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There is growing evidence of evolutionary genome plasticity. The evolution ofrepetitive DNA elements, the major components of most eukaryotic genomes, involves the amplification of various classes of mobile genetic elements, the expansion of satellite DNA, the transfer of fragments or entire organellar genomes and may have connections with viruses. In addition to variousrepetitive DNA elements, a plethora of large and small RNAs migrate within and between cells during individual development as well as during evolution and contribute (...) to changes of genome structure and function. Such migration of DNA and RNA molecules often results in horizontal gene transfer, thus shaping the whole genomic network of interconnected species. Here, we propose that a high evolutionary dynamism ofrepetitive genome components is often related to the migration/movement of DNA or RNA molecules. We speculate that the cytoplasm is probably an ideal compartment for such evolutionary experiments. (shrink)

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Cells are cognitive entities possessing great computational power. DNA serves as a multivalent information storage medium for these computations at various time scales. Information is stored in sequences, epigenetic modifications, and rapidly changing nucleoprotein complexes. Because DNA must operate through complexes formed with other molecules in the cell, genome functions are inherently interactive and involve two-way communication with various cellular compartments. Both coding sequences andrepetitive sequences contribute to the hierarchical systemic organization of the genome. By virtue of nucleoprotein (...) complexes, epigenetic modifications, and natural genetic engineering activities, the genome can serve as a read-write storage system. An interactive informatic conceptualization of the genome allows us to understand the functional importance of DNA that does not code for protein or RNA structure, clarifies the essential multidirectional and systemic nature of genomic information transfer, and emphasizes the need to investigate how cellular computation operates in reproduction and evolution. (shrink)

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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 functionalrepetitive 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 longrepetitive telomeres and centromeres. (shrink)

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DNA helicases are a class of molecular motors that catalyze processive unwinding of double stranded DNA. In spite of much study, we know relatively little about the mechanisms by which these enzymes carry out the function for which they are named. Most current views are based on inferences from crystal structures. A prominent view is that the canonical ATPase motor exerts a force on the ssDNA resulting in “pulling” the duplex across a “pin” or “wedge” in the enzyme leading to (...) a mechanical separation of the two DNA strands. In such models, DNA base pair separation is tightly coupled to ssDNA translocation of the motors. However, recent studies of the Escherichia coli RecBCD helicase suggest an alternative model in which DNA base pair melting and ssDNA translocation occur separately. In this view, the enzyme‐DNA binding free energy is used to melt multiple DNA base pairs in an ATP‐independent manner, followed by ATP‐dependent translocation of the canonical motors along the newly formed ssDNA tracks. Repetition of these two steps results in processive DNA unwinding. We summarize recent evidence suggesting this mechanism for RecBCD helicase action. (shrink)

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Although genome‐scale analyses have provided insights into the connection between genetic variability and complex human phenotypes, much trait variation is still not fully understood. Genetic variation withinrepetitive elements, such as the multi‐copy, multi‐locus ribosomal DNA (rDNA), has emerged as a potential contributor to trait variation. Whereas rDNA was long believed to be largely uniform within a species, recent studies have revealed substantial variability in the locus, both within and across individuals. This variation, which takes the form of copy (...) number, structural arrangement, and sequence differences, has been found to be associated with human phenotypes. This review summarizes what is currently known about human rDNA variation, its causes, and its association with phenotypic outcomes, highlighting the technical challenges the field faces and the solutions proposed to address them. Finally, we suggest experimental approaches that can help clarify the elusive mechanisms underlying the phenotypic consequences of rDNA variation. (shrink)

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The genomes of the slime moulds are relatively small when compared with those of higher eukaryotes. They also contain far fewer families ofrepetitive sequences. Nevertheless, the general patterns of organization of theirrepetitive DNA are similar. The slime moulds can therefore help us to investigate the structure and evolution ofrepetitive DNA in “simple” eukaryotes and to understand how these sequences contribute to the architecture and function of the eukaryotic genome. Several questions remain, including perhaps the (...) most important: dorepetitive sequences perform some definable function?. (shrink)

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The recent publication by Wylie et al. is reviewed, demonstrating that the p53 protein regulates the movement of transposons. While this work presents genetic evidence for a piRNA‐mediated p53 interaction with transposons in Drosophila and zebrafish, it is herein placed in the context of a decade or so of additional work that demonstrated a role for p53 in regulating transposons and otherrepetitive elements. The line of thought in those studies began with the observation that transposons damage DNA and (...) p53 regulates DNA damage. The presence of transposon movement can increase the rate of evolution in the germ line and alter genes involved in signal transduction pathways. Transposition can also play an important role in cancers where the p53 gene function is often mutated. This is particularly interesting as recent work has shown that de‐repression ofrepetitive elements in cancer has important consequences for the immune system and tumor microenvironment. (shrink)

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The presence of small polydisperse extrachromosomal circular (spc) DNAs composed entirely of chromosomal sequences seems to reflect the plasticity of eukaryotic genomes. The size distribution and number of spc DNAs is found to vary with development, growth state and mitotic capacity. In particular, spc DNAs are observed to be several fold smaller in established immortal cell lines than in diploid cells with a limited life span. Analysis of cloned spc DNA fragments revealed that: (1) most of the spc DNAs thus (...) far investigated containrepetitive sequences; (2) some of therepetitive sequences are enriched in spc DNA clones relative to their representation in the chromosome; (3) variousrepetitive sequences of different reiteration frequency were found in spc DNA from immortal cell lines while a particular sequence of retroposon was predominant in primary lymphoid tissue cells and stem cells; (4) most of these spc DNAs appear to represent the extra copies generated by replicon‐misfiring in immortal cell lines or by retrotranscription in stem cells, and intermediates or by‐products produced by abortive rearrangement in diploid cells with a finite replicative capacity. (shrink)

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In spite of the importance of point mutations for evolution and human diseases, their natural spectrum of incidence in different species is not known. Here I propose to determine these spectra by comparing consecutive sequence periods in stretches ofrepetitive DNA. The article presents the analysis of more than 51,000 such point mutations identified by this approach in the genomes of human, chimpanzee, rat, mouse, pufferfish, zebrafish, and sea squirt. I propose to explain the observed spectra by auto‐mutagenic mechanisms (...) of genome variation involving the inter‐conversions of nucleotides, single base‐pair inversions and their combinations. (shrink)

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A diploid human genome contains approximately six billion nucleotides. This enormous amount of genetic information can be replicated with great accuracy in only a few hours. However, because DNA strands are oriented antiparallel while DNA polymerization only occurs in the 5′ → 3′ direction, semi‐conservative replication of double‐stranded DNA is an asymmetric process, i.e., there is a leading and a lagging strand. This provides a considerable opportunity for non‐random error rates, because the architecture of the two strands as well as (...) the DNA polymerases that replicate them may be different. In addition, the proteins that start or finish chains may well be different from those that perform the bulk of chain elongation. Furthermore, while replication fidelity depends on the absolute and relative concentrations of the four deoxyribonucleotide precursors, these are not equal in vivo, not constant throughout the cell cycle, and not necessarily equivalent in all cell types. Finally, the fidelity of DNA synthesis is sequence‐dependent and the eukaryotic nuclear genome is a heterogeneous substrate. It containsrepetitive and non‐repetitive sequences and can actually be considered as two subgenomes that differ in nucleotide composition and gene content and that replicate at different times. The effects that each of these asymmetries may have on error rates during replication of the eukaryotic genome are discussed. (shrink)

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The replicative bypass of lesions in DNA and the induction of mutations by agents which react with DNA to produce damaged bases can be understood on the basis of a simple kinetic model. Bypass can be analyzed by separately considering three processes: (a) addition of a base opposite a lesion, (b) a proofreading excision process, and (c) a rate limiting elongation step. Adenine nucleotides are preferentially added opposite many lesions making it possible to predict mutational specificity. Replicative bypass (translesion synthesis) (...) is dependent on modulation of proofreading exonuclease activity but loss of exonuclease activity alone is not sufficient to ensure bypass. Frameshift mutation is the result of the failure of translesion synthesis accompanied by rearrangement of the template, particularly atrepetitive sites. (shrink)

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Telomeres are shortrepetitive DNA sequences capping the ends of chromosomes. Telomere shortening occurs during cell division and may be accelerated by oxidative damage or ameliorated by telomere maintenance mechanisms. Consequently, telomere length changes with age, which was recently confirmed in a large meta‐analysis across vertebrates. However, based on the correlation between telomere length and age, it was concluded that telomere length can be used as a tool for chronological age estimation in animals. Correlation should not be confused with (...) predictability, and the current data and studies suggest that telomeres cannot be used to reliably predict individual chronological age. There are biological reasons for why there is large individual variation in telomere dynamics, which is mainly due to high susceptibility to a wide range of environmental, but also genetic factors, rendering telomeres unfeasible as a tool for age estimation. The use of telomeres for chronological age estimation is largely a misguided effort, but its occasional reappearance in the literature raises concerns that it will mislead resources in wildlife conservation. (shrink)

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The placenta invades the adjacent uterus and controls the maternal immune system, like a cancer invades surrounding organs and suppresses the local immune response. Intriguingly, placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silencerepetitive DNA sequences that are silenced in healthy somatic cells. In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is thought to (...) contribute to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence. Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion. This alludes to an interesting paradox, that while placental retrotransposon-derived genes are essential for promoting early hominid life, the same genes promote disease-susceptibility and death through cancer. Placental and cancer cells fail to silence retrotransposons that are normally silenced in healthy tissues. This has created new genes that are essential for placental function, yet they are also expressed in cancer. We hypothesize that active retrotransposons are a double-edged sword, contributing both adaptive and deleterious functions to biology. (shrink)

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It is becoming increasingly evident that the driving forces of evolutionary novelty are not randomly derived chance mutations of the genetic text, but a precise genome editing by omnipresent viral agents. These competences integrate the whole toolbox of natural genetic engineering, replication, transcription, translation, genomic imprinting, genomic creativity, enzymatic inventions and all types of genetic repair patterns. Even the non-coding,repetitive DNA sequences which were interpreted as being ancient remnants of former evolutionary stages are now recognized as being of (...) viral descent and crucial for higher-order regulatory and constitutional functions of protein structural vocabulary. In this article I argue that non-randomly derived natural genome editing can be envisioned as (a) combinatorial (syntactic), (b) context-specific (pragmatic) and (c) content-sensitive (semantic) competences of viral agents. These three-leveled biosemiotic competences could explain the emergence of complex new phenotypes in single evolutionary events. After short descriptions of the non-coding regulatory networks, major viral life strategies and pre-cellular viral life three of the major steps in evolution serve as examples: There is growing evidence that natural genome-editing competences of viruses are essential (1) for the evolution of the eukaryotic nucleus, (2) the adaptive immune system and (3) the placental mammals. (shrink)

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Horizontal transfer (HT) is the transmission of genetic material between non‐mating species, a phenomenon thought to occur rarely in multicellular eukaryotes. However, many transposable elements (TEs) are not only capable of HT, but have frequently jumped between widely divergent species. Here we review and integrate reported cases of HT in retrotransposons of the BovB family, and DNA transposons, over a broad range of animals spanning all continents. Our conclusions challenge the paradigm that HT in vertebrates is restricted to infective long (...) terminal repeat (LTR) retrotransposons or retroviruses. This raises the possibility that other non‐LTR retrotransposons, such as L1 or CR1 elements, believed to be only vertically transmitted, can horizontally transfer between species. Growing evidence indicates that the process of HT is much more general across different TEs and species than previously believed, and that it likely shapes eukaryotic genomes and catalyses genome evolution. (shrink)

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Dawkins in his The Selfish Gene(1) quite aptly applies the term “selfish” to parasiticrepetitive DNA sequences endemic to eukaryotic genomes, especially vertebrates. Doolittle and Sapienza(2) as well as Orgel and Crick(3) enlivened this notion of selfish DNA with the identification of suchrepetitive sequences as remnants of mobile elements such as transposons. In addition, Orgel and Crick(3) associated parasitic DNA with a potential to outgrow their host genomes by propagating both vertically via conventional genome replication as well (...) as infectiously by horizontal gene transfer (HGT) to other genomes. Still later, Doolittle(4) speculated that unchecked HGT between unrelated genomes so complicates phylogeny that the conventional representation of a tree of life would have to be replaced by a thicket or a web of life.(4) In contrast, considerable data now show that reconstructions based on whole genome sequences are consistent with the conventional “tree of life”.(5–10) Here, we identify natural barriers that protect modern genome populations from the inroads of rampant HGT. BioEssays 27:741–747, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

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It is becoming increasingly clear thatrepetitive DNA is of biological significance as well as experimental importance. Here we review the information available about one type ofrepetitive DNA, the trinucleotide repeat (CAC)n, and briefly compare it with other trinucleotide repeats. Although much work has been done in analysing DNA fingerprinting patterns produced using the synthetic oligonucleotide (CAC)5 as a probe, there is relatively little information about individual (CAC)n‐containing sequences and their abundance, organisation and distribution in mammalian DNA. (...) From the data that is available, it is clear that there are at least two areas that should repay further study: (1) the organisation and generation of long sequences that contain (CAC)n motifs as part of a larger repeating unit (minisatellites) and (2) the distribution of small (CAC)n sequences (microsatellites), in particular their relationship to genes. (shrink)

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DNA repetitions may provoke heterochromatinization. We explore here a model in which multiple cis‐acting sequences that display no silencing activity on their own (protosilencers) may cooperate to establish and maintain a heterochromatin domain efficiently. Protosilencers, first defined in budding yeast, have now been found in a wide range of genomes where they appear to stabilize and to extend the propagation of heterochromatin domains. Strikingly, isolated or moderately repeated protosilencers can also be found in promoters where they participate in transcriptional activation (...) and have insulation functions. This suggests that the proper juxtaposition of a threshold number of protosilencers converts them from neutral or transactivating elements into ones that nucleate heterochromatin. Interactions might be transient or permanent, and are likely to occur over distances by looping. This model provides a conceptual framework for as varied phenomena as telomere‐driven silencing in Drosophila, X inactivation in mammals, and rDNA silencing in S. cerevisiae. It may also account for the silencing that occurs when multiple copies of a transgene are inserted in tandem. BioEssays 24:828–835, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

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Short interspersedrepetitive elements, or SINEs, are tRNA-derived retroposons that are dispersed throughout eukaryotic genomes and can be present in well over 104 total copies. The enormous volume of SINE amplifications per organism makes them important evolutionary agents for shaping the diversity of genomes, and the irreversible, independent nature of their insertion allows them to be used for diagnosing common ancestry among host taxa with extreme confidence. As such, they represent a powerful new tool for systematic biology that can (...) be strategically integrated with other conventional phylogenetic characters, most notably morphology and DNA sequences. This review covers the basic aspects of SINE evolution that are especially relevant to their use as systematic characters and describes the practical methods of characterizing SINEs for cladogram construction. It also discusses the limits of their systematic utility, clarifies some recently published misunderstandings, and illustrates the effective application of SINEs for vertebrate phylogenetics with results from selected case studies. BioEssays 22:148–160, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

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Mammalian cells frequently depend on homologous recombination (HR) to repair DNA damage accurately and to help rescue stalled or collapsed replication forks. The essence of HR is an exchange of nucleotides between identical or nearly identical sequences. Although HR fulfills important biological roles, recombination between inappropriate sequence partners can lead to translocations or other deleterious rearrangements and such events must be avoided. For example, the recombination machinery must follow stringent rules to preclude recombination between the manyrepetitive elements in (...) a mammalian genome that share significant but imperfect homology. This paper takes a conceptual approach in addressing the homology requirements for recombination in mammalian genomes as well as the general strategy used by cells to reject recombination between similar but imperfectly matched sequences. A mechanism of heteroduplex rejection that involves the unwinding of recombination intermediates that may form between mismatched sequences is discussed. BioEssays 30:1163–1171, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

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Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of mammalian (...) genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which largerepetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

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The classical view of the gene prevailing during the 1910s and 1930s comprehended the gene as the indivisible unit of genetic transmission, genetic recombination, gene mutation and gene function. The discovery of intragenic recombination in the early 1940s led to the neoclassical concept of the gene, which prevailed until the 1970s. In this view the gene or cistron, as it was now called, was divided into its constituent parts, the mutons and recons, materially identified as nucleotides. Each cistron was believed (...) to be responsible for the synthesis of one single mRNA and concurrently for one single polypeptide. The discoveries of DNA technology, beginning in the early 1970s, have led to the second revolution in the concept of the gene in which none of the classical or neoclassical criteria for the definition of the gene hold strictly true. These are the discoveries concerning gene repetition and overlapping, movable genes, complex promoters, multiple polyadenylation sites, polyprotein genes, editing of the primary transcript, pseudogenes and gene nesting. Thus, despite the fact that our comprehension of the structure and organization of the genetic material has greatly increased, we are left with a rather , open and general concept of the gene. This article discusses past and present contemplations of genes, genomes, genotypes and phenotypes as well as the most recent advances of the study of the organization of genomes. (shrink)

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The orderly sequence of events that constitutes the cell cycle is carefully regulated. A part of this regulation depends upon the ubiquitous calcium signalling system. Many growth factors utilize the messenger inositol trisphosphate (InsP3) to set up prolonged calcium signals, often organized in an oscillatory pattern. Theserepetitive calcium spikes require both the entry of external calcium and its release from internal stores. One function of this calcium signal is to activate the immediate early genes responsible for inducing resting (...) cells (G0) to re‐enter the cell cycle. It may also promote the initiation of DNA synthesis at the G1/S transition. Finally, calcium contributes to the completion of the cell cycle by stimulating events at mitosis. The role of calcium in cell proliferation is highlighted by the increasing number of anticancer therapies and immunosuppressant drugs directed towards this calcium signalling pathway. (shrink)

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Telomerase is a cellular reverse transcriptase responsible for telomere maintenance in most organisms. It does so by adding telomere repeats onto pre‐existing ends using an integral RNA component as template. Compared to “prototypical” reverse transcriptases, telomerase is unique in being able to repetitively copy a short templating RNA segment, thus adding multiple copies of the repeat to the DNA substrate following a single binding event. This uniquely processive property hints at the intricate conformational alterations that the enzyme must choreograph during (...) its reaction cycles. Recent studies have identified distinct structural elements within both the RNA and protein components of telomerase that modulate enzyme processivity. Pharmacological and genetic analysis suggest that telomerase processivity is a significant determinant of telomere length. Because telomere maintenance and the lack thereof have been linked to tumor progression and aging, further investigation of telomerase processivity may lead to novel medical intervention strategies. BioEssays 26:955–962, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

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Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of mammalian (...) genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which largerepetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

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Parental age at offspring conception often influences offspring longevity, but the mechanisms underlying this link are poorly understood. One mechanism that may be important is telomeres, highly conserved,repetitive sections of non‐coding DNA that form protective caps at chromosome ends and are often positively associated with longevity. Here, the potential pathways by which the age of the parents at the time of conception may impact offspring telomeres are described first, including direct effects on parental gamete telomeres and indirect effects (...) on offspring telomere loss during pre‐ or post‐natal development. Then a surge of recent studies demonstrating the effects of parental age on offspring telomeres in diverse taxa are reviewed. In doing so, important areas for future research and experimental approaches that will enhance the understanding of how and when these effects likely occur are highlighted. It is concluded by considering the potential evolutionary consequences of parental age on offspring telomeres. (shrink)

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Despite acknowledgment that performance failure among new salespeople is a prevalent issue for organizations, researchers do not fully understand the consequences ofrepetitive periods of failure on new salespeople’s unethical selling behaviors. Further, little is known about how a sales force’s reward structure and managerial attempts to intervene following failure affect new salespeople’s behavior. Combining an experiment with longitudinal growth models, we show thatrepetitive periods of failure increase unethical behaviors, and interventions intended to remind the salesperson to (...) behave in the customer’s best interests attenuate this effect under a non-contingent reward structure. However, counter to managerial assumptions, under a contingent reward structure these customer-oriented interventions actually backfire by amplifying the original relationship betweenrepetitive failure and unethical behaviors. The results have potentially important managerial implications for those who manage new salespeople learning how to sell or during other failure-prone periods. (shrink)

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In his late years, Thomas Kuhn became interested in the process of scientific specialization, which does not seem to possess the destructive element that is characteristic of scientific revolutions. It therefore makes sense to investigate whether and how Kuhn’s insights about specialization are consistent with, and actually fit, his model of scientific progress through revolutions. In this paper, I argue that the transition toward a new specialty corresponds to a revolutionary change for the group of scientists involved in such a (...) transition. I will clarify the role of the scientific community in revolutionary changes and characterize the incommensurability across specialties as possessing both semantic and methodological aspects. The discussion of the discovery of the structure of DNA will serve both as an illustration of my main argument and as reply to one criticism raised against Kuhn—namely, that his model cannot capture cases of revolutionary yet non-disruptive episodes of scientific progress. Revisiting Kuhn’s ideas on specialization will shed new light on some often overlooked features of scientific change. (shrink)

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ObjectivesSeveral studies have examined the effects ofrepetitive transcranial magnetic stimulation (rTMS) on associative memory (AM) but findings were inconsistent. Here, we aimed to test whether twice-daily rTMS could significantly improve AM.MethodsIn this single-blind, sham-controlled experiment, 40 participants were randomized to receive twice-daily sham or real rTMS sessions for five consecutive days (a total of 16,000 pulses). The stimulation target in left inferior parietal lobule (IPL) exhibiting peak functional connectivity to the left hippocampus was individually defined for each participant. (...) Participants completed both a picture-cued word association task and Stroop test at baseline and 1 day after the final real or sham rTMS session. Effects of twice-daily rTMS on AM and Stroop test performance were compared using two-way repeated measures analysis of variance with main factors Group (real vs. sham) and Time (baseline vs. post-rTMS).ResultsThere was a significant Group × Time interaction effect. AM score was significantly enhanced in the twice-daily real group after rTMS, but this difference could not survive the post hoc analysis after multiple comparison correction. Further, AM improvement in the twice-daily real group was not superior to a previously reported once-daily rTMS group receiving 8,000 pulses. Then, we combined the twice- and once-daily real groups, and found a significant Group × Time interaction effect. Post hoc analysis indicated that the AM score was significantly enhanced in the real group after multiple comparisons correction.ConclusionOur prospective experiment did not show significant rTMS effect on AM, but this effect may become significant if more participants could be recruited as revealed by our retrospective analysis. (shrink)

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Synchronous oscillations are ubiquitous throughout the cortex, but the frequency of oscillations differs from area to area. To elucidate the mechanistic architectures underlying various rhythmic activities, we tested whether spontaneous neural oscillations in different local cortical areas and large-scale networks can be phase-entrained by direct perturbation with distinct frequencies ofrepetitive transcranial magnetic stimulation. While recording the electroencephalogram, we applied single-pulse TMS and rTMS at 5, 11, and 23 Hz over the motor or visual cortex. We assessed local and (...) global modulation of phase dynamics using the phase-locking factor. sp-TMS to the motor and the visual cortex triggered a transient increase in PLF in distinct frequencies that peaked at 21 and 8 Hz, respectively. rTMS at 23 Hz over the motor cortex and 11 Hz over the visual cortex induced a prominent and progressive increase in PLF that lasted for a few cycles after the termination of rTMS. Moreover, the local increase in PLF propagated to other cortical areas. These results suggest that distinct cortical areas have area-specific oscillatory frequencies, and the manipulation of oscillations in local areas impacts other areas through the large-scale oscillatory network with the corresponding frequency specificity. We speculate that rTMS that is close to area-specific frequencies enables direct manipulation of brain dynamics and is thus useful for investigating the causal roles of synchronous neural oscillations. Moreover, this technique could be used to treat clinical symptoms associated with impaired oscillations and synchrony. (shrink)

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ObjectivePrevious studies have demonstrated altered brain activity in strabismic amblyopia. In this study, low-frequencyrepetitive transcranial magnetic stimulation was applied in children with strabismic amblyopia after they had undergone strabismus surgery. The effect of rTMS was investigated by measuring the changes of brain features using the amplitude of low-frequency fluctuation.Materials and MethodsIn this study, 21 SA patients were recruited based on their age, weight, and sex. They all had SA in their left eyes and they received rTMS treatment one (...) month after strabismus surgery. Their vision before and after surgery were categorized as pre-rTMS and post-rTMS. All participants received rTMS treatment, underwent magnetic resonance imaging, and their data were analyzed using the repeated measures t-test. The team used correlation analysis to explore the relationship between logMAR visual acuity and ALFF.ResultsPre- versus post-rTMS values of ALFF were significantly different within individuals. In the POT group, ALFF values were significantly decreased in the Angular_R, Parietal_Inf_L, and Cingulum_Mid_R while ALFF values were significantly increased in the Fusiform_R and Frontal_Inf_Orb_L compared to the PRT stage.ConclusionOur data showed that ALFF recorded from some brain regions was changed significantly after rTMS in strabismic amblyopes. The results may infer the pathological basis of SA and demonstrate that visual function may be improved using rTMS in strabismic amblyopic patients. (shrink)

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Training under high interference conditions through interleaved practice results in performance suppression during training but enhances long-term performance relative torepetitive practice involving low interference. Previous neuroimaging work addressing this contextual interference effect of motor learning has relied heavily on the blood-oxygen-level-dependent response using functional magnetic resonance imaging methodology resulting in mixed reports of prefrontal cortex recruitment under IP and RP conditions. We sought to clarify these equivocal findings by imaging bilateral PFC recruitment using functional near-infrared spectroscopy while discrete (...) key pressing sequences were trained under IP and RP schedules and subsequently tested following a 24-h delay. An advantage of fNIRS over the fMRI BOLD response is that the former measures oxygenated and deoxygenated hemoglobin changes independently allowing for assessment of cortical hemodynamics even when there is neurovascular decoupling. Despite slower sequence performance durations under IP, bilateral PFC oxygenated and deoxygenated hemoglobin values did not differ between practice conditions. During test, however, slower performance from those previously trained under RP coincided with hemispheric asymmetry in PFC recruitment. Specifically, following RP, test deoxygenated hemoglobin values were significantly lower in the right PFC. The present findings contrast with previous behavioral demonstrations of increased cognitive demand under IP to illustrate a more complex involvement of the PFC in the contextual interference effect. IP and RP incur similar levels of bilateral PFC recruitment, but the processes underlying the recruitment are dissimilar. PFC recruitment during IP supports action reconstruction and memory elaboration while RP relies on PFC recruitment to maintain task variation information in working memory from trial to trial. While PFC recruitment under RP serves to enhance immediate performance, it does not support long-term performance. (shrink)

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The neuromodulatory effects of brain stimulation therapies notably involvingrepetitive transcranial magnetic stimulation on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to investigate (...) cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex. All-night polysomnography data was acquired at four time points: Adaptation, Baseline, Post-1, and Post-2. Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II–IV at four electrode sites: F3, F4, P3, and P4. Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation. (shrink)

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A core feature of drug-resistant epilepsy is hyperexcitability in the motor cortex, and low-frequencyrepetitive transcranial magnetic stimulation is a suitable treatment for seizures. However, the antiepileptic effect causing network reorganization has rarely been studied. Here, we assessed the impact of rTMS on functional network connectivity in resting functional networks and their relation to treatment response. Fourteen patients with medically intractable epilepsy received inhibitive rTMS with a figure-of-eight coil over the vertex for 10 days spread across two weeks. We (...) designed a 6-week follow-up phase divided into four time points to investigate FNC and rTMS-induced timing-dependent plasticity, such as seizure frequency and abnormal interictal discharges on electroencephalography. For psychiatric comorbidities, the Hamilton Depression Scale and the Hamilton Anxiety Scale were applied to measure depression and anxiety before and after rTMS. FNC was also compared to that of a cohort of 17 healthy control subjects. The after-effects of rTMS included all subjects that achieved the significant decrease rate of more than 50% in interictal epileptiform discharges and seizure frequency, 12 patients with the reduction rate above 50% compared to the baseline, as well as emotional improvements in depression and anxiety. In the analysis of RSNs, we found a higher synchronization between the sensorimotor network and posterior default-mode network in epileptic patients than in healthy controls. In contrast to pre-rTMS, the results demonstrated a weaker FNC between the anterior DMN and SMN after rTMS, while the FNC between the aDMN and dorsal attention network was greater. Importantly, the depressive score was anticorrelated with the FNC of the aDMN-SMN, which was markedly different in the good and bad response groups treated with rTMS. Based on the vertex suppression by rTMS, it is possible to achieve temporary clinical efficacy by modulating network reorganization in the DMN and SMN for patients with refractory epilepsy. (shrink)

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Proprioceptive acuity is of great significance in basic research exploring a possible neural mechanism of fine motor control and in neurorehabilitation practice promoting motor function recovery of limb-disabled people. Moreover, body representation relies on the integration of multiple somatic sensations, including proprioception that is mainly generated in muscles and tendons of human joints. This study aimed to examine two hypotheses: First, different extension positions of wrist joint have different proprioceptive acuities, which might indicate different body representations of wrist joint in (...) the brain. Second,repetitive peripheral magnetic stimulation applied peripherally to the forearm radial nerve and extensors could change proprioceptive acuity at the wrist joint. Thirty-five healthy participants were recruited then randomly divided into the real stimulation group and the sham stimulation group. The participants’ non-dominant side wrist joint position sense was tested at six extension positions within the physiological joint motion range both before stimulation and after stimulation. Results showed that proprioceptive bias among six extension positions could be divided into lower-extension position and higher-extension position. One session rPMS could influence proprioceptive bias in lower-extension position but not in higher-extension position. However, proprioceptive precision was not influenced. To conclude, proprioceptive bias may vary between different wrist extension positions due to different hand postures being related to changes in body representation, and different functions relating to proprioceptive bias and proprioceptive precision may underlie two aspects of body representation. (shrink)

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In 1869, Johann Friedrich Miescher discovered a new substance in the nucleus of living cells. The substance, which he called nuclein, is now known as DNA, yet both Miescher’s name and his theoretical ideas about nuclein are all but forgotten. This paper traces the trajectory of Miescher’s reception in the historiography of genetics. To his critics, Miescher was a “contaminator,” whose preparations were impure. Modern historians portrayed him as a “confuser,” whose misunderstandings delayed the development of molecular biology. Each of (...) these portrayals reflects the disciplinary context in which Miescher’s work was evaluated. Using archival sources to unearth Miescher’s unpublished speculations—including an analogy between the hereditary material and language, and a speculation that a series of asymmetric carbon atoms could account for hereditary variation—this paper clarifies the ways in which the past was judged through the lens of contemporary concerns. It also shows how organization, structure, function, and information were already being considered when nuclein was first discovered nearly 150 years ago. (shrink)

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Genomic function is dictated by a combination of DNA sequence and the molecular mechanisms controlling access to genetic information. Access to DNA can be determined by the interpretation of covalent modifications that influence the packaging of DNA into chromatin, including DNA methylation and histone modifications. These modifications are believed to be forms of “epigenetic codes” that exist in discernable combinations that reflect cellular phenotype. Although DNA methylation is known to play important roles in gene regulation and genomic function, its contribution (...) to the encoding of epigenetic information is just beginning to emerge. Here we discuss paradigms associated with the various components of DNA methylation/demethylation and recent advances in the understanding of its dynamic regulation in the genome, integrating these mechanisms into a framework to explain how DNA methylation could contribute to epigenetic codes. (shrink)

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A clear, introductory overview of the issues surrounding gene patenting.

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Graphical AbstractThere are four major hypotheses (H1, H2, H3, and H4) as to the source of missing heritability. We propose that estimates obtained from GWAS underestimate heritability by not taking into account non-DNA (epigenetic) sources of heritability. Taking those factors into account (H4) should result in increased heritability estimates.

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Briefly summarized here are some reasons why the DNA/genetic model of life appears to be inadequate (for more details see previous OJPP paper). Given its foundational role with regards to our understanding of life and its challenges, this is significant. The traditional dualistic reincarnation model is introduced. That model is then considered, along with the DNA model, as potential explanations for our natural religious instincts. Next, the two models are considered as possible bases for the phenomenon of kin orientation or (...) bias. Together the case is made that a soul-based reincarnation model offers some explanatory advantages therein over the genetic-based (material-only) model. Finally, and of potential practical and philosophical significance, the corresponding imports for life and meaning are considered. (shrink)

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The theory of evolution by natural selection did not spring fully formed and unprecedented from the brain of Charles Darwin. The idea of evolution had been around, in various guises, since the time of Ancient Greece. And nor did theorizing about evolution stop with what Daniel Dennett called "Darwin's dangerous idea." In this riveting new book, bestselling science writers John and Mary Gribbin explore the history of the idea of evolution, showing how Darwin's theory built on what went before and (...) how it was developed in the twentieth century, through an understanding of genetics and the biochemical basis of evolution, into the so-called "modern synthesis" and beyond. Darwin deserves his recognition as the primary proponent of the idea of natural selection, but as the authors show, his contribution was one link in a chain that extends back into antiquity and is still being forged today. (shrink)

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The distinction between causal role and selected effect functions is typically framed in terms of their respective explanatory roles. However, much of the controversy over functions in genomics takes place in an investigative, not an explanatory context. Specifically, the process of component-driven functional investigation begins with the designation of some genetic or epigenetic element as functional —i.e. not junk— because it possesses properties that, arguably, suggest some biologically interesting organismal effect. The investigative process then proceeds, in a bottom-up fashion, to (...) search for those effects. I argue that this process encounters a problem reminiscent of one that Gould and Lewontin associated with the adaptationist program. Just as their stereotypical adaptationst became trapped in the myopic pursuit of one selectionist hypothesis after another, so can the investigation of CR functions in genomics lead to an unending series putative organism-level CR functions for junk DNA. This is an acute problem for genomics, because eukaryotic genomes are littered with transposable elements and their deactivated descendants which often masquerade as interesting CR-functional components and it is experimentally onerous to determine whether they lack such a function. I further argue that selectionist reasoning about TE-host coevolutionary dynamics can greatly streamline the investigative process. Importantly, selectionist hypotheses need not be well confirmed to be illuminating in this context. Informed selectionist reasoning about the strategic roles of TEs in the genome offers a corrective to the idea that most of our DNA is somehow CR functional for the organism. (shrink)

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The series Topics in Current Chemistry presents critical reviews of the present and future trends in modern chemical research. The scope of coverage is all areas of chemical science including the interfaces with related disciplines such as biology, medicine and materials science. The goal of each thematic volume is to give the non-specialist reader, whether in academia or industry, a comprehensive insight into an area where new research is emerging which is of interest to a larger scientific audience. Each review (...) within the volume critically surveys one aspect of that topic and places it within the context of the volume as a whole. The most significant developments of the last 5 to 10 years are presented using selected examples to illustrate the principles discussed. The coverage is not intended to be an exhaustive summary of the field or include large quantities of data, but should rather be conceptual, concentrating on the methodological thinking that will allow the non-specialist reader to understand the information presented. Contributions also offer an outlook on potential future developments in the field. Review articles for the individual volumes are invited by the volume editors. Readership: research chemists at universities or in industry, graduate students. (shrink)

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