Muscle wasting in myotonic dystrophies: a model of premature aging

Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia ll/Iyotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

Natural actor and belief critic: Reinforcement algorithm for learning parameters of dialogue systems modelled as POMDPs

This article presents a novel algorithm for learning parameters in statistical dialogue systems which are modeled as Partially Observable Markov Decision Processes (POMDPs). The three main components of a POMDP dialogue manager are a dialogue model representing dialogue state information; a policy that selects the system's responses based on the inferred state; and a reward function that specifies the desired behavior of the system. Ideally both the model parameters and the policy would be designed to maximize the cumulative reward. However, while there are many techniques available for learning the optimal policy, no good ways of learning the optimal model parameters that scale to real-world dialogue systems have been found yet. The presented algorithm, called the Natural Actor and Belief Critic (NABC), is a policy gradient method that offers a solution to this problem. Based on observed rewards, the algorithm estimates the natural gradient of the expected cumulative reward. The resulting gradient is then used to adapt both the prior distribution of the dialogue model parameters and the policy parameters. In addition, the article presents a variant of the NABC algorithm, called the Natural Belief Critic (NBC), which assumes that the policy is fixed and only the model parameters need to be estimated. The algorithms are evaluated on a spoken dialogue system in the tourist information domain. The experiments show that model parameters estimated to maximize the expected cumulative reward result in significantly improved performance compared to the baseline hand-crafted model parameters. The algorithms are also compared to optimization techniques using plain gradients and state-of-the-art random search algorithms. In all cases, the algorithms based on the natural gradient work significantly better. © 2011 ACM.

Guidelines for evaluating the ease of reconfiguration of manufacturing systems

This paper presents guidelines for evaluating the ease of reconfiguration of manufacturing systems. Based reconfigurability measurement tools proposed in the past [1], [2]and a reconfiguration process model, the paper proposes a method that can be used to assess different system characteristics. After the guideline is presented, an example of how the method can be applied to a batch processing system is given. It is found that the proposed method can be applied to batch processing systems based on ISA S88 batch server commercial software. ©2008 IEEE.

An organizing center in a planar model of neuronal excitability

This paper studies the excitability properties of a generalized FitzHugh-Nagumo model. The model differs from the classical FitzHugh-Nagumo model in that it accounts for the effect of cooperative gating variables such as activation of calcium currents. Excitability is explored by unfolding a pitchfork bifurcation that is shown to organize five different types of excitability. In addition to the three classical types of neuronal excitability, two novel types are described and distinctly associated to the presence of cooperative variables. © 2012 Society for Industrial and Applied Mathematics.

Slow peaking and low-gain designs for global stabilization of nonlinear systems

This paper presents an analysis of the slow-peaking phenomenon, a pitfall of low-gain designs that imposes basic limitations to large regions of attraction in nonlinear control systems. The phenomenon is best understood on a chain of integrators perturbed by a vector field up(x, u) that satisfies p(x, 0) = 0. Because small controls (or low-gain designs) are sufficient to stabilize the unperturbed chain of integrators, it may seem that smaller controls, which attenuate the perturbation up(x, u) in a large compact set, can be employed to achieve larger regions of attraction. This intuition is false, however, and peaking may cause a loss of global controllability unless severe growth restrictions are imposed on p(x, u). These growth restrictions are expressed as a higher order condition with respect to a particular weighted dilation related to the peaking exponents of the nominal system. When this higher order condition is satisfied, an explicit control law is derived that achieves global asymptotic stability of x = 0. This stabilization result is extended to more general cascade nonlinear systems in which the perturbation p(x, v) v, v = (ξ, u) T, contains the state ξ and the control u of a stabilizable subsystem ξ = a(ξ, u). As an illustration, a control law is derived that achieves global stabilization of the frictionless ball-and-beam model.

An integrated 2-D model of a lithium ion battery: The effect of material parameters and morphology on storage particle stress

An integrated 2-D model of a lithium ion battery is developed to study the mechanical stress in storage particles as a function of material properties. A previously developed coupled stress-diffusion model for storage particles is implemented in 2-D and integrated into a complete battery system. The effect of morphology on the stress and lithium concentration is studied for the case of extraction of lithium in terms of previously developed non-dimensional parameters. These non-dimensional parameters include the material properties of the storage particles in the system, among other variables. We examine particles functioning in isolation as well as in closely-packed systems. Our results show that the particle distance from the separator, in combination with the material properties of the particle, is critical in predicting the stress generated within the particle. © 2012 Springer-Verlag.

Fusion dynamics of symmetric systems near barrier energies

Within the framework of the improved isospin-dependent quantum molecular dynamics (ImIQMD) model,he fusion dynamics of symmetric reaction systems are investigated systematically. Calculations show that the number of nucleon transfer in the neck region is appreciably dependent on the incident energies, but strongly on he reaction systems. A comparison of the neck dynamics is performed for the symmetric reactions 58Ni+58Niand 64Ni+64Ni at energies in the vicinity of the Coulomb barrier. An increase of the ratios of the neutron to proton in the neck region at initial collision stage is observed and obvious for the latter system, which reduces the fusion barrier of two colliding nuclei. The distribution of the dynamical fusion barriers and the fusion excitation functions are calculated and compared with the available experimental data.

Temperature dependence of the distribution of the first passage time: Results from discontinuous molecular dynamics simulations of an all-atom model of the second beta-hairpin fragment of protein G

More than 22 000 folding kinetic simulations were performed to study the temperature dependence of the distribution of first passage time (FPT) for the folding of an all-atom Go-like model of the second beta-hairpin fragment of protein G. We find that the mean FPT (MFPT) for folding has a U (or V)-shaped dependence on the temperature with a minimum at a characteristic optimal folding temperature T-opt*. The optimal folding temperature T-opt* is located between the thermodynamic folding transition temperature and the solidification temperature based on the Lindemann criterion for the solid. Both the T-opt* and the MFPT decrease when the energy bias gap against nonnative contacts increases. The high-order moments are nearly constant when the temperature is higher than T-opt* and start to diverge when the temperature is lower than T-opt*. The distribution of FPT is close to a log-normal-like distribution at T* greater than or equal to T-opt*. At even lower temperatures, the distribution starts to develop long power-law-like tails, indicating the non-self-averaging intermittent behavior of the folding dynamics. It is demonstrated that the distribution of FPT can also be calculated reliably from the derivative of the fraction not folded (or fraction folded), a measurable quantity by routine ensemble-averaged experimental techniques at dilute protein concentrations.

AMAR: A Computational Model of Autosegmental Phonology

This report describes a computational system with which phonologists may describe a natural language in terms of autosegmental phonology, currently the most advanced theory pertaining to the sound systems of human languages. This system allows linguists to easily test autosegmental hypotheses against a large corpus of data. The system was designed primarily with tonal systems in mind, but also provides support for tree or feature matrix representation of phonemes (as in The Sound Pattern of English), as well as syllable structures and other aspects of phonological theory. Underspecification is allowed, and trees may be specified before, during, and after rule application. The association convention is automatically applied, and other principles such as the conjunctivity condition are supported. The method of representation was designed such that rules are designated in as close a fashion as possible to the existing conventions of autosegmental theory while adhering to a textual constraint for maximum portability.

A Simple Model of Circuit Design

A simple analog circuit designer has been implemented as a rule based system. The system can design voltage followers. Miller integrators, and bootstrap ramp generators from functional descriptions of what these circuits do. While the designer works in a simple domain where all components are ideal, it demonstrates the abilities of skilled designers. While the domain is electronics, the design ideas are useful in many other engineering domains, such as mechanical engineering, chemical engineering, and numerical programming. Most circuit design systems are given the circuit schematic and use arithmetic constraints to select component values. This circuit designer is different because it designs the schematic. The designer uses a unidirectional CONTROL relation to find the schematic. The circuit designs are built around this relation; it restricts the search space, assigns purposes to components and finds design bugs.

On the Size Distribution of Autonomous Systems

This paper explores reasons for the high degree of variability in the sizes of ASes that have recently been observed, and the processes by which this variable distribution develops. AS size distribution is important for a number of reasons. First, when modeling network topologies, an AS size distribution assists in labeling routers with an associated AS. Second, AS size has been found to be positively correlated with the degree of the AS (number of peering links), so understanding the distribution of AS sizes has implications for AS connectivity properties. Our model accounts for AS births, growth, and mergers. We analyze two models: one incorporates only the growth of hosts and ASes, and a second extends that model to include mergers of ASes. We show analytically that, given reasonable assumptions about the nature of mergers, the resulting size distribution exhibits a power law tail with the exponent independent of the details of the merging process. We estimate parameters of the models from measurements obtained from Internet registries and from BGP tables. We then compare the models solutions to empirical AS size distribution taken from Mercator and Skitter datasets, and find that the simple growth-based model yields general agreement with empirical data. Our analysis of the model in which mergers occur in a manner independent of the size of the merging ASes suggests that more detailed analysis of merger processes is needed.

A Model of Cerebellar Adaptation of Grip Forces During Lifting

We investigated adaptive neural control of precision grip forces during object lifting. A model is presented that adjusts reactive and anticipatory grip forces to a level just above that needed to stabilize lifted objects in the hand. The model obeys priciples of cerebellar structure and function by using slip sensations as error signals to adapt phasic motor commands to tonic force generators associated with output synergies controlling grip aperture. The learned phasic commands are weight and texture-dependent. Simulations of the new curcuit model reproduce key aspects of experimental observations of force application. Over learning trials, the onset of grip force buildup comes to lead the load force buildup, and the rate-of-rise of grip force, but not load force, scales inversely with the friction of the gripped object.

A Neural Model of Surface Perception: Lightness, Anchoring, and Filling-in

This article develops a neural model of how the visual system processes natural images under variable illumination conditions to generate surface lightness percepts. Previous models have clarified how the brain can compute the relative contrast of images from variably illuminate scenes. How the brain determines an absolute lightness scale that "anchors" percepts of surface lightness to us the full dynamic range of neurons remains an unsolved problem. Lightness anchoring properties include articulation, insulation, configuration, and are effects. The model quantatively simulates these and other lightness data such as discounting the illuminant, the double brilliant illusion, lightness constancy and contrast, Mondrian contrast constancy, and the Craik-O'Brien-Cornsweet illusion. The model also clarifies the functional significance for lightness perception of anatomical and neurophysiological data, including gain control at retinal photoreceptors, and spatioal contrast adaptation at the negative feedback circuit between the inner segment of photoreceptors and interacting horizontal cells. The model retina can hereby adjust its sensitivity to input intensities ranging from dim moonlight to dazzling sunlight. A later model cortical processing stages, boundary representations gate the filling-in of surface lightness via long-range horizontal connections. Variants of this filling-in mechanism run 100-1000 times faster than diffusion mechanisms of previous biological filling-in models, and shows how filling-in can occur at realistic speeds. A new anchoring mechanism called the Blurred-Highest-Luminance-As-White (BHLAW) rule helps simulate how surface lightness becomes sensitive to the spatial scale of objects in a scene. The model is also able to process natural images under variable lighting conditions.

AIRSTREAM: A Neural Network Model of Auditory Scene Analysis and Source Segregation

Multiple sound sources often contain harmonics that overlap and may be degraded by environmental noise. The auditory system is capable of teasing apart these sources into distinct mental objects, or streams. Such an "auditory scene analysis" enables the brain to solve the cocktail party problem. A neural network model of auditory scene analysis, called the AIRSTREAM model, is presented to propose how the brain accomplishes this feat. The model clarifies how the frequency components that correspond to a give acoustic source may be coherently grouped together into distinct streams based on pitch and spatial cues. The model also clarifies how multiple streams may be distinguishes and seperated by the brain. Streams are formed as spectral-pitch resonances that emerge through feedback interactions between frequency-specific spectral representaion of a sound source and its pitch. First, the model transforms a sound into a spatial pattern of frequency-specific activation across a spectral stream layer. The sound has multiple parallel representations at this layer. A sound's spectral representation activates a bottom-up filter that is sensitive to harmonics of the sound's pitch. The filter activates a pitch category which, in turn, activate a top-down expectation that allows one voice or instrument to be tracked through a noisy multiple source environment. Spectral components are suppressed if they do not match harmonics of the top-down expectation that is read-out by the selected pitch, thereby allowing another stream to capture these components, as in the "old-plus-new-heuristic" of Bregman. Multiple simultaneously occuring spectral-pitch resonances can hereby emerge. These resonance and matching mechanisms are specialized versions of Adaptive Resonance Theory, or ART, which clarifies how pitch representations can self-organize durin learning of harmonic bottom-up filters and top-down expectations. The model also clarifies how spatial location cues can help to disambiguate two sources with similar spectral cures. Data are simulated from psychophysical grouping experiments, such as how a tone sweeping upwards in frequency creates a bounce percept by grouping with a downward sweeping tone due to proximity in frequency, even if noise replaces the tones at their interection point. Illusory auditory percepts are also simulated, such as the auditory continuity illusion of a tone continuing through a noise burst even if the tone is not present during the noise, and the scale illusion of Deutsch whereby downward and upward scales presented alternately to the two ears are regrouped based on frequency proximity, leading to a bounce percept. Since related sorts of resonances have been used to quantitatively simulate psychophysical data about speech perception, the model strengthens the hypothesis the ART-like mechanisms are used at multiple levels of the auditory system. Proposals for developing the model to explain more complex streaming data are also provided.

A Quantitative Evaluation of the AVITEWRITE Model of Handwriting Learning

Much sensory-motor behavior develops through imitation, as during the learning of handwriting by children. Such complex sequential acts are broken down into distinct motor control synergies, or muscle groups, whose activities overlap in time to generate continuous, curved movements that obey an intense relation between curvature and speed. The Adaptive Vector Integration to Endpoint (AVITEWRITE) model of Grossberg and Paine (2000) proposed how such complex movements may be learned through attentive imitation. The model suggest how frontal, parietal, and motor cortical mechanisms, such as difference vector encoding, under volitional control from the basal ganglia, interact with adaptively-timed, predictive cerebellar learning during movement imitation and predictive performance. Key psycophysical and neural data about learning to make curved movements were simulated, including a decrease in writing time as learning progresses; generation of unimodal, bell-shaped velocity profiles for each movement synergy; size scaling with isochrony, and speed scaling with preservation of the letter shape and the shapes of the velocity profiles; an inverse relation between curvature and tangential velocity; and a Two-Thirds Power Law relation between angular velocity and curvature. However, the model learned from letter trajectories of only one subject, and only qualitative kinematic comparisons were made with previously published human data. The present work describes a quantitative test of AVITEWRITE through direct comparison of a corpus of human handwriting data with the model's performance when it learns by tracing human trajectories. The results show that model performance was variable across subjects, with an average correlation between the model and human data of 89+/-10%. The present data from simulations using the AVITEWRITE model highlight some of its strengths while focusing attention on areas, such as novel shape learning in children, where all models of handwriting and learning of other complex sensory-motor skills would benefit from further research.