A model of gestural sequencing in speech is proposed that aspires to producing biologically plausible fluent and efficient movement in generating an utterance. We have previously proposed a modification of the well-known task dynamic implementation of articulatory phonology such that any given articulatory movement can be associated with a quantification of effort (Simko & Cummins, 2010). To this we add a quantitative cost that decreases as speech gestures become more precise, and hence intelligible, and a third cost component that places (...) a premium on the duration of an utterance. Together, these three cost elements allow us to derive algorithmically optimal sequences of gestures and dynamical parameters for generating articulator movement. We show that the optimized movement displays many timing characteristics that are representative of real speech movement, capturing subtle details of relative timing between gestures. Optimal movement sequences also display invariances in timing that suggest syllable-level coordination for CV sequences. We explore the behavior of the model as prosodic context is manipulated in two dimensions: clarity of articulation and speech rate. Smooth, fluid, and efficient movements result. (shrink)

Background: The proprioceptive neuromuscular facilitation reciprocal contraction pattern has the potential to increase the maximum rate of torque development. However, it is a more complex resistive exercise task and may interfere with improvements in the maximum rate of torque development due to motor skill learning, as observed for unidirectional contractions. The purpose of this study was to examine the cost-benefit of using the PNF exercise technique to increase the maximum rate of torque development.Methods: Twenty-six participants completed isometric (...) maximal extension-to-flexion or flexion-only contractions at the wrist. Ten of the assigned contractions were performed on each of three sessions separated by 48-h for skill acquisition. Retention was assessed with 5 contractions performed 2-weeks after acquisition. Torque and surface electromyographic activity were analyzed for evidence of facilitated contractions between groups, as well as alterations in muscle coordination assessed across test sessions. The criterion measures were: mean maximal isometric wrist flexion toque; the maximal rate of torque development ; root-mean-square error variability of the rate of torque versus torque phase-plane; the rate of wrist flexion muscle activation ; a coactivation ratio for wrist flexor and extensor sEMG activity; and wrist flexor electromechanical delay.Results: There were no significant differences between groups with respect to maximal wrist flexion torque, dτ/dtmax or RMSE variability of torque trajectories. Both groups exhibited a progressive increase in maximal strength and in dτ/dtmax from the start of acquisition to retention. RMSE was lowest after a 2-week rest interval. There were no significant differences between groups in the rate of muscle activation or the coactivation ratio. There was a reduction in coactivation that was retained after a 2-week rest interval. Alternatively, EMD was significantly greater in the experimental group across all sessions. However, both groups had a similar pattern of improvement to the third consecutive day of testing, but returned close to baseline value after the 2-week rest interval.Discussion: The wrist extension-to-flexion contraction pattern did not result in a greater maximal rate of torque development than simple contractions of the wrist flexors. There was no difference between groups with respect to motor skill learning. The main adaptation in neuromotor control was a decrease in coactivation, not the maximal rate of muscle activation. (shrink)

The production of complex sequences like music or speech requires the rapid and temporally precise production of events (e.g., notes and chords), often at fast rates. Memory retrieval in these circumstances may rely on the simultaneous activation of both the current event and the surrounding context (Lashley, 1951). We describe an extension to a model of incremental retrieval in sequence production (Palmer & Pfordresher, 2003) that incorporates this logic to predict overall error rates and speed—accuracy trade-offs, as well as (...) types of serial ordering errors. The model—assumes that retrieval of the current event is influenced by activations of surrounding events. Activations of surrounding events increase over time, such that both the accessibility of distant events and overall accuracy increases at slower production rates. The model's predictions were tested in an experiment in which pianists performed unfamiliar music at 8 different tempi. Model fits to speed—accuracy data and to serial ordering errors support model predictions. Parameter fits to individual data further suggest that working memory contributes to the retrieval of serial order and overall accuracy is influenced in addition by motor dexterity and domain-specific skill. (shrink)

Individuals typically produce auditory sequences, such as speech or music, at a consistent spontaneous rate or tempo. We addressed whether spontaneous rates would show patterns of convergence across the domains of music and language production when the same participants spoke sentences and performed melodic phrases on a piano. Although timing plays a critical role in both domains, different communicative and motor constraints apply in each case and so it is not clear whether music and speech would display similar timing (...) mechanisms. We report the results of two experiments in which adult participants produced sequences from memory at a comfortable spontaneous (uncued) rate. In Experiment 1, monolingual pianists in Buffalo, New York engaged in three production tasks: speaking sentences from memory, performing short melodies from memory, and tapping isochronously. In Experiment 2, English-French bilingual pianists in Montréal, Canada produced melodies on a piano as in Experiment 1, and spoke short rhythmically-structured phrases repeatedly. Both experiments led to the same pattern of results. Participants exhibited consistent spontaneous rates within each task. People who produced one spoken phrase rapidly were likely to produce another spoken phrase rapidly. This consistency across stimuli was also found for performance of different musical melodies. In general, spontaneous rates across speech and music tasks were not correlated, whereas rates of tapping and music were correlated. Speech rates (for syllables) were faster than music rates (for tones) and speech showed a smaller range of spontaneous rates across individuals than did music or tapping rates. Taken together, these results suggest that spontaneous rate reflects cumulative influences of endogenous rhythms (in consistent self-generated rates within domain), peripheral motor constraints (in finger movements across tapping and music), and communicative goals based on the cultural transmission of auditory information (slower rates for to-be-synchronized music than for speech). (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)

It is proposed that early in phylogeny a large proportion of amino acid substitutions were selectively neutral, but that bursts of adaptive substitutions during major radiations of life so increased selective constraints that most mutations in modern proteins are detrimental. Recent findings on DNA nucleotide sequences indicate that decreasing mutation rates further slowed the rate of molecular evolution in the lineage to humans.

Recent advances in DNA sequencing have revolutionized the field of genomics, making it possible for even single research groups to generate large amounts of sequence data very rapidly and at a substantially lower cost. These high‐throughput sequencing technologies make deep transcriptome sequencing and transcript quantification, whole genome sequencing and resequencing available to many more researchers and projects. However, while the cost and time have been greatly reduced, the error profiles and limitations of the new platforms differ significantly from those (...) of previous sequencing technologies. The selection of an appropriate sequencing platform for particular types of experiments is an important consideration, and requires a detailed understanding of the technologies available; including sources of error, error rate, as well as the speed and cost of sequencing. We review the relevant concepts and compare the issues raised by the current high‐throughput DNA sequencing technologies. We analyze how future developments may overcome these limitations and what challenges remain. (shrink)

In 2011, Hibbard suggested an intelligence measure for agents who compete in an adversarial sequence prediction game. We argue that Hibbard’s idea should actually be considered as two separate ideas: first, that the intelligence of such agents can be measured based on the growth rates of the runtimes of the competitors that they defeat; and second, one specific (somewhat arbitrary) method for measuring said growth rates. Whereas Hibbard’s intelligence measure is based on the latter growth-rate-measuring method, we survey (...) other methods for measuring function growth rates, and exhibit the resulting Hibbard-like intelligence measures and taxonomies. Of particular interest, we obtain intelligence taxonomies based on Big-O and Big-Theta notation systems, which taxonomies are novel in that they challenge conventional notions of what an intelligence measure should look like. We discuss how intelligence measurement of sequence predictors can indirectly serve as intelligence measurement for agents with Artificial General Intelligence (AGIs). (shrink)

High‐throughput DNA analyses are increasingly being used to detect rare mutations in moderately sized genomes. These methods have yielded genome mutation rates that are markedly higher than those obtained using pre‐genomic strategies. Recent work in a variety of organisms has shown that mutation rate is strongly affected by sequence context and genome position. These observations suggest that high‐throughput DNA analyses will ultimately allow researchers to identify trans‐acting factors and cis sequences that underlie mutation rate variation. Such work (...) should provide insights on how mutation rate variability can impact genome organization and disease progression. (shrink)

Recombination maps of ancestral species can be constructed from comparative analyses of genomes from closely related species, exemplified by a recently published map of the human‐chimpanzee ancestor. Such maps resolve differences in recombination rate between species into changes along individual branches in the speciation tree, and allow identification of associated changes in the genomic sequences. We describe how coalescent hidden Markov models are able to call individual recombination events in ancestral species through inference of incomplete lineage sorting along a (...) genomic alignment. In the great apes, speciation events are sufficiently close in time that a map can be inferred for the ancestral species at each internal branch ‐ allowing evolution of recombination rate to be tracked over evolutionary time scales from speciation event to speciation event. We see this approach as a way of characterizing the evolution of recombination rate and the genomic properties that influence it. (shrink)

Previous studies of auditory expectation have focused on the expectedness perceived by listeners retrospectively in response to events. In contrast, this research examines predictive uncertainty —a property of listeners' prospective state of expectation prior to the onset of an event. We examine the information-theoretic concept of Shannon entropy as a model of predictive uncertainty in music cognition. This is motivated by the Statistical Learning Hypothesis, which proposes that schematic expectations reflect probabilistic relationships between sensory events learned implicitly through exposure. Using (...) probability estimates from an unsupervised, variable-order Markov model, 12 melodic contexts high in entropy and 12 melodic contexts low in entropy were selected from two musical repertoires differing in structural complexity (simple and complex). Musicians and non-musicians listened to the stimuli and provided explicit judgments of perceived uncertainty (explicit uncertainty). We also examined an indirect measure of uncertainty computed as the entropy of expectedness distributions obtained using a classical probe-tone paradigm where listeners rated the perceived expectedness of the final note in a melodic sequence (inferred uncertainty). Finally, we simulate listeners' perception of expectedness and uncertainty using computational models of auditory expectation. A detailed model comparison indicates which model parameters maximize fit to the data and how they compare to existing models in the literature. The results show that listeners experience greater uncertainty in high-entropy musical contexts than low-entropy contexts. This effect is particularly apparent for inferred uncertainty and is stronger in musicians than non-musicians. Consistent with the Statistical Learning Hypothesis, the results suggest that increased domain-relevant training is associated with an increasingly accurate cognitive model of probabilistic structure in music. (shrink)

The major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate‐limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the details of (...) each GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate‐limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders. (shrink)

In this paper we develop a method for finding, under general conditions, explicit and highly uniform rates of convergence for the Picard iteration sequences for selfmaps on bounded metric spaces from ineffective proofs of convergence to a unique fixed point. We are able to extract full rates of convergence by extending the use of a logical metatheorem recently proved by Kohlenbach. In recent case studies we were able to find such explicit rates of convergence in two concrete cases. Our novel (...) method now provides an explanation in logical terms for these findings. This amounts, loosely speaking, to general conditions under which we in this specific setting can transform a ∀∃∀-sentence into a ∀∃-sentence via an argument involving product spaces. This reduction in logical complexity allows us to use the existing machinery to extract quantitative bounds of the sort we need. (shrink)

The hallmark of implicit learning is that complex knowledge can be acquired unconsciously. The second order conditionals of Reed and Johnson were developed to be complex, and they are popular materials for implicit learning research. Recently, it was demonstrated that in a sequence made noisy , shared features of the SOCs may be learned explicitly . What are these shared features? We hypothesized that low reversal frequency may play a significant role. We have varied reversal frequency, and discovered that (...) reversal frequency affected response times, inclusion exclusion behavior, and recognition ratings. Not only does it appear to be important to distinguish implicit and explicit knowledge, but also to distinguish what the knowledge is of. (shrink)

The gray prediction model, based on the GM method, is an important branch of gray theory with the most active research and the most fruitful results, and it is the most widely used because of its small sample size, simple modeling process, and easy to use. Such advantages have been successfully applied in many fields such as transportation, agriculture, energy, medicine, and environment and have been gradually developed into a mainstream predictive modeling method. This study combines the Three-parameter Whitenization Grey (...) Model ), which fits the inhomogeneous exponential law sequence, and the Particle Swarm Algorithm to optimize the order and background value coefficients under the condition of the minimum sum of squares of simulation errors, and hence, to solve the problem that the cumulative order is fixed to “1” and the background value coefficient value is fixed to “0.5.” As a result, a parameter-optimized gray system model with flexibility, adaptability, and dynamic adjustment is designed to simulate and predict China’s higher education gross enrollment rate. The application shows that the model has better overall simulation and prediction performance than others. On the one hand, the parametric optimization model significantly improves its own performance, and on the other hand, its intelligent and adjustable adaptivity improves the accuracy and further extends its application. (shrink)

During the early 1960s, Morris Goodman used a variety of immunological tests to demonstrate the very close genetic relationships among humans, chimpanzees, and gorillas. Molecular anthropologists often point to this early research as a critical step in establishing their new specialty. Based on his molecular results, Goodman challenged the widely accepted taxonomie classification that separated humans from chimpanzees and gorillas in two separate families. His claim that chimpanzees and gorillas should join humans in family Hominidae sparked a well-known conflict with (...) George Gaylord Simpson, Ernst Mayr, and other prominent evolutionary biologists. Less well known, but equally significant, were a series of disagreements between Goodman and other prominent molecular evolutionists concerning both methodological and theoretical issues. These included qualitative versus quantitative data, the role of natural selection, rates of evolution, and the reality of molecular clocks. These controversies continued throughout Goodman's career, even as he moved from immunological techniques to protein and DNA sequence analysis. This episode highlights the diversity of methods used by molecular evolutionists and the conflicting conclusions drawn from the data that these methods generated. (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)

A total of 944 expressed sequence tags generated 2212 EST loci mapped to homoeologous group 1 chromosomes in hexaploid wheat. EST deletion maps and the consensus map of group 1 chromosomes were constructed to show EST distribution. EST loci were unevenly distributed among chromosomes 1A, 1B, and ID with 660, 826, and 726, respectively. The number of EST loci was greater on the long arms than on the short arms for all three chromosomes. The distribution of ESTs along chromosome (...) arms was nonrandom with EST clusters occurring in the distal regions of short arms and middle regions of long arms. Duplications of group 1 ESTs in other homoeologous groups occurred at a rate of 35.5%. Seventy-five percent of wheat chromosome 1 ESTs had significant matches with rice sequences, where large regions of conservation occurred between wheat consensus chromosome 1 and rice chromosome 5 and between the proximal portion of the long arm of wheat consensus chromosome 1 and rice chromosome 10. Only 9.5% of group 1 ESTs showed significant matches to Arabidopsis genome sequences. The results presented are useful for gene mapping and evolutionary and comparative genomics of grasses. (shrink)

Aging is accompanied by changes in general cognitive functioning which may impact the learning rate of older adults; however, this is often not controlled for in cognitive aging studies. We investigated the contribution of differences in learning rates to age-related differences in landmark knowledge acquired from route learning. In Experiment 1 we used a standard learning procedure in which participants received a fixed amount of exposure to a route. Consistent with previous research, we found age-related deficits in associative cue (...) and landmark sequence knowledge. Experiment 2 controlled for differences in learning rates by using a flexible exposure learning procedure. Specifically, participants were trained to a performance criterion during route learning before being tested on the content of their route knowledge. While older adults took longer to learn the route than younger adults, the age-related differences in associative cue knowledge were abolished. The deficit in landmark sequence knowledge, however, remained. Experiment 3 replicated these results and introduced a test situation in which a deficit in landmark sequence knowledge yielded an increased likelihood of disorientation in older adults. The findings of this study suggest that age-related deficits in landmark associative cue knowledge are attenuated by controlling for learning rates. In contrast, landmark sequence knowledge deficits persist and are best explained by changes in the learning strategy of older adults to acquire task essential associative cue knowledge at the expense of supplementary sequence knowledge. (shrink)

Aging is associated with declines in sensorimotor function. Several studies have demonstrated that transcranial direct current stimulation, a form of non-invasive brain stimulation, can be combined with training to mitigate age-related cognitive and motor declines. However, in some cases, the application of tDCS disrupts performance and learning. Here, we applied anodal tDCS either over the left prefrontal cortex, right PFC, supplementary motor complex, the left M1, or in a sham condition while older adults practiced a Discrete Sequence Production, an (...) explicit motor sequence, task across 3 days. We hypothesized that stimulation to either the right or left PFC would enhance motor learning for older adults, based on the extensive literature showing increased prefrontal cortical activity during motor task performance in older adults. Contrary to our predictions, stimulation to the right and left PFC resulted in slowed motor learning, as evidenced by a slower reduction rate of reduction of reaction time and the number of sequence chunks across trials relative to sham in session one and session two, respectively. These findings suggest an integral role of the right PFC early in sequence learning and a role of the left PFC in chunking in older adults, and contribute to mounting evidence of the difficultly of using tDCS in an aging population. (shrink)

Three competing ‘methods’ have been endorsed for inferring phylogenetic hypotheses: parsimony, likelihood, and Bayesianism. The latter two have been claimed superior because they take into account rates of sequence substitution. Can rates of substitution be justified on its own accord in inferences of explanatory hypotheses? Answering this question requires addressing four issues: (1) the aim of scientific inquiry, (2) the nature of why-questions, (3) explanatory hypotheses as answers to why-questions, and (4) acknowledging that neither parsimony, likelihood, nor Bayesianism are (...) inferential actions leading to explanatory hypotheses. The aim of scientific inquiry is to acquire causal understanding of effects. Observation statements of organismal characters lead to implicit or explicit why-questions. Those questions, conveyed in data matrices, assume the truth of observation statements, which is contrary to subsequently invoking substitution rates within inferences to phylogenetic hypotheses. Inferences of explanatory hypotheses are abductive in form, such that some version of an evolutionary theory(ies) is/are included or implied. If rates of sequence evolution are to be considered, it must be done prior to, rather than within abduction, which requires renaming those putatively-shared nucleotides subject to substitution rates. There are, however, no epistemic grounds for renaming characters to accommodate rates, calling into question the legitimacy of causally accounting for sequence data. (shrink)

Human responses to probabilities can be studied through gambling and through experiments presenting biased sequences of stimuli. In both cases, participants are sensitive to base rates. They adjust automatically to changes in base rate; such adjustment is incompatible with conformity to Bayes' Theorem. is therefore specific to the exercises in mental arithmetic reviewed in the target article.

When speaking or producing music, people rely in part on auditory feedback – the sounds associated with the performed action. Three experiments investigated the degree to which alterations of auditory feedback during music performances influence the experience of agency and the possible link between agency and the disruptive effect of AAF on production. Participants performed short novel melodies from memory on a keyboard. Auditory feedback during performances was manipulated with respect to its pitch contents and/or its synchrony with actions. Participants (...) rated their experience of agency after each trial. In all experiments, AAF reduced judgments of agency across conditions. Performance was most disrupted when AAF led to an ambiguous experience of agency, suggesting that there may be some causal relationship between agency and disruption. However, analyses revealed that these two effects were probably independent. A control experiment verified that performers can make veridical judgments of agency. (shrink)

The forms of words as they appear in text and speech are central to theories and models of lexical processing. Nonetheless, current methods for simulating their learning and representation fail to approach the scale and heterogeneity of real wordform lexicons. A connectionist architecture termed thesequence encoderis used to learn nearly 75,000 wordform representations through exposure to strings of stress‐marked phonemes or letters. First, the mechanisms and efficacy of the sequence encoder are demonstrated and shown to overcome problems with traditional (...) slot‐based codes. Then, two large‐scale simulations are reported that learned to represent lexicons of either phonological or orthographic wordforms. In doing so, the models learned the statistics of their lexicons as shown by better processing of well‐formed pseudowords as opposed to ill‐formed (scrambled) pseudowords, and by accounting for variance in well‐formedness ratings. It is discussed how the sequence encoder may be integrated into broader models of lexical processing. (shrink)

The rate of human health care-associated infections caused by Acinetobacter baumannii has increased significantly in recent years for its remarkable resistance to desiccation and most antibiotics. Phospholipases, capable of destroying a phospholipid substrate, are heterologous group of enzymes which are believed to be the bacterial virulence determinants. There is a need for in silico studies to identify potential vaccine candidates. A. baumannii phospholipase D role has been proved in increasing organism’s resistance to human serum, destruction of host epithelial cell (...) and pathogenesis in murine model. In this in silico study high potentials of A. baumannii PLD in elicitation of humoral and cellular immunities were elucidated. Thermal stability, long half-life, non-similarity to human and gut flora proteome and non-allergenicity were in a list of A. baumannii PLD positive properties. Potential epitopic sequences were also identified that could be used as peptide vaccines against A. baumannii and various other human bacterial pathogens. (shrink)

In many species the mutation rate is higher in males than in females, a phenomenon denoted as male mutation bias. This is often observed in animals where males produce many more sperm than females produce eggs, and is thought to result from differences in the number of replication‐associated mutations accumulated in each sex. Thus, studies of male mutation bias have the capacity to reveal information about the replication‐dependent or replication‐independent nature of different mutations. The availability of whole genome sequences (...) for many species, as well as for multiple individuals within a species, has opened the door to studying factors, both sequence‐specific and those acting on the genome globally, that affect differences in mutation rates between males and females. Here, we assess the advantages that genomic sequences provide for studies of male mutation bias and general mutation mechanisms, discuss major challenges left unresolved, and speculate about the direction of future studies. (shrink)

Precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis, and treatment of many diseases from bench-to-bedside. Especially in the COVID-19 pandemic, molecular techniques and biotechnological innovation have proven to be of utmost importance for rapid developments in disease diagnostics and treatment, including DNA and RNA sequencing technology, treatment with drugs and natural products and vaccine development. The COVID-19 crisis, however, has also demonstrated the need for systemic thinking and transdisciplinarity and the limits (...) of MSM: the neglect of the bio-psycho-social systemic nature of humans and their context as the object of individual therapeutic and population-oriented interventions. COVID-19 illustrates how a medical problem requires a transdisciplinary approach in epidemiology, pathology, internal medicine, public health, environmental medicine, and socio-economic modeling. Regarding the need for conceptual integration of these different kinds of knowledge we suggest the application of general system theory (GST). This approach endorses an organism-centered view on health and disease, which according to Ludwig von Bertalanffy who was the founder of GST, we call Organismal Systems Medicine (OSM). We argue that systems science offers wider applications in the field of pathology and can contribute to an integrative systems medicine by (i) integration of evidence across functional and structural differentially scaled subsystems, (ii) conceptualization of complex multilevel systems, and (iii) suggesting mechanisms and non-linear relationships underlying the observed phenomena. We underline these points with a proposal on multi-level systems pathology including neurophysiology, endocrinology, immune system, genetics, and general metabolism. An integration of these areas is necessary to understand excess mortality rates and polypharmacological treatments. In the pandemic era this multi-level systems pathology is most important to assess potential vaccines, their effectiveness, short-, and long-time adverse effects. We further argue that these conceptual frameworks are not only valid in the COVID-19 era but also important to be integrated in a medicinal curriculum. (shrink)

Transcriptional enhancer sequences have been shown to play a pivotal role in the regulation of some highly expressed genes. First described in eukaryotic viruses, the discovery of enhancers has augmented the previously defined control‐sequence motifs to give a more complete understanding of eukaryotic transcriptional regulatory mechanisms. Some properties of enhancers that distinguish them from other regulatory sequences include their ability to function in a position‐ and orientation‐independent manner. Furthermore, the observation that some enhancers and transcriptional promoters exhibit tissue specificity (...) in their activity has generated considerable interest. Enhancer activation is thought to involve sequence‐specific DNA‐binding proteins but the process by which this leads to an increase in the initiation of transcription remains obscure. Although viral enhancers are more fully characterized, several cellular enhancers have recently been identified. One such enhancer sequence has been detected in a 3′ flanking region of a highly expressed human placental lactogen gene. This enhancer can increase the transcriptional rate of an adjacent gene by at least 50‐fold. (shrink)

Comparative studies of DNA sequences provide opportunities for testing the neutral and the selection theories of molecular evolution. In particular, the separate estimation of the numbers of synonymous and nonsynonymous substitutions is a powerful tool for detecting selection of the latter. The difference in the patterns of these two types of substitutions of mammalian genes turned out to be in accord with the slightly deleterious or nearly neutral mutation theory for nonsynonymous changes. Interaction systems at the amino acid level were (...) suggested to be responsible for such nearly neutral, or very weak, selection. Synonymous substitutions are not strictly neutral, but because of their minute effect, random drift predominates such that the rate of substitution is only slightly less than the completely neutral prediction. It was concluded that the strictly neutral theory has not held up as well as the nearly neutral theory, yet remains invaluable as a null hypothesis for detecting selection. On the other hand, the main difference between the nearly neutral and the traditional selection theories is that the former predicts rapid evolution in small populations, whereas the latter predicts rapid evolution in large populations. (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)

Naive observers viewed a sequence of colored Mondrian patterns, simulated on a color monitor. Each pattern was presented twice in succession, first under one daylight illuminant with a correlated color temperature of either 16,000 or 4,000 K and then under the other, to test for color constancy. The observers compared the central square of the pattern across illuminants, either rating it for sameness of material appearance or sameness of hue and saturation or judging an objective property—that is, whether its (...) change of color originated from a change in material or only from a change in illumination. Average color constancy indices were high for material appearance ratings and binary judgments of origin and low for hue–saturation ratings. Individuals’ performance varied, but judgments of material and of hue and saturation remained demarcated. Observers seem able to separate phenomenal percepts from their ontological projections of mental appearance onto physical phenomena; thus, even when a chromatic change alters perceived hue and saturation, observers can reliably infer the cause, the constancy of the underlying surface spectral reflectance. (shrink)

To formalize the human judgment of rhythm complexity, we used five measures from information theory and algorithmic complexity to measure the complexity of 48 artificially generated rhythmic sequences. We compared these measurements to human prediction accuracy and easiness judgments obtained from a listening experiment, in which 32 participants guessed the last beat of each sequence. We also investigated the modulating effects of musical expertise and general pattern identification ability. Entropy rate and Kolmogorov complexity were correlated with prediction accuracy, (...) and highly correlated with easiness judgments. A logistic regression showed main effects of musical training, entropy rate, and Kolmogorov complexity, and an interaction between musical training and both entropy rate and Kolmogorov complexity. These results indicate that information-theoretic concepts capture some salient features of the human judgment of rhythm complexity, and they confirm the influence of musical expertise on complexity judgments. (shrink)

Whereas a growing bulk of work has demonstrated that both adults and children are sensitive to frequently occurring word sequences, little is known about the potential role of meaning in the processing of such multiword chunks. Here, we take a first step toward assessing the contribution of meaningfulness in the processing of multiword sequences, using items that varied in chunk meaningfulness. In a phrasal-decision study, we compared reaction times for triads of three-word sequences, corresponding to idiomatic expressions, compositional phrases, and (...) phrasal fragments, while controlling for phrase and substring frequencies. Chunk meaningfulness, as assessed by a separate subjective rating study, was found to speed up decision times for all three types of strings: The more meaningful a multiword sequence was judged to be, the faster it was processed, independently of whether it was idiomatic, compositional in nature, or a phrasal fragment. These results highlight the importance of taking meaning into account when considering the processing of multiword chunks, consistent with predictions of construction-based approaches to language. (shrink)

Aneuploidy, an aberrant number of chromosomes in a cell, is a feature of several syndromes associated with cognitive and developmental defects. In addition, aneuploidy is considered a hallmark of cancer cells and has been suggested to play a role in neurodegenerative disease. To better understand the relationship between aneuploidy and disease, various methods to measure the chromosome numbers in cells have been developed, each with their own advantages and limitations. While some methods rely on dividing cells and thus bias aneuploidy (...) rates to that population, other, more unbiased methods can only detect the average aneuploidy rates in a cell population, cloaking cell‐to‐cell heterogeneity. Furthermore, some techniques are more prone to technical artefacts, which can result in over‐ or underestimation of aneuploidy rates. In this review, we provide an overview of several “traditional” karyotyping methods as well as the latest high throughput next generation sequencing karyotyping protocols with their respective advantages and disadvantages. (shrink)

We consider the extent to which one can compute bounds on the rate of convergence of a sequence of ergodic averages. It is not difficult to construct an example of a computable Lebesgue measure preserving transformation of [0, 1] and a characteristic function f = χA such that the ergodic averages Anf do not converge to a computable element of L2([0, 1]). In particular, there is no computable bound on the rate of convergence for that sequence. (...) On the other hand, we show that, for any nonexpansive linear operator T on a separable Hilbert space and any element f , it is possible to compute a bound on the rate of convergence of Anf from T , f , and the norm f ∗ of the limit. In particular, if T is the Koopman operator arising from a computable ergodic measure preserving transformation of a probability space X and f is any computable element of L2 (X ), then there is a computable bound on the rate of convergence of the sequence Anf. (shrink)

Peter Brugger & Kirsten Taylor regard positive extrasensory perception test results as methodical artifacts. In their view, sequences of guessing, e.g. of symbol cards, being non-random, overlap with finite sequences of non-random targets, and surpluses of hits from chance are deemed to be due to correlated non- randomness. The present author's ESP test data obtained from his 'ball drawing test ' applied with N = 231 psychology majors were used for testing five hypotheses derived from B&T's claims. B&T would expect (...) increased hit rates by intra-systemic pattern correlation of both guesses with guesses and targets with targets which are most favourable conditions for B&T's matching mechanism. But hit rates do not increase under such conditions, they decrease significantly. Moreover, Brugger's 1992 result does not replicate. B&T's 'deadly blow' directed at parapsychology turns out to be a boomerang. The authors wanted to get a 'phantom slain'. They got one slain - their own. (shrink)

Appreciating human movement can be a powerful aesthetic experience. We have used apparent biological motion to investigate the aesthetic effects of three levels of movement representation: body postures, movement transitions and choreographic structure. Symmetrical and asymmetrical sequences of apparent movement were created from static postures, and were presented in an artificial grammar learning paradigm. Additionally, “good” continuation of apparent movements was manipulated by changing the number of movement path reversals within a sequence. In an initial exposure phase, one group (...) of participants saw only symmetrical sequences, while another group saw only asymmetrical sequences. In a subsequent test phase, both groups rated all sequences on an aesthetic evaluation scale. We found that posture, movement, and choreographic structure all influenced aesthetic ratings. Separate ratings for the static body postures presented individually showed that both groups preferred a posture that maximized spatial symmetry. Ratings for the experimental sequences showed that both groups gave higher ratings to symmetrical sequences with “good” continuation and lower ratings to sequences with many path reversals. Further, participants who had been initially familiarized with asymmetrical sequences showed increased liking for asymmetrical sequences, suggesting a structural mere exposure effect. Aesthetic preferences thus depend on body postures, apparent movement continuation and choreographic structure. We propose a hierarchical model of aesthetic perception of human movement with distinct processing levels for body postures, movements and choreographic structure. (shrink)

Summary Research is regarded as transformations of complexes composed of knowledge, problems and (hardware and software) instruments. Sequences of such transformations are embedded in human settings in which they are given directions. Problems and the work of solving them are divided into empirical and theoretical ones. In an advanced science like physics empirical and theoretical work are interrelated by means of flows of problem-generating information. Empirical and theoretical researchers work also on problems of their own making. Residuals of knowledge which (...) cannot be systematized at the same rate as it is produced as well as clashes between new and old knowledge are potential starting points of new lines of research. (shrink)

Research indicates that norms matter for ordinary causal attributions. Across a range of cases in which two agents jointly bring about an outcome, with one violating a norm while the other does not, causal ratings are higher for the agent who violates the norm. Building off such findings, Kominsky et al. note a related phenomenon that they term “causal superseding”—whether or not one agent violates a norm also affects causal ratings for the other agent. Kominsky et al. offer an explanation (...) of this phenomenon and describe the results of four experiments testing their account. In this paper, I explore the proposed phenomenon further. I present a sequence of new studies covering a range of cases, finding that the superseding effect is not as consistent as Kominsky et al. would predict, that the effect does not occur in all of the cases where they say it should, and that it sometimes occurs in cases where they say it shouldn’t. Finally, I offer an alternative deflationary explanation of causal superseding, presenting evidence suggesting that it is simply a context effect. (shrink)

Decision making is the physician's major activity. Every day, in doctors' offices throughout the world, patients describe their symptoms and com plaints while doctors perform examinations, order tests, and, on the basis of these data, decide what is wrong and what should be done. Although the process may appear routine-even to the physicians in volved-each step in the sequence requires skilled clinical judgment. Physicians must decide: which symptoms are important, whether any laboratory tests should be done, how the various (...) items of clinical data should be combined, and, finally, which of several treatments (including doing nothing) is indicated. Although much of the information used in clinical decision making is objective, the physician's values (a belief that pain relief is more important than potential addiction to pain-killing drugs, for example) and subjectivity are as much a part of the clinical process as the objective findings of laboratory tests. In recent years, both physicians and psychologists have come to realize that patient management decisions are not only subjective but also prob abilistic (although this is not always acknowledged overtly). When doc tors argue that an operation is fairly safe because it has a mortality rate of only 1 %, they are at least implicitly admitting that the outcome of their decision is based on probability. (shrink)

The dominated convergence theorem implies that if is a sequence of functions on a probability space taking values in the interval [0, 1], and converges pointwise a.e., then converges to the integral of the pointwise limit. Tao [26] has proved a quantitative version of this theorem: given a uniform bound on the rates of metastable convergence in the hypothesis, there is a bound on the rate of metastable convergence in the conclusion that is independent of the sequence (...) and the underlying space. We prove a slight strengthening of Tao’s theorem which, moreover, provides an explicit description of the second bound in terms of the first. Specifically, we show that when the first bound is given by a continuous functional, the bound in the conclusion can be computed by a recursion along the tree of unsecured sequences. We also establish a quantitative version of Egorov’s theorem, and introduce a new mode of convergence related to these notions. (shrink)

Research on sequence effects on learning visual categories has shown that interleaving (i.e., studying the categories in a mixed manner) facilitates category induction as compared to blocking (i.e., studying the categories one by one), but learners are unaware of the interleaving effect and prefer blocking. However, little attention has been paid to sequence effects in perceptual learning across further sensory modalities. The present (preregistered) research addresses this shortcoming by using auditory (birdcalls), olfactory (tealeaves), gustatory (ingredient mixtures), and tactile (...) (stones) stimuli across four analog experiments. The number of participants per experiment was determined based on a medium effect size of interleaving. Participants studied six categories (with six exemplars, respectively) either interleaved or blocked. No single experiment showed a significant effect of interleaving. We ran a comprehensive meta‐analysis based on the data from all experiments, which revealed a significant small effect of interleaving, demonstrating its applicability to perceptual learning across all sensory modalities. Learners in the interleaved condition underestimated their classification performance. Overall, learners did not rate interleaving as less effective than blocking, which is at odds with previous studies that consistently demonstrated a metacognitive preference of blocking. Our findings suggest that learners rely less on conventional beliefs about the effectivity of study sequence when dealing with unfamiliar (blindfolded) perceptual learning tasks. (shrink)

I have addressed a wide range of topics in my work, from fiction, the ontology of art, phenomenology, social ontology, and work on ordinary objects generally, through more recent work on metametaphysics, modality, and conceptual engineering. On the surface, these themes might seem to have little in common. Here, however, I trace back how this sequence of interests developed, as I kept stepping backwards from first-order ontological concerns, to ask what underlying presuppositions (about language, modality, and the nature of (...) metaphysics) led metaphysicians astray into a range of eliminativist and revisionary views, and into debates that often made metaphysics seem fruitless, epistemologically mysterious, and like a second-rate rival to the sciences. As my work has developed, I have aimed (partly inspired by work in phenomenology, ordinary language philosophy, and neo-pragmatism) to diagnose where much work in recent metaphysics has gone wrong. More importantly, I have sought to develop an alternative, positive view of what philosophy can do, and how we can do it, that makes philosophy clear, epistemologically transparent and relevant to human life. (shrink)

Our eyes move in response to stimulus statistics, reacting to surprising events, and adapting to predictable ones. Cortical and subcortical pathways contribute to generating context-specific eye-movement dynamics, and oculomotor dysfunction is recognized as one the early clinical markers of Parkinson's disease. We asked if covert computations of environmental statistics generating temporal expectations for a potential target are registered by eye movements, and if so, assuming that temporal expectations rely on motor system efficiency, whether they are impaired in PD. We used (...) a repeating tone sequence, which generates a hazard rate distribution of target probability, and analyzed the distribution of blinks when participants were waiting for the target, but the target did not appear. Results show that, although PD participants tend to produce fewer and less temporally organized blink events relative to healthy controls, in both groups blinks became more suppressed with increasing target probability, leading to a hazard rate of oculomotor inhibition effects. The covert generation of temporal predictions may reflect a key feature of cognitive resilience in Parkinson's Disease. (shrink)

Clouds are therefore a fine metaphor for intermediary and automatic beings… Trees too are clouds: only, they are slower at occupying space. In the new landscape of media archaeology—especially variantology, which insists on ramified rather than convergent developments—media, too, appear to be imperceptibly changing from stable trees into metastable clouds. If we accelerate that motion, then the whole McLuhan-Kittler-Parikka media forest of semi-separate specimens starts to look like a self-rearranging ballet—a murmuration across species. At a certain historical rate, in (...) other words, problems of media ontology and phylogenesis tend to turn into animated sequences in which individual or individuated media.. (shrink)