It was (not) me: Causal Inference of Agency in goal-directed actions

Summary: 
The perception of one’s own actions depends on both sensory information and predictions derived from internal forward models [1]. The integration of these information sources depends critically on whether perceptual consequences are associated with one’s own action (sense of agency) or with changes in the external world that are not related to the action. The perceived effects of actions should thus critically depend on the consistency between the predicted and the actual sensory consequences of actions. To test this idea, we used a virtual-reality setup to manipulate the consistency between pointing movements and their visual consequences and investigated the influence of this manipulation on self-action perception. We then asked whether a Bayesian causal inference model, which assumes a latent agency variable controlling the attributed influence of the own action on perceptual consequences [2,3], would account for the empirical data: if the percept was attributed to the own action, visual and internal information should fuse in a Bayesian optimal manner, while this should not be the case if the visual stimulus was attributed to external influences. The model correctly fits the data, showing that small deviations between predicted and actual sensory information were still attributed to one’s own action, while this was not the case for large deviations when subjects relied more on internal information. We discuss the performance of this causal inference model in comparison to alternative biologically feasible statistical models applying methods for Bayesian model comparison.

Experiment: 
Participants were seated in front of a horizontal board on which their right hand was placed with the index finger on a haptic marker, representing the starting point for each trial. Participants were instructed to execute straight, fast (quasi-ballistic) pointing movements of fixed amplitude, but without an explicit visual target. The hand was obstructed from the view of the participants, and visual feedback about the peripheral part of the movement was provided by a cursor. Feedback was either veridical or rotated against the true direction of the hand movement by predefined angles. After each trial participants were asked to report the subjectively experienced direction of the executed hand movement by placing a mouse-cursor into that direction.

Model: 
We compared two probabilistic models: Both include a binary random gating variable (agency) that models the sense of ‘agency’; that is the belief that the visual feedback is influenced by the subject’s motor action. The first model assumes that both the visual feedback xv and the internal motor state estimate xe are directly caused by the (unobserved) real motor state xt (Fig. 1). The second model assumes instead that the expected visual feedback depends on the perceived direction of the own motor action xe (Fig. 2). 
Results: Both models are in good agreement with the data. Fig. A shows the model fit for Model 1 superpositioned to the data from a single subject. Fig. B shows the belief that the visual stimulus was influenced by the own action, which decreases for large deviations between predicted and real visual feedback. Bayesian model comparison shows a better fit for model 1.
Citations
[1] Wolpert D.M, Ghahramani, Z, Jordan, M. (1995) Science, 269, 1880-1882.
[2] Körding KP, Beierholm E, Ma WJ, Quartz S, Tenenbaum JB, et al (2007) PLoS ONE 2(9): e943.
[3] Shams, L., Beierholm, U. (2010) TiCS, 14: 425-432.
Acknowledgements
This work was supported by the BCCN Tübingen (FKZ: 01GQ1002), the CIN Tübingen, the European Union (FP7-ICT-215866 project SEARISE), the DFG and the Hermann and Lilly Schilling Foundation

Difference in response reliability predicted by STRFs in the cochlear nuclei of barn owls

The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability

Networking Phylogeny for Indo-European and Austronesian Languages

Harnessing cognitive abilities of many individuals, a language evolves upon their mutual interactions establishing a persistent social environment to which language is closely attuned. Human history is encoded in the rich sets of linguistic data by means of symmetry patterns that are not always feasibly represented by trees. Here we use the methods developed in the study of complex networks to decipher accurately symmetry records on the language phylogeny of the Indo-European and the Austronesian language families, considering, in both cases, the samples of fifty different languages. In particular, we support the Anatolian theory of Indo-European origin and the ‘express train’ model of Austronesian expansion from South-East Asia, with an essential role for the Batanes islands located between the Philippines and Taiwan

Novel approaches, including systems biology, to HIV vaccine research and development: Report from a Global HIV Vaccine Enterprise Working Group

The Global HIV Vaccine Enterprise convened a two-day workshop on August 10-11 2009, at the Fred Hutchison Cancer Research Center offices in Seattle, WA, to discuss the application of novel approaches,including systems biology, to HIV vaccine research and development. The goals of this Working Group were to identify key scientific issues and opportunities that have emerged since the Enterprise Scientific Strategic Plan1 was published in 2005, and to make recommendations to Enterprise stakeholders

The genetic equidistance result of molecular evolution is independent of mutation rates

The well-established genetic equidistance result shows that sister species are approximately equidistant to a simpler outgroup as measured by DNA or protein dissimilarity. The equidistance result is the most direct evidence, and remains the only evidence, for the constant mutation rate interpretation of this result, known as the molecular clock. However, data independent of the equidistance result have steadily accumulated in recent years that often violate a constant mutation rate. Many have automatically inferred non-equidistance whenever a non-constant mutation rate was observed, based on the unproven assumption that the equidistance result is an outcome of constant mutation rate. Here it is shown that the equidistance result remains valid even when different species can be independently shown to have different mutation rates. A random sampling of 50 proteins shows that nearly all proteins display the equidistance result despite the fact that many proteins have non-constant mutation rates. Therefore, the genetic equidistance result does not necessarily mean a constant mutation rate. Observations of different mutation rates do not invalidate the genetic equidistance result. New ideas are needed to explain the genetic equidistance result that must grant different mutation rates to different species and must be independently testable

Inverse relationship between genetic diversity and epigenetic complexity

Early studies of molecular evolution revealed a correlation between genetic distance and time of species divergence. This observation provoked the molecular clock hypothesis and in turn the ‘Neutral Theory’, which however remains an incomplete explanation since it predicts a constant mutation rate per generation whereas empirical evidence suggests a constant rate per year. Data inconsistent with the molecular clock hypothesis have steadily accumulated in recent years that show no correlation between genetic distance and time of divergence. It has therefore become a challenge to find a testable idea that can reconcile the seemingly conflicting data sets. Here, an inverse relationship between genetic diversity and epigenetic complexity was deduced from a simple intuition in building complex systems. Genetic diversity, i.e., genetic distance or dissimilarity in DNA or protein sequences between individuals or species, is restricted by the complexity of epigenetic programs. This inverse relationship logically deduces the maximum genetic diversity hypothesis, which suggests that macroevolution from simple to complex organisms involves a punctuational increase in epigenetic complexity that in turn causes a punctuational loss in genetic diversity. The hypothesis explains a diverse set of biological phenomena, including both for and against the correlation between genetic distance and time of divergence.
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Systems biology of energetic and atomic costs in the yeast transcriptome, proteome, and metabolome

Proteins vary in their cost to the cell and natural selection may favour the use of proteins that are cheaper to produce. We develop a novel approach to estimate the amino acid biosynthetic cost based on genome-scale metabolic models, and directly investigate the effects of biosynthetic cost on transcriptomic, proteomic and metabolomic data in _Saccharomyces cerevisiae_. We find that our systems approach to formulating biosynthetic cost produces a novel measure that explains similar levels of variation in gene expression compared with previously reported cost measures. Regardless of the measure used, the cost of amino acid synthesis is weakly associated with transcript and protein levels, independent of codon usage bias. In contrast, energetic costs explain a large proportion of variation in levels of free amino acids. In the economy of the yeast cell, there appears to be no single currency to compute the cost of amino acid synthesis, and thus a systems approach is necessary to uncover the full effects of amino acid biosynthetic cost in complex biological systems that vary with cellular and environmental conditions

Hierarchical nanomechanics of collagen microfibrils

Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to connective tissues. Collagen is also the dominating material in the extracellular matrix (ECM) and is thus crucial for cell differentiation, growth and pathology. However, fundamental questions remain with respect to the origin of the unique mechanical properties of collagenous tissues, and in particular its stiffness, extensibility and nonlinear mechanical response. By using x-ray diffraction data of a collagen fibril reported by Orgel et al. (Proceedings of the National Academy of Sciences USA, 2006) in combination with protein structure identification methods, here we present an experimentally validated model of the nanomechanics of a collagen microfibril that incorporates the full biochemical details of the amino acid sequence of the constituting molecules. We report the analysis of its mechanical properties under different levels of stress and solvent conditions, using a full-atomistic force field including explicit water solvent. Mechanical testing of hydrated collagen microfibrils yields a Young’s modulus of ≈300 MPa at small and ≈1.2 GPa at larger deformation in excess of 10% strain, in excellent agreement with experimental data. Dehydrated, dry collagen microfibrils show a significantly increased Young’s modulus of ≈1.8 to 2.25 GPa (or ≈6.75 times the modulus in the wet state) owing to a much tighter molecular packing, in good agreement with experimental measurements (where an increase of the modulus by ≈9 times was found). Our model demonstrates that the unique mechanical properties of collagen microfibrils can be explained based on their hierarchical structure, where deformation is mediated through mechanisms that operate at different hierarchical levels. Key mechanisms involve straightening of initially disordered and helically twisted molecules at small strains, followed by axial stretching of molecules, and eventual molecular uncoiling at extreme deformation. These mechanisms explain the striking difference of the modulus of collagen fibrils compared with single molecules, which is found in the range of 4.8±2 GPa or ≈10-20 times greater. These findings corroborate the notion that collagen tissue properties are highly scale dependent and nonlinear elastic, an issue that must be considered in the development of models that describe the interaction of cells with collagen in the extracellular matrix. A key impact the atomistic model of collagen microfibril mechanics reported here is that it enables the bottom-up elucidation of structure-property relationships in the broader class of collagen materials such as tendon or bone, including studies in the context of genetic disease where the incorporation of biochemical, genetic details in material models of connective tissue is essential

The use of Web Ontology Language (OWL) to Combine Extant Controlled Vocabularies in Biodiversity Informatics Appears Redundant

Implementation of PESI requires data to be combined from multiple source databases. Some of the shared fields in the source databases used different controlled vocabularies of terms. OWL DL was investigated as a mechanism to build an extensible, shared ontology of species occurrence terms that permitted the source database to continue using and extending their own vocabularies whilst formally mapping to a more generic shared vocabulary. The merits of this approach were explored and it was concluded that the building of such a complex mapping ontology probably wasn't worthwhile. The level of semantic complexity involved outweighed the costs of simply imposing a flat list of well defined terms onto data suppliers. The main problem with exiting vocabularies appear to be the overloading of terms. A candidate list of terms was proposed

Information on Transcriptional Regulation and Signal Transduction of _Escherichia coli_ K-12 Integrated in the Database RegulonDB.

Since its inception, RegulonDB ("http://regulondb.ccg.unam.mx/":http://regulondb.ccg.unam.mx/) has been a database that compiles information about the regulation of transcription initiation of _Escherichia coli_ K-12. However, we are aware that transcriptional regulation is not an isolated process; instead, it is the response to the different environmental conditions that trigger a series of concatenated reactions that end in transcriptional regulation, and it implies an adequate response in terms of induced and repressed gene products. We are working now to include all these new data in RegulonDB. As a consequence, transcriptional regulation in RegulonDB will be part of a unit that initiates with the signal, continues with the signal transduction to the core of regulation to modify expression of the affected set of target genes, and ends with an adequate response. We refer to these units as genetic sensory response units, or geSorgans.

The inclusion of geSorgans will bring a dramatic change and expansion of RegulonDB, due to the fact that we will be adding several new types of reactions and interactions. We started to collect data about signal transduction of the sigma factors, the two-component systems, of some transcription factors involved in carbon source utilization, and of genes involved in the synthesis of amino acids. We plan a high-level curation with super-pathways summarizing concatenated sets of reactions linked to those other databases that curate such information, while enabling with RegulonDB a compilation of complete geSorgans.

In addition, the number of DNA binding sites for some transcription factors has grown considerably, and therefore we decided to review systematically those sites whose lengths ranging from 40 to 60 bp with orientation and consensus sequences that are not easy to identify. The current version of RegulonDB is the beginning of a higher-level curation of gene regulation information, and eventually our database will include all regulatory mechanisms and their regulated genes. 
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