Caenorhabditis elegans mutants resistant to phosphine toxicity show increased longevity and cross-resistance to the synergistic action of oxygen

Phosphine (hydrogen phosphide, PH3) is the fumigant most widely used to protect stored products from pest infestation. Despite the importance of this chemical, little is known about its mode of action. We have created three phosphine-resistant lines (pre-1, pre-7, pre-33) in the model organism C. elegans, with LC50 values 2, 5, and 9 times greater than the fully susceptible parental strain. Molecular oxygen was shown to be an extremely effective synergist with phosphine as, under hyperoxic conditions, 100% mortality was observed in wild-type nematodes exposed to 0.1 mg/l phosphine, a nonlethal concentration in air. All three mutants were resistant to the synergistic effects of oxygen in proportion to their resistance to phosphine with one mutant, pre-33, showing complete resistance to this synergism. We take the proportionality of cross-resistance between phosphine and the synergistic effect of oxygen to imply that all three mutants circumvent a mechanism of phosphine toxicity that is directly coupled to oxygen metabolism. Compared with the wild-type strain, all three mutants have an extended average life expectancy of from 12.5 to 25.3%. This is consistent with the proposed involvement of oxidative stress in both phosphine toxicity and ageing. Because the wild-type and mutant nematodes develop at the same rate, the longevity is unlikely to be caused by a clk-type reduction in oxidative metabolism, a potential alternative mechanism of phosphine resistance.

Constraints on the spatiotemporal accuracy of interceptive action: effects of target size on hitting a moving object

Results of two experiments are reported that examined how people respond to rectangular targets of different sizes in simple hitting tasks. If a target moves in a straight line and a person is constrained to move along a linear track oriented perpendicular to the targetrsquos motion, then the length of the target along its direction of motion constrains the temporal accuracy and precision required to make the interception. The dimensions of the target perpendicular to its direction of motion place no constraints on performance in such a task. In contrast, if the person is not constrained to move along a straight track, the targetrsquos dimensions may constrain the spatial as well as the temporal accuracy and precision. The experiments reported here examined how people responded to targets of different vertical extent (height): the task was to strike targets that moved along a straight, horizontal path. In experiment 1 participants were constrained to move along a horizontal linear track to strike targets and so target height did not constrain performance. Target height, length and speed were co-varied. Movement time (MT) was unaffected by target height but was systematically affected by length (briefer movements to smaller targets) and speed (briefer movements to faster targets). Peak movement speed (Vmax) was influenced by all three independent variables: participants struck shorter, narrower and faster targets harder. In experiment 2, participants were constrained to move in a vertical plane normal to the targetrsquos direction of motion. In this task target height constrains the spatial accuracy required to contact the target. Three groups of eight participants struck targets of different height but of constant length and speed, hence constant temporal accuracy demand (different for each group, one group struck stationary targets = no temporal accuracy demand). On average, participants showed little or no systematic response to changes in spatial accuracy demand on any dependent measure (MT, Vmax, spatial variable error). The results are interpreted in relation to previous results on movements aimed at stationary targets in the absence of visual feedback.

Hitting a moving target: Perception and action in the timing of rapid interceptions

Different interceptive tasks and modes of interception (hitting or capturing) do not necessarily involve similar control processes. Control based on preprogramming of movement parameters is possible for actions with brief movement times but is now widely rejected; continuous perceptuomotor control models are preferred for all types of interception. The rejection of preprogrammed control and acceptance of continuous control is evaluated for the timing of rapidly executed, manual hitting actions. It is shown that a preprogrammed control model is capable of providing a convincing account of observed behavior patterns that avoids many of the arguments that have been raised against it. Prominent continuous perceptual control models are analyzed within a common framework and are shown to be interpretable as feedback control strategies. Although these models can explain observations of on-line adjustments to movement, they offer only post hoc explanations for observed behavior patterns in hitting tasks and are not directly supported by data. It is proposed that rapid manual hitting tasks make up a class of interceptions for which a preprogrammed strategy is adopted-a strategy that minimizes the role of visual feedback. Such a strategy is effective when the task demands a high degree of temporal accuracy.

Probabilistic Action System Trace Semantics

Action systems are a construct for reasoning about concurrent, reactive systems, in which concurrent behaviour is described by interleaving atomic actions. Sere and Troubitsyna have proposed an extension to action systems in which actions may be expressed and composed using discrete probabilistic choice as well as demonic nondeterministic choice. In this paper we develop a trace-based semantics for probabilistic action systems. This semantics provides a simple theoretical base on which practical refinement rules for probabilistic action systems may be justified.

The influence of joint position on the dynamics of perception-action coupling

Six right-handed subjects performed rhythmic flexion and extension movements of the index finger in time with an auditory metronome. On each block of trials, the wrist of the response hand was placed in a extended, neutral or flexed position. In the flex-on-the-beat condition, subjects were instructed to coordinate maximum excursion in the direction of finger flexion with each beat of the metronome. In the extend-on-the-beat condition, subjects were instructed to coordinate maximum excursion in the direction of finger extension with each beat of the metronome. The frequency of the metronome was increased from 2.00 Hz to 3.75 Hz in 8 steps (8 s epochs) of 0.25 Hz. During trials prepared in the extend-on-the-beat pattern, all subjects exhibited transitions to either a flex-on-the-beat pattern or to phase wandering as the frequency of pacing was increased. The time at which these transitions occurred was reliably influenced by the position of the wrist. Four subjects exhibited qualitative departures from the flex-on-the-beat pattern at pacing frequencies that were greater than those at which the extend-on-the-beat pattern could be maintained. The lime at which these departures occurred was not influenced by the position of the wrist. These results are discussed with reference to the constraints imposed on the coordination dynamics by the intrinsic properties of the neuromuscular-skeletal system.

Functional significance of the beta-hairpin in the insecticidal neurotoxin omega-atracotoxin-Hv1a

omega -Atracotoxin-Hv1a is an insect-specific neurotoxin whose phylogenetic specificity derives from its ability to antagonize insect, but not vertebrate, voltage-gated calcium channels. In order to help understand its mechanism of action and to enhance its utility as a lead compound for insecticide development, we used a combination of protein engineering and site-directed mutagenesis to probe the toxin for key functional regions. First, we constructed a Hairpinless mutant in which the C-terminal beta -hairpin, which is highly conserved in this family of neurotoxins, was excised without affecting the fold of the residual disulfide-rich core of the toxin. The Hairpinless mutant was devoid of insecticidal activity, indicating the functional importance of the hairpin. We subsequently developed a highly efficient system for production of recombinant toxin and then probed the hairpin for key functional residues using alanine-scanning mutagenesis followed by a second round of mutagenesis based on initial hits from the alanine scan. This revealed that two spatially proximal residues, Asn(27) and Arg(35), form a contiguous molecular surface that is essential for toxin activity. We propose that this surface of the beta -hairpin is a key site for interaction of the toxin with insect calcium channels.

Attentional modulation of neural responses to action observation: Implications for models of the human 'mirror' system

In primates, the observation of meaningful, goaldirected actions engages a network of cortical areas located within the premotor and inferior parietal lobules. Current models suggest that activity within these regions arises relatively automatically during passive action observation without the need for topdown control. Here we used functional magnetic resonance imaging to determine whether cortical activit)' associated with action observation is modulated by the strategic allocation of selective attention. Normal observers viewed movie clips of reach-to-grasp actions while performing an easy or difficult visual discrimination at the fovea. A wholebrain analysis was performed to determine the effects of attentional load on neural responses to observed hand actions. Our results suggest that cortical areas involved in action observation are significantiy modulated by attentional load. These findings have important implications for recent attempts to link the human action-observation system to response properties of "mirror neurons" in monkeys.

Gestational diabetes mellitus: From consensus to action on screening and treatment

The 1998 consensus guidelines on the management of gestational diabetes mellitus from the Australasian Diabetes in Pregnancy Society emphasised that, “due to a lack of good quality randomised controlled clinical trials in the area of [gestational diabetes mellitus], these guidelines are based on what is a reasonable consensus of informed opinion in Australasia”.1 The clear benefits of treating women with gestational diabetes according to these guidelines have now been demonstrated by the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS).2 This study randomised 1000 women with gestational diabetes to either routine antenatal care or to an intervention that comprised home glucose monitoring, review by a diabetes educator, dietitian and physician, and insulin therapy if glycaemic targets were not met. Serious adverse perinatal outcomes occurred in 1% of the intervention group versus 4% of the routine-care group (adjusted relative risk, 0.33 [95% CI, 0.14–0.75]). The percentage of infants who were large for gestational age was lower in the intervention group (13% v 22%), with no increase in those who were small for gestational age. Although induction of labour was more common in the intervention group (39% v 29%), rates of caesarean delivery were similar (around 31%). Measures of maternal quality of life were more favourable in the intervention group. To prevent one serious perinatal outcome, 34 women needed to be treated. The 1998 guidelines were equivocal in regard to screening for gestational diabetes, allowing either for universal screening or for selective screening based on clinical risk factors in relatively lowrisk populations. In the light of the findings of ACHOIS, we believe that universal screening should now be accepted and implemented.

Premovement activity of the pre-supplementary motor area and the readiness for action: Studies of time-resolved event-related functional MRI

The supplementary motor area (SMA) is thought to play in important role in the preparation and organisation of voluntary movement. It has long been known that cortical activity begins to increase up to 2 s prior to voluntary self-initiated movement. This increasing premovement activity measured in EEG is known as the Bereitschaftspotential or readiness potential. Modern functional brain imaging methods, using event-related and time-resolved functional MRI techniques, are beginning to reveal the role of the SMA, and in particular the more anterior pre-SMA, in premovement activity associated with the readiness for action. In this paper we review recent studies using event-related time-resolved fMRI methods to examine the time-course of activation changes within the SMA throughout the preparation, readiness and execution of action. These studies suggest that the preSMA plays a common role in encoding or representing actions prior to our own voluntary self-initiated movements, during motor imagery, and from the observation of others' actions. We suggest that the pre-SMA generates and encodes motor representations which are then maintained in readiness for action. (c) 2005 Elsevier B.V. All rights reserved.