A Bayesian model predicts the response of axons to molecular gradients

Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.

Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

An examination of monotony and hypovigilance, independent of fatigue : relevance to road safety

Driving is a vigilance task, requiring sustained attention to maintain performance and avoid crashes. Hypovigilance (i.e., marked reduction in vigilance) while driving manifests as poor driving performance and is commonly attributed to fatigue (Dinges, 1995). However, poor driving performance has been found to be more frequent when driving in monotonous road environments, suggesting that monotony plays a role in generating hypovigilance (Thiffault & Bergeron, 2003b). Research to date has tended to conceptualise monotony as a uni-dimensional task characteristic, typically used over a prolonged period of time to facilitate other factors under investigation, most notably fatigue. However, more often than not, more than one exogenous factor relating to the task or operating environment is manipulated to vary or generate monotony (Mascord & Heath, 1992). Here we aimed to explore whether monotony is a multi-dimensional construct that is determined by characteristics of both the task proper and the task environment. The general assumption that monotony is a task characteristic used solely to elicit hypovigilance or poor performance related to fatigue appears to have led to there being little rigorous investigation into the exact nature of the relationship. While the two concepts are undoubtedly linked, the independent effect of monotony on hypovigilance remains largely ignored. Notwithstanding, there is evidence that monotony effects can emerge very early in vigilance tasks and are not necessarily accompanied by fatigue (see Meuter, Rakotonirainy, Johns, & Wagner, 2005). This phenomenon raises a largely untested, empirical question explored in two studies: Can hypovigilance emerge as a consequence of task and/or environmental monotony, independent of time on task and fatigue? In Study 1, using a short computerised vigilance task requiring responses to be withheld to infrequent targets, we explored the differential impacts of stimuli and task demand manipulations on the development of a monotonous context and the associated effects on vigilance performance (as indexed by respone errors and response times), independent of fatigue and time on task. The role of individual differences (sensation seeking, extroversion and cognitive failures) in moderating monotony effects was also considered. The results indicate that monotony affects sustained attention, with hypovigilance and associated performance worse in monotonous than in non-monotonous contexts. Critically, performance decrements emerged early in the task (within 4.3 minutes) and remained consistent over the course of the experiment (21.5 minutes), suggesting that monotony effects can operate independent of time on task and fatigue. A combination of low task demands and low stimulus variability form a monotonous context characterised by hypovigilance and poor task performance. Variations to task demand and stimulus variability were also found to independently affect performance, suggesting that monotony is a multi-dimensional construct relating to both task monotony (associated with the task itself) and environmental monotony (related to characteristics of the stimulus). Consequently, it can be concluded that monotony is multi-dimensional and is characterised by low variability in stimuli and/or task demands. The proposition that individual differences emerge under conditions of varying monotony with high sensation seekers and/or extroverts performing worse in monotonous contexts was only partially supported. Using a driving simulator, the findings of Study 1 were extended to a driving context to identify the behavioural and psychophysiological indices of monotony-related hypovigilance associated with variations to road design and road side scenery (Study 2). Supporting the proposition that monotony is a multi-dimensional construct, road design variability emerged as a key moderating characteristic of environmental monotony, resulting in poor driving performance indexed by decrements in steering wheel measures (mean lateral position). Sensation seeking also emerged as a moderating factor, where participants high in sensation seeking tendencies displayed worse driving behaviour in monotonous conditions. Importantly, impaired driving performance was observed within 8 minutes of commencing the driving task characterised by environmental monotony (low variability in road design) and was not accompanied by a decline in psychophysiological arousal. In addition, no subjective declines in alertness were reported. With fatigue effects associated with prolonged driving (van der Hulst, Meijman, & Rothengatter, 2001) and indexed by drowsiness, this pattern of results indicates that monotony can affect driver vigilance, independent of time on task and fatigue. Perceptual load theory (Lavie, 1995, 2005) and mindlessness theory (Robertson, Manly, Andrade, Baddley, & Yiend, 1997) provide useful theoretical frameworks for explaining and predicting monotony effects by positing that the low load (of task and/or stimuli) associated with a monotonous task results in spare attentional capacity which spills over involuntarily, resulting in the processing of task-irrelevant stimuli or task unrelated thoughts. That is, individuals – even when not fatigued - become easily distracted when performing a highly monotonous task, resulting in hypovigilance and impaired performance. The implications for road safety, including the likely effectiveness of fatigue countermeasures to mitigate monotony-related driver hypovigilance are discussed.

Emergent task-specific object semantics through distributed experience networks

Autonomous development of sensorimotor coordination enables a robot to adapt and change its action choices to interact with the world throughout its lifetime. The Experience Network is a structure that rapidly learns coordination between visual and haptic inputs and motor action. This paper presents methods which handle the high dimensionality of the network state-space which occurs due to the simultaneous detection of multiple sensory features. The methods provide no significant increase in the complexity of the underlying representations and also allow emergent, task-specific, semantic information to inform action selection. Experimental results show rapid learning in a real robot, beginning with no sensorimotor mappings, to a mobile robot capable of wall avoidance and target acquisition.

Stochastic analysis of the VEGF receptor response curve

Recently, an analysis of the response curve of the vascular endothelial growth factor (VEGF) receptor and its application to cancer therapy was described in [T. Alarcón, and K. Page, J. R. Soc. Lond. Interface 4, 283–304 (2007)]. The analysis is significantly extended here by demonstrating that an alternative computational strategy, namely the Krylov FSP algorithm for the direct solution of the chemical master equation, is feasible for the study of the receptor model. The new method allows us to further investigate the hypothesis of symmetry in the stochastic fluctuations of the response. Also, by augmenting the original model with a single reversible reaction we formulate a plausible mechanism capable of realizing a bimodal response, which is reported experimentally but which is not exhibited by the original model. The significance of these findings for mechanisms of tumour resistance to antiangiogenic therapy is discussed.

The effect of ocular surface conditions on blink rate and completeness

A healthy human would be expected to show periodic blinks, making a brief closure of the eyelids. Most blinks are spontaneous, occurring regularly with no external stimulus. However a reflex blink can occur in response to external stimuli such as a bright light, a sudden loud noise, or an object approaching toward the eyes. A voluntary or forced blink is another type of blink in which the person deliberately closes the eyes and the lower eyelid raises to meet the upper eyelid. A complete blink, in which the upper eyelid touches the lower eyelid, contributes to the health of ocular surface by providing a fresh layer of tears as well as maintaining optical integrity by providing a smooth tear film over the cornea. The rate of blinking and its completeness vary depending on the task undertaken during blink assessment, the direction of gaze, the emotional state of the subjects and the method under which the blink was measured. It is also well known that wearing contact lenses (both rigid and soft lenses) can induce significant changes in blink rate and completeness. It is been established that efficient blinking plays an important role in ocular surface health during contact lens wear and for improving contact lens performance and comfort. Inefficient blinking during contact lens wear may be related to a low blink rate or incomplete blinking and can often be a reason for dry eye symptoms or ocular surface staining. It has previously been shown that upward gaze can affect blink rate, causing it to become faster. In the first experiment, it was decided to expand on previous studies in this area by examining the effect of various gaze directions (i.e. upward gaze, primary gaze, downward gaze and lateral gaze) as well as head angle (recumbent position) on normal subjects’ blink rate and completeness through the use of filming with a high-speed camera. The results of this experiment showed that as the open palpebral aperture (and exposed ocular surface area) increased from downward gaze to upward gaze, the number of blinks significantly increased (p<0.04). Also, the size of closed palpebral aperture significantly increased from downward gaze to upward gaze (p<0.005). A weak positive correlation (R² = 0.18) between the blink rate and ocular surface area was found in this study. Also, it was found that the subjects showed 81% complete blinks, 19% incomplete blinks and 2% of twitch blinks in primary gaze, consistent with previous studies. The difference in the percentage of incomplete blinks between upward gaze and downward gaze was significant (p<0.004), showing more incomplete blinks in upward gaze. The findings of this experiment suggest that while blink rate becomes slower in downward gaze, the completeness of blinking is typically better, thereby potentially reducing the risk of tear instability. On the other hand, in upward gaze while the completeness of blinking becomes worse, this is potentially offset by increased blink frequency. In addition, blink rate and completeness were not affected by lateral gaze or head angle, possibly because these conditions have similar size of the open palpebral aperture compared with primary gaze. In the second experiment, an investigation into the changes in blink rate and completeness was carried out in primary gaze and downward gaze with soft and rigid contact lenses in unadapted wearers. Not surprisingly, rigid lens wear caused a significant increase in the blink rate in both primary (p<0.001) and downward gaze (p<0.02). After fitting rigid contact lenses, the closed palpebral aperture (blink completeness) did not show any changes but the open palpebral aperture showed a significant narrowing (p<0.04). This might occur from the subjects’ attempt to avoid interaction between the upper eyelid and the edge of the lens to minimize discomfort. After applying topical anaesthetic eye drops in the eye fitted with rigid lenses, the increased blink rate dropped to values similar to that before lens insertion and the open palpebral aperture returned to baseline values, suggesting that corneal and/or lid margin sensitivity was mediating the increased blink rate and narrowed palpebral aperture. We also investigated the changes in the blink rate and completeness with soft contact lenses including a soft sphere, double slab-off toric design and periballast toric design. Soft contact lenses did not cause any significant changes in the blink rate, closed palpebral aperture, open palpebral aperture and the percentage of incomplete blinks in either primary gaze or downward gaze. After applying anaesthetic eye drops, the blink rate reduced in both primary gaze and downward gaze, however this difference was not statistically significant. The size of the closed palpebral aperture and open palpebral aperture did not show any significant changes after applying anaesthetic eye drops. However it should be noted that the effects of rigid and soft contact lenses that we observed in these studies were only the immediate reaction to contact lenses and in the longer term, it is likely that these responses will vary as the eye adapts to the presence of the lenses.

Frequency response function based structural damage detection using artificial neural networks

Damage detection in structures has become increasingly important in recent years. While a number of damage detection and localization methods have been proposed, few attempts have been made to explore the structure damage with frequency response functions (FRFs). This paper illustrates the damage identification and condition assessment of a beam structure using a new frequency response functions (FRFs) based damage index and Artificial Neural Networks (ANNs). In practice, usage of all available FRF data as an input to artificial neural networks makes the training and convergence impossible. Therefore one of the data reduction techniques Principal Component Analysis (PCA) is introduced in the algorithm. In the proposed procedure, a large set of FRFs are divided into sub-sets in order to find the damage indices for different frequency points of different damage scenarios. The basic idea of this method is to establish features of damaged structure using FRFs from different measurement points of different sub-sets of intact structure. Then using these features, damage indices of different damage cases of the structure are identified after reconstructing of available FRF data using PCA. The obtained damage indices corresponding to different damage locations and severities are introduced as input variable to developed artificial neural networks. Finally, the effectiveness of the proposed method is illustrated and validated by using the finite element modal of a beam structure. The illustrated results show that the PCA based damage index is suitable and effective for structural damage detection and condition assessment of building structures.

An analytical and experimental study of the vibration response of a clamped ribbed plate

An analytical solution is presented in this paper for the vibration response of a ribbed plate clamped on all its boundary edges by employing a travelling wave solution. A clamped ribbed plate test rig is also assembled in this study for the experimental investigation of the ribbed plate response and to provide verification results to the analytical solution. The dynamic characteristics and mode shapes of the ribbed plate are measured and compared to those obtained from the analytical solution and from finite element analysis (FEA). General good agreements are found between the results. Discrepancies between the computational and experimental results at low and high frequencies are also discussed. Explanations are offered in the study to disclose the mechanism causing the discrepancies. The dependency of the dynamic response of the ribbed plate on the distance between the excitation force and the rib is also investigated experimentally. It confirms the findings disclosed in a previous analytical study [T. R. Lin and J. Pan, A closed form solution for the dynamic response of finite ribbed plates. Journal of the Acoustical Society of America 119 (2006) 917-925] that the vibration response of a clamped ribbed plate due to a point force excitation is controlled by the plate stiffness when the source is more than a quarter plate bending wavelength away from the rib and from the plate boundary. The response is largely affected by the rib stiffness when the source location is less than a quarter bending wavelength away from the rib.