The use of an internal representation in fast goal-directed movements: a modelling approach

This study investigates the role of the human central nervous system (CNS) in the control of fast goaldirected movements. The main problem is that the latencies inherent in the transmission of physiological signals cause a delayed feedback of sensory information. Therefore, the muscle command signals cannot be explained by a simple servo-loop, so a more sophisticated control structure is required. Our hypothesis is that the CNS employs an internal representation of the controlled system in order to circumvent the drawbacks of the physiological loop delay. To test this hypothesis a mathematical model based on an internal representation and an internal state feedback has been developed. Computer simulations of double-step stimuli (control behaviour), tendon vibration and torque disturbances (disturbance behaviour) and load perturbations (adaptation behaviour) proved to agree remarkably well with experimental observations. The proposed control model can explain the open-loop and closed-loop aspects of human motor control. Hence, the use of an internal representation in generating the muscle command signals is very plausible.     

Tracking of fast moving neuronal vesicles with ageladine A

O-Linked β-N-acetylglucosaminylation (O-GlcNAcylation) of nucleocytoplasmic proteins is a ubiquitous post-translational modification in multicellular organisms studied so far. Since aberrant O-GlcNAcylation has a link with insulin resistance, it is important to establish the status of O-GlcNAcylation in differentiation of mesenchymal cells such as preadipocytes. In this study, we found a differentiation-dependent drastic increase in the level of O-GlcNAcylation in mouse 3T3-L1 preadipocytes. The occurrence of the increase in O-GlcNAcylation, which correlated with the expression of C/EBPα, was in part due to increased expression of O-GlcNAc transferase. In addition to the well-known O-GlcNAcylated proteins such as nucleoporins and vimentin, pyruvate carboxylase, long chain fatty acid-CoA ligase 1, and Ewing sarcoma protein were identified as the proteins which are heavily O-GlcNAcylated with the adipocyte differentiation. Both adipocyte differentiation and the differentiation-dependent increase in O-GlcNAcylation were blocked by 6-diazo-5-oxo-norleucine. These results suggest that O-GlcNAcylation particilates, at least in part, in adipogenesis.     

Adaptive movement compensation for in vivo imaging of fast cellular dynamics within a moving tissue

In vivo non-linear optical microscopy has been essential to advance our knowledge of how intact biological systems work. It has been particularly enabling to decipher fast spatiotemporal cellular dynamics in neural networks. The power of the technique stems from its optical sectioning capability that in turn also limits its application to essentially immobile tissue. Only tissue not affected by movement or in which movement can be physically constrained can be imaged fast enough to conduct functional studies at high temporal resolution. Here, we show dynamic two-photon Ca(2+) imaging in the spinal cord of a living rat at millisecond time scale, free of motion artifacts using an optical stabilization system. We describe a fast, non-contact adaptive movement compensation approach, applicable to rough and weakly reflective surfaces, allowing real-time functional imaging from intrinsically moving tissue in live animals. The strategy involves enslaving the position of the microscope objective to that of the tissue surface in real-time through optical monitoring and a closed feedback loop. The performance of the system allows for efficient image locking even in conditions of random or irregular movements.     

Activity rhythms and position preferences of domestic chicks which can see a moving object

The activity levels of isolated domestic chicks in home pens maintained at constant light and temperature were monitored for 4–6 days after hatching. The data were analysed using correlograms, spectrograms and multiple regression. Most chicks showed 24 h periodicities and also shorter periodicities of 1.5–4 h and about 30 min, but there was considerable individual variation. The importance of short-term rhythms in studies of responsiveness is emphasized. Chicks which could see a small, rotating ball from their home pens were more active than those which could not see a moving object and spent more time near it. The more pronounced 24 h periodicities, shown when a moving object could be seen, were partly due to greater activity, especially that near the object.     

IQPNNI: moving fast through tree space and stopping in time

An efficient tree reconstruction method (IQPNNI) is introduced to reconstruct a phylogenetic tree based on DNA or amino acid sequence data. Our approach combines various fast algorithms to generate a list of potential candidate trees. The key ingredient is the definition of so-called important quartets (IQs), which allow the computation of an intermediate tree in O(n(2)) time for n sequences. The resulting tree is then further optimized by applying the nearest neighbor interchange (NNI) operation. Subsequently a random fraction of the sequences is deleted from the best tree found so far. The deleted sequences are then re-inserted in the smaller tree using the important quartet puzzling (IQP) algorithm. These steps are repeated several times and the best tree, with respect to the likelihood criterion, is considered as the inferred phylogenetic tree. Moreover, we suggest a rule which indicates when to stop the search. Simulations show that IQPNNI gives a slightly better accuracy than other programs tested. Moreover, we applied the approach to 218 small subunit rRNA sequences and 500 rbcL sequences. We found trees with higher likelihood compared to the results by others. A program to reconstruct DNA or amino acid based phylogenetic trees is available online (http://www.bi.uni-duesseldorf.de/software/iqpnni).     

Hierarchical action encoding in prefrontal cortex of freely moving macaques

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Prediction of Ras-effector interactions using position energy matrices

MOTIVATION: One of the more challenging problems in biology is to determine the cellular protein interaction network. Progress has been made to predict protein-protein interactions based on structural information, assuming that structural similar proteins interact in a similar way. In a previous publication, we have determined a genome-wide Ras-effector interaction network based on homology models, with a high accuracy of predicting binding and non-binding domains. However, for a prediction on a genome-wide scale, homology modelling is a time-consuming process. Therefore, we here successfully developed a faster method using position energy matrices, where based on different Ras-effector X-ray template structures, all amino acids in the effector binding domain are sequentially mutated to all other amino acid residues and the effect on binding energy is calculated. Those pre-calculated matrices can then be used to score for binding any Ras or effector sequences. RESULTS: Based on position energy matrices, the sequences of putative Ras-binding domains can be scanned quickly to calculate an energy sum value. By calibrating energy sum values using quantitative experimental binding data, thresholds can be defined and thus non-binding domains can be excluded quickly. Sequences which have energy sum values above this threshold are considered to be potential binding domains, and could be further analysed using homology modelling. This prediction method could be applied to other protein families sharing conserved interaction types, in order to determine in a fast way large scale cellular protein interaction networks. Thus, it could have an important impact on future in silico structural genomics approaches, in particular with regard to increasing structural proteomics efforts, aiming to determine all possible domain folds and interaction types. AVAILABILITY: All matrices are deposited in the ADAN database (http://adan-embl.ibmc.umh.es/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

VL position 34 is a key determinant for the engineering of stable antibodies with fast dissociation rates

Predictive engineering of antibodies exhibiting fast kinetic properties could provide reagents for biotechnological applications such as continuous monitoring of compounds or affinity chromatography. Based on covariance analysis of murine germline antibody variable domains, we selected position L34 (Kabat numbering) for mutational studies. This position is located at the VL/VH interface, at the base of the paratope but with limited antigen contacts, thus making it an attractive position for mild alterations of antigen binding properties. We introduced a serine at position L34 in two different antibodies: Fab (fragment antigen binding) 57P (Asn34Ser) and scFv (single chain fragment variable) 1F4 (Gln34Ser), that recognize peptides derived from the coat protein of tobacco mosaic virus and the oncoprotein E6, respectively. Both mutated antibodies exhibited similar properties: (i) expression levels of active fragments in Escherichia coli were markedly improved; (ii) thermostability was enhanced; and (iii) dissociation rate parameters (k(off)) were increased by 2- and at least 57-fold for scFv1F4 and Fab57P, respectively, while their association rate parameters (k(on)) remained unchanged. The L34 Ala and Thr mutants of both antibody fragments did not possess these properties. This first demontration of similar effects observed in two antibodies with different specificities may open the way to the predictive design of molecules with enhanced stability and fast dissociation rates.     

Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect

Twelve dominant enhancers of position effect variegation, representing four loci on the second and third chromosomes of Drosophila melanogaster, have been induced by P-element mutagenesis. Instead of simple transposon insertions, seven of these mutations are cytologically visible duplications and three are deficiencies. The duplications define two distinct regions, each coinciding with a locus that also behaves as a dominant haplo-dependent suppressor of variegation. Conversely, two of the deficiencies overlap with a region that contains a haplo-dependent enhancer of variegation while duplications of this same region act to suppress variegation. The third deficiency defines another haplo-dependent enhancer. These data indicate that loci capable of modifying variegation do so in an antipodal fashion through changes in the wild-type gene copy number and may be divided into two reciprocally acting classes. Class I modifiers enhance variegation when duplicated or suppress variegation when deficient. Class II modifiers enhance when deficient but suppress when duplicated. From our data, and those of others, we propose that in Drosophila there are about 20 to 30 dominant loci that modify variegation. Most appear to be of the class I type whereas only two class II modifiers have been identified so far. From these observations we put forth a model, based on the law of mass action, for understanding how such suppressor-enhancer loci function. We propose that each class I modifier codes for a structural protein component of heterochromatin and their effects on variegation are a consequence of their dosage dependent influence on the extent of the assembly of heterochromatin at the chromosomal site of the position effect. It is further proposed that class II modifiers may inhibit the class I products directly, bind to hypothetical termination sites that define heterochromatin boundaries or promote euchromatin formation. Consistent with our mass action model we find that combining two enhancers together produce additive and not epistatic effects. Also, since different enhancers have different relative strengths on different variegating mutants, we suggest that heterochromatic domains are constructed by a combinatorial association of proteins. The mass action model proposed here is of general significance for any assembly driven reaction and has implications for understanding a wide variety of biological phenomena.(ABSTRACT TRUNCATED AT 400 WORDS)     

Education as a tool for addressing the extinction crisis: moving students from understanding to action

Human activity is leading to mass species extinctions worldwide. Conservation biology (CB) courses, taught worldwide at universities, typically focus on the proximal causes of extinction without teaching students how to respond to this crisis. The Extinction of Species 360 course has been taught yearly each fall semester to several hundred students at the University of Wisconsin-Madison for over two decades. In 2007 the instructor and five teaching assistants combined principles driving extinctions, based on traditional lectures and discussion sections, with action-oriented education targeting individual consumer habits, to a group of 285 students. Students learn the science underpinning conservation efforts, as evidenced by highly significant learning (< .001) gains in a 22 question survey in every measured category, and also make direct and immediate changes in their lifestyle and consumption habits. This course succeeded in each of its three primary goals: a) informed students about the value of and threats to biodiversity, similar to traditional CB courses, b) emphasized our personal role (as consumers) in perpetuating the extinction crisis and c) facilitated activities to reduce our impact and help alleviate the crisis. The results suggested students learned CB concepts and understood biodiversity's value, increased their awareness of the connection between personal consumption and extinction, and reduced their collective ecological footprints. Furthermore, students complemented their learning and multiplied the potential for consumption reduction, by participating in action-based activities. Such academic courses can provide a rigorous treatment of the direct and indirect causes of extinction while developing a student's sense of personal empowerment to help slow the extinction crisis.     

Braking slows passive flexion during goal-directed movements of a small limb

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Comparative action of X-rays and fast neutrons on thymus endocrine function

Whole-body exposure of rats to X-rays (4, 6 and 8 Gy) and neutron radiation (1, 1.5 and 2 Gy) causes a dose-dependent inhibition of endocrine function of thymus and death of its lymphoid cells. Shielding of thymus somewhat reduces the degree and duration of inhibition of thymus hormone secretion.     

The role of kinaesthetic feedback in goal-directed movements

The purpose of this study was to investigate the role of kinaesthetic feedback in the control of goal-directed movements. The subjects were qualified basketball and handball players compared to weightlifters as controls. The body measures and the general motor tests verified fit physical condition of the subjects, and detected no sign that would disturb the execution of special motor tests. The special motor tests were free-throw shootings with basketball to the basket, free shootings with handball to a rectangular frame, zigzag dribbling with basketball to 14 m among traffic cones 2 m apart, and stopping at a mark after running to 10 m. These tests were performed both with open eyes and closed eyes. The results of all special motor tests decreased significantly in the lack of visual information. Furthermore, in contrast to the significantly different results obtained from the three different groups with open eyes, these groups produced equally minor results with closed eyes. It is concluded that the practice of goal-directed movement, learned under visual guidance, does not make the kinaesthetic feedback able to compensate the lack of visual input.     

Joint coding of visual input and eye/head position in V1 of freely moving mice

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Modeling investigation of learning a fast elbow flexion in the horizontal plane--prediction of muscle forces and motor units action

Experimental investigation of practicing a dynamic, goal-directed movement reveals significant changes in kinematics. Modeling can provide insight into the alterations in muscle activity, associated with the kinematic adaptations, and reveal the potential motor unit (MU) firing patterns that underlie those changes. In this paper, a previously developed muscle model and software (Raikova and Aladjov, Journal of Biomechanics, 35, 2002) have been used to investigate changes in MU control, while practicing fast elbow flexion to a target in the horizontal plane. The first trial (before practice) and the last trial (after extensive practice) of two subjects have been simulated. The inputs for the simulation were the calculated external moments at the elbow joint. The external moments were countered by the action of three flexor muscles and two extensor ones. The muscles have been modeled as a mixture of MUs of different types. The software has chosen the MU firing times necessary to accomplish the movement. The muscle forces and MUs firing statistics were then calculated. Three hypotheses were tested and confirmed: (1) peak muscle forces and antagonist co-contraction increase during training; (2) there is an increase in the firing frequency and the synchronization between MUs; and (3) the recruitment of fast-twitch MUs dominates the action.     

The modifying action of caffeine on the effect of fast neutrons in human cells

The cytogenetic data obtained indicate a real possibility to intensify damage of the human cells as affected by rapid neurons. It can be achieved by combination of reparation inhibitors (caffeine) and rare-ionizing radiation (gamma rays) and is expressed in 5.5-fold increase of yield of chromosome damages in caffeine case and in increase of yield of exchange aberrations in the case of combination with gamma radiation.