skipped during replication, leaving a gap), and (3) double‐strand breaks (i.e. the DNA strand opposite a gap can be cut). In Escherichia coli, the recA gene product is involved in repairs of all three types of lesions – repair of daughter‐strand gaps (2) and double‐strand breaks (3) constitutes post‐replication repair. The (...) evidence suggests, furthermore, that recA‐dependent repair of excision gaps (1) produced in DNA replicated prior to UV irradiation (pre‐replication repair) appears to occur by similar mechanisms. (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)

Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress‐induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress‐induced mutation that are being revealed experimentally in laboratory settings provide (...) compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double‐strand‐break‐dependent stress‐induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti‐evolvability therapeutics for infectious disease and cancer. (shrink)

Conventional wisdom suggests mid-task rest as a potential approach to relieve the time-on-task (TOT) effect while accumulating evidence indicated that acute exercise might also effectively restore mental fatigue. However, few studies have explored the neural mechanism underlying these different break types, and the results were scattered. This study provided one of the first looks at how different types of fatigue-recovery break exerted influence on the cognitive processes by evaluating the corresponding behavioral improvement and neural response (EEG power spectral) in a (...) sustained attention task. Specifically, 19 participants performed three sessions of psychomotor vigilance tasks (PVT), with one session including a continuous 30-min PVT while the other two sessions additionally inserted a 15-min mid-task cycling and rest break, respectively. For behavioral performance, both types of break could restore objective vigilance transiently, while subjective feeling was only maintained after mid-task rest. Moreover, divergent patterns of EEG change were observed during post-break improvement. In detail, relative theta decreased and delta increased immediately after mid-task exercise, while decreased delta was found near the end of the rest-inserted task. Meanwhile, theta and delta could serve as neurological indicators to predict the reaction time change for exercise and rest intervention, respectively. In sum, our findings provided novel evidence to demonstrate divergent neural patterns following the mid-task exercise and rest intervention to counter TOT effects, which might lead to new insights into the nascent field of neuroergonomics for mental fatigue restoration. (shrink)

The motivation of the study is to explore the nexus tourism-led sustainable human capital development in Brazil, Russia, India, China, and South Africa for the period 1984–2019. The study applied several econometrical techniques for exposing the empirical association between tourism and HCD, such as the conventional and structural break unit root test, the combined cointegration test, long-run and short-run coefficients detected through implementing the Augmented Autoregressive Distributed Lagged, and directional causality by following Toda-Yamamoto with Fourier function. The unit-roots test established (...) variables are integrated in mixed order, wherein variables are stationary at a level or after the first difference. The estimated test statistics from the combined cointegration test and AARDL confirmed the long-run association between tourism, gross capital formation, financial development, and HCD. Tourism revealed a positive and statistically significant tie with HCD in the long run. Moreover, the joint effects of interactive terms TOR*GCF and TOR*FD established a positive and statistically significant relationship with HCD. In addition, the causality test revealed the feedback hypothesis available between tourism and HCD in all sample countries except India. In conclusion, the role of tourism development is critically important for sustainable HCD in BRICS. Therefore, in case of a policymaking concern, it is inevitable to address the tourism issues with care for capitalizing on the benefits for tourism development. (shrink)

Replication protein A (RPA), the major single‐stranded DNA‐binding protein in eukaryotic cells, is required for processing of single‐stranded DNA (ssDNA) intermediates found in replication, repair, and recombination. Recent studies have shown that RPA binding to ssDNA is highly dynamic and that more than high‐affinity binding is needed for function. Analysis of DNA binding mutants identified forms of RPA with reduced affinity for ssDNA that are fully active, and other mutants with higher affinity that are inactive. Single molecule studies (...) showed that while RPA binds ssDNA with high affinity, the RPA complex can rapidly diffuse along ssDNA and be displaced by other proteins that act on ssDNA. Finally, dynamic DNA binding allows RPA to prevent error‐prone repair of double‐stranded breaks and promote error‐free repair. Together, these findings suggest a new paradigm where RPA acts as a first responder at sites with ssDNA, thereby actively coordinating DNA repair and DNA synthesis. (shrink)

The bacterium Deinococcus (formerly Micrococcus) radiodurans and other members of the eubacterial family Deinococaceae are extremely resistant to ionizing radiation and many other agents that damage DNA. Stationary phase D. radiodurans exposed to 1.0‐1.5 Mrad γ‐irradiation sustains >120 DNA double‐strand breaks (dsbs) per chromosome; these dsbs are mended over a period of hours with 100% survival and virtually no mutagenesis. This contrasts with nearly all other organisms in which just a few ionizing radiation induced‐dsbs per chromosome are lethal. In this (...) article we present an hypothesis that resistance of D. radiodurans to ionizing radiation and its ability to mend radiation‐induced dsbs are due to a special form of redundancy wherein chromosomes exist in pairs, linked to each other by thousands of four‐stranded (Holliday) junctions. Thus, a dsb is not a lethal event because the identical undamaged duplex is nearby, providing an accurate repair template. As addressed in this article, much of what is known about D. radiodurans suggests that it is particularly suited for this proposed novel form of DNA repair. (shrink)

This paper shows the relevance of an evolutionary model for the study of language change. We focus on a cognitive and usage-based approach to language change, namely the Theory of Utterance Selection developed by Croft (2000). Croft's evolutionary approach takes its inspiration from neo-Darwinian evolutionary theory, particularly the Generalized Theory of Selection developed by Hull (1988), a philosopher of science. Language is viewed as a system of use governed by convention, and language change results from breaking with convention and propagating (...) this innovation through the linguistic community until it becomes a new convention. Crucially, altered replication can be equated with language innovation, and propagation of individual changes is the linguistic counterpart of the differential perpetuation or selection of replicators. We will argue within the framework of Cognitive Linguistics (Geeraerts & Cuyckens, 2007) for a more systematic integration of cognitive and social factors in the explanation of language change. The mechanisms for language innovation are cognitive, as the pnnciples of cognitive efficiency like prototypicality constitute the main motivations for language change and metaphor and metonymy the main cognitive mechanisms of semantic change. The mechanisms for propagation are essentially social, including processes such as accommodation, identity and prestige. All of these mechanisms occur in individual communicative acts and operate like an "invisible hand" (Keller, 1994). We illustrate the sociocognitive evolutionary model of language change with some case studies on semantic change in Portuguese. (shrink)

A widely accepted assumption in radiobiology is that ionizing radiation kills cells by inducing forms of damage in DNA structures that lead to the formation of lethal chromosome aberrations. One goal of radiation biology research is the identification of these forms of DNA damage, the characterization of the mechanisms involved in their repair and the elucidation of the processes involved in their transformation to chromosome damage, In recent years, evidence has accumulated implicating DNA double stranded breaks as lesions relevant for (...) cell killing. Here, the available information on this topic is reviewed together with the methods most commonly used to quantitate induction and repair of this type of lesion. The presentation concludes with an outline of present research directions and future goals. (shrink)

Myc‐driven tumorigenesis involves a non‐transcriptional role for Myc in over‐activating replicative Cdc45‐MCM‐GINS (CMG) helicases. Excessive stimulation of CMG helicases by Myc mismanages CMG function by diminishing the number of reserve CMGs necessary for fidelity of DNA replication and recovery from replicative stresses. One potential outcome of these events is the creation of DNA damage that alters genomic structure/function, thereby acting as a driver for tumorigenesis and tumor heterogeneity. Intriguingly, another potential outcome of this Myc‐induced CMG helicase over‐activation is the (...) creation of a vulnerability in cancer whereby tumor cells specifically lack enough unused reserve CMG helicases to recover from fork‐stalling drugs commonly used in chemotherapy. This review provides molecular and clinical support for this provocative hypothesis that excessive activation of CMG helicases by Myc may not only drive tumorigenesis, but also confer an exploitable “reserve CMG helicase vulnerability” that supports developing innovative CMG‐focused therapeutic approaches for cancer management. (shrink)

Last year, we reported a new mechanism of DNA replication in mammals. It occurs inside mitochondria and entails the use of processed transcripts, termed bootlaces, which hybridize with the displaced parental strand as the replication fork advances. Here we discuss possible reasons why such an unusual mechanism of DNA replication might have evolved. The bootlace mechanism can minimize the occurrence and impact of single‐strand breaks that would otherwise threaten genome stability. Furthermore, by providing an implicit mismatch recognition (...) system, it should limit the occurrence of replication‐dependent deletions and insertions, and defend against invading elements. Such a mechanism may also limit attempts to manipulate the mammalian mitochondrial genome. (shrink)

Brain states, which correlate with specific motor, cognitive, and emotional states, may be monitored with noninvasive techniques such as electroencephalography and magnetoencephalography that measure macroscopic cortical activity manifested as oscillatory network dynamics. These rhythmic cortical signatures provide insight into the neuronal activity used to identify pathological cortical function in numerous neurological and psychiatric conditions. Sensory and transcranial stimulation, entraining the brain with specific brain rhythms, can effectively induce desired brain states correlated with such cortical rhythms. Because brain states have distinct (...) neural correlates, it may be possible to induce a desired brain state by replicating these neural correlates through stimulation. To do so, we propose recording brain waves from a “donor” in a particular brain state using EEG/MEG to extract cortical signatures of the brain state. These cortical signatures would then be inverted and used to entrain the brain of a “recipient” via sensory or transcranial stimulation. We propose that brain states may thus be transferred between people by acquiring an associated cortical signature from a donor, which, following processing, may be applied to a recipient through sensory or transcranial stimulation. This technique may provide a novel and effective neuromodulation approach to the noninvasive, non-pharmacological treatment of a variety of psychiatric and neurological disorders for which current treatments are mostly limited to pharmacotherapeutic interventions. (shrink)

Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN (...) and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN‐BRCA2 genetic interaction under conditions of replication stress. (shrink)

The simian virus 40 chromosome, a model for the mammalian replicon, is a uniquely powerful system for the study of drugs and treatments which target enzymes of the mammalian replication apparatus. High resolution gel electrophoretic analysis of normal and aberrant viral replication intermediates can be used effectively to understand the molecular events of replication failure. These events include breakage of replication forks, aberrant topoisomerase action, failure to separate daughter chromosomes, protein‐DNA crosslinking, single and double strand DNA (...) breakage, alterations in topology and inactivation of replication intermediates. The SV40 replication system can also be used to study the recombinational events which often follow drug‐induced replication failure. (shrink)

A classic finding reported in Beck (1966a) is that observers tend to indicate a more natural texture break between a set of T’s and tilted T’s than between a set of T’s and backward L’s. This finding has played a prominent role in discussions about the properties of texture segmentation and in the development of computational theories of texture segmentation. Due to the small sample size of the original study, we replicated the original experiment with a larger sample. Regrettably, we (...) discovered that the description in Beck (1966a) is insufficient to allow us to reproduce the stimuli. For our replication, we created stimuli that seem consistent with the spirit of the original study. The results of the replication study partly matchBeck’s original data (r = .59), but conclusions indicated by these results deviate from some of Beck’s key conclusions.We also further explored the influential claim derived from a second experiment in Beck (1966a) that texture segmentation was not related to the perceived similarity of elements. Contrary to this claim, a re-analysis of Beck’s data indicates the counterintuitive conclusion that observers tend to indicate stronger texture segmentation between regions that are rated as being more similar. In a replication of the second experiment, this relation flipped so that the replication observers indicated stronger texture segmentation for regions with lower similarity ratings. Despite being influential, we conclude that there are substantial problems with the stimuli, analyses, and conclusions in Beck (1966a). (shrink)

Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers (...) stress tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment. PTEN is a guardian of the genome. However, the role of PTEN in guarding the genome has not been revealed until recently. PTEN controls multiple fundamental processes of genomic transmission. By physically interacting with key molecules in DNA replication, DNA repair/decatenation, and chromosome segregation during the cell cycle, PTEN maintains genomicintegrity and fitness. (shrink)

Symmetry-based explanations using symmetry breaking as the key explanatory tool have complemented and replaced traditional causal explanations in various domains of physics. The process of spontaneous SB is now a mainstay of contemporary explanatory accounts of large chunks of condensed-matter physics, quantum field theory, nonlinear dynamics, cosmology, and other disciplines. A wide range of empirical research into various phenomena related to symmetries and SB across biological scales has accumulated as well. Led by these results, we identify and explain some common (...) features of the emergence, propagation, and cascading of SB-induced layers across the biosphere. These features are predicated on the thermodynamic openness and intrinsic functional incompleteness of the systems at stake and have not been systematically analyzed from a general philosophical and methodological perspective. We also consider possible continuity of SB across the physical and biological world and discuss the connection between Darwinism and SB-based analysis of the biosphere and its history. (shrink)

The voluntary suspension of play is a putative fair play norm that has emerged in the last 20 years in association football, though there is no reason in principle why it is limited to that sport. It occurs in football when an injury appears to have been sustained and another player deliberately puts the ball out of play so that the injury can receive rapid attention. It is widely understood as a positive development within the sport and philosophers have added (...) their support on the basis that VSP is a way of players exercising autonomous moral responsibility. It is represented as a case of athletes putting care for their competitors before care for the contest. In this paper, however, it is argued that moral praise for VSP is misplaced. Attempts to induce a VSP almost always occur when a team is seeking to hold a position within a game. As a delaying tactic, it encourages the faking of injuries, which is all the more reprehensible because it exploits someone else's concern for that apparent injury. Conditions for the possibility of VSP within a sport are analysed as well as conditions for the abuse of VSP. VSP occurs because of a loophole, and ways in which this can be closed are presented. In an appendix, some initial empirical evidence is presented that backs the evaluative claims of the paper. (shrink)

Enzymatic misrepair of ionizing‐radiation‐induced DNA damage can produce large‐scale rearrangements of the genome, such as translocations and dicentrics. These and other chromosome exchange aberrations can cause major phenotypic alterations, including cell death, mutation and neoplasia. Exchange formation requires that two (or more) genomic loci come together spatially. Consequently, the surprisingly rich aberration spectra uncovered by recently developed techniques, when combined with biophysically based computer modeling, help characterize large‐scale chromatin architecture in the interphase nucleus. Most results are consistent with a picture (...) whereby chromosomes are mainly confined to territories, chromatin motion is limited, and interchromosomal interactions involve mainly territory surfaces. Aberration spectra and modeling also help characterize DNA repair/misrepair mechanisms. Quantitative results for mammalian cells are best described by a breakage‐and‐reunion model, suggesting that the dominant recombinational mechanism during the G0/G1 phase of the cell cycle is non‐homologous end‐joining of radiogenic DNA double strand breaks. In turn, better mechanistic and quantitative understanding of aberration formation gives new insights into health‐related applications. BioEssays 24:714–723, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted multiple (...) pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

It is pointed out that the Higgs field may be supplanted by an ordinary Klein-Gordon field conformally coupled to the space-time curvature, and with very small, real, rest mass. Provided there is a bare cosmological constant of order of its square mass, this field can induce spontaneous symmetry breaking with a mass scale that can be as large as the Planck-Wheeler mass, but may be smaller. It can thus play a natural role in grand unified theories. In the theory presented (...) here the physical cosmological constant is small, being of order of the squared mass, and can meet observational constraints without having to be cancelled accurately. The physical gravitational constant differs somewhat from the coupling constant in Einstein's equation, and is temperature dependent in the broken symmetry regime. Symmetry restoration occurs at high temperature. (shrink)

Cells mitigate the detrimental consequences of DNA damage on genome stability by attempting high fidelity repair. Homologous recombination templates DNA double‐strand break (DSB) repair on an identical or near identical donor sequence in a process that can in principle access the entire genome. Other physiological processes, such as homolog recognition and pairing during meiosis, also harness the HR machinery using programmed DSBs to physically link homologs and generate crossovers. A consequence of the homology search process by a long nucleoprotein filament (...) is the formation of multi‐invasions (MI), a joint molecule in which the damaged ssDNA has invaded more than one donor molecule. Processing of MI joint molecules can compromise the integrity of both donor sites and lead to their rearrangement. Here, two mechanisms for the generation of rearrangements as a pathological consequence of MI processing are detailed and the potential relevance for non‐allelic homologous recombination discussed. Finally, it is proposed that MI‐induced crossover formation may be a feature of physiological recombination. (shrink)

Small tandem DNA duplications in the range of 15 to 300 base‐pairs play an important role in the aetiology of human disease and contribute to genome diversity. Here, we discuss different proposed mechanisms for their occurrence and argue that this type of structural variation mainly results from mutagenic repair of chromosomal breaks. This hypothesis is supported by both bioinformatical analysis of insertions occurring in the genome of different species and disease alleles, as well as by CRISPR/Cas9‐based experimental data from different (...) model systems. Recent work points to fill‐in synthesis at double‐stranded DNA breaks with complementary sequences, regulated by end‐joining mechanisms, to account for small tandem duplications. We will review the prevalence of small tandem duplications in the population, and we will speculate on the potential sources of DNA damage that could give rise to this mutational signature. With the development of novel algorithms to analyse sequencing data, small tandem duplications are now more frequently detected in the human genome and identified as oncogenic gain‐of‐function mutations. Understanding their origin could lead to optimized treatment regimens to prevent therapy‐induced activation of oncogenes and might expose novel vulnerabilities in cancer. (shrink)

Cohesin establishes sister‐chromatid cohesion during S phase to ensure proper chromosome segregation in mitosis. It also facilitates postreplicative homologous recombination repair of DNA double‐strand breaks by promoting local pairing of damaged and intact sister chromatids. In G2 phase, cohesin that is not bound to chromatin is inactivated, but its reactivation can occur in response to DNA damage. Recent papers by Koshland's and Sjögren's groups describe the critical role of the known cohesin cofactor Eco1 (Ctf7) and ATR checkpoint kinase in damage‐induced (...) reactivation of cohesin, revealing an intricate mechanism that regulates sister‐chromatid pairing to maintain genome integrity.1,2 BioEssays 30:5–9, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Spontaneous polarization without spatial cues, or symmetry breaking, is a fundamental problem of spatial organization in biological systems. This question has been extensively studied using yeast models, which revealed the central role of the small GTPase switch Cdc42. Active Cdc42‐GTP forms a coherent patch at the cell cortex, thought to result from amplification of a small initial stochastic inhomogeneity through positive feedback mechanisms, which induces cell polarization. Here, I review and discuss the mechanisms of Cdc42 activity self‐amplification and dynamic turnover. (...) A robust Cdc42 patch is formed through the combined effects of Cdc42 activity promoting its own activation and active Cdc42‐GTP displaying reduced membrane detachment and lateral diffusion compared to inactive Cdc42‐GDP. I argue the role of the actin cytoskeleton in symmetry breaking is not primarily to transport Cdc42 to the active site. Finally, negative feedback and competition mechanisms serve to control the number of polarization sites. (shrink)

This study shows how precise simple analytical solutions for the generalized Dirac equation with repulsive vector and attractive energy-dependent Lorentz scalar potentials, position-dependent mass potential, and a tensor interaction term can be obtained within the framework of both similarity transformation and the asymptotic iteration methods. These methods yield a significant improvement over existing approaches and provide more plausible and applicable ways in explaining the pseudospin symmetry’s breaking mechanism in nuclei.

Aquinas is often presented as following Aristotle's "Nicomachean Ethics" when treating moral virtue. Less often do philosophers consider that Aquinas's conception of the highest good and its relation to the functional character of human activity led him to break with Aristotle by replicating each of the acquired moral virtues on an infused level. The author suggests that we can discern reasons for this move by examining Aquinas's commentary on the "Sententiae" of Peter the Lombard and the "Summa theologiae" within their (...) historical context. The author's thesis is that Dominican pastoral and intellectual concerns led Aquinas to argue that moral virtue must necessarily be ordered toward the highest good. Understanding this purpose helps to explain his presentation of moral virtue and its implications for standard philosophical interpretations of his work. (shrink)

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double‐strand‐break‐inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA‐strand breaks trigger widespread activation of ATM through changes in chromatin structure.1 This review discusses a checkpoint activation model in which chromatin perturbations lead to the (...) conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells. BioEssays 25:627–630, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Interferon stimulated gene 15 (ISG15) encodes a ubiquitin‐like protein that is highly induced upon activation of interferon signaling and cytoplasmic DNA sensing pathways. As part of the innate immune system ISG15 acts to inhibit viral replication and particle release via the covalent conjugation to both viral and host proteins. Unlike ubiquitin, unconjugated ISG15 also functions as an intracellular and extra‐cellular signaling molecule to modulate the immune response. Several recent studies have shown ISG15 to also function in a diverse array (...) of cellular processes and pathways outside of the innate immune response. This review explores the role of ISG15 in maintaining genome stability, particularly during DNA replication, and how this relates to cancer biology. It puts forth the hypothesis that ISG15, along with DNA sensors, function within a DNA replication fork surveillance pathway to help maintain genome stability. (shrink)

In their cognitive theory of emotion, Schachter and Singer proposed that feelings are separable from what they are about. As a test, they induced feelings of arousal by injecting epinephrine and then molded them into different emotions. They illuminated how feelings in one moment lead into the next to form a stream of conscious experience. We examine the construction of emotion in a similar spirit. We use the sensory integration process to understand how the brain combines disparate sources of information (...) to construct both perceptual and emotional models of the world even as the world continues to change. We emphasize two processes: affect segmentation (isolating the felt component of an emotion) and affect integration (recombining this feeling with its object). (shrink)

Emotional stimuli (e.g. words, images) are often remembered better than neutral stimuli. However, little is known about how memory is affected by an environmentally induced emotional state (without any overtly emotional occurrences) – the focus of this study. Participants were randomly assigned to discovery (n = 305) and replication (n = 306) subsamples and viewed a desktop virtual environment before rating their emotions and completing objective (i.e. item, temporal-order, duration) and subjective (e.g. vividness, sensory detail, coherence) memory measures. In (...) both samples, a Partial Least Squares Correlation analysis showed that an emotional state characterised by high negative emotion (i.e. threat, fear, anxiety) and arousal was reliably associated with better memory in both objective (i.e. item) and subjective (i.e. vividness and sensory detail) domains. No reliable associations were observed for any temporal memory measures (objective or subjective). Thus, an environmentally induced state of negative emotion corresponds with enhanced memory for indices of episodic memory pertaining to “what” happened, but not necessarily “when” it happened. (shrink)

Inhibiting the progress of replication forks in E. coli makes them susceptible to breakage. Broken replication forks are evidently reassembled by the RecBCD recombinational repair pathway. These findings explain a particular pattern of DNA degradation during inhibition of chromosomal replication, the role of recombination in the viability of mutants with displaced replication origin, and hyper‐recombination observed in the Terminus of the E. coli chromosome in rnh mutants. Breakage and repair of inhibited replication forks could be (...) the reason for the recombination‐dependence of inducible stable DNA replication. A mechanism by which RecABCD‐dependent recombination between very short inverted repeats may help E. coli to invert an operon, transcribed in the direction opposite to that of DNA replication, is discussed. (shrink)

Homologous recombination (HR) is required to protect and restart stressed replication forks. Paradoxically, the Mrc1 branch of the S phase checkpoints, which is activated by replicative stress, prevents HR repair at breaks and arrested forks. Indeed, the mechanisms underlying HR can threaten genome integrity if not properly regulated. Thus, understanding how cells avoid genetic instability associated with replicative stress, a hallmark of cancer, is still a challenge. Here I discuss recent results that support a model by which HR responds (...) to replication stress through replicative and repair activities that operate at different stages of the cell cycle (S and G2, respectively) and in distinct subnuclear structures. Remarkably, the replication checkpoint appears to control this scenario by inhibiting the assembly of HR repair centers at stressed forks during S phase, thereby avoiding genetic instability. (shrink)

Rewards are reinforcement mechanisms that organizations use to shape desirable employee behaviors. However, rewards may also have unintended consequences, such as building expectations for receiving extra benefits and weakening employee barriers to unethical acts. This article investigates the dark side of the reward–behavior association, and exploring what is referred to as the reward–theft parity effect (RTPE). The authors hypothesize that receiving rewards induces a corresponding type of theft. In Study 1, survey results (n = 634) show initial support for the (...) RTPE between rewards and same‐category theft, and that perceptions of procedural justice attenuate this association. Study 2 involved a 2 (reward) × 2 (theft opportunity) between‐subjects experimental design (n = 300) and provides further support for the RTPE by revealing greater theft under a reward–theft parity condition than under a reward–theft disparity condition. Study 3 replicates these findings in a field experiment (n = 285) and finds that the RTPE is exacerbated when the reward–behavior task is perceived as unjust. Collectively, these findings provide new theoretical insights while also giving managers a more complete understanding of the dark side of behavioral reinforcement mechanisms. (shrink)

DNA double‐strand breaks (DSBs) are extremely hazardous lesions for all DNA‐bearing organisms and the mechanisms of DSB repair are highly conserved. In the eukaryotic mitotic cell cycle, DSBs are often present following DNA replication while, in meiosis, hundreds of DSBs are generated as a prelude to the reshuffling of the maternally and paternally derived genomes. In both cases, the DSBs are repaired by a process called homologous recombinational repair (HRR), which utilises an intact DNA molecule as the repair template. (...) Mitotic and meiotic HRR are managed by ‘checkpoints’ that inhibit cell division until DSB repair is complete. Here we attempt to summarise the substantial recent progress in understanding the checkpoint management of HRR in mitosis (focussing mainly on mammals) and then go on to use this information as a framework for understanding the presumed checkpoint management of HRR in mammalian meiosis. BioEssays 29:974–986, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In addition to probabilities of monetary gains and losses, personality traits, socio-economic factors, and specific contexts such as emotions and framing influence financial risk taking. Here, we investigated the effects of joyful, neutral, and sad mood states on participants’ risk-taking behaviour in a simple task with safe and risky options. We also analysed the effect of framing on risk taking. In different trials, a safe option was framed in terms of either financial gains or losses. Moreover, we investigated the effects (...) of emotional contagion and sensation-seeking personality traits on risk taking in this task. We did not observe a significant effect of induced moods on risk taking. Sad mood resulted in a slight non-significant trend of risk aversion compared to a neutral mood. Our results partially replicate previous findings regarding the presence of the framing effect. As a novel finding, we observed that participants with a low emotional contagion score demonstrated increased risk aversion during a sad mood and a similar trend at the edge of significance was present in high sensation seekers. Overall, our results highlight the importance of taking into account personality traits of experimental participants in financial risk-taking studies. (shrink)

Hope, gratitude, fear, and disgust may all be key to encouraging preventative action in the context of COVID-19. We pre-registered a longitudinal experiment, which involved monthly data collections from September 2020 to September 2021 and a six-month follow-up. We predicted that a hope recall task would reduce negative emotions and elicit higher intentions to engage in COVID-19 preventative behaviours. At the first time point, participants were randomly allocated to a recall task condition (gratitude, hope, or control). At each time point, (...) we measured willingness to engage in COVID-19 preventative behaviours, as well as experienced hope, gratitude, fear, and disgust. We then conducted a separate, follow-up study in February 2022, to see if the effects replicated when COVID-19 restrictions were relaxed in the UK. In the main study, contrary to our pre-registered hypothesis, we found that a gratitude recall task elicited more willingness to engage in COVID-19 preventative behaviours in comparison to the neutral recall task. We also found that experienced gratitude, hope, and fear were positively related to preventative action, while disgust was negatively related. These results present advancement of knowledge of the role of specific emotions in the COVID-19 pandemic. (shrink)

According to evolutionary theory, emotions are psychological mechanisms that have evolved to enhance fitness in specific situations by motivating appropriate (adaptive) behavior. Taking this perspective, a previous study examined the relationship between mood and preference for natural environments. It reported that participants’ anxiety level was associated with a preference for landscapes offering what Appleton called "refuge," while participants’ anger and cheerfulness were both associated with a preference for landscapes offering what Appleton called "prospect." We attempted to replicate these results and (...) to improve on the study by experimentally manipulating mood. Using a between-subjects design, 80 participants were instructed to self-induce one of four moods: anger, sadness, anxiety, or joy. After the mood induction, they viewed fourteen landscape photographs and recorded the seven most preferred. It was hypothesized that subjects experiencing anger or joy would prefer landscapes rich in "prospect" features, whereas participants experiencing sadness or anxiety would prefer landscapes rich in "refuge" features. In contrast to the previous study, the predictions were not supported: artificially induced moods may not provide ecological validity as a test of the "mood as motivator" model; alternatively, the first study may have reported an alpha error. To see whether the model has practical value, we recommend a study of landscape preference using participants with clinically significant levels of mood dysphoria. (shrink)

Abstract‘[T]he “mainstream” of global governance has changed course’ and in so doing, might well have ‘outrun the standard tools of critical, progressive, and reform-minded international lawyers’, Fleur Johns wrote in 2019. It is especially the critical tools of ‘appeals to history, context, language [and] the grassroots’ in response to universalist planning that Johns sees absorbed in the turn to prototyping as a new ‘style’ of governance. In this article, we take on this observation and explore how the ‘lean start-up mentality’ (...) that Johns described has taken hold of tech-based climate governance. We base our reflections on the ‘Tech for Our Planet’ challenge that took place over 2021 and was showcased at the UNFCCC COP26 in Glasgow. While a turn ‘from planning to prototypes’ is observable, we question how exactly this ‘change of course’ affects the high modernist style of global governance and its critique by international lawyers. The ‘digital solutions for climate challenges’ that were showcased in Glasgow are indeed based on localized experiments with data science, thereby seemingly overcoming high modernist impulses towards universalist ideals. Yet, these experimental prototypes are developed with the ambition of being replicable and scaled up, to become a stack of tools deployable in any given scenario. This form of scaling up neither breaks with modernist aspirations based on technologically-mediated replicability—of moving the same logic inscribed in code to different sites and contexts—nor with a modernist understanding of knowledge as universal in its application. In our analysis, the determining feature is then not so much a matter of planning or prototyping in ideal type forms, but of replicability of knowledge production and scalability of technological know-how that underpin both planning and prototyping. Prototyping in the start-up space does not depart from, but rather reinscribes, a modernist representation of the human subject that forces its epistemological lens onto a world of nonhuman objects amenable to governance. Critical international lawyers’ toolkits must therefore be reconfigured with a focus on a governance style of disembodied knowledge production that runs through both planning and prototyping. (shrink)

People judge positive information to be more alike than negative information. This good-bad asymmetry in similarity was argued to constitute a true property of the information ecology (Alves, H., Koch, A., & Unkelbach, C. (2017). Why good is more alike than bad: Processing implications. Trends in Cognitive Sciences, 21, 69–79). Alternatively, the asymmetry may constitute a processing outcome itself, namely an influence of phasic affect on information processing. Because no research has yet tested whether phasic affect influences perceived similarity among (...) stimuli, we conducted 5 Experiments that also tested whether phasic affect can account for the higher judged similarity among positive compared to negative stimuli. In three experiments, we affectively charged pictures of different Pokemon by pairing them with monetary gains and losses (Exp. 1a, 1b) as well as positive and negative trait words (Exp. 2); yet, the evaluative charge did not differentially influence perceived similarity among the Pokemon. Experiment 3 replicated the basic similarity asymmetry among positive and negative words, and found that it was unaffected by externally induced phasic affect. Experiment 4 showed that phasic affect had no influence on perceived similarity of non-evaluative words either. We conclude that albeit a weak influence of phasic affect on perceived similarity of stimuli cannot be ruled out entirely, it can most likely not account for the typically medium to large sized asymmetry in similarity among positive and negative stimuli. (shrink)

Attention is automatically allocated to stimuli that are opposite in valence to the current motivational focus (Rothermund, 2003; Rothermund, Voss, & Wentura, 2008). We tested whether this incongruency effect is due to affective–motivational counter-regulation or to an increased salience of stimuli that mismatch with cognitively activated information. Affective processing biases were assessed with a search task in which participants had to detect the spatial position at which a positive or negative stimulus was presented. In the motivational condition, positive or negative (...) affective–motivational states were induced by performance feedback after each trial. In the cognitive activation condition, participants memorised the word “good” or “bad” during the search task. The affective incongruency effect was replicated in the motivational condition, whereas an affective congruency effect obtained in the cognitive activation condition. These findings support an explanation of affective incongruency effects in terms of automatic counter-regulation that is motivational in nature. (shrink)

Objective: Persuasive messages regarding fruit and vegetable consumption often meet defensive reactions from recipients, which may lower message effectiveness. Individual differences in emotion regulation and gender are expected to predict these reactions. In the working memory account of persuasion, inducing voluntary eye movements during the processing of the auditory persuasive information might prevent defensiveness and thereby increase message effectiveness.Methods: Participants in two independently recruited samples from the general population listened to a negatively framed auditory persuasive message advocating fruit and vegetable (...) consumption. Half of them were asked to keep following a regularly moving stimulus on their screen with their eyes. At pretest, the individual differences of cognitive self-affirmation inclination and gender were assessed to predict defensive reactions.Results: In Study 1, induced eye movements significantly increased self-reported consumption after 2 weeks when CSAI was low, but only in males, as indicated by a significant three-way interaction. With negative self-evaluative emotions as dependent variable, this three-way interaction was also significant, suggesting that induced eye movements prevented defensiveness in low CSAI males. Study 2 did not assess consumption but replicated the latter three-way interaction.Conclusion: The studies replicated our earlier findings regarding the moderating effects of individual differences in emotion regulation on persuasion, but they also revealed gender differences in persuasion that are related to the working memory. The working memory account of persuasion provides new theoretical as well as practical angles on persuasion to target individuals in persuasion to increase fruit and vegetable consumption. (shrink)

Previous research has shown that the proactive deprioritization of emotional distractors through the provision of information about the distractors or passive habituation of emotional distractors may attenuate emotion-induced blindness (EIB) in the rapid serial visual presentation stream. However, whether prior memory encoding of emotional distractors could bias the EIB effect remains unknown. To address this question, this study employed a three-phase paradigm integrating an item-method direct forgetting (DF) procedure with a classic EIB procedure. Participants completed a memory coding phase to (...) either remember or forget negative pictures, then performed an intermediate phase of the EIB test, and finally finished a recognition test. Critically, the same to-be-forgotten (TBF) and to-be-remembered (TBR) negative pictures in the memory learning phase were used as emotional distractors in the intermediate EIB test. The results replicated the typical DF effect by showing higher recognition accuracies for TBR pictures compared to those for TBF pictures. More importantly, the TBF negative distractors attenuated the EIB effect compared to the TBR negative distractors, but showed a comparable EIB effect as the novel negative distractors. These findings indicate that prior memory encoding manipulations of negative distractors could bias subsequent EIB effects, providing an important approach to modulate the EIB effect. (shrink)

RNA polymerase II is recruited to DNA double‐strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage‐induced long non‐coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA‐like molecules or degraded by different ribonucleases. They can also form double‐stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute to (...) the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR. (shrink)

Memory is modified through the act of retrieval. Although retrieving a target piece of information may strengthen the retrieved information itself, it may also serve to weaken retention of related information. This phenomenon, termed retrieval-induced forgetting, has garnered substantial interest for its implications as to why forgetting occurs. The present study attempted to replicate the seminal work by Anderson, Bjork, and Bjork (1994) on retrieval-induced forgetting, given the apparent sensitivity of the effect to certain deviations from the original paradigm developed (...) to study the phenomenon. The study extends the conditions under which retrieval-induced forgetting has been examined by utilizing both a traditional college undergraduate sample (Experiment 1), along with a more diverse internet sample (Experiment 2). In addition, Experiment 3 details a replication attempt of retrieval-induced forgetting using Anderson and Spellman’s (1995) independent cue procedure. Retrieval-induced forgetting was observed when using the traditional retrieval practice paradigm with undergraduate (Experiment 1) and internet (Experiment 2) samples, though the effect was not found when using the independent cue procedure (Experiment 3). Thus, the study can provide an indication as to the robustness of retrieval-induced forgetting to deviations from the traditional college undergraduate samples that have been used in the majority of existing research on the effect. (shrink)