Avoiding spurious submovement decompositions: a globally optimal algorithm

Evidence for the existence of discrete submovements underlying continuous human movement has motivated many attempts to extract them. Although they produce visually convincing results, all of the methodologies that have been employed are prone to produce spurious decompositions. Examples of potential failures are given. A branch-and-bound algorithm for submovement extraction, capable of global nonlinear minimization (and hence capable of avoiding spurious decompositions), is developed and demonstrated.     

Design of optimal cancer chemotherapy using a continuous-time state model of cell kinetics

A continuous bilinear model in state space is used to describe the cell kinetics of a tumor-cell population under the effects of chemotherapy. Firstly, the time-course behavior of a Chinese-hamster-ovary (CHO) cell population is simulated to demonstrate the utility of the model. Then, an optimal strategy for cancer treatment is derived, based on the need to balance the effects on both cancerous and normal tissues. The performance index minimized is the sum of the weighted tumor population and the weighted total drug dosage. The optimization problem has resulted in a two-point boundary-value problem (TPBVP) with a bang-bang control policy, which is solved by the switching-time variation method (STVM). Computer simulation of CHO cells is also carried out as a numerical example of determining optimal cancer chemotherapy.     

The existence of a hypnotic state revealed by eye movements

Hypnosis has had a long and controversial history in psychology, psychiatry and neurology, but the basic nature of hypnotic phenomena still remains unclear. Different theoretical approaches disagree as to whether or not hypnosis may involve an altered mental state. So far, a hypnotic state has never been convincingly demonstrated, if the criteria for the state are that it involves some objectively measurable and replicable behavioural or physiological phenomena that cannot be faked or simulated by non-hypnotized control subjects. We present a detailed case study of a highly hypnotizable subject who reliably shows a range of changes in both automatic and volitional eye movements when given a hypnotic induction. These changes correspond well with the phenomenon referred to as the "trance stare" in the hypnosis literature. Our results show that this 'trance stare' is associated with large and objective changes in the optokinetic reflex, the pupillary reflex and programming a saccade to a single target. Control subjects could not imitate these changes voluntarily. For the majority of people, hypnotic induction brings about states resembling normal focused attention or mental imagery. Our data nevertheless highlight that in some cases hypnosis may involve a special state, which qualitatively differs from the normal state of consciousness.     

Sample phenotype clusters in high-density oligonucleotide microarray data sets are revealed using Isomap,a nonlinear algorithm

Background  

Life processes are determined by the organism's genetic profile and multiple environmental variables. However the interaction between these factors is inherently non-linear [1]. Microarray data is one representation of the nonlinear interactions among genes and genes and environmental factors. Still most microarray studies use linear methods for the interpretation of nonlinear data. In this study, we apply Isomap, a nonlinear method of dimensionality reduction, to analyze three independent large Affymetrix high-density oligonucleotide microarray data sets.     

Invasibility of plankton food webs along a trophic state gradient

Biological invasions are becoming more common, yet the majority of introduced exotic species fail to establish viable populations in new environments. Current ecological research suggests that invasion success may be determined by properties of the native ecosystem, such as the supply rate of limiting nutrients (i.e. trophic state). We examined how trophic state influences invasion success by introducing an exotic zooplankter, Daphnia lumholtzi into native plankton communities in a series of experimental mesocosms exposed to a strong nutrient gradient. We predicted that the attributes of nutrient-enriched communities would increase the likelihood of a successful invasion attempt by D. lumholtzi . Contrary to our original predictions, we found that D. lumholtzi was often absent from mesocosms that developed under high nutrient supply rates. Instead, the presence of D. lumholtzi was associated with systems that had low nutrients, low zooplankton biomass, and high zooplankton species diversity. Using generalized estimating equations (GEE) and multivariate species data, we found that the presence–absence of D. lumholtzi could be explained by variations in zooplankton community structure, which was itself strongly influenced by nutrient supply rate. We argue that the apparent invasion success of D. lumholtzi was inhibited by the dominance of another cladoceran species, Chydorus sphaericus . These results suggest that the interaction between trophic state and species identity influenced the invasion success of introduced D. lumholtzi .     

Hyper-mobility of water around actin filaments revealed using pulse-field gradient spin-echo H NMR and fluorescence spectroscopy

This paper reports that water molecules around F-actin, a polymerized form of actin, are more mobile than those around G-actin or in bulk water. A measurement using pulse-field gradient spin-echo ¹H NMR showed that the self-diffusion coefficient of water in aqueous F-actin solution increased with actin concentration by ∼5%, whereas that in G-actin solution was close to that of pure water. This indicates that an F-actin/water interaction is responsible for the high self-diffusion of water. The local viscosity around actin was also investigated by fluorescence measurements of Cy3, a fluorescent dye, conjugated to Cys 374 of actin. The steady-state fluorescence anisotropy of Cy3 attached to F-actin was 0.270, which was lower than that for G-actin, 0.334. Taking into account the fluorescence lifetimes of the Cy3 bound to actin, their rotational correlation times were estimated to be 3.8 and 9.1 ns for F- and G-actin, respectively. This indicates that Cy3 bound to F-actin rotates more freely than that bound to G-actin, and therefore the local water viscosity is lower around F-actin than around G-actin.     

Exploring optimal current stimuli that provide membrane voltage tracking in a neuron model

Studying neurons from an energy efficiency perspective has produced results in the research literature. This paper presents a method that enables computation of low energy input current stimuli that are able to drive a reduced Hodgkin–Huxley neuron model to approximate a prescribed time-varying reference membrane voltage. An optimal control technique is used to discover an input current that optimally minimizes a user selected balance between the square of the input stimulus current (input current ‘energy’) and the difference between the reference voltage and the membrane voltage (tracking error) over a stimulation period. Selecting reference signals to be membrane voltages produced by the neuron model in response to common types of input currents i(t) enables a comparison between i(t) and the determined optimal current stimulus i*(t). The intent is not to modify neuron dynamics, but through comparison of i(t) and i*(t) provide insight into neuron dynamics. Simulation results for four different bifurcation types demonstrate that this method consistently finds lower energy stimulus currents i*(t) that are able to approximate membrane voltages as produced by higher energy input currents i(t) in this neuron model.     

On optimal control policy for probabilistic Boolean network: a state reduction approach

Background

Probabilistic Boolean Network (PBN) is a popular model for studying genetic regulatory networks. An important and practical problem is to find the optimal control policy for a PBN so as to avoid the network from entering into undesirable states. A number of research works have been done by using dynamic programming-based (DP) method. However, due to the high computational complexity of PBNs, DP method is computationally inefficient for a large size network. Therefore it is natural to seek for approximation methods.

Results

Inspired by the state reduction strategies, we consider using dynamic programming in conjunction with state reduction approach to reduce the computational cost of the DP method. Numerical examples are given to demonstrate both the effectiveness and the efficiency of our proposed method.

Conclusions

Finding the optimal control policy for PBNs is meaningful. The proposed problem has been shown to be ${\sum }_2^p\mathsf{\text{ - hard}}$. By taking state reduction approach into consideration, the proposed method can speed up the computational time in applying dynamic programming-based algorithm. In particular, the proposed method is effective for larger size networks.

     

Exponential gradient maker using a disposable syringe

With a simple modification, any disposable syringe can become a reliable and easy to use exponential gradient maker. The modification consists of two notches, made with a razor blade, in the borders of the rubber sealing tip of the plunger. A clamp in the tube connected to the syringe allows control over solution flow. With the clamp prohibiting drainage, the body of the syringe is filled with the desired volume of starting solution I. A magnetic stir bar, small enough to spin inside the syringe is included. The notched plunger is introduced until no air space remains. This forms the fixed volume, closed mixing chamber, while the rest of the volume of the syringe forms the open chamber. The two chambers are connected through the notches in the plunger. The ending solution II is poured after the introduction of the plunger. Opening the clamp allows solution I in the closed chamber to flow out, and the solution II in the open chamber flows through the notches and mixes with solution I. This exponential gradient maker can be reused many times, but the low cost of the components makes it potentially disposable. This feature is especially useful when using toxic chemicals, or when pouring polyacrylamide gradient gels, since the apparatus may be disposed of after contamination or eventual polymerization.     

Unique residues crucial for optimal editing in yeast cytoplasmic Leucyl-tRNA synthetase are revealed by using a novel knockout yeast strain

Leucyl-tRNA synthetase (LeuRS) contains an editing domain that discriminates leucine from noncognate amino acids to ensure translational fidelity. In this study, a knock-out strain for Saccharomyces cerevisiae LeuRS was constructed to analyze in vivo the tRNA aminoacylation properties of S. cerevisiae and human cytoplasmic LeuRSs. The activities of several editing-defective mutants of ycLeuRS were determined in vitro and compared with those obtained in vivo in a complementation assay performed in the knock-out strain. The editing activities of these mutants were analyzed in the presence of either norvaline, a leucine analogue, or AN2690, a specific inhibitor that targets the editing active site. In general, the in vivo data are consistent with those obtained in vitro. Our results show that ycLeuRS post-transfer editing plays a crucial role in the establishment of the aminoacylation fidelity. When impaired, the viability of cells bearing editing-defective mutants is drastically decreased in the presence of noncognate amino acid. This study also emphasizes the crucial function of some semi-conserved residues around the editing site in modulating the editing efficiency. The assay system can be used to test the effect of compounds that potentially target the aminoacylation or editing active site of fungal LeuRS.     

Hyper-mobility of water around actin filaments revealed using pulse-field gradient spin-echo 1H NMR and fluorescence spectroscopy

This paper reports that water molecules around F-actin, a polymerized form of actin, are more mobile than those around G-actin or in bulk water. A measurement using pulse-field gradient spin-echo (1)H NMR showed that the self-diffusion coefficient of water in aqueous F-actin solution increased with actin concentration by ～5%, whereas that in G-actin solution was close to that of pure water. This indicates that an F-actin/water interaction is responsible for the high self-diffusion of water. The local viscosity around actin was also investigated by fluorescence measurements of Cy3, a fluorescent dye, conjugated to Cys 374 of actin. The steady-state fluorescence anisotropy of Cy3 attached to F-actin was 0.270, which was lower than that for G-actin, 0.334. Taking into account the fluorescence lifetimes of the Cy3 bound to actin, their rotational correlation times were estimated to be 3.8 and 9.1ns for F- and G-actin, respectively. This indicates that Cy3 bound to F-actin rotates more freely than that bound to G-actin, and therefore the local water viscosity is lower around F-actin than around G-actin.     

Sequencing-by-hybridization at the information-theory bound: an optimal algorithm.

In a recent paper (Preparata et aL, 1999) we introduced a novel probing scheme for DNA sequencing by hybridization (SBH). The new gapped-probe scheme combines natural and universal bases in a well-defined periodic pattern. It has been shown (Preparata et al, 1999) that the performance of the gapped-probe scheme (in terms of the length of a sequence that can be uniquely reconstructed using a given size library of probes) is significantly better than the standard scheme based on oligomer probes. In this paper we present and analyze a new, more powerful, sequencing algorithm for the gapped-probe scheme. We prove that the new algorithm exploits the full potential of the SBH technology with high-confidence performance that comes within a small constant factor (about 2) of the information-theory bound. Moreover, this performance is achieved while maintaining running time linear in the target sequence length.     

Giant clams discriminate threats along a risk gradient and display varying habituation rates to different stimuli

It is often beneficial for animals to discriminate between different threats and to habituate to repeated exposures of benign stimuli. While much is known about risk perception in vertebrates and some invertebrates, risk perception in marine invertebrates is less extensively studied. One method to study risk perception is to habituate animals to a series of exposures to one stimulus, and then present a novel stimulus to test if it transfers habituation. Transfer of habituation is seen as a continued decrease in response while lack of transfer is seen either by having a similar or greater magnitude response. We asked whether giant clams (Tridacna maxima) discriminate between biologically relevant types of threats along a risk gradient. Giant clams retract their mantle and close their shell upon detecting a threat. While closed, they neither feed nor photosynthesize, and prior work has shown that the cost of being closed increases as the duration of their response increases. We recorded a clam's latency to emerge after simulated threats chosen to represent a risk gradient: exposure to a small shading event, a medium shading event, a large shading event (chosen to simulate fish swimming above them), tapping on their shell and touching their mantle (chosen to simulate different degrees of direct attack). Although these stimuli are initially perceived as threatening, we expected clams to habituate to them because they are ultimately non‐damaging and it would be costly for clams to remain closed for extended periods of time when there is no threat present. Clams had different initial latencies to emerge and different habituation rates to these treatments, and they did not transfer habituation to higher risk stimuli and to some lower risk stimuli. These results suggest that clams discriminated between these stimuli along a risk gradient and the lack of habituation transfer shows that the new stimulus was perceived as a potential threat. This study demonstrates that sessile bivalves can discern between levels of predatory threat. These photosynthetic clams may benefit from being able to categorize predator cues for efficient energy allocation.     

The role of terminal-link stimuli in concurrent-chain schedules: revisited using a behavioral-history procedure

A behavioral-history procedure was used to study the function of terminal-link stimuli as conditioned reinforcers in multiple concurrent-chain schedules of reinforcement. First, three pigeons were exposed to multiple concurrent-chain schedules in which the two multiple-schedule components were correlated with a blue and a white stimulus, respectively. In each component the initial links were equal independent variable-interval (VI) 15 s schedules. A fixed-interval (FI) 10 s schedule operated on the red key in one terminal link while extinction operated on the green key in the alternative terminal link. When large preferences for the red stimulus had been established, two tests were conducted. In the terminal-link test, under new initial-link stimuli--purple and brown--an FI 10 s schedule operated for both the red and green terminal-link stimuli. In the subsequent initial-link test, the blue and white initial-link stimuli were reintroduced, and, as in the terminal-link test, FI 10s operated for both the red and the green terminal-link stimuli. In the terminal-link test, the three pigeons showed no preference for the terminal links with the red stimulus, but showed clear and consistent preferences for the red stimulus when blue and white stimuli were reintroduced as initial-link stimuli in the initial-link test. This suggests that there are multiple sources of control over initial-link response allocation in concurrent-chains, including control by both terminal- and initial-link stimuli.     

Involvement of post-translational modification of neuronal plasticity-related proteins in hyperalgesia revealed by a proteomic analysis

To clarify roles of an endogenous pain modulatory system of the central nervous system (CNS) in hyperalgesia, we tried to identify qualitative and quantitative protein changes by a proteomic analysis using an animal model of hyperalgesia. Specifically, we first induced functional hyperalgesia on male Wistar rats by repeated cold stress (specific alternation of rhythm in temperature, SART). We then compared proteomes of multiple regions of CNS and the dorsal root ganglion between the hyperalgetic rats and non-treated ones by 2-D PAGE in the pI range of 4.0-7.0. We found that SART changed the proteomes prominently in the mesencephalon and cerebellum. We thus analyzed the two brain regions in more detail using gels with narrower pI ranges. As a result, 29 and 23 protein spots were significantly changed in the mesencephalon and the cerebellum, respectively. We successfully identified 12 protein spots by a MALDI-TOF/TOF MS and subsequent protein database searching. They included unc-18 protein homolog 67K, collapsin response mediator protein (CRMP)-2 and CRMP-4, which were reported to be involved in neurotransmitter release or axon elongation. Interestingly, mRNA expression levels of these three proteins were not changed significantly by the induction of hyperalgesia. Instead, we found that the detected changes in the protein spots are caused by the post-translational modification (PTM) of proteolysis or phosphorylation. Taken together, development of the hyperalgesia would be linked to PTM of these three CNS proteins. PTM regulation may be one of the useful ways to treat hyperalgesia.     

Approximate parameter inference in systems biology using gradient matching: a comparative evaluation

Background

A challenging problem in current systems biology is that of parameter inference in biological pathways expressed as coupled ordinary differential equations (ODEs). Conventional methods that repeatedly numerically solve the ODEs have large associated computational costs. Aimed at reducing this cost, new concepts using gradient matching have been proposed, which bypass the need for numerical integration. This paper presents a recently established adaptive gradient matching approach, using Gaussian processes (GPs), combined with a parallel tempering scheme, and conducts a comparative evaluation with current state-of-the-art methods used for parameter inference in ODEs. Among these contemporary methods is a technique based on reproducing kernel Hilbert spaces (RKHS). This has previously shown promising results for parameter estimation, but under lax experimental settings. We look at a range of scenarios to test the robustness of this method. We also change the approach of inferring the penalty parameter from AIC to cross validation to improve the stability of the method.

Methods

Methodology for the recently proposed adaptive gradient matching method using GPs, upon which we build our new method, is provided. Details of a competing method using RKHS are also described here.

Results

We conduct a comparative analysis for the methods described in this paper, using two benchmark ODE systems. The analyses are repeated under different experimental settings, to observe the sensitivity of the techniques.

Conclusions

Our study reveals that for known noise variance, our proposed method based on GPs and parallel tempering achieves overall the best performance. When the noise variance is unknown, the RKHS method proves to be more robust.