Over the past decade, sequence learning has gradually become a central paradigm through which to study implicit learning. In this chapter, we start by briefly summarizing the results obtained with different variants of the sequence learning paradigm. We distinguish three subparadigms in terms of whether the stimulus material is generated either by following a fixed and repeating sequence (e.g., Nissen & Bullemer, 1987), by relying on a complex set of rules from which one can produce several alternative deterministic sequences (...) (e.g., Lewicki, Hill & Bizot, 1988; Stadler, 1989), or by following the output of a probabilistic set of rules such as instantiated by noisy finite-state grammars (Cleeremans & McClelland, 1991; Jiménez, Mendéz & Cleeremans, 1996). Next, we focus on the processes involved in sequence representation and acquisition. We suggest that the sensitivity to the sequential structure observed in the probabilistic subparadigm can only be a result of the acquisition of a representation of the statistical constraints of the material, and that this sensitivity emerges through the operation of mechanisms that are well instantiated by connectionist models such as the Simple Recurrent Network (Elman, 1990; Cleeremans, 1993b). We present new simulation work meant to explore to what extent the model can also account for specific data obtained in a paradigmatic instance of deterministic, rule-based sequence learning task: Lewicki et al. (1988)'s situation. Finally, we report on the results of an experiment that compares learning on otherwise similar deterministic and probabilistic structures, and we show that learning of both types of structures is equivalent only under conditions that maximally hinder explicit acquisition. Taken together, these simulation and experimental data lend support to the claim that implicit learning in all three sequence learning subparadigms can amount to a form of statistical sequence learning. They also suggest that distinguishing among several theories of sequence representation and acquisition may require us to analize the data in great detail. Hopefully, however, some truth can be found in such details.. (shrink)

We now know that the evolution of multidomain proteins has frequently involved genetic duplication events. These, however, are sometimes difficult to trace because of low sequence similarity between duplicated segments. Spectrin, the major component of the membrane skeleton that provides elasticity to the cell, contains tandemly repeated sequences of 106 amino acid residues. The same repeats are also present in α‐actinin, dystrophin and utrophin. Sequence alignments and phylogenetic trees of these domains allow us to interpret the evolutionary relationship between (...) these proteins, concluding that spectrin evolved from α‐actinin by an elongation process that included two duplications of a block of seven repeats. This analysis shows how a modular protein unit can be used in the evolution of large cytoskeletal structures. (shrink)

The basic premise of the host‐defense theory is that genomic imprinting, the parent‐of‐origin expression of a subset of mammalian genes, derives from mechanisms originally dedicated to silencing repeated and retroviral‐like sequences that deeply colonized mammalian genomes. We propose that large clusters of tandemly‐repeated C/D‐box small nucleolar RNAs (snoRNAs) or microRNAs represent a novel category of sequences recognized as “genomic parasites”, contributing to the emergence of genomic imprinting in a subset of chromosomal regions that contain them. Such a view (...) is supported by evidence derived from studies of the imprinted snoRNA‐ and/or miRNA‐encoding Dlk1‐Dio3, Snurf‐Snrpn, Sfbmt2, and C19MC domains. While adding a new piece to the challenging puzzle of mammalian genome history, this hypothesis also reinforces the notion that dissecting the features and molecular mechanisms that discriminate between “foreign” and “endogenous” sequences is of crucial importance in the field of mammalian epigenetics. (shrink)

Over 20 unstable microsatellite repeats have been identified as the cause of neurological disease in humans. The repeat nucleotide sequences, their location within the genes, the ranges of normal and disease‐causing repeat length and the clinical outcomes differ. Unstable repeats can be located in the coding or the non‐coding region of a gene. Different pathogenic mechanisms that are hypothesised to underlie the diseases are discussed. Evidence is given both from studies in simple model systems and from studies (...) on human material and in animal models. Since somatic instability might affect the clinical outcome, this is briefly touched on. Available data and theories on the timing and mechanisms of the repeat instability itself are discussed, along with factors that have been observed to affect instability. Finally, the question of why the often harmful unstable repeats have been maintained throughout evolution is addressed. (shrink)

The processing of fluent speech involves complex computational steps that begin with the segmentation of the continuous flow of speech sounds into syllables and words. One question that naturally arises pertains to the type of syllabic information that speech processes act upon. Here, we used functional magnetic resonance imaging to profile regions, using a combination of whole-brain and exploratory anatomical region-of-interest (ROI) approaches, that were sensitive to syllabic information during speech perception by parametrically manipulating syllabic complexity along two dimensions: (1) (...) individual syllable complexity, and (2) sequence complexity (supra-syllabic). We manipulated the complexity of the syllable by using the simplest syllable template—a consonant and vowel (CV)-and inserting an additional consonant to create a complex onset (CCV). The supra-syllabic complexity was manipulated by creating sequences composed of the same syllable repeated 6 times (e.g. /pa-pa-pa-pa-pa-pa/) and sequences of 3 different syllables each repeated twice (e.g. /pa-ta-ka-pa-ta-ka/). This parametrical design allowed us to identify brain regions sensitive to (1) syllabic complexity independent of supra-syllabic complexity, (2) supra-syllabic complexity independent of syllabic complexity and, (3) both syllabic and supra-syllabic complexity. High-resolution scans were acquired for 15 healthy adults. An exploratory anatomical ROI analysis of the supratemporal plane (STP) identified bilateral regions within the anterior two-third of the planum temporale, the primary auditory cortices as well as the anterior two-third of the superior temporal gyrus that showed different patterns of sensitivity to syllabic and supra-syllabic information. These findings demonstrate that during passive listening of syllable sequences, sublexical information is processed automatically, and sensitivity to syllabic and supra-syllabic information is localized almost exclusively within the STP. (shrink)

Genomes of higher eukaryotes contain abundant non‐coding repeated sequences whose overall biological impact is unclear. They comprise two categories. The first consists of retrotransposon‐derived elements. These are three major families of retroelements (LINEs, SINEs and LTRs). SINEs are clustered in gene‐rich regions and are found in promoters of genes while LINEs are concentrated in gene‐poor regions and are depleted from promoters. The second class consists of non‐coding tandem repeats (satellite DNAs and TTAGGG arrays), which are associated with mammalian centromeres, (...) heterochromatin and telomeres. Terminal TTAGGG arrays are involved in telomere capping and satellite DNAs are located in heterochromatin, which is implicated in transcription silencing by gene repositioning (relocalization). It is unknown whether interstitial TTAGGG sequences, which are present in many vertebrates, have a function. Here, evidence will be presented that retroelements and TTAGGG arrays are involved in regulation of gene expression. Retroelements can provide binding sites for transcription factors and protect promoter CpG islands from repressive chromatin modifications, and may be also involved in nuclear compartmentalization of transcriptionally active and inactive domains. Interstitial telomere‐like sequences can form dynamically maintained three‐dimensional nuclear networks of transcriptionally inactive domains, which may be involved in transcription silencing like classic heterochromatin. BioEssays 30:338–348, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

We present evidence of a potentially serious source of error intrinsic to all spotted cDNA microarrays that use IMAGE clones of expressed sequence tags (ESTs). We found that a high proportion of these EST sequences contain 5V-end poly(dT) sequences that are remnants from the oligo(dT)-primed reverse transcription of polyadenylated mRNA templates used to generate EST cDNA for sequence clone libraries. Analysis of expression data from two single-dye cDNA microarray experiments showed that ESTs whose sequences contain repeats of (...) consecutive 5V- end dT residues appeared to be strongly coexpressed, while expression data of all other sequences exhibited no such pattern. Our analysis suggests that expression data from sequences containing 5V poly(dT) tracts are more likely to be due to systematic cross-hybridization of these poly(dT) tracts than to true mRNA coexpression. This indicates that existing data generated by cDNA microarrays containing IMAGE clone ESTs should be filtered to remove expression data containing significant 5V poly(dT) tracts. D 2003 Elsevier Inc. All rights reserved. (shrink)

According to L.E.J. Brouwer, there is room for non-definable real numbers within the intuitionistic ontology of mental constructions. That room is allegedly provided by freely proceeding choice sequences, i.e., sequences created by repeated free choices of elements by a creating subject in a potentially infinite process. Through an analysis of the constitution of choice sequences, this paper argues against Brouwer’s claim.

We present evidence of a potentially serious source of error intrinsic to all spotted cDNA microarrays that use IMAGE clones of expressed sequence tags (ESTs). We found that a high proportion of these EST sequences contain 5V-end poly(dT) sequences that are remnants from the oligo(dT)-primed reverse transcription of polyadenylated mRNA templates used to generate EST cDNA for sequence clone libraries. Analysis of expression data from two single-dye cDNA microarray experiments showed that ESTs whose sequences contain repeats of (...) consecutive 5V- end dT residues appeared to be strongly coexpressed, while expression data of all other sequences exhibited no such pattern. Our analysis suggests that expression data from sequences containing 5V poly(dT) tracts are more likely to be due to systematic cross-hybridization of these poly(dT) tracts than to true mRNA coexpression. This indicates that existing data generated by cDNA microarrays containing IMAGE clone ESTs should be filtered to remove expression data containing significant 5V poly(dT) tracts. D 2003 Elsevier Inc. All rights reserved. (shrink)

Recent analysis of the contribution of replication slippage to genome evolution shows that it has played a significant role in all species from eubacteria to humans. The overall level of repetition in genomes is related to genome size and to the degree of repetition that can be measured within individual ribosomai RNA genes, suggesting that the entire genome accepts simple sequences in a concerted manner when its size increases. Although coding sequences accept simple sequences much less readily (...) than non‐coding sequences, they accept some repeats, particularly (CAG)n, preferentially. This may have consequences for the evolution of the genes involved in trinucleotide expansion diseases and the transcriptional networks of which they may form a part. (shrink)

Cet article se propose d’appréhender le segment du point de vue de la production, en analysant les séquences identifiées lors du processus d’écriture, c’est-à-dire les unités langagières produites de manière spontanée et ininterrompue (entre deux pauses). Ces unités, que nous appelons jets textuels, ont été enregistrées grâce à l’outil de suivi de rédaction Inputlog. Nous avons tenté de caractériser les jets textuels en les mettant en regard avec divers types d’unités segmentales de langage, qu’elles soient issues de la segmentation des (...) textes finalisés, ou reconnues comme des segments préfabriqués propres à un système lexical ou syntaxique, c’est-à-dire des figements au sens large du terme. Nous nous sommes plus particulièrement penchés sur un parcours de segmentation parallèle, en production (jets textuels) et en réception (segments répétés), pour interroger quelques concepts théoriques et méthodologiques qui sous-tendent les démarches de segmentation : pré-construit, automatisme, mémorisation, figement, enracinement cognitif, fréquence, répétition. (shrink)

The structures of specific chromosome regions, centromeres and telomeres, present a number of puzzles. As functions performed by these regions are ubiquitous and essential, their DNA, proteins and chromatin structure are expected to be conserved. Recent studies of centromeric DNA from human, Drosophila and plant species have demonstrated that a hidden universal centromere‐specific sequence is highly unlikely. The DNA of telomeres is more conserved consisting of a tandemly repeated 6–8 bp Arabidopsis‐like sequence in a majority of organisms as diverse as (...) protozoan, fungi, mammals and plants. However, there are alternatives to short DNA repeats at the ends of chromosomes and for telomere elongation by telomerase. Here we focus on the similarities and diversity that exist among the structural elements, DNA sequences and proteins, that make up terminal domains (telomeres and subtelomeres), and how organisms use these in different ways to fulfil the functions of end‐replication and end‐protection. BioEssays 27:685–697, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Beliefs like the Gambler's Fallacy and the Hot Hand have interested cognitive scientists, economists, and philosophers for centuries. We propose that these judgment patterns arise from the observer's mental models of the sequence-generating mechanism, moderated by the strength of belief in an a priori base rate. In six behavioral experiments, participants observed one of three mechanisms generating sequences of eight binary events: a random mechanical device, an intentional goal-directed actor, and a financial market. We systematically manipulated participants’ beliefs about (...) the base rate probabilities at which different outcomes were generated by each mechanism. Participants judged 18 sequences of outcomes produced by a mechanism with either an unknown base rate, a specified distribution of three equiprobable base rates, or a precise, fixed base rate. Six target sequences ended in streaks of between two and seven identical outcomes. The most common predictions for subsequent events were best described as pragmatic belief updating, expressed as an increasingly strong expectation that a streak of identical signals would repeat as the length of that streak increased. The exception to this pattern was for sequences generated by a random mechanical device with a fixed base rate of.50. Under this specific condition, participants exhibited a bias toward reversal of streaks, and this bias was larger when participants were asked to make a dichotomous choice versus a numerical probability rating. We review alternate accounts for the anomalous judgments of sequences and conclude with our favored interpretation that is based on Rabin's version of Tversky & Kahneman's Law of Small Numbers. (shrink)

Turns-at-talk are fundamental units of participation in talk-in-interaction, and turn-constructional-units are the basic building blocks for turns. Possible completion of a TCU is, in principle, the possible completion of the turn, but multi-unit turns are not uncommon, and participants have practices for constructing multi-unit turns and for recognizing them in the course of their production. This article offers an account of one practice usable by speakers and recipients to convey and recognize the designed completion of a multi-TCU turn and/or a (...) multi-turn sequence in which ‘answering’ is being done: returning to, or ‘re-using’, a word or phrase from the start of the turn or sequence, whether articulated by same or different speaker, whether used to refer to same or different referents. This practice is one of the resources by which the overall structural organization of an interactional unit and its local realization are mutually realized. (shrink)

In human languages, a palindrome reads the same forward as backward (e.g., ‘madam’). In regulatory DNA, a palindrome is an inverted sequence repeat that allows a transcription factor to bind as a homodimer or as a heterodimer with another type of transcription factor. Regulatory palindromes are typically imperfect, that is, the repeated sequences differ in at least one base pair, but the functional significance of this asymmetry remains poorly understood. Here, we review the use of imperfect palindromes in (...) Drosophila photoreceptor differentiation and mammalian steroid receptor signaling. Moreover, we discuss mechanistic explanations for the predominance of imperfect palindromes over perfect palindromes in these two gene regulatory contexts. Lastly, we propose to elucidate whether specific imperfectly palindromic variants have specific regulatory functions in steroid receptor signaling and whether such variants can help predict transcriptional outcomes as well as the response of individual patients to drug treatments. (shrink)

This article examines the prosody and sequential organisation of repeats in French talk-in-interaction. Repeats in French are used for initiating repair, as well as for registering receipt. I show for two sequential contexts – after first pair parts and after second pair parts – that the action import of the repeat depends on its prosodic design; prosody allows participants to differentiate between repair-initiating and receipt-registering repeats. While questioning repeats make a response conditionally relevant, registering repeats do not – however, (...) they do not preclude a response either. Registering repeats are sometimes responded to with confirmation tokens, and sometimes not; when produced, such responses are a contingent possibility rather than an expectable second pair part. In the selection and design of confirmation tokens, participants distinguish between solicited and volunteered confirmations. The article relates these findings to prior research on repetition and sequence organisation in French and also in English, Russian and Finnish. (shrink)

It is becoming increasingly clear that repetitive DNA is of biological significance as well as experimental importance. Here we review the information available about one type of repetitive 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)

A basic function of cognition is to detect regularities in sensory input to facilitate the prediction and recognition of future events. It has been proposed that these implicit expectations arise from an internal predictive coding model, based on knowledge acquired through processes such as statistical learning, but it is unclear how different types of statistical information affect listeners’ memory for auditory stimuli. We used a combination of behavioral and computational methods to investigate memory for non-linguistic auditory sequences. Participants repeatedly (...) heard tone sequences varying systematically in their information-theoretic properties. Expectedness ratings of tones were collected during three listening sessions, and a recognition memory test was given after each session. Information-theoretic measures of sequential predictability significantly influenced listeners’ expectedness ratings, and variations in these properties had a significant impact on memory performance. Predictable sequences yielded increasingly better memory performance with increasing exposure. Computational simulations using a probabilistic model of auditory expectation suggest that listeners dynamically formed a new, and increasingly accurate, implicit cognitive model of the information-theoretic structure of the sequences throughout the experimental session. (shrink)

Replication protein A (RPA) is the main eukaryotic single‐stranded DNA (ssDNA) binding protein, having essential roles in all DNA metabolic reactions involving ssDNA. RPA binds ssDNA with high affinity, thereby preventing the formation of secondary structures and protecting ssDNA from the action of nucleases, and directly interacts with other DNA processing proteins. Here, we discuss recent results supporting the idea that one function of RPA is to prevent annealing between short repeats that can lead to chromosome rearrangements by microhomology‐mediated end (...) joining or the formation of hairpin structures that are substrates for structure‐selective nucleases. We suggest that replication fork catastrophe caused by depletion of RPA could result from cleavage of secondary structures by nucleases, and that failure to cleave hairpin structures formed at DNA ends could lead to gene amplification. These studies highlight the important role RPA plays in maintaining genome integrity. (shrink)

We explore whether children’s willingness to produce unfamiliar sequences of words reflects their experience with similar lexical patterns. We asked children to repeat unfamiliar sequences that were identical to familiar phrases (e.g.,A piece of toast) but for one word (e.g., a novel instantiation ofA piece ofX, likeA piece of brick). We explore two predictions—motivated by findings in the statistical learning literature—that children are likely to have detected an opportunity to substitute alternative words into the final position of (...) a four‐word sequence if (a) it is difficult to predict the fourth word given the first three words and (b) the words observed in the final position are distributionally similar. Twenty‐eight 2‐year‐olds and thirty‐one 3‐year‐olds were significantly more likely to correctly repeat unfamiliar variants of patterns for which these properties held. The results illustrate how children’s developing language is shaped by linguistic experience. (shrink)

Tumour‐associated genetic changes frequently involve DNA translocation or deletion. Many of these events will have arisen from initial genomic damage, induced by either the activity of endogenous metabolic processes or from exposure to environmental genotoxic agents. Although initial genomic damage will have been widely distributed, tumorigenic events are confined to certain DNA target sites. Furthermore, within these target sites there appear to be regions of preferential DNA rearrangement, and examination of these sites implies that the location and extent of such (...) rearrangement may be influenced by DNA primary and secondary structure rather than simply by the point of damage. We selectively review evidence relating to DNA structures that may predispose certain regions of the genome to damage‐induced rearrangement, and discuss the possible role of interstitial, inverted telomere‐like sequence arrays in promoting chromosomal events of a type known to be associated with some human and animal tumours. (shrink)

The present study examined trajectories of change in the frequency of overgeneral autobiographical memory (OGM) over the course of repeated trials, and tested whether particular dimensions of depressive symptomatology (somatic and cognitive‐affective distress), self‐esteem, and neuroticism account for individual differences in these trajectories. Given that depression is associated with impairments in effortful processing, we predicted that over repeated trials depression would be associated with increasingly OGM. Generalised Linear Mixed Models with Penalised Quasi‐Likelihood demonstrated significant linear and quadratic trends in OGM (...) over repeated trials, and somatic distress and self‐esteem moderated these slopes. The form of these interactions suggested that somatic distress and low self‐esteem primarily contribute to OGM during the second half of the trial sequence. The present findings demonstrate the value of a novel analytical approach to OGM that estimates individual trajectories of change over repeated trials. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Kennedy Institute of Ethics Journal 10.3 (2000) 265-281 [Access article in PDF] Scope Note 39 Genes, Patents, and Bioethics-Will History Repeat Itself? Susan Cartier Poland Gene patenting--the very notion sounds absurd! How can anyone claim to have invented the genes with which one is born? To make matters worse, genetic makeup precedes birth, meaning the existence of the invention predates the existence of the inventor. So, do we (...) really own our genes, or do they belong to our parents, or our governments, or a Supreme Being? Ownership is only one bioethical issue involved in gene patenting. But before looking at the issues, some essential and basic terms must be understood, namely genes and patents. Genes In his book On the Origin of Species, published in 1859, the biologist Charles Darwin proposed a theory called "natural selection," whereby living things changed over time or evolved through generations due to competition and variation. By experimenting with the garden pea in the 1860s, Gregor Mendel, a monk and accomplished horticulturalist, provided the mechanism of inheritance supporting the natural selection theory of his contemporary Darwin. That mechanism is the gene, or, as Mendel described it, a discrete "factor." The gene has also been defined as "the fundamental unit of heredity" (United States 1987, p. 157). Each individual has two copies of a gene, one from each parent, but that individual passes down to offspring only one of the two copies. Because of Mendel, the gene has become a scientific concept and the basis of a new scientific field: genetics.David C. Page (2000) of the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology explained today's terms for genetics structures using an analogy taken from the home. In his view, the cell is a kitchen, the genome is a shelf in the kitchen, the chromosome is a cookbook on the shelf, the gene is a recipe in the cookbook, and a base-pair (either adenine with thymine or guanine with cytosine) is a single letter in the recipe. A protein, the [End Page 265] working molecule blueprinted by a gene, is a dish ready to eat, and an ingredient in the dish is an amino acid, which is a building block of the protein as specified by a string of base-pairs.Colin Tudge (1993), a British science journalist, would disagree with Page's description of the gene as a recipe. A recipe is like a blueprint: both are directions that precede the work. But a gene is not passive according to Tudge; it actively administers the cell's work, and it also responds to cellular events (Aldridge 1996).The current focus of scientific research and funding is on the gene and the completion of the sequencing of all the genes that comprise the human genome, portrayed in the press as a race between the U.S. government's Human Genome Project and the private corporation Celera Genomics. The real action, however, is at the protein level. The gene only holds the information to produce a protein; it is the three-dimensional shaped protein that does the work. In order to produce energy, eliminate waste, and perform other functions specific to a cell or tissue, proteins must bind, thus creating "biological pathways." Proteins bind (or not) and detach as a function of their shapes, which are determined by their precise chemical composition as spelled out in their genetic code. IBM will spend the next five years making one computer, Blue Gene, that will then take an entire year to come up with the chemical map for only one protein (Gillis 2000). It is estimated that there are about 40,000 proteins in the human body.Despite these overwhelming numbers, modern biology has been able to achieve significant results within the Human Genome Project's 15-year time frame, from 1990 to 2005. The genetic map was completed in 1993; the physical map was completed in 1995; and the genetic sequence is expected to be completed in 2002, with 97 to 99 percent completed as of 26 June 2000. This... (shrink)

The proportion of the genome encoding intrinsically unstructured proteins increases with the complexity of organisms, which demands specific mechanism(s) for generating novel genetic material of this sort. Here it is suggested that one such mechanism is the expansion of internal repeat regions, i.e., coding micro‐ and minisatellites. An analysis of 126 known unstructured sequences shows the preponderance of repeats: the percentage of proteins with tandemly repeated short segments is much higher in this class (39%) than earlier reported for (...) all Swiss‐Prot (14%), yeast (18%) or human (28%) proteins. Furthermore, prime examples, such as salivary proline‐rich proteins, titin, eukaryotic RNA polymerase II, the prion protein and several others, demonstrate that the repetitive segments carry fundamental function in these proteins. In addition, their repeat numbers show functionally significant interspecies variation and polymorphism, which underlines that these regions have been shaped by intense evolutionary activity. In all, the major point of this paper is that the genetic instability of repetitive regions combined with the structurally and functionally permissive nature of unstructured proteins has powered the extension and possible functional expansion of this newly recognized protein class. BioEssays 25:847–855, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A few years ago no one would have suspected that the well‐known disorder of connective tissue, Marfan syndrome, could be caused by mutations in a recently discovered extracellular component, fibrillin. Likewise, nobody would have predicted that fibrillin represents a small family of proteins that are associated with several pheno‐typically overlapping disorders. The fibrillins are integral constituents of the non‐collagenous microfibrils, with an average diameter of 10 nm. These aggregates are distributed in the extracellular matrix of virtually every tissue. Microfibrillar bundles (...) provide the external coating to elastin in elastic fibers, and serve an anchoring function in non‐elastic tissues. At higher resolution, individual microfibrils have a “beads‐on‐a‐string” appearance resulting from the head‐to‐tail polymerization of multiple fibrillin aggregates. Structurally, fibrillin contains a series of repeated sequences homologous to the epidermal growth factor calcium‐binding motif. Characterization of fibrillin mutations in Marfan syndrome patients, together with the elucidation of the structure of the fibrillin proteins, have provided new insights, and raised new questions, about the function of the 10 nm microfibrils. For example, it is possible that the fibrillins, in addition to serving a structural function, might also be involved in regulating cellular activities and morphogenetic programs. It is fitting that the long search for the Marfan syndrome gene has brought a novel group of proteins to the forefront of extracellular matrix biology. (shrink)

The telomere is a functional domain of the chromosome, located at the extreme ends, and is essential for normal chromosome stability. Chromosomes lacking telomeres are inherited improperly, and mutations in the telomeric repeat sequences are thought to lead to senescence and possibly to cancer. The molecular mechanisms maintaining chromosomes by telomeres, however, have been unclear. Results recently reported by Kirk et al.(1) offer an insight into new telomerase function. They have identified a novel telomerase mutation that blocks sister (...) chromatid separation in mitosis. (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)

Recent sequencing of the metazoan Oikopleura dioica genome has provided important insights, which challenges the current understanding of eukaryotic genome evolution. Many genomic features of O. dioica show deviation from the commonly observed trends in other eukaryotic genomes. For instance, O. dioica has a rapidly evolving, highly compact genome with a divergent intron‐exon organization. Additionally, O. dioica lacks the minor spliceosome and key DNA repair pathway genes. Even with a compact genome, O. dioica contains tandem repeats, comparable to other eukaryotes, (...) and shows lineage‐specific expansion of certain protein domains. Here, we review its genomic features in the context of current knowledge, discuss implications for contemporary biology and identify areas for further research. Analysis of the O. dioica genome suggests that non‐adaptive forces such as elevated mutation rates might influence the evolution of genome architecture. The knowledge of unique genomic features and splicing mechanisms in O. dioica may be exploited for synthetic biology applications, such as generation of orthogonal splicing systems. (shrink)

Mammals have an XX:XY system of chromosomal sex determination in which a small heterochromatic Y controls male development. The Y contains the testis determining factor SRY, as well as several genes important in spermatogenesis. Comparative studies show that the Y was once homologous with the X, but has been progressively degraded, and now consists largely of repeated sequences as well as degraded copies of X linked genes. The small original X and Y have been enlarged by cycles of autosomal (...) addition to one partner, recombination onto the other and continuing attrition of the compound Y. This addition–attrition hypothesis predicts that the pseudoautosomal region of the human X is merely the last relic of the latest addition. Genes (including SRY) on the conserved or added region of the Y evolved functions in male sex determination and differentiation distinct from the general functions of their X‐linked partners. Although the gonadogenesis pathway is highly conserved in vertebrates, its control has probably changed radically and rapidly in vertebrate – even mammalian – evolution. (shrink)

The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of “difficult to repair” lesions such as double‐strand breaks without a repair template and eroded telomeres in telomerase‐deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure‐forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat (...) locus to the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC‐facilitated repair. (shrink)

The discoveries, advancements and continuing controversies in the field of molecular evolution are reviewed. Topics summarized are (1) the evolution of the genetic code, (2) gene evolution including the demonstration of homology, estimation of sequence divergence, phylogenetic trees, the molecular clock and the origin of genes and gene families by various genetic mechanisms, and (3) eukaryotic genome evolution, including the highly repeated satellite sequences, the interspersed and potentially mobile repeated sequences and the unique sequence fraction of the genome.

Fragile X syndrome is the most common cause of inherited mental retardation in humans. The fragile X gene (FMR1) has been cloned and the mutation causing the disease is known. The molecular basis of the disease is an expansion of a trinucleotide repeat sequence (CGG) present in the first exon within the 5′ untranslated region of the FMR1 gene. Affected individuals have repeat CGG sequences of above 200. As a result the gene is not producing protein. It (...) has been shown that the FMR1 protein has RNA binding activity, but the function of this RNA binding activity is not known. The timing and mechanism of repeat amplification are not yet understood. An animal model for fragile X syndrome has been generated, which can be used to study the clinical and biochemical abnormalities caused by absence of FMR1 protein product. (shrink)

Long DNA palindromes pose a threat to genome stability. This instability is primarily mediated by slippage on the lagging strand of the replication fork between short directly repeated sequences close to the ends of the palindrome. The role of the palindrome is likely to be the juxtaposition of the directly repeated sequences by intrastrand base‐pairing. This intra‐strand base‐pairing, if present on both strands, results in a cruciform structure. In bacteria, cruciform structures have proved difficult to detect in vivo, (...) suggesting that if they form, they are either not replicated or are destroyed. SbcCD, a recently discovered exonuclease of Escherichia coli, is responsible for preventing the replication of long palindromes. These observations lead to the proposal that cells may have evolved a post‐replicative mechanism for the elimination and/or repair of large DNA secondary structures. (shrink)

The mammalian chromosome is longitudinally heterogeneous in structure and function and this is the basis for the specific banding patterns produced by various chromosome staining techniques. The two most frequently used techniques are G, or Giemsa banding and R, or reverse banding. Each type of stained band is characterised by variations in gene density, time of replication, base composition, density of repeat sequences, and chromatin packaging. It is increasingly apparent that R and G bands, which are complementary to (...) each other, represent separate compartments of the euchromatic human genome, with R bands containing the vast majority of genes. R bands are also more GC‐rich, contain a higher density of Alu repeats, and replicate earlier in S phase, than G bands. These properties may be interdependent and may have coevolved. (shrink)

Eukaryotic genomes harbor a large number of homologous repeat sequences that are capable of recombining. Their potential to disrupt genome stability highlights the need to understand how homologous recombination processes are coordinated. The Saccharomyces cerevisiae Rad1–Rad10 endonuclease performs an essential role in recombination between repeated sequences, by processing 3′ single‐stranded intermediates formed during single‐strand annealing and gene conversion events. Several recent studies have focused on factors involved in Rad1–Rad10‐dependent removal of 3′ nonhomologous tails during homologous recombination, including (...) Msh2–Msh3, Slx4, and the newly identified Saw1 protein. Together, this new work provides a model for how Rad1–Rad10‐dependent end processing is coordinated: Msh2–Msh3 stabilizes and prepares double‐strand/single‐strand junctions for Rad1–Rad10 cleavage, Saw1 recruits Rad1–Rad10 to 3′ tails, and Slx4 mediates crosstalk between the DNA damage checkpoint machinery and Rad1–Rad10. (shrink)

A substantial portion of the human genome has been found to consist of simple sequence repeats, including microsatellites and minisatellites. Microsatellites, tandem repeats of 1–6 nucleotides, form the template for dynamic mutations, which involve heritable changes in the lengths of repeat sequences. In recent years, a large number of human disorders have been found to be caused by dynamic mutations, the most common of which are trinucleotide repeat expansion diseases. Dynamic mutations are common to numerous nervous system (...) disorders, including Huntington's disease, various spinocerebellar ataxias, fragile X syndrome, fragile X tremor/ataxia syndrome, Friedreich ataxia and other neurodegenerative disorders. The involvement of dynamic mutations in brain disorders will be reviewed, with a focus on the large group caused by CAG/glutamine repeat expansions. We will also outline a proposed role of tandem repeat polymorphisms (TRPs), with unique ‘digital’ genetic distributions, in modulating brain development and normal function, so as to generate additional mutational diversity upon which natural selection may act. BioEssays 29:525–535, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This paper aims to extend Romanshyn's reading of van den Berg's metabletics as a process of recovering metaphoricity. Drawing upon research in contemporary cognitive linguistics, metabletics can be recast in terms of a process of re-metaphorization that requires a repeated sequence of stages. Initially a collective figuration exists in the culture as a form of negative metonymy, which serves the function of concealing a latent and taken-for-granted cultural meaning. By transforming the figuration from a form of negative metonymy to positive (...) metonymy, the metabletic method reveals how one cultural event has stood for another cultural event. In the final stage of the metabletic process, the researcher shows how the cultural event not only has stood for another cultural event, but can been understood metaphorically in terms of, or through, the other cultural event. This final step recovers the metaphoricity of the cultural meaning, which in turn frees up the possibility for creating new meanings that were previously foreclosed. (shrink)

The acidic (leucine‐rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N‐terminal leucine‐rich repeat domain and a C‐terminal low‐complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having a (...) whip‐like structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context‐dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities. (shrink)

There are two principles that lend Brouwer's mathematics the extra power beyond arithmetic. Both are presented in Brouwer's writings with little or no argument. One, the principle of bar induction, will not concern us here. The other, the continuity principle for numbers, occurs for the first time in print in [4]. It is formulated and immediately applied to show that the set of numerical choice sequences is not enumerable. In fact, the idea of the continuity property can be dated (...) fairly precisely, it is to be found in the margin of Brouwer's notes for his course on Pointset Theory of 1915/16. The course was repeated in 1916/17 and he must have inserted his first formulation of the continuity principle in the fall of 1916 as new material right at the beginning of the course.In modern language, the principle readswhere α and β range over choice sequences of natural numbers, m and x over natural numbers, and stands for ⟨α, α, …, α⟩, the initial segment of α of length m.An immediate consequence of WC-N is that all full functions are continuous, and, as a corollary, that the continuum is unsplittable [28]. Note that WC-N is incompatible with Church's thesis, [22], section 4.6.After Brouwer asserted WC-N, Troelstra was the first to ask in print for a conceptual motivation, but he remained an exception; most authors followed Brouwer by simply asserting it, cf. [18].Let us note first that in one particular case the principle is obvious indeed, namely in the case of the lawless sequences. The notion of lawless sequence surfaced fairly late in the history of intuitionism. Kreisel introduced it in [17] for metamathematical purposes. There is a letter from Brouwer to Heyting in which the phenomenon also occurs [7]. This is an important and interesting fact since it is the only time that Brouwer made use of a possibility expressly stipulated in, e.g., [5], see below. (shrink)

Studies on Neurospora chromosome segment duplications (Dps) performed since the publication of Perkins's comprehensive review in 1997 form the focus of this article. We present a brief summary of Perkins's seminal work on chromosome rearrangements, specifically, the identification of insertional and quasiterminal translocations that can segregate Dp progeny when crossed with normal sequence strains (i.e., T × N). We describe the genome defense process called meiotic silencing by unpaired DNA that renders Dp‐heterozygous crosses (i.e., Dp × N) barren, which provides (...) a basis for identifying Dps, and discuss whether other processes also might contribute to the barren phenotype of Dp × N and Dp × Dp crosses. We then turn to studies suggesting that large Dps (i.e., >300 kbp) can allow smaller gene‐sized duplications to escape another genome defense process called repeat‐induced point mutation (RIP), possibly by titration of the RIP machinery. Finally, we assess whether in natural populations dominant RIP suppressor Dps provide an “RIP‐free” niche for evolution of new genes following the duplication of existing genes. (shrink)

Several canonical experimental paradigms (e.g., serial reaction time task, discrete sequence production task,m×ntask) have been proposed to study the typical behavioral phenomenon and the nature of learning in sequential keypress tasks. A characteristic feature of most paradigms is that they are representative ofexternally-specifiedsequencing—motor tasks where the environment or task paradigm extrinsically provides the sequence of stimuli, i.e., the responses are stimulus-driven. Previous studies utilizing such canonical paradigms have largely overlooked the learning behaviors in a more realistic class of motor tasks (...) that involveinternally-guidedsequencing—where the sequence of motor actions is self-generated or internally-specified. In this work, we use the grid-navigation task as an instance of internally-guided sequencing to investigate the nature of learning in such paradigms. The participants performed Grid-Sailing Task (GST), which required navigating (by executing sequential keypresses) a 5 × 5 grid from start to goal (SG) position while using a particular key-mapping (KM) among the three cursor-movement directions and the three keyboard buttons. The participants performed two behavioral experiments—Single-SG and Mixed-SG condition. The Single-SG condition required performing GST on a single SG position repeatedly, whereas the Mixed-SG condition involved performing GST using the same KM on two novel SG positions presented in a random, inter-mixed manner. In the Single-SG condition, we show that motor learning contributes to the sequence-specific learning in GST with the repeated execution of the same trajectories. In the Mixed-SG condition, since the participants utilize the previously learned KM, we anticipate a transfer of learning from the Single-SG condition. The acquisition and transfer of a KM-specific internal model facilitates efficient trajectory planning on novel SG conditions. The acquisition of such a KM-specific internal model amounts to trajectory-independent cognitive learning in GST. We show that cognitive learning contributes to the learning in GST by showing transfer-related performance improvements in the Mixed-SG condition. In sum, we show the role of cognitive and motor learning processes in internally-guided sequencing and further make a case for using GST-like grid-navigation paradigms in investigating internally guided skill learning. (shrink)

Sequential action makes up the bulk of human daily activity, and yet much remains unknown about how people learn such actions. In one motor learning paradigm, the serial reaction time (SRT) task, people are taught a consistent sequence of button presses by cueing them with the next target response. However, the SRT task only records keypress response times to a cued target, and thus it cannot reveal the full time‐course of motion, including predictive movements. This paper describes a mouse movement (...) trajectory SRT task in which the cursor must be moved to a cued location. We replicated keypress SRT results, but also found that predictive movement—before the next cue appears—increased during the experiment. Moreover, trajectory analyses revealed that people developed a centering strategy under uncertainty. In a second experiment, we made prediction explicit, no longer cueing targets. Thus, participants had to explore the response alternatives and learn via reinforcement, receiving rewards and penalties for correct and incorrect actions, respectively. Participants were not told whether the sequence of stimuli was deterministic, nor if it would repeat, nor how long it was. Given the difficulty of the task, it is unsurprising that some learners performed poorly. However, many learners performed remarkably well, and some acquired the full 10‐item sequence within 10 repetitions. Comparing the high‐ and low‐performers’ detailed results in this reinforcement learning (RL) task with the first experiment's cued trajectory SRT task, we found similarities between the two tasks, suggesting that the effects in Experiment 1 are due to predictive, rather than reactive processes. Finally, we found that two standard model‐free reinforcement learning models fit the high‐performing participants, while the four low‐performing participants provide better fit with a simple negative recency bias model. (shrink)

Sequential action makes up the bulk of human daily activity, and yet much remains unknown about how people learn such actions. In one motor learning paradigm, the serial reaction time (SRT) task, people are taught a consistent sequence of button presses by cueing them with the next target response. However, the SRT task only records keypress response times to a cued target, and thus it cannot reveal the full time‐course of motion, including predictive movements. This paper describes a mouse movement (...) trajectory SRT task in which the cursor must be moved to a cued location. We replicated keypress SRT results, but also found that predictive movement—before the next cue appears—increased during the experiment. Moreover, trajectory analyses revealed that people developed a centering strategy under uncertainty. In a second experiment, we made prediction explicit, no longer cueing targets. Thus, participants had to explore the response alternatives and learn via reinforcement, receiving rewards and penalties for correct and incorrect actions, respectively. Participants were not told whether the sequence of stimuli was deterministic, nor if it would repeat, nor how long it was. Given the difficulty of the task, it is unsurprising that some learners performed poorly. However, many learners performed remarkably well, and some acquired the full 10‐item sequence within 10 repetitions. Comparing the high‐ and low‐performers’ detailed results in this reinforcement learning (RL) task with the first experiment's cued trajectory SRT task, we found similarities between the two tasks, suggesting that the effects in Experiment 1 are due to predictive, rather than reactive processes. Finally, we found that two standard model‐free reinforcement learning models fit the high‐performing participants, while the four low‐performing participants provide better fit with a simple negative recency bias model. (shrink)

Glossolalia (“speaking in tongues”) is a rhythmic utterance of word‐like strings of sounds, regularly occurring in religious mass gatherings or various forms of private religious practices (e.g., prayer and meditation). Although specific verbal learning capacities may characterize glossolalists, empirical evidence is lacking. We administered three statistical learning tasks (artificial grammar, phoneme sequence, and visual‐response sequence) to 30 glossolalists and 30 matched control volunteers. In artificial grammar, participants decide whether pseudowords and sentences follow previously acquired implicit rules or not. In sequence (...) learning, they gradually draw out rules from repeating regularities in sequences of speech sounds or motor responses. Results revealed enhanced artificial grammar and phoneme sequence learning performances in glossolalists compared to control volunteers. There were significant positive correlations between daily glossolalia activity and artificial grammar learning. These results indicate that glossolalists exhibit enhanced abilities to extract the statistical regularities of verbal information, which may be related to their unusual language abilities. (shrink)

Drosophila telomeres comprise DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase‐based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase‐generated short repeats. Regardless of the DNA sequence, several end‐binding proteins are evolutionarily conserved. Away from the end, the Drosophila telomeric and subtelomeric DNA sequences are complexed with unique combinations of (...) proteins that also modulate chromatin structure elsewhere in the genome. Maintaining and regulating the transcriptional activity of the telomeric retrotransposons in Drosophila requires specific chromatin structures and, while telomeric silencing spreads from the terminal repeats in yeast, the source of telomeric silencing in Drosophila is the subterminal arrays. However, the subterminal arrays in both species may be involved in telomere–telomere associations and/or communication. BioEssays 30:25–37, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

In this Hypothesis and Theory paper, we consider the problem of learning deeply structured knowledge representations in the absence of predefined ontologies, and in the context of long-term learning. In particular, we consider this process as a sequence of re-representation steps, of various kinds. The Information Dynamics of Thinking theory (IDyOT) admits such learning, and provides a hypothetical mechanism for the human-like construction of hierarchical memory, with the provision of symbols constructed by the system that embodies the theory. The combination (...) of long-term learning and meaning construction in terms of symbols grounded in perceptual experience entails that the system, like a human, be capable of memory consolidation, to manage the complex and inconsistent structures that can result from learning of information that becomes more complete over time. Such consolidation changes memory structures, and thus changes their meaning. Therefore, memory consolidation entails re-representation, while re-representation entails changes of meaning. Ultimately, the theory proposes that the processes of learning and consolidation should be considered as repeated re-representation of what is learned. (shrink)

A folk tune is brief enough to be readily grasped and remembered as a whole; it has an inner unity that makes it shapely to the ear and mind. As a temporal event, or succession of notes, it consists of a little tour through a sonic landscape; so that as we follow the course we recognize its topography; the setting forth, the approach to a turning point, a moment of heightened interest, a pause of retrospection or anticipation, a homecoming. It (...) falls naturally into related, self-defining stages of its whole extent, revealing balance, contrast, and decision. The balance normally relies on approximately the same number of stresses in corresponding phrases; the contrast usually on tonal sequence and management; the decision appears in cadential statement, and held, or repeating, notes, like signposts at an intersection or junction. Because the tune is seized as a whole, and because several parts have these mutual references, we gain already the suggestion of stanzas of a certain pattern and identical length. Since the phrasal cadences get their weight and meaning from their relative emphasis and relation to the tonic, they inherently prompt corresponding verbal emphases of rhyme or pause. By their perceptible division or separation they exert, moreover, a pressure on the verbal partner, so that the total syntactical and rhetorical structure is palpably affected, and restricted, by their influence. Bertrand H. Bronson is the author of such influential works as Joseph Ritson: Scholar-at-Arms, Johnson Agonistes and Other Essays, In Search of Chaucer, and Facets of the Enlightenment and is the editor of the four-volume The Traditional Tunes of the Child Ballads. Among other honors, he has received the American Council of Learned Sciences Award. "Traditional Ballads Musically Considered" will appear in a slightly different version as the introduction to Singing Tradition, to be published by Princeton University Press. (shrink)