Evaluating suicide attitudes and suicide literacy in adolescents.

BACKGROUND: Two of the most common modifiable barriers to help-seeking for mental health problems during adolescence are stigma and poor mental health literacy. However, relatively little is known about stigma as it relates to suicide, and knowledge about suicidality in this age group. AIMS: To assess levels of suicide literacy and suicide attitudes in an adolescent sample, and to identify correlates of these constructs. METHODS: Data were drawn from the pre-intervention survey of the Sources of Strength Australia Project. A total of 1019 adolescents aged between 11 and 17 years participated. Suicide literacy and attitudes were measured alongside potential correlates including psychological distress, suicidal ideation, mastery, previous exposure to suicidal thinking and behaviour, and demographics. RESULTS: Participants more strongly endorsed attitudes attributing suicide to isolation/depression, compared to attitudes glorifying or stigmatising suicide. Gaps in knowledge about suicide included the risk factors, signs and symptoms. Key correlates of suicide attitudes and literacy included age, gender and cultural background. CONCLUSION: Findings highlight the need for further education activities in schools and public awareness campaigns that address the gaps in suicide knowledge and attitudes. Such activities would assist in the identification of suicide risk among young people and improve help-seeking in this population.

Bacterial wobble modifications of NNA-decoding tRNAs.

Nucleotides of transfer RNAs (tRNAs) are highly modified, particularly at the anticodon. Bacterial tRNAs that read A-ending codons are especially notable. The U34 nucleotide canonically present in these tRNAs is modified by a wide range of complex chemical constituents. An additional two A-ending codons are not read by U34-containing tRNAs but are accommodated by either inosine or lysidine at the wobble position (I34 or L34). The structural basis for many N34 modifications in both tRNA aminoacylation and ribosome decoding has been elucidated, and evolutionary conservation of modifying enzymes is also becoming clearer. Here we present a brief review of the structure, function, and conservation of wobble modifications in tRNAs that translate A-ending codons. © 2019 IUBMB Life, 2019 © 2019 IUBMB Life, 71(8):1158-1166, 2019.

MD Simulations of tRNA and Aminoacyl-tRNA Synthetases: Dynamics, Folding, Binding, and Allostery.

While tRNA and aminoacyl-tRNA synthetases are classes of biomolecules that have been extensively studied for decades, the finer details of how they carry out their fundamental biological functions in protein synthesis remain a challenge. Recent molecular dynamics (MD) simulations are verifying experimental observations and providing new insight that cannot be addressed from experiments alone. Throughout the review, we briefly discuss important historical events to provide a context for how far the field has progressed over the past few decades. We then review the background of tRNA molecules, aminoacyl-tRNA synthetases, and current state of the art MD simulation techniques for those who may be unfamiliar with any of those fields. Recent MD simulations of tRNA dynamics and folding and of aminoacyl-tRNA synthetase dynamics and mechanistic characterizations are discussed. We highlight the recent successes and discuss how important questions can be addressed using current MD simulations techniques. We also outline several natural next steps for computational studies of AARS:tRNA complexes.

Evidence for late resolution of the aux codon box in evolution.

Recognition strategies for tRNA aminoacylation are ancient and highly conserved, having been selected very early in the evolution of the genetic code. In most cases, the trinucleotide anticodons of tRNA are important identity determinants for aminoacylation by cognate aminoacyl-tRNA synthetases. However, a degree of ambiguity exists in the recognition of certain tRNA(Ile) isoacceptors that are initially transcribed with the methionine-specifying CAU anticodon. In most organisms, the C34 wobble position in these tRNA(Ile) precursors is rapidly modified to lysidine to prevent recognition by methionyl-tRNA synthetase (MRS) and production of a chimeric Met-tRNA(Ile) that would compromise translational fidelity. In certain bacteria, however, lysidine modification is not required for MRS rejection, indicating that this recognition strategy is not universally conserved and may be relatively recent. To explore the actual distribution of lysidine-dependent tRNA(Ile) rejection by MRS, we have investigated the ability of bacterial MRSs from different clades to differentiate cognate tRNACAU(Met) from near-cognate tRNACAU(Ile). Discrimination abilities vary greatly and appear unrelated to phylogenetic or structural features of the enzymes or sequence determinants of the tRNA. Our data indicate that tRNA(Ile) identity elements were established late and independently in different bacterial groups. We propose that the observed variation in MRS discrimination ability reflects differences in the evolution of genetic code machineries of emerging bacterial clades.

Misacylation of specific nonmethionyl tRNAs by a bacterial methionyl-tRNA synthetase.

Aminoacyl-tRNA synthetases perform a critical step in translation by aminoacylating tRNAs with their cognate amino acids. Although high fidelity of aminoacyl-tRNA synthetases is often thought to be essential for cell biology, recent studies indicate that cells tolerate and may even benefit from tRNA misacylation under certain conditions. For example, mammalian cells selectively induce mismethionylation of nonmethionyl tRNAs, and this type of misacylation contributes to a cell's response to oxidative stress. However, the enzyme responsible for tRNA mismethionylation and the mechanism by which specific tRNAs are mismethionylated have not been elucidated. Here we show by tRNA microarrays and filter retention that the methionyl-tRNA synthetase enzyme from Escherichia coli (EcMRS) is sufficient to mismethionylate two tRNA species, and , indicating that tRNA mismethionylation is also present in the bacterial domain of life. We demonstrate that the anticodon nucleotides of these misacylated tRNAs play a critical role in conferring mismethionylation identity. We also show that a certain low level of mismethionylation is maintained for these tRNAs, suggesting that mismethionylation levels may have evolved to confer benefits to the cell while still preserving sufficient translational fidelity to ensure cell viability. EcMRS mutants show distinct effects on mismethionylation, indicating that many regions in this synthetase enzyme influence mismethionylation. Our results show that tRNA mismethionylation can be carried out by a single protein enzyme, mismethionylation also requires identity elements in the tRNA, and EcMRS has a defined structure-function relationship for tRNA mismethionylation.

The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

Sex differences in the use of delayed semantic context when listening to disrupted speech.

Female as opposed to male listeners were better able to use a delayed informative cue at the end of a long sentence to report an earlier word which was disrupted by noise. Informative (semantically related) or uninformative (semantically unrelated) word cues were presented 2, 6, or 10 words after a target word whose initial phoneme had been replaced with noise. A total of 84 young adults (45 males) listened to each sentence and then repeated it after its offset. The semantic benefit effect (SBE) was the difference in the accuracy of report of the disrupted target word during informative vs. uninformative sentences. Women had significantly higher SBEs than men even though there were no significant sex differences in terms of number of non-target words reported, the effect of distance between the disrupted target word and the informative cue, or kinds of errors generated. We suggest that the superior ability of women to use delayed semantic information to decode an earlier ambiguous speech signal may be linked to women's tendency to engage the hemispheres more bilaterally than men during word processing. Since the maintenance of semantic context under ambiguous conditions demands more right than left hemispheric resources, this may give women an advantage.

Adaptation to Overflow Metabolism by Mutations That Impair tRNA Modification in Experimentally Evolved Bacteria.

When microbes grow in foreign nutritional environments, selection may enrich mutations in unexpected pathways connecting growth and homeostasis. An evolution experiment designed to identify beneficial mutations in Burkholderia cenocepacia captured six independent nonsynonymous substitutions in the essential gene tilS, which modifies tRNAIle2 by adding a lysine to the anticodon for faithful AUA recognition. Further, five additional mutants acquired mutations in tRNAIle2, which strongly suggests that disrupting the TilS-tRNAIle2 interaction was subject to strong positive selection. Mutated TilS incurred greatly reduced enzymatic function but retained capacity for tRNAIle2 binding. However, both mutant sets outcompeted the wild type by decreasing the lag phase duration by ~3.5 h. We hypothesized that lysine demand could underlie fitness in the experimental conditions. As predicted, supplemental lysine complemented the ancestral fitness deficit, but so did the additions of several other amino acids. Mutant fitness advantages were also specific to rapid growth on galactose using oxidative overflow metabolism that generates redox imbalance, not resources favoring more balanced metabolism. Remarkably, 13 tilS mutations also evolved in the long-term evolution experiment with Escherichia coli, including four fixed mutations. These results suggest that TilS or unknown binding partners contribute to improved growth under conditions of rapid sugar oxidation at the predicted expense of translational accuracy. IMPORTANCE There is growing evidence that the fundamental components of protein translation can play multiple roles in maintaining cellular homeostasis. Enzymes that interact with transfer RNAs not only ensure faithful decoding of the genetic code but also help signal the metabolic state by reacting to imbalances in essential building blocks like free amino acids and cofactors. Here, we present evidence of a secondary function for the essential enzyme TilS, whose only prior known function is to modify tRNAIle(CAU) to ensure accurate translation. Multiple nonsynonymous substitutions in tilS, as well as its cognate tRNA, were selected in evolution experiments favoring rapid, redox-imbalanced growth. These mutations alone decreased lag phase and created a competitive advantage, but at the expense of most primary enzyme function. These results imply that TilS interacts with other factors related to the timing of exponential growth and that tRNA-modifying enzymes may serve multiple roles in monitoring metabolic health.

Antibiotic review kit for hospitals (ARK-Hospital): a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotic use. There is scarce evidence for how to support these decisions. We evaluated a multifaceted behaviour change intervention (ie, the antibiotic review kit) designed to reduce antibiotic use among adult acute general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review. METHODS: We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of eligible hospitals in seven calendar-time blocks in the UK. Hospitals were eligible for inclusion if they admitted adult non-elective general or medical inpatients, had a local representative to champion the intervention, and could provide the required study data. Hospital clusters were randomised to an implementation date occurring at 1-2 week intervals, and the date was concealed until 12 weeks before implementation, when local preparations were designed to start. The intervention effect was assessed using data from pseudonymised routine electronic health records, ward-level antibiotic dispensing, Clostridioides difficile tests, prescription audits, and an implementation process evaluation. Co-primary outcomes were monthly antibiotic defined daily doses per adult acute general medical admission (hospital-level, superiority) and all-cause mortality within 30 days of admission (patient level, non-inferiority margin of 5%). Outcomes were assessed in the modified intention-to-treat population (ie, excluding sites that withdrew before implementation). Intervention effects were assessed by use of interrupted time series analyses within each site, estimating overall effects through random-effects meta-analysis, with heterogeneity across prespecified potential modifiers assessed by use of meta-regression. This trial is completed and is registered with ISRCTN, ISRCTN12674243. FINDINGS: 58 hospital organisations expressed an interest in participating. Three pilot sites implemented the intervention between Sept 25 and Nov 20, 2017. 43 further sites were randomised to implement the intervention between Feb 12, 2018, and July 1, 2019, and seven sites withdrew before implementation. 39 sites were followed up for at least 14 months. Adjusted estimates showed reductions in total antibiotic defined daily doses per acute general medical admission (-4·8% per year, 95% CI -9·1 to -0·2) following the intervention. Among 7 160 421 acute general medical admissions, the ARK intervention was associated with an immediate change of -2·7% (95% CI -5·7 to 0·3) and sustained change of 3·0% (-0·1 to 6·2) in adjusted 30-day mortality. INTERPRETATION: The antibiotic review kit intervention resulted in sustained reductions in antibiotic use among adult acute general medical inpatients. The weak, inconsistent intervention effects on mortality are probably explained by the onset of the COVID-19 pandemic. Hospitals should use the antibiotic review kit to reduce antibiotic overuse. FUNDING: UK National Institute for Health and Care Research.

Role for a conserved structural motif in assembly of a class I aminoacyl-tRNA synthetase active site.

The catalytic domains of class I aminoacyl-tRNA synthetases are built around a conserved Rossmann nucleotide binding fold, with additional polypeptide domains responsible for tRNA binding or hydrolytic editing of misacylated substrates. Structural comparisons identified a conserved motif bridging the catalytic and anticodon binding domains of class Ia and Ib enzymes. This stem contact fold (SCF) has been proposed to globally orient each enzyme's cognate tRNA by interacting with the inner corner of the L-shaped tRNA. Despite the structural similarity of the SCF among class Ia/Ib enzymes, the sequence conservation is low. We replaced amino acids of the MetRS SCF with portions of the structurally similar glutaminyl-tRNA synthetase (GlnRS) motif or with alanine residues. Chimeric variants retained significant tRNA methionylation activity, indicating that structural integrity of the helix-turn-strand-helix motif contributes more to tRNA aminoacylation than does amino acid identity. In contrast, chimeras were significantly reduced in methionyl adenylate synthesis, suggesting a role for the SCF in formation of a structured active site domain. A highly conserved aspartic acid within the MetRS SCF is proposed to make an electrostatic interaction with an active site lysine; these residues were replaced with alanines or conservative substitutions. Both methionyl adenylate formation and methionine transfer were impaired, and activity was not significantly recovered by making the compensatory double substitution.

The neuroscience of positive emotions and affect: Implications for cultivating happiness and wellbeing.

This review paper provides an integrative account regarding neurophysiological correlates of positive emotions and affect that cumulatively contribute to the scaffolding for happiness and wellbeing in humans and other animals. This paper reviews the associations among neurotransmitters, hormones, brain networks, and cognitive functions in the context of positive emotions and affect. Consideration of lifespan developmental perspectives are incorporated, and we also examine the impact of healthy social relationships and environmental contexts on the modulation of positive emotions and affect. The neurophysiological processes that implement positive emotions are dynamic and modifiable, and meditative practices as well as flow states that change patterns of brain function and ultimately support wellbeing are also discussed. This review is part of "The Human Affectome Project" (http://neuroqualia.org/background.php), and in order to advance a primary aim of the Human Affectome Project, we also reviewed relevant linguistic dimensions and terminology that characterizes positive emotions and wellbeing. These linguistic dimensions are discussed within the context of the neuroscience literature with the overarching goal of generating novel recommendations for advancing neuroscience research on positive emotions and wellbeing.

Putting amino acids onto tRNAs: The aminoacyl-tRNA synthetases as catalysts.

In this chapter we consider the catalytic approaches used by aminoacyl-tRNA synthetase (AARS) enzymes to synthesize aminoacyl-tRNA from cognate amino acid and tRNA. This ligase reaction proceeds through an activated aminoacyl-adenylate (aa-AMP). Common themes among AARSs include use of induced fit to drive catalysis and transition state stabilization by class-conserved sequence and structure motifs. Active site metal ions contribute to the amino acid activation step, while amino acid transfer to tRNA is generally a substrate-assisted concerted mechanism. A distinction between classes is the rate-limiting step for aminoacylation. We present some examples for each aspect of aminoacylation catalysis, including the experimental approaches developed to address questions of AARS chemistry.

A Novel Aminoacyl-tRNA Synthetase Appended Domain Can Supply the Core Synthetase with Its Amino Acid Substrate.

The structural organization and functionality of aminoacyl-tRNA synthetases have been expanded through polypeptide additions to their core aminoacylation domain. We have identified a novel domain appended to the methionyl-tRNA synthetase (MetRS) of the intracellular pathogen Mycoplasma penetrans. Sequence analysis of this N-terminal region suggests the appended domain is an aminotransferase, which we demonstrate here. The aminotransferase domain of MpMetRS is capable of generating methionine from its α-keto acid analog, 2-keto-4-methylthiobutyrate (KMTB). The methionine thus produced can be subsequently attached to cognate tRNAMet in the MpMetRS aminoacylation domain. Genomic erosion in the Mycoplasma species has impaired many canonical biosynthetic pathways, causing them to rely on their host for numerous metabolites. It is still unclear if this bifunctional MetRS is a key part of pathogen life cycle or is a neutral consequence of the reductive evolution experienced by Mycoplasma species.

Effect of a domain-spanning disulfide on aminoacyl-tRNA synthetase activity.

Enzymes regulated by allostery undergo conformational rearrangement upon binding effector molecules. For modular proteins, a flexible interface may mediate reorientation of the protein domains and transmit binding events to activate catalysis at a distance. Aminoacyl-tRNA synthetases (aaRSs) that use tRNA anticodons as identity elements can be considered allosteric enzymes in which aminoacylation of the tRNA acceptor stem is enhanced upon anticodon binding. We reasoned that anticodon-triggered conformational change might be restricted upon introduction of a disulfide linkage near the core of an aaRS. Here we show that a double cysteine mutation engineered at the Escherichia coli MetRS domain interface spontaneously generates a disulfide linkage. This disulfide clamp has no effect on methionyl adenylate formation but reduces the level of tRNA(Met) aminoacylation approximately 2-fold. Activity is restored upon chemical reduction of the disulfide, demonstrating that E. coli MetRS requires a flexible interface domain for full catalytic efficiency.

Trauma, Resilience, and Mental Health in Migrant and Non-Migrant Youth: An International Cross-Sectional Study Across Six Countries.

Resilience is a dynamic process of positive adaptation to significant adversity. While there has been substantial focus on risks and negative outcomes associated with youth migrancy, there is limited evidence of the relationship between the adversity of migration, and resilience, wellbeing, and positive mental health in adolescents. This international study aimed to explore the differences in resilience, wellbeing, and mental health behaviors in migrant and non-migrant adolescents tested across six countries (Australia, New Zealand, UK, China, South Africa, and Canada) with varying levels of trauma exposure. The study was a cross-sectional survey design with a convenience sample of 194 10-17 year old migrants and non-migrants. The migrant sample included both "internal" migrants (change of residence within a country) and "external" migrants (change of residence across national borders) for comparison. Across the sites, migrants reported a higher mean number of traumatic events for the past year than non-migrants, with internal migrants reporting more events than external migrants overall. South African adolescents reported a higher mean number of traumatic events for the past year than all other sites. External migrants reported higher resilience scores yet reduced prosocial behaviors relative to internal migrants and non-migrants, whereas both internal and external migrants reported higher peer problems than non-migrants. When considering the interacting effects of trauma, the presence or absence of trauma did not appear to impact migrant scores in terms of resilience, wellbeing, or conduct problems. In comparison, trauma-exposed non-migrants showed detriments relative to trauma-exposed migrant peers for all of these measures. In conclusion, the survey tool was found to be reliable and acceptable for use in international studies of different samples of adolescent migrants. Overall, migrant adolescents showed greater resilience resources than non-migrants and, although the migrants experienced more traumatic events, the impact of trauma on mental health outcomes was greater in the non-migrants. There is a need for further research with larger prospective sample sizes to investigate how levels of resilience and wellbeing vary over time and across countries, and the ways resilience can be promoted in adolescents exposed to trauma, regardless of migrancy status.

11th IUBMB Focused Meeting on the Aminoacyl-tRNA Synthetases: Sailing a New Sea of Complex Functions in Human Biology and Disease.

The 11th IUBMB Focused Meeting on Aminoacyl-tRNA Synthetases was held in Clearwater Beach, Florida from 29 October⁻2 November 2017, with the aim of presenting the latest research on these enzymes and promoting interchange among aminoacyl-tRNA synthetase (ARS) researchers. Topics covered in the meeting included many areas of investigation, including ARS evolution, mechanism, editing functions, biology in prokaryotic and eukaryotic cells and their organelles, their roles in human diseases, and their application to problems in emerging areas of synthetic biology. In this report, we provide a summary of the major themes of the meeting, citing contributions from the oral presentations in the meeting.

Structure and Dynamics of tRNAMet Containing Core Substitutions.

The fidelity of protein synthesis is largely dominated by the accurate recognition of transfer RNAs (tRNAs) by their cognate aminoacyl-tRNA synthetases. Aminoacylation of each tRNA with its cognate amino acid is necessary to maintain the accuracy of genetic code input. Aminoacylated tRNAMet functions in both initiation and elongation steps during protein synthesis. As a precursor to the investigation of a methionyl-tRNA synthetase-tRNAMet complex, presented here are the results of molecular dynamics (MD) for single nucleotide substitutions in the D-loop of tRNAMet (G15A, G18A, and G19A) probing structure/function relationships. The core of tRNAMet likely mediates an effective communication between the tRNA anticodon and acceptor ends, contributing an acceptor stem rearrangement to fit into the enzyme-active site. Simulations of Escherichia coli tRNAMet were performed for 1 µs four times each. The MD simulations showed changes in tRNA flexibility and long-range communication most prominently in the G18A variant. The results indicate that the overall tertiary structure of tRNAMet remains unchanged with these substitutions; yet, there are perturbations to the secondary structure. Network-based analysis of the hydrogen bond structure and correlated motion indicates that the secondary structure elements of the tRNA are highly intraconnected, but loosely interconnected. Specific nucleotides, including U8 and G22, stabilize the mutated structures and are candidates for substitution in future studies.

Systematic review of aged care interventions for older prisoners.

OBJECTIVE: The care of older prisoners is a growing problem. This review examined aged care interventions in prisons. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines. A total of 1186 abstracts were screened for inclusion. Quantitative and qualitative studies were included. RESULTS: Two quantitative studies and five qualitative studies examined aged care interventions (n = 7). An intervention involving physical health activities was not effective in reducing distress compared to a control, and an intervention of psychosocial, physical and spiritual health activities for veterans was not effective when compared to a comparison group. Qualitative analysis generated themes that apply to best practices: addressing older prisoners' needs, identifying barriers for older prisoners and staff, considering the prison culture, program delivery and cultivating older prisoners and staff attitudes. CONCLUSION: This review found no significant interventions in prisons. However, the qualitative findings showed evidence of best practice.

Using molecular dynamics to map interaction networks in an aminoacyl-tRNA synthetase.

Long-range functional communication is a hallmark of many enzymes that display allostery, or action-at-a-distance. Many aminoacyl-tRNA synthetases can be considered allosteric, in that their trinucleotide anticodons bind the enzyme at a site removed from their catalytic domains. Such is the case with E. coli methionyl-tRNA synthase (MetRS), which recognizes its cognate anticodon using a conserved tryptophan residue 50 A away from the site of tRNA aminoacylation. The lack of details regarding how MetRS and tRNA(Met) interact has limited efforts to deconvolute the long-range communication that occurs in this system. We have used molecular dynamics simulations to evaluate the mobility of wild-type MetRS and a Trp-461 variant shown previously by experiment to be deficient in tRNA aminoacylation. The simulations reveal that MetRS has significant mobility, particularly at structural motifs known to be involved in catalysis. Correlated motions are observed between residues in distant structural motifs, including the active site, zinc binding motif, and anticodon binding domain. Both mobility and correlated motions decrease significantly but not uniformly upon substitution at Trp-461. Mobility of some residues is essentially abolished upon removal of Trp-461, despite being tens of Angstroms away from the site of mutation and solvent exposed. This conserved residue does not simply participate in anticodon binding, as demonstrated experimentally, but appears to mediate the protein's distribution of structural ensembles. Finally, simulations of MetRS indicate that the ligand-free protein samples conformations similar to those observed in crystal structures with substrates and substrate analogs bound. Thus, there are low energetic barriers for MetRS to achieve the substrate-bound conformations previously determined by structural methods.

A temporally dynamic context effect that disrupts voice onset time discrimination of rapidly successive stimuli.

Across three experiments, voice onset time discrimination along a/ba/-/pa/ continuum was found to be influenced by the order of presentation of rapidly successive stimuli. Specifically, discrimination was disrupted when a relatively unambiguous /pa/ syllable was presented before, rather than after, a more ambiguous /pa/ or/ba/ syllable. In Experiments 1 and 2, for between-category discrimination, this order effect was significant at interstimulus intervals (ISIs) below 250 msec, but not at 250 or 1,000 msec. In Experiments 2 and 3, the order effect was also significant for within-category discrimination at ISIs below 250 msec. In addition, in Experiment 3 this order effect was not diminished by provision of performance feedback across eight testing sessions. These findings reveal a particular vulnerability of phonological processing in response to rapidly successive stimuli and may have implications for mathematical and neural models of speech processing of normal and impaired populations.