Phase resetting analysis of high potassium epileptiform activity in CA3 region of the rat hippocampus

The theory of phase resetting can reveal important information about the dynamic behavior of a periodic system when a single brief stimulus is applied to that system at the appropriate time. Phase resetting studies have revealed the existence in some biological systems of a vulnerable stimulus window generating desynchronization and suppression of the activity. The objective of this study was to test the hypothesis that a "singular" stimulus could annihilate this activity. Perfusion with the high-K solution produced synchronous, quasi-periodic population bursts with inter-burst interval of ~0.8-1.5 seconds. A single 0.1 ms duration anodic pulse of programmable delay and magnitude was applied to the somatic layer of the CA3 pyramidal cells. Three types of phase-resetting behavior were observed: (1) Weak resetting with little or no effect on the timing of the subsequent burst, (2) Strong resetting where the applied current pulse delayed the next event by one time period, (3) Singular behavior where the applied pulse partially or completely suppressed the subsequent bursting. The singular stimulus parameter window, however, was very narrow making it difficult to generate the singular behavior reliably. Nevertheless, the results indicate that singularities exist for high potassium neural activity and that a well timed pulse applied with the right amplitude can suppress this activity. This study suggests that phase resetting of a population of neurons is possible for quasi-periodic interictal activity and similar techniques could be applied to the control of epileptic seizures.     

Interpreting Frequency Responses to Dose-Conserved Pulsatile Input Signals in Simple Cell Signaling Motifs

Many hormones are released in pulsatile patterns. This pattern can be modified, for instance by changing pulse frequency, to encode relevant physiological information. Often other properties of the pulse pattern will also change with frequency. How do signaling pathways of cells targeted by these hormones respond to different input patterns? In this study, we examine how a given dose of hormone can induce different outputs from the target system, depending on how this dose is distributed in time. We use simple mathematical models of feedforward signaling motifs to understand how the properties of the target system give rise to preferences in input pulse pattern. We frame these problems in terms of frequency responses to pulsatile inputs, where the amplitude or duration of the pulses is varied along with frequency to conserve input dose. We find that the form of the nonlinearity in the steady state input-output function of the system predicts the optimal input pattern. It does so by selecting an optimal input signal amplitude. Our results predict the behavior of common signaling motifs such as receptor binding with dimerization, and protein phosphorylation. The findings have implications for experiments aimed at studying the frequency response to pulsatile inputs, as well as for understanding how pulsatile patterns drive biological responses via feedforward signaling pathways.     

Linear Population Allocation by Bistable Switches in Response to Transient Stimulation

Many cellular decision processes, including proliferation, differentiation, and phenotypic switching, are controlled by bistable signaling networks. In response to transient or intermediate input signals, these networks allocate a population fraction to each of two distinct states (e.g. OFF and ON). While extensive studies have been carried out to analyze various bistable networks, they are primarily focused on responses of bistable networks to sustained input signals. In this work, we investigate the response characteristics of bistable networks to transient signals, using both theoretical analysis and numerical simulation. We find that bistable systems exhibit a common property: for input signals with short durations, the fraction of switching cells increases linearly with the signal duration, allowing the population to integrate transient signals to tune its response. We propose that this allocation algorithm can be an optimal response strategy for certain cellular decisions in which excessive switching results in lower population fitness.     

Testosterone and 11-ketotestosterone have different regulatory effects on electric communication signals of male Brachyhypopomus gauderio

The communication signals of electric fish can be dynamic, varying between the sexes on a circadian rhythm and in response to social and environmental cues. In the gymnotiform fish Brachyhypopomus gauderio waveform shape of the electric organ discharge (EOD) is regulated by steroid and peptide hormones. Furthermore, EOD amplitude and duration change on different timescales and in response to different social stimuli, suggesting that they are regulated by different mechanisms. Little is known about how androgen and peptide hormone systems interact to regulate signal waveform. We investigated the relationship between the androgens testosterone (T) and 11-ketotestosterone (11-KT), the melanocortin peptide hormone α-MSH, and their roles in regulating EOD waveform of male B. gauderio. Males were implanted with androgen (T, 11-KT, or blank), and injected with α-MSH before and at the peak of androgen effect. We compared the effects of androgen implants and social interactions by giving males a size-matched male stimulus with which they could interact electrically. Social stimuli and both androgens increased EOD duration, but only social stimuli and 11-KT elevated amplitude. However, no androgen enhanced EOD amplitude to the extent of a social stimulus, suggesting that a yet unidentified hormonal pathway regulates this signal parameter. Additionally, both androgens increased response of EOD duration to α-MSH, but only 11-KT increased response of EOD amplitude to α-MSH. Social stimuli had no effect on EOD response to α-MSH. The finding that EOD amplitude is preferentially regulated by 11-KT in B. gauderio may provide the basis for independent control of amplitude and duration.     

MAPK cascade possesses decoupled controllability of signal amplification and duration

The three important characteristics of the output signal of mitogen activated protein kinase (MAPK) cascade are time delay between stimulus and response, amplitude gain, and duration of the output signal. In this study, we performed a sensitivity analysis on the computational model of epidermal growth factor receptor (EGFR) activated MAPK cascade developed by Schoeberl and co-workers (1) to identify the sensitive steps of the pathway affecting these characteristics. We show that the signaling network is sensitive in a decoupled manner, which provides the ability to control its output amplitude and duration one at a time. Signal duration is found sensitive only to the phosphatase reactions at the MEK level. In contrast, signal amplitude is found most sensitive to the phosphatase reactions at the ERK level. Time delay is found to be a robust characteristic of the system.     

Investigations of the steric effect on electrochemical transduction in a quinone-based DNA sensor

Electrochemical biosensors for DNA hybridization are receiving increasing interest. A key point for their efficiency is to obtain a high signal level for low DNA concentration. This implies the design of an efficient transducing surface. Conducting polymers are interesting for this purpose but the great majority of conducting polymer-based electrodes present a signal decrease upon hybridization (a “signal-off” behavior), which impedes their response and makes them sensitive to false positive ones. The sensor described here presents a “signal-on” behavior, due to the use of a quinone group as the transducing agent. The specific aim of this work is to study the steric effect on transduction. To this end, the electrochemical response was monitored versus the DNA target length, for a constant DNA probe length. The results indicate that the current depends on the length of the double strand. A model which can explain the electrochemical behavior takes into account the steric hindrance of the ODN strands.     

Measurements of human responses to short duration impact

Thirty human volunteers participated in 75 exposures to short duration impact (less than 10 msec). The tests were conducted to investigate the ability of the subjects to discriminate different pulse durations in the short duration region. Theoretical studies done previously imply that the subjects should only be sensitive to velocity change and not pulse duration below 10 msec duration. The tests were conducted on a free-fall facility with the subject in a seated position (G₂). The deceleration pulses were Gaussian in shape. Two durations (4 and 8 msec) were investigated at three velocity levels (2·6 m/sec, 3·5 m/sec, and 4·1 m/sec). The decelerations were accomplished with a coefficient of restitution from 0·4 to 0·6. The peak G ranged from 80 to 210. The tests were conducted in three phases. Phase I established the safety of the peak velocity level by proceeding in small increments from a known safe level. Phase II was conducted by exposing 9 subjects to each of the three velocity levels in a counterbalanced experimental design. The pulse duration was 8 msec. Phase III was a duplicate of Phase II, except that a 4 msec pulse was used. A physical or subjective tolerance level was not reached in these experiments, but the 4·1 m/sec velocity level prompted several subjects to discontinue participation in such exposures. A “Physical Symptom Survey” conducted by questionaire, which asked the subject to score severity of sensation by anatomic area, showed a correlation with velocity level and pulse duration. Symptomatology was diffuse but related primarily to the musculoskeletal system and central nervous system. The results of these tests and data derived are discussed relative to physical tolerance and injury potential.     

The effects of reversibility and noise on stochastic phosphorylation cycles and cascades

The phosphorylation-dephosphorylation cycle is a common motif in cellular signaling networks. Previous work has revealed that, when driven by a noisy input signal, these cycles may exhibit bistable behavior. Here, a recently introduced theorem on network bistability is applied to prove that the existence of bistability is dependent on the stochastic nature of the system. Furthermore, the thermodynamics of simple cycles and cascades is investigated in the stochastic setting. Because these cycles are driven by the ATP hydrolysis potential, they may operate far from equilibrium. It is shown that sufficient high ATP hydrolysis potential is necessary for the existence of a bistable steady state. For the single-cycle system, the ensemble average behavior follows the ultrasensitive response expected from analysis of the corresponding deterministic system, but with significant fluctuations. For the two-cycle cascade, the average behavior begins to deviate from the expected response of the deterministic system. Examination of a two-cycle cascade reveals that the bistable steady state may be either propagated or abolished along a cascade, depending on the parameters chosen. Likewise, the variance in the response can be maximized or minimized by tuning the number of enzymes in the second cycle.     

Social regulation of electric signal plasticity in male Brachyhypopomus gauderio

In animal communication, the social context that elicits particular dynamic changes in the signal can provide indirect clues to signal function. Female presence should increase the expression of male signal traits relevant for mate-choice, while male presence should promote the enhancement of traits involved in male-male competition. The electric fish Brachyhypopomus gauderio produces a biphasic electric pulse for electrolocation and communication. Pulse amplitude predicts the signaler’s body size while pulse duration predicts circulating androgen levels. Males enhance pulse amplitude and duration when the numbers of males and females increase simultaneously. Here we tested the relative effects of female presence and male presence on male signal enhancement, and whether the size of the male competitor affected this enhancement. We found that male presence drives the enhancement of both pulse amplitude and second phase duration, independently of the size of the male competitor. Female presence induces the enhancement of pulse duration, but not pulse amplitude. These data suggest that males probably attend to information about a competitor’s body size coded by pulse amplitude and attend to aggressiveness coded by a competitor’s pulse duration, both potential predictors of fight outcome. Females may be primarily concerned about information on reproductive condition coded by pulse duration.     

南极假丝酵母脂肪酶B在离子液体/超临界流体体系中的稳定性模拟

脂肪酶在离子液体/超临界流体体系中的结构稳定性是影响其活性的重要因素。本文采用分子动力学方法分别研究了南极假丝酵母脂肪酶B(CALB)在离子液体CYPHOS IL-201/极性超临界流体CHF_3两相体系和离子液体CYPHOS IL-201/非极性超临界流体CO_2两相体系中的结构稳定性,揭示影响CALB结构稳定性的因素。研究结果表明,在超临界CHF_3中,CHF_3破坏蛋白维持α螺旋结构的氢键是蛋白结构不稳定的主要原因;在超临界CO_2中,CALB蛋白的结构紧密性降低,有序二级结构发生了变化,导致稳定性下降。离子液体和两种超临界流体均形成了两相体系,蛋白处于离子液体相中,离子液体不溶于超临界流体,但超临界流体部分进入离子液体相,降低了离子液体相的黏度。其中,相比于CYPHOS IL-201/CO_2体系,CYPHOS IL-201/CHF_3体系的黏度降低多。在离子液体CYPHOS IL-201与超临界流体(CHF_3、CO_2)形成的两相体系中,离子液体CYPHOS IL-201具有保护蛋白结构的作用,使CALB蛋白结构更加稳定。     

Spider senses - technical perfection and biology

This essay deals with sensory biology in a broad sense. It takes mechanosensory systems of spiders to illustrate a few basic issues. Particular attention is given to two aspects. 1. There is a remarkable “ingenuity” in the uptake and transformation of the adequate stimuli way out in the sensory periphery, which is reflected by an intimate relationship between the physical properties of the stimuli and the characteristics of the structures receiving and transforming them. We need to understand the details of this relationship in order to understand the relationship of an organism to its environment. 2. Sensory systems represent interfaces between the environment and behavior. As highly selective filters they have not evolved to provide abstract knowledge but to guide a particular behavior. The signals sent to the central nervous system are meaningful only in regard to their behavioral significance. – Some details of stimulus transformation in biological strain gauges (slit sensilla), airflow detectors (trichobothria) and touch receptors (tactile hairs) are described. Some of the refinement in the periphery is then meshed with the behavior of the whole organism. In this way the value shall be underlined of trying to understand reductionist details as building blocks of the complexity which enables an organism to behave in its own particular way in its species specific environment.     

Adaptive mechanisms underlying the bat biosonar behavior

For survival, bats of the suborder Microchiropetra emit intense ultrasonic pulses and analyze the weak returning echoes to extract the direction, distance, velocity, size, and shape of the prey. Although these bats and other mammals share the common layout of the auditory pathway and sound coding mechanism, they have highly developed auditory systems to process biologically relevant pulses at the expense of a reduced visual system. During this active biosonar behavior, they progressively shorten the pulse duration, decrease the amplitude and pulse-echo gap as they search, approach and finally intercept the prey. Presumably, these changes in multiple pulse parameters throughout the entire course of hunting enable them to extract maximal information about localized prey from the returning echoes. To hunt successfully, the auditory system of these bats must be less sensitive to intense emitted pulses but highly sensitive to weak returning echoes. They also need to recognize and differentiate the echoes of their emitted pulses from echoes of pulses emitted by other conspecifics. Past studies have shown the following mechanical and neural adaptive mechanisms underlying the successful bat biosonar behavior: (1) Forward orienting and highly mobile pinnae for effective scanning, signal reception, sound pressure transformation and mobile auditory sensitivity; (2) Avoiding and detecting moving targets more successfully than stationary ones; (3) Coordinated activity of highly developed laryngeal and middle ear muscles during pulse emission and reception; (4) Mechanical and neural attenuation of intense emitted pulses to prepare for better reception of weak returning echoes; (5) Increasing pulse repetition rate to improve multiple-parametric selectivity to echoes; (6) Dynamic variation of duration selectivity and recovery cycle of auditory neurons with hunting phase for better echo analysis; (7) Maximal multiple-parametric selectivity to expected echoes returning within a time window after pulse emission; (8) Pulse-echo delaysensitive neurons in higher auditory centers for echo ranging; (9) Corticofugal modulation to improve on-going multiple-parametric signal processing and reorganize signal representation, and (10) A large area of the superior colliculus, pontine nuclei and cerebellum that is sensitive to sound for sensori-motor integration. All these adaptive mechanisms facilitate the bat to effectively extract prey features for successful hunting.     

Influence of Stimuli Spatial Proximity on a SSVEP-Based BCI Performance

Objective: Steady-State Visual Evoked Potentials based Brain-Computer Interfaces (SSVEP-based BCIs) systems have been shown as promising technology due to their short response time and ease of use. SSVEP-based BCIs use brain responses to a flickering visual stimulus as an input command to an external application or device, and it can be influenced by stimulus properties, signal recording, and signal processing. We aim to investigate the system performance varying the stimuli spatial proximity (a stimulus property).Material and methods: We performed a comparative analysis of two visual interface designs (named cross and square) for an SSVEP-based BCI. The power spectrum density (PSD) was used as feature extraction and the Support Machine Vector (SVM) as classification method. We also analyzed the effects of five flickering frequencies (6.67, 8.57, 10, 12 e 15 Hz) between and within interfaces.Results: We found higher accuracy rates for the flickering frequencies of 10, 12, and 15 Hz. The stimulus of 10 Hz presented the highest SSVEP amplitude response for both interfaces. The system presented the best performance (highest classification accuracy and information transfer rate) using the cross interface (lower visual angle).Conclusion: Our findings suggest that the system has the highest performance in the spatial proximity range from 4° to 13° (visual angle). In addition, we conclude that as the stimulus spatial proximity increases, the interference from other stimuli reduces, and the SSVEP amplitude response decreases, which reduces system accuracy. The inter-stimulus distance is a visual interface parameter that must be chosen carefully to increase the efficiency of an SSVEP-based BCI.     

Multivariate phenotypic selection on a complex sexual signal

Animal signals are complex, comprising multiple components that receivers may use to inform their decisions. Components may carry information of differing value to receivers, and selection on one component could modulate or reverse selection on another, necessitating a multivariate approach to estimating selection gradients. However, surprisingly few empirical studies have estimated the strength of phenotypic selection on complex signals with appropriate design and adequate power to detect nonlinear selection. We used phonotaxis assays to measure sexual selection on the advertisement signal of Cope's gray tree frog, Hyla chrysoscelis. Female preferences were assessed for five signal components using single‐ and two‐stimulus behavioral assays. Linear, quadratic, and correlational selection gradients were estimated from the single‐stimulus data. Significant directional selection is acting on call duration, call rate, pulse rate, and relative amplitude; stabilizing selection is acting on call duration and call rate. Under the two‐stimulus paradigm, conclusions were qualitatively different, revealing nonlinear selection on all components except call duration. For individual subjects, the outcomes of single‐ and two‐stimulus trials were frequently discordant, suggesting that the choice of testing paradigm may affect conclusions drawn from experiments.     

Mathematical and computational analysis of adaptation via feedback inhibition in signal transduction pathways

We perform a systematic analysis of mechanisms of feedback regulation that underlie short-term adaptation in intracellular signaling systems. Upon receiving an external cue, these systems generate a transient response that quickly returns to basal levels even if the stimulus persists. Signaling pathways capable of short-term adaptation are found in systems as diverse as the high osmolarity response of yeast, gradient sensing in Dictyostelium, and the cytokine response in vertebrates. Using mathematical analysis and computational experiments, we compare different feedback architectures in terms of response amplitude and duration, ability to adapt, and response to variable stimulus levels. Our analysis reveals three important features of these systems: 1), multiple step signaling cascades improve sensitivity to low doses by an effect distinct from signal amplification; 2), some feedback architectures act as signal transducers converting stimulus strength into response duration; and 3), feedback deactivation acts as a dose-dependent switch between transient and sustained responses. Finally, we present characteristic features for each form of feedback regulation that can aid in their identification.     

Noise enhanced hormonal signal transduction through intracellular calcium oscillations.

In a wide range of non-linear dynamical systems, noise may enhance the detection of weak deterministic input signals. Here, we demonstrate this phenomenon for transmembrane signaling in a hormonal model system of intracellular Ca(2+) oscillations. Adding Gaussian noise to a subthreshold extracellular pulsatile stimulus increased the sensitivity in the dose-response relation of the Ca(2+) oscillations compared to the same noise signal added as a constant mean level. These findings may have important physiological consequences for the operation of hormonal and other physiological signal transduction systems close to the threshold level.     

Sensory cues for the gradual frequency fall responses of the gymnotiform electric fish, Rhamphichthys rostratus

The sensory cues for a less known form of frequency shifting behavior, gradual frequency falls, of electric organ discharges (EODs) in a pulse-type gymnotiform electric fish, Rhamphichthys rostratus, were identified. We found that the gradual frequency fall occurs independently of more commonly observed momentary phase shifting behavior, and is due to perturbation of sensory feedback of the fish's own EODs by EODs of neighboring fish. The following components were identified as essential features in the signal mixture of the fish's own and the neighbor's EOD pulses: (1) the neighbor's pulses must be placed within a few millisecond of the fish's own pulses, (2) the neighbor's pulses, presented singly at low frequencies (0.2–4 Hz), were sufficient, (3) the frequency of individual pulse presentation must be below 4 Hz, (4) amplitude modulation of the sensory feedback of the fish's own pulses induced by such insertions of the neighbor's pulses must contain a high frequency component: sinusoidal amplitude modulation of the fish's own EOD feedback at these low frequencies does not induce gradual frequency falls. Differential stimulation across body surfaces, which is required for the jamming avoidance response (JAR) of wave-type gymnotiform electric fish, was not necessary for this behavior. We propose a cascade of high-pass and low-pass frequency filters within the amplitude processing pathway in the central nervous system as the mechanism of the gradual frequency fall response.Abbreviations EOD electric organ discharge - f frequency of EOD or pacemaker command signal - JAR jamming avoidance response - S ₁ stimulus mimicking fish's own EOD - f ₁ frequency of S₁ - S ₂ stimulus mimicking neighbor's EOD - f ₂ frequency of S₂