Development of breeding values for susceptibility to virulent footrot in sheep: A strategy to accommodate variable disease progression at time of scoring.

Genetic evaluations utilising footrot scores from industry flocks in their essence, incorporate data from a wide range of challenge environments, resulting in potentially large differences in means, variances and distribution of scores across challenges. The date that commencement of infection occurs is generally unknown, and progression of the infection varies with the prevailing environmental and management conditions, virulence of the bacterium Dichelobacter nodosus, as well as the genetic potential and (permanent) environmental ability of animals to resist footrot. In practice, animals are unlikely to be repeatedly scored to identify the best time for comparison, or monitor development of disease progression. Furthermore, field challenges are limited by the need to treat animals before their welfare is compromised. Therefore, the duration and intensity of infection varies and this affects comparisons between animals for their susceptibility. Diseases such as footrot are characterised by multiple categorical scores reflecting clinical stages that describe the progression and relative impact of the disease. This provides the opportunity for the transformation of the data to a standardised prevalence. Scoring events from multiple footrot field challenges under a standardised protocol were used to establish a series of transition matrices to describe disease progression between scores over time. These transition matrices were used to standardise challenge events to the more severe scoring events, observed later in the challenge. The accuracy of the transition technique was tested by comparing the ranking of animals and sires against the observed scores. Transitioning the data from low disease prevalence to the higher prevalence at the subsequent scoring event improved the correlations between the scoring events, at the animal level, by upwards of 0.10 across challenges. The utilisation of a transition matrix to transform low prevalence disease challenges by taking into account the natural biological rate of progression through the clinical stages of the disease provides a more accurate technique to account for variation in disease prevalence. The transition technique increases the acceptable range of disease expression targeted by producers when scoring virulent footrot challenges reducing the need for repeat scoring and allowing earlier treatment and reducing the impact of the disease on the host animal.

Electrophysiological correlates of processes supporting memory for faces.

The retrieval processes supporting recognition memory for faces were investigated using event-related potentials (ERPs). The focus for analyses was ERP old/new effects, which are the differences between neural activities associated with correct judgments to old (studied) and new (unstudied) test stimuli. In two experiments it was possible to identify three old/new effects that behaved as neural indices of the process of recollection. In both experiments there was one old/new effect that behaved as an index of the process of familiarity. These outcomes are relevant to the ongoing debate about the functional significance of ERP old/new effects and the implications that scalp-recorded electrophysiological data have for theories of the processes supporting long-term memory judgments.

Electrophysiological insights into control over recollection.

Electrophysiological correlates of successful episodic retrieval were measured in an experiment where participants switched frequently between two different episodic retrieval conditions. They completed three trials of each condition before switching to the other condition. The key contrasts were between neural indices of successful retrieval that were separated according to the number of successive trials of the same condition that had been completed. An electrophysiological correlate of recollection--the left-parietal event-related potential (ERP) old/new effect--was smaller on the first and second trial than on the third successive trial that participants completed for each condition. This ERP old/new effect is assumed to index the extent to which recollection has occurred, and this outcome suggests that control over recovery of task-relevant episodic content is compromised when additional cognitive demands are imposed around the time of retrieval.

Working memory capacity is related to variations in the magnitude of an electrophysiological marker of recollection.

The links between the resources available for cognitive control and the ability to recover and maintain episodic content were investigated by contrasting an ERP index of recollection (the left-parietal ERP old/new effect) with a measure of working memory capacity (WMC). Participants were given the O-Span measure of WMC and completed a retrieval task in which they had to make responses on one key to previously studied words (targets) and responses on a second key to words that were presented at retrieval on either one or two occasions (new words and non-targets, respectively). The size of the ERP index of recollection associated with correct responses to targets was correlated with WMC, a finding consistent with the view that this ERP effect is linked to operations associated with maintaining information on-line in service of task goals. In addition, the degree to which left-parietal ERP old/new effects for targets were larger than for non-targets increased as WMC increased. Larger left-parietal ERP old/new effects for targets than for non-targets have been interpreted as evidence of successful prioritisation of recollection of target information. The link with WMC reported here is consistent this view, in so far as WMC indexes the availability of resources that are necessary to exert cognitive control over memory retrieval.

An electrophysiological study of boundary conditions for control of recollection in the exclusion task.

Event-related potentials (ERPs) were collected in a memory retrieval task that was designed to assess the resolution with which people exerted control over memory retrieval. Participants were first required to indicate whether the objects denoted by concrete nouns (i) had pleasant or unpleasant connotations, (ii) were typically smaller or larger than a shoebox, or (iii) were easy or difficult to draw. They then completed a retrieval task where old (studied) and new words were presented. Participants pressed one key for words encountered in the drawing task, and a second key for all other test words (new words as well as those encountered in the pleasantness and size judgment tasks). The left-parietal ERP old/new effect--an electrophysiological index of recollection--was reliable for words from the drawing task only. This finding is consistent with the view that participants were successful at prioritising recollection of some kinds of information over others. The data also provide an insight into the resolution with which this prioritisation can be implemented, because there was little evidence of a left-parietal ERP old/new effect for words to which a size judgment was made, despite the fact that visual imagery is likely to have been employed for drawing as well as for size judgments.

Magnetoencephalographic correlates of processes supporting long-term memory judgments.

The sensitivity of event-related fields (ERFs) to memory retrieval processes is not well determined. This stands in sharp contrast to event-related potential (ERP) studies, as ERPs have been employed widely to address questions about the functional architecture supporting memory retrieval. Despite their success in this endeavour, however, the sensitivity of ERPs to one retrieval process-familiarity-is somewhat limited. This experiment was designed to determine the sensitivity of ERFs to familiarity, and thus to examine the functional leverage that is available to investigate item familiarity via magnetic means of indexing retrieval processing in real-time. The analyses of the ERF data focused on old/new effects, which are differences between the neural activities associated with old (previously studied) and new test items that attract correct memory judgments. The ERFs showed a level of sensitivity to changes in item familiarity superior to that reported previously in very similar studies where ERPs were acquired. Moreover, analyses of the ERF data revealed four functionally distinct old/new effects. These findings provide strong incentives for employing ERFs in subsequent studies of human memory retrieval processing operations.

Electrophysiological measures of episodic memory control and memory retrieval.

Event-related potentials (ERPs) index processes that occur before, during and after retrieval of information from episodic memory. In this selective review we provide a loose theoretical framework within which retrieval processes operating at these different stages can be considered. We go on to describe how ERPs have been employed in order to index processes operating at each of these stages. These data have contributed to current understanding of the processes that are engaged around the time of episodic memory retrieval, and also illustrate the potential that ERPs have for understanding in detail how memory retrieval processes changes in populations with memory impairments.

Electrophysiological correlates of familiarity in recognition memory and exclusion tasks.

ERPs were acquired in the test phases of three memory experiments, where three classes of word were presented. These were: (i) words encountered in a prior study phase (studied words), (ii) words presented at test for the first time (new words), and (iii) new words repeated after a lag of 7-9 intervening words (repeated test words). In experiments 1 and 2, participants were asked to respond on one key to studied words and on another to new as well as to repeated test words. In experiment 3, a binary response was again required, but in this case repeated test and studied words were assigned to the same key. In each experiment, the principal focus for analysis was on the differences between the ERPs at mid-frontal electrode locations from 300 to 500 ms post-stimulus that were associated with incorrect responses to studied words (misses) and correct responses to new words. It has been proposed that relatively greater positivity for studied than for new words at this locus reflects the greater familiarity of studied than of unstudied words. ERPs elicited by misses were reliably more positive-going than those elicited by correct rejections in experiments 1 and 2 only. These findings support the link between this modulation of the electrical record and familiarity in so far as the designs of the experiments lead to the prediction that the average level of familiarity associated with misses should be higher in the first two experiments than in the third. In combination with findings in other studies, these data support dual-process accounts of recognition memory.

The influence of criterion shifts on electrophysiological correlates of recognition memory.

The claim that event-related potentials (ERPs) index familiarity was assessed by acquiring ERPs during a recognition memory task in which participants were instructed to adopt different decision criteria in separate retrieval phases. In one, the instructions were to respond "old" only when confident that this was the correct response, and to respond "new" otherwise (the conservative condition). In the other, the instructions were to respond new only when confident that this was the correct response (the liberal condition). The rationale for this approach was that the level of familiarity licensing an old response would be higher in the conservative than in the liberal condition, and if ERPs index familiarity, this would be reflected in changes to the putative ERP index. This index comprises relatively more positive-going neural activity for correct judgments to old than to new items, which is evident from 300 to 500 msec poststimulus at mid-frontal scalp locations. In keeping with task instructions, participants made more old responses in the liberal than in the conservative condition. There were reliable mid-frontal ERP old/new effects in both conditions, and the ERPs evoked by correct judgments to words in the conservative condition were relatively more positive-going than those in the liberal condition. This finding is consistent with the view that the mid-frontal ERP old/new effect indexes familiarity, and in combination with other ERP findings, provides strong support for dual-process accounts of recognition memory.

Brain and behavioral indices of retrieval mode.

In recent event-related potential (ERP) studies of episodic retrieval, ERPs have been acquired in tasks where participants have been cued trial-by-trial to prepare either to make episodic or semantic retrieval judgments. ERPs elicited during this preparatory cue period and separated according to retrieval task have diverged at right frontal scalp electrodes, with a relatively greater positivity associated with preparation for episodic rather than for semantic retrieval. Importantly, this pattern of differences has been observed only on 'stay' trials: those trials where the participant was cued to prepare for the same retrieval task on the previous trial. These findings have provided the basis for the proposal that the ERP modulations index processes that support the adoption or configuration of retrieval mode - a tonic process that can be sustained while recovery of episodic information is required and which facilitates the retrieval process. In these studies, however, the preparatory period on each trial was no more than 2000 ms, raising the possibility that, with more time available, neural correlates of these preparatory processes would not be restricted to stay trials. In this experiment, participants were cued trial-by-trial to complete either an episodic or a semantic retrieval task, and the preparatory period was greater than 4000 ms on the majority of trials. In keeping with previous findings, the ERPs elicited by these two cue types diverged principally on stay trials at right frontal electrode locations, suggesting that time to prepare is not the primary determinant of the onset of task-specific preparatory retrieval processing. In an important addition to previous findings, moreover, the accuracy of episodic memory judgments increased with the number of successive trials of the same task that participants completed, a finding consistent with the view that adopting a retrieval mode successfully can influence the accuracy of episodic memory judgments.

Memory retrieval processing: neural indices of processes supporting episodic retrieval.

Event-related potentials (ERPs) were acquired during separate test phases of a verbal recognition memory exclusion task in order to contribute to current understanding of the functional significance of differences between ERPs elicited by new (unstudied) test words, which are assumed to index processes engaged in pursuit of task-relevant information. Participants were asked to endorse old words from one study task (targets), and to reject new test words as well as those from a second study task (non-targets). The study task designated as the target category varied across test phases. The left-parietal ERP old/new effect - the electrophysiological signature of recollection - was reliable for targets and for non-targets in all test phases, consistent with the view that participants recollected information about both of these classes of test word. The contrast between the ERPs evoked by new test words separated according to target designation revealed no reliable differences. These findings contrast with those in a recent study in which the same tasks were used, but in which the accuracy of task judgments was markedly higher (Dzulkifli, M.A., & Wilding, E. L. (2005). Electrophysiological indices of strategic episodic retrieval processing. Neuropsychologia, 43, 1152-1162). In that study, there were reliable differences between the ERPs evoked by the two classes of new words, but reliable left-parietal ERP old/new effects for targets only. In combination, the findings suggest that differences between ERPs evoked by new test words can reflect processes that are important for controlling what kinds of information will and will not be recollected.

Neural correlates of control processes engaged before and during recovery of information from episodic memory.

Preparing to retrieve episodic information engages content-specific pre-retrieval processes--retrieval orientations--that vary according to the episodic information that is to be retrieved [Rugg, M.D., Wilding, E.L., 2000. Retrieval processing and episodic memory. Trends Cogn. Sci. 4, 108-115]. Retrieval orientations are retrieval sets which can be maintained tonically and which influence the ways in which subsequent stimuli are processed, presumably in order to facilitate recovery of the required episodic information. Indices of processes related to the adoption of a retrieval orientation can therefore be obtained by acquiring measures of neural activity during preparation to retrieve, while processes contingent upon the successful adoption of an orientation can be obtained by measuring the neural activity that is elicited by stimuli to which memory judgments are required. Across three experiments, electrophysiological indices of the former class of process were obtained only when frequent switches between different retrieval tasks were required, confirming that this measure of brain activity reflects processes important for the adoption of a relevant retrieval orientation. Stimulus-specific indices of retrieval orientations were obtained primarily when few switches between retrieval tasks were required, consistent with the view that the engagement of stimulus-specific retrieval processing operations is achieved only when an appropriate retrieval orientation has been adopted fully.

Indexing strategic retrieval of colour information with event-related potentials.

Event-related potentials (ERPs) were acquired during two experiments in order to determine boundary conditions for when recollection of colour information can be controlled strategically. In initial encoding phases, participants saw an equal number of words presented in red or green. In subsequent retrieval phases, all words were shown in white. Participants were asked to endorse old words that had been shown at encoding in one colour (targets), and to reject new test words as well as old words shown in the alternate colour (non-targets). Study and test lists were longer in Experiment 1, and as a result, the accuracy of memory judgments was superior in Experiment 2. The left-parietal ERP old/new effect--the electrophysiological signature of recollection--was reliable for targets in both experiments, and reliable for non-targets in Experiment 1 only. These findings are consistent with the view that participants were able to restrict recollection to targets in Experiment 2, while recollecting information about targets as well as non-targets in Experiment 1. The fact that this selective strategy was implemented in Experiment 2 despite the close correspondence between the kinds of information associated with targets and non-targets indicates that participants were able to exert considerable control over the conditions under which recollection of task-relevant information occurred.

An electrophysiological investigation of factors facilitating strategic recollection.

Episodic memory is thought to be mediated by executive processes that facilitate the retrieval of task-relevant information at the expense of irrelevant information. The exclusion task [A process dissociation framework: Separating automatic from intentional uses of memory. Journal of Memory and Language, 30, 513-541, 1991] can be used to explore these processes. In this task, studied items from one source ("targets") are endorsed on one response key, whereas new and studied items from another source ("nontargets") are rejected on another key. Herron and Rugg [Strategic influences on recollection in the exclusion task: Electrophysiological evidence. Psychonomic Bulletin and Review, 10, 703-710, 2003] reported that nontargets elicited the ERP correlate of recollection (the "left parietal old/new effect") when target accuracy was low, but not when it was high. Their explanation for this was that participants only focused exclusively on the recollection of target information when the likelihood of target recollection was high, as under these conditions this strategy is one that that will give rise to accurate task performance. The fact, however, that targets were encoded in different tasks in the high- and low-accuracy groups means that the results can also be explained in terms of the encoding operations performed at study rather than in terms of target accuracy. This study was designed to distinguish between these competing accounts. All targets were encoded elaboratively. Target accuracy was reduced in one condition with a 40-min study-test interval. Nontargets elicited no left parietal effect in either condition, suggesting that target-specific strategic retrieval is facilitated by certain classes of encoding operations rather than simply high target accuracy per se.

Electrophysiological indices of strategic episodic retrieval processing.

Event-related potentials (ERPs) were acquired during test phases of a recognition memory exclusion task, in order to contribute to current understanding of the processes responsible for the ways in which memory retrieval can be controlled strategically. Participants were asked to endorse old words from one study task (targets) and to reject new test words as well as those from a second study task (non-targets). The study task designated as the target category varied across test phases. The left-parietal ERP old/new effect--the electrophysiological signature of recollection--was reliable for targets only in all test phases, consistent with the view that participants control recollection strategically in service of task demands. The contrast between the ERPs evoked by new test words separated according to target designation revealed reliable differences at midline, anterior and right-hemisphere locations. These differences likely reflect processes that form part of a retrieval attempt and are interpreted here as indices of processes that are important for the strategic regulation of episodic retrieval.

An electrophysiological dissociation of retrieval mode and retrieval orientation.

The relationship between two classes of retrieval process-retrieval orientation and retrieval mode-was investigated by recording event-related potentials (ERPs) during the period in which participants were preparing to retrieve information from memory. Participants were cued on a trial-by-trial basis to complete either a semantic retrieval task or one of two episodic retrieval tasks (remember spatial location or remember encoding task). ERPs were recorded time-locked to the cues indicating which task to complete. There were commonalities between the ways in which ERPs evoked by the two episodic retrieval cues diverged from those evoked by the semantic cue. These shared differences are a likely correlate of processes related to retrieval mode. Critically, there were also reliable differences between the ERPs evoked by the two episodic cues. This novel finding is consistent with the view that participants adopted task-specific retrieval sets-retrieval orientations-which varied according to the kinds of episodic information that were to be retrieved.

Separating item-related electrophysiological indices of retrieval effort and retrieval orientation.

The relationship between two classes of retrieval process-retrieval orientation and retrieval effort-was investigated using electrophysiological (ERP) and behavioural measures. ERPs were recorded during retrieval phases of exclusion tasks in which participants focused on retrieval of either phonological or semantic associates that were generated in a prior study phase. Participants were separated into two groups on the basis of the relative accuracy of their memory judgments in the retrieval tasks (high vs. low relative difficulty) as a means of assessing retrieval effort. The critical contrasts were between the ERPs evoked by unstudied test items separated according to group and emphasis of the retrieval task (semantic vs. phonological). Reliable differences according to task were evident in the high relative difficulty group only. This finding is consistent with the view that, for this task pair at least, ERPs are sensitive to the processes set in train in pursuit of task relevant information (retrieval orientations) only when relative difficulty is high.

The influence of response-time demands on electrophysiological correlates of successful episodic retrieval.

Event-related potentials (ERPs) were acquired in two memory retrieval tasks. In Experiment 1 a 2.5 s response-time limit was imposed at test, while in Experiment 2 there was no explicit upper limit. There were no other structural differences between the two experiments. The response-time manipulation did not influence the accuracy of memory judgements, but resulted in qualitative changes in the ERP old/new effects that were elicited in the two tasks. In Experiment 2, the ERP old/new effects from 700 ms post-stimulus onwards comprised a relatively greater positivity for correct judgements to old items in comparison to correct judgements to new items. In keeping with findings in previous studies, this relative positivity was largest at anterior sites over the right hemisphere. In Experiment 1, by contrast, the ERP old/new effects during the same time window were most prominent at right hemisphere central electrode locations, and comprised a relatively greater positivity for correct judgements to new rather than to old test items. In combination, the findings in the two experiments are consistent with the view that the imposition of different response-time demands results in the engagement of neurally and functionally distinct processes during episodic retrieval. The time course of these distinct ERP old/new effects suggests that different post-retrieval monitoring operations were engaged according to the time available to make memory judgements.

Enterococcus faecalis acetoacetyl-coenzyme A thiolase/3-hydroxy-3-methylglutaryl-coenzyme A reductase, a dual-function protein of isopentenyl diphosphate biosynthesis.

Many bacteria employ the nonmevalonate pathway for synthesis of isopentenyl diphosphate, the monomer unit for isoprenoid biosynthesis. However, gram-positive cocci exclusively use the mevalonate pathway, which is essential for their growth (E. I. Wilding et al., J. Bacteriol. 182:4319-4327, 2000). Enzymes of the mevalonate pathway are thus potential targets for drug intervention. Uniquely, the enterococci possess a single open reading frame, mvaE, that appears to encode two enzymes of the mevalonate pathway, acetoacetyl-coenzyme A thiolase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Western blotting revealed that the mvaE gene product is a single polypeptide in Enterococcus faecalis, Enterococcus faecium, and Enterococcus hirae. The mvaE gene was cloned from E. faecalis and was expressed with an N-terminal His tag in Escherichia coli. The gene product was then purified by nickel affinity chromatography. As predicted, the 86.5-kDa mvaE gene product catalyzed both the acetoacetyl-CoA thiolase and HMG-CoA reductase reactions. Temperature optima, DeltaH(a) and K(m) values, and pH optima were determined for both activities. Kinetic studies of acetoacetyl-CoA thiolase implicated a ping-pong mechanism. CoA acted as an inhibitor competitive with acetyl-CoA. A millimolar K(i) for a statin drug confirmed that E. faecalis HMG-CoA reductase is a class II enzyme. The oxidoreductant was NADP(H). A role for an active-site histidine during the first redox step of the HMG-CoA, reductase reaction was suggested by the ability of diethylpyrocarbonate to block formation of mevalonate from HMG-CoA, but not from mevaldehyde. Sequence comparisons with other HMG-CoA reductases suggest that the essential active-site histidine is His756. The mvaE gene product represents the first example of an HMG-CoA reductase fused to another enzyme.