Controlling stick balancing on a linear track: Delayed state feedback or delay-compensating predictor feedback?

A planar stick balancing task was investigated using stabilometry parameters (SP); a concept initially developed to assess the stability of human postural sway. Two subject groups were investigated: 6 subjects (MD) with many days of balancing a 90 cm stick on a linear track and 25 subjects (OD) with only one day of balancing experience. The underlying mechanical model is a pendulum-cart system. Two control force models were investigated by means of numerical simulations: (1) delayed state feedback (DSF); and (2) delay-compensating predictor feedback (PF). Both models require an internal model and are subject to certainty thresholds with delayed switching. Measured and simulated time histories were compared quantitatively using a cost function in terms of some essential SPs for all subjects. Minimization of the cost function showed that the control strategy of both OD and MD subjects can better be described by DSF. The control mechanism for the MD subjects was superior in two aspects: (1) they devoted less energy to controlling the cart's position; and (2) their perception threshold for the stick's angular velocity was found to be smaller. Findings support the concept that when sufficient sensory information is readily available, a delay-compensating PF strategy is not necessary.

Introduction to Focus Issue: Dynamical disease: A translational approach.

The concept of Dynamical Diseases provides a framework to understand physiological control systems in pathological states due to their operating in an abnormal range of control parameters: this allows for the possibility of a return to normal condition by a redress of the values of the governing parameters. The analogy with bifurcations in dynamical systems opens the possibility of mathematically modeling clinical conditions and investigating possible parameter changes that lead to avoidance of their pathological states. Since its introduction, this concept has been applied to a number of physiological systems, most notably cardiac, hematological, and neurological. A quarter century after the inaugural meeting on dynamical diseases held in Mont Tremblant, Québec [Bélair et al., Dynamical Diseases: Mathematical Analysis of Human Illness (American Institute of Physics, Woodbury, NY, 1995)], this Focus Issue offers an opportunity to reflect on the evolution of the field in traditional areas as well as contemporary data-based methods.

The effects of sensory quantization and control torque saturation on human balance control.

The effect of reaction delay, temporal sampling, sensory quantization, and control torque saturation is investigated numerically for a single-degree-of-freedom model of postural sway with respect to stability, stabilizability, and control effort. It is known that reaction delay has a destabilizing effect on the balancing process: the later one reacts to a perturbation, the larger the possibility of falling. If the delay is larger than a critical value, then stabilization is not even possible. In contrast, numerical analysis showed that quantization and control torque saturation have a stabilizing effect: the region of stabilizing control gains is greater than that of the linear model. Control torque saturation allows the application of larger control gains without overcontrol while sensory quantization plays a role of a kind of filter when sensory noise is present. These beneficial effects are reflected in the energy demand of the control process. On the other hand, neither control torque saturation nor sensory quantization improves stabilizability properties. In particular, the critical delay cannot be increased by adding saturation and/or sensory quantization.

Establishing metrics and control laws for the learning process: ball and beam balancing.

Understanding how dexterity improves with practice is a fundamental challenge of motor control and neurorehabilitation. Here we investigate a ball and beam implementation of a dexterity puzzle in which subjects stabilize a ball at the mid-point of a beam by manipulating the angular position of the beam. Stabilizability analysis of different biomechanical models for the ball and beam task with time-delayed proportional-derivative feedback identified the angular position of the beam as the manipulated variable. Consequently, we monitored the changes in the dynamics with learning by measuring changes in the control parameters. Two types of stable motion are possible: node type (nonoscillatory) and spiral type (oscillatory). Both types of motion are observed experimentally and correspond to well-defined regions in the parameter space of the control gains. With practice the control gains for each subject move close to or on the portion of the boundary which separates the node-type and spiral-type solutions and which is associated with the rightmost characteristic exponent of smallest real part. These observations suggest that with learning the control gains for ball and beam balancing change in such a way that minimizes overshoot and the settling time. This study provides an example of how mathematical analysis together with careful experimental observations can shed light onto the early stages of skill acquisition. Since the difficulty of this task depends on the length of the beam, ball and beam balancing tasks may be useful for the rehabilitation of children with dyspraxia and those recovering from a stroke.

An integrate-and-fire model for pulsatility in the neuroendocrine system.

A model for pulsatility in neuroendocrine regulation is proposed which combines Goodwin-type feedback control with impulsive input from neurons located in the hypothalamus. The impulsive neural input is modeled using an integrate-and-fire mechanism; namely, inputs are generated only when the membrane potential crosses a threshold, after which it is reset to baseline. The resultant model takes the form of a functional-differential equation with continuous and impulsive components. Despite the impulsive nature of the inputs, realistic hormone profiles are generated, including ultradian and circadian rhythms, pulsatile secretory patterns, and even chaotic dynamics.

Mineral profiling of muscle and hepatic tissues of Australian Merino, Damara and Dorper lambs: Effect of weight loss.

Seasonal weight loss (SWL) is a major constraint to extensive animal production systems. The Australian sheep production is based on merino sheep, a European breed not tolerant to SWL. Tolerant alternative breeds such as the fat-tailed Damara and the Dorper have been increasingly used in Australia and elsewhere, due to their robustness. The aim of this study was to understand the mineral profile of muscle and liver tissues of Australian Merino, Damara and Dorper, when subjected to SWL in order to understand SWL-tolerance physiology. Twenty-four lambs were divided randomly between growing (control) and nutritionally restricted groups for each breed. The trial lasted 42 days. Animals were weighed bi-weekly and at the end of the trial, lambs were slaughtered. Liver and muscle samples were taken immediately after slaughter. Mineral assessment was carried out using inductively coupled plasma-optical emission spectrometry. Analysis of variance showed mineral concentrations were generally increased in the muscle of restricted animals, mainly because of fat tissue mobilization. An increase in Zn and Fe concentrations indicates an increase of enzymatic activity in the liver of restricted sheep as well as differential abundance of Fe-containing proteins. High concentrations of Cu in the liver of Dorper indicate higher ability to accumulate this element, even under SWL.

Outgrowing seizures in Childhood Absence Epilepsy: time delays and bistability.

We formulate a conductance-based model for a 3-neuron motif associated with Childhood Absence Epilepsy (CAE). The motif consists of neurons from the thalamic relay (TC) and reticular nuclei (RT) and the cortex (CT). We focus on a genetic defect common to the mouse homolog of CAE which is associated with loss of GABAA receptors on the TC neuron, and the fact that myelination of axons as children age can increase the conduction velocity between neurons. We show the combination of low GABAA mediated inhibition of TC neurons and the long corticothalamic loop delay gives rise to a variety of complex dynamics in the motif, including bistability. This bistability disappears as the corticothalamic conduction delay shortens even though GABAA activity remains impaired. Thus the combination of deficient GABAA activity and changing axonal myelination in the corticothalamic loop may be sufficient to account for the clinical course of CAE.

Acting together, destabilizing influences can stabilize human balance.

The causes of falling in the elderly are multi-factorial. Three factors that influence balance stability are the time delay, a sensory dead zone and the maximum ankle torque that can be generated by muscular contraction. Here, the effects of these contributions are evaluated in the context of a model of an inverted pendulum stabilized by time-delayed proportional-derivative (PD) feedback. The effect of the sensory dead zone is to produce a hybrid type of control in which the PD feedback is switched ON or OFF depending on whether or not the controlled variable is larger or smaller than the detection threshold, Π. It is shown that, as Π increases, the region in the plane of control parameters where the balance time (BT) is greater than 60 s is increased slightly. However, when maximum ankle torque is also limited, there is a dramatic increase in the parameter region associated with BTs greater than 60 s. This increase is due to the effects of a torque limitation on over-control associated with bang-bang type switching controllers. These observations show that acting together influences, which are typically thought to destabilize balance, can actually stabilize balance. This article is part of the theme issue 'Nonlinear dynamics of delay systems'.

Quantization improves stabilization of dynamical systems with delayed feedback.

We show that an unstable scalar dynamical system with time-delayed feedback can be stabilized by quantizing the feedback. The discrete time model corresponds to a previously unrecognized case of the microchaotic map in which the fixed point is both locally and globally repelling. In the continuous-time model, stabilization by quantization is possible when the fixed point in the absence of feedback is an unstable node, and in the presence of feedback, it is an unstable focus (spiral). The results are illustrated with numerical simulation of the unstable Hayes equation. The solutions of the quantized Hayes equation take the form of oscillations in which the amplitude is a function of the size of the quantization step. If the quantization step is sufficiently small, the amplitude of the oscillations can be small enough to practically approximate the dynamics around a stable fixed point.

Fatty acid composition of the ovine longissimus dorsi muscle: effect of feed restriction in three breeds of different origin.

BACKGROUND: Muscle fatty acid profile reflects the body condition of animals and has a noticeable effect on meat quality. Herein, longissimus dorsi muscle of three different sheep breeds, Damara (a fat-tailed breed), Dorper and Australian Merino sheep, was analysed for fatty acid composition. The three breeds were subjected to two distinctive feeding levels (ad libitum and restricted feeding) over 42 days. RESULTS: The Damara sheep revealed several differences compared to the other two breeds, namely a higher concentration of polyunsaturated fatty acids, which can be related to being a fat-tailed breed. Even in restricted feeding conditions, this breed revealed the highest levels compared to Merino and Dorper sheep respectively, of linoleic acid (+31% and +28%), linolenic acid (+97% and +51%), eicosapentaenoic acid (EPA) (+65% and +37%), docosapentanenoic acid (DPA) (+31% Merino) and dodosahexanenoic acid (DHA) (+63% and +77%). EPA, DPA and DHA are three omega-3 fatty acids, with described beneficial characteristics. CONCLUSION: With this work we show other qualities (higher levels of the omega-3 fatty acids, EPA, DPA and DHA) of Damara meat that might present this breed as an interesting alternative for animal production in semi-arid climates.

Sensory uncertainty and stick balancing at the fingertip.

The effects of sensory input uncertainty, [Formula: see text], on the stability of time-delayed human motor control are investigated by calculating the minimum stick length, [Formula: see text], that can be stabilized in the inverted position for a given time delay, [Formula: see text]. Five control strategies often discussed in the context of human motor control are examined: three time-invariant controllers [proportional-derivative, proportional-derivative-acceleration (PDA), model predictive (MP) controllers] and two time-varying controllers [act-and-wait (AAW) and intermittent predictive controllers]. The uncertainties of the sensory input are modeled as a multiplicative term in the system output. Estimates based on the variability of neural spike trains and neural population responses suggest that [Formula: see text]-13 %. It is found that for this range of uncertainty, a tapped delay-line type of MP controller is the most robust controller. In particular, this controller can stabilize inverted sticks of the length balanced by expert stick balancers (0.25-0.5 m when [Formula: see text] s). However, a PDA controller becomes more effective when [Formula: see text]. A comparison between [Formula: see text] for human stick balancing at the fingertip and balancing on the rubberized surface of a table tennis racket suggest that friction likely plays a role in balance control. Measurements of [Formula: see text], and a variability of the fluctuations in the vertical displacement angle, an estimate of [Formula: see text], may make it possible to study the changes in control strategy as motor skill develops.

Accurate whole human genome sequencing using reversible terminator chemistry.

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.

Longitudinal HCR-20 scores in a high-secure psychiatric hospital.

BACKGROUND: The HCR-20 is a widely used 20 item structured professional judgement aid to risk assessment and management, but longitudinal studies of its value are rare, particularly with people at high risk of reoffending. AIMS: To investigate whether the HCR-20 discriminates between patient subgroups in one high-security hospital in England, whether scores reduce with hospital treatment and whether lower scores predict discharge. METHODS: Repeated HCR-20 ratings were made by clinical teams across five services within the hospital, two of them (women and men with intellectual disability) national services. A database of 3337 HCR-20 ratings, from 532 patients over a period of 5 years, was examined using mixed effects models. RESULTS: As expected, HCR-20 scores were high overall, but there were differences between services in the ratings obtained. Female patients and men with intellectual disability had the highest total score. There was a significant relationship between discharge and lower clinical risk score, but not between total and risk scale scores and discharge. There were significant changes in scores over time, although these were small and may not be clinically meaningful. Differences between services were observed, with women evidencing greater change. CONCLUSIONS: It is unsurprising that patients in two national services (for men with intellectual disability and women) have the highest HCR-20 scores; however, the finding of relatively greater risk reduction in women needs further investigation. Although we did not find ceiling effects in this sample, the clinical value of frequently repeated HCR-20 ratings may be limited for high-risk populations where any change is likely to be slow.

Pole balancing on the fingertip: model-motivated machine learning forecasting of falls.

Introduction: There is increasing interest in developing mathematical and computational models to forecast adverse events in physiological systems. Examples include falls, the onset of fatal cardiac arrhythmias, and adverse surgical outcomes. However, the dynamics of physiological systems are known to be exceedingly complex and perhaps even chaotic. Since no model can be perfect, it becomes important to understand how forecasting can be improved, especially when training data is limited. An adverse event that can be readily studied in the laboratory is the occurrence of stick falls when humans attempt to balance a stick on their fingertips. Over the last 20 years, this task has been extensively investigated experimentally, and presently detailed mathematical models are available. Methods: Here we use a long short-term memory (LTSM) deep learning network to forecast stick falls. We train this model to forecast stick falls in three ways: 1) using only data generated by the mathematical model (synthetic data), 2) using only stick balancing recordings of stick falls measured using high-speed motion capture measurements (human data), and 3) using transfer learning which combines a model trained using synthetic data plus a small amount of human balancing data. Results: We observe that the LTSM model is much more successful in forecasting a fall using synthetic data than it is in forecasting falls for models trained with limited available human data. However, with transfer learning, i.e., the LTSM model pre-trained with synthetic data and re-trained with a small amount of real human balancing data, the ability to forecast impending falls in human data is vastly improved. Indeed, it becomes possible to correctly forecast 60%-70% of real human stick falls up to 2.35 s in advance. Conclusion: These observations support the use of model-generated data and transfer learning techniques to improve the ability of computational models to forecast adverse physiological events.

New cyclodextrin-bearing 8-hydroxyquinoline ligands as multifunctional molecules.

Recent investigations have rekindled interest in 8-hydroxyquinolines as therapeutic agents for cancer, Alzheimer's disease, and other neurodegenerative disorders. Three new ß-cyclodextrin conjugates of 8-hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.

A cyclodextrin-capped histone deacetylase inhibitor.

We have synthesized a ß-cyclodextrin (ßCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 by a large saccharidic scaffold "cap". HDAC inhibition was observed for 3, to a lesser extent than SAHA, and rationalized by molecular docking into the active site of HDAC8. However, compound 3 displayed no cellular activity.

Whole-body vibration applied during upper body exercise improves performance.

Whole-body vibration (WBV) training has exercisers perform static and dynamic resistance training exercises on a ground-based platform. Exposure to WBV exposure has demonstrated benefits and no effect on lower body strength, power, and performance. The aim of this study was to determine if WBV exposure (50 Hz, 2.51 mm) has any potentiating effects postexercise by measuring the kinematic variables of a set of upper body elbow-extensor exercise (70% one-repetition maximum [1RM]) to volitional exhaustion. Sixteen recreationally active students (12 male and 4 female) performed 3 different experimental conditions on separate days. Each condition had the subjects perform 1 set of elbow-extension exercise to fatigue with 1 of 3 WBV treatments: WBV simultaneously during the set (AE); 60 seconds after application of WBV for 30 seconds (RE); and no WBV (CTRL). Kinematic parameters of each repetition were monitored by linking a rotary encoder to the highest load plate. The mean velocity and acceleration throughout the set and perceived exertion were analyzed. A significant increase (p < 0.05) was observed in the mean velocity for the whole set in the AE condition vs. the CTRL condition. The mean acceleration was significantly higher (p < 0.05) in the AE condition in comparison with RE (increased by 45.3%) and CTRL (increased by 50.4%) conditions. The positive effect induced by WBV on upper-limb performance is only achieved when the stimulus is applied during the exercise. However, WBV applied 60 seconds before upper body exercise results in no benefit.

Assessing carcass and meat characteristics of Damara, Dorper and Australian Merino lambs under restricted feeding.

Seasonal weight loss (SWL) is the most pressing constraint in ruminant production systems in tropical climates. SWL is controlled using supplementation, which is costly and difficult to implement in extensive systems, or using breeds adapted to tropical hot dry climates, like the Damara and Dorper. Albeit 15 years in Australia, little is known on how these sheep compare to Australian Merino. Here, the responses of the Damara, Dorper and Merino breeds to nutritional stress were compared. Seventy-two 6-month-old ram lambs, 24 from each breed, were allocated to growth (gaining 100 g/day) or restricted diets (losing 100 g/day, 85% of maintenance needs). Animals were weighed and carcass and meat characteristics determined. Results point out to the existence of important differences between the three genotypes, in particular between the Merino and the Southern African breeds. Additionally, Merino ram lambs seem to have been more influenced by SWL than the other two, with consequences on meat characteristics.

Neuronal avalanches, epileptic quakes and other transient forms of neurodynamics.

Power-law behaviors in brain activity in healthy animals, in the form of neuronal avalanches, potentially benefit the computational activities of the brain, including information storage, transmission and processing. In contrast, power-law behaviors associated with seizures, in the form of epileptic quakes, potentially interfere with the brain's computational activities. This review draws attention to the potential roles played by homeostatic mechanisms and multistable time-delayed recurrent inhibitory loops in the generation of power-law phenomena. Moreover, it is suggested that distinctions between health and disease are scale-dependent. In other words, what is abnormal and defines disease it is not the propagation of neural activity but the propagation of activity in a neural population that is large enough to interfere with the normal activities of the brain. From this point of view, epilepsy is a disease that results from a failure of mechanisms, possibly located in part in the cortex itself or in the deep brain nuclei and brainstem, which truncate or otherwise confine the spatiotemporal scales of these power-law phenomena.

Modeling pulsativity in the hypothalamic-pituitary-adrenal hormonal axis.

A new mathematical model for biological rhythms in the hypothalamic-pituitary-adrenal (HPA) axis is proposed. This model takes the form of a system of impulsive time-delay differential equations which include pulsatile release of adrenocorticotropin (ACTH) by the pituitary gland and a time delay for the release of glucocorticoid hormones by the adrenal gland. Numerical simulations demonstrate that the model's response to periodic and circadian inputs from the hypothalamus are consistent with those generated by recent models which do not include a pulsatile pituitary. In contrast the oscillatory phenomena generated by the impulsive delay equation mode occur even if the time delay is zero. The observation that the time delay merely introduces a small phase shift suggesting that the effects of the adrenal gland are "downstream" to the origin of pulsativity. In addition, the model accounts for the occurrence of ultradian oscillations in an isolated pituitary gland. These observations suggest that principles of pulse modulated control, familiar to control engineers, may have an increasing role to play in understanding the HPA axis.